Family Of Molecules Research Articles

In Vitro Evaluation of the Antibacterial Activity of the Peptide Fractions Extracted from the Hemolymph of Hermetia illucens (Diptera: Stratiomyidae)

Antimicrobial peptides (AMPs) are a chemically and structurally heterogeneous family of molecules produced by a large variety of living organisms, whose expression is predominant in the sites most exposed to microbial invasion. One of the richest natural sources of AMPs is insects which, over the course of their very long evolutionary history, have adapted to numerous and different habitats by developing a powerful innate immune system that has allowed them to survive but also to assert themselves in the new environment. Recently, due to the increase in antibiotic-resistant bacterial strains, interest in AMPs has risen. In this work, we detected AMPs in the hemolymph of Hermetia illucens (Diptera, Stratiomyidae) larvae, following infection with Escherichia coli (Gram negative) or Micrococcus flavus (Gram positive) and from uninfected larvae. Peptide component, isolated via organic solvent precipitation, was analyzed by microbiological techniques. Subsequent mass spectrometry analysis allowed us to specifically identify peptides expressed in basal condition and peptides differentially expressed after bacterial challenge. We identified 33 AMPs in all the analyzed samples, of which 13 are specifically stimulated by Gram negative and/or Gram positive bacterial challenge. AMPs mostly expressed after bacterial challenge could be responsible for a more specific activity.

Exploring circular MET RNA as a potential biomarker in tumors exhibiting high MET activity

BackgroundMET-driven acquired resistance is emerging with unanticipated frequency in patients relapsing upon molecular therapy treatments. However, the determination of MET amplification remains challenging using both standard and next-generation sequencing-based methodologies. Liquid biopsy is an effective, non-invasive approach to define cancer genomic profiles, track tumor evolution over time, monitor treatment response and detect molecular resistance in advance. Circular RNAs (circRNAs), a family of RNA molecules that originate from a process of back-splicing, are attracting growing interest as potential novel biomarkers for their stability in body fluids.MethodsWe identified a circRNA encoded by the MET gene (circMET) and exploited blood-derived cell-free RNA (cfRNA) and matched tumor tissues to identify, stratify and monitor advanced cancer patients molecularly characterized by high MET activity, generally associated with genomic amplification.ResultsUsing publicly available bioinformatic tools, we discovered that the MET locus transcribes several circRNA molecules, but only one candidate, circMET, was particularly abundant. Deeper molecular analysis revealed that circMET levels positively correlated with MET expression and activity, especially in MET-amplified cells. We developed a circMET-detection strategy and, in parallel, we performed standard FISH and IHC analyses in the same specimens to assess whether circMET quantification could identify patients displaying high MET activity. Longitudinal monitoring of circMET levels in the plasma of selected patients revealed the early emergence of MET amplification as a mechanism of acquired resistance to molecular therapies.ConclusionsWe found that measurement of circMET levels allows identification and tracking of patients characterized by high MET activity. Circulating circMET (ccMET) detection and analysis could be a simple, cost-effective, non-invasive approach to better implement patient stratification based on MET expression, as well as to dynamically monitor over time both therapy response and clonal evolution during treatment.

9-O Acetylated Gangliosides in Health and Disease.

Glycosphingolipids comprise a lipid class characterized by the presence of sugar moieties attached to a ceramide backbone. The role of glycosphingolipids in pathophysiology has gained relevance in recent years in parallel with the development of analytical technologies. Within this vast family of molecules, gangliosides modified by acetylation represent a minority. Described for the first time in the 1980s, their relation to pathologies has resulted in increased interest in their function in normal and diseased cells. This review presents the state of the art on 9-O acetylated gangliosides and their link to cellular disorders.

SLAM-family receptors come of age as a potential molecular target in cancer immunotherapy.

The signaling lymphocytic activation molecule (SLAM) family receptors were discovered in immune cells for the first time. The SLAM-family receptors are a significant player in cytotoxicity, humoral immune responses, autoimmune diseases, lymphocyte development, cell survival, and cell adhesion. There is growing evidence that SLAM-family receptors have been involved in cancer progression and heralded as a novel immune checkpoint on T cells. Previous studies have reported the role of SLAMs in tumor immunity in various cancers, including chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, head and neck squamous cell carcinoma, pancreas, lung, and melanoma. Evidence has deciphered that the SLAM-family receptors may be targeted for cancer immunotherapy. However, our understanding in this regard is not complete. This review will discuss the role of SLAM-family receptors in cancer immunotherapy. It will also provide an update on recent advances in SLAM-based targeted immunotherapies.

Gram-negative quorum sensing signalling enhances biofilm formation and virulence traits in gram-positive pathogen Enterococcus faecalis

ABSTRACT Acyl-homoserine lactones (AHLs) are typical quorum-sensing molecules of gram-negative bacteria. Recent evidence suggests that AHLs may also affect gram-positives, although knowledge of these interactions remains scarce. Here, we assessed the effect of AHLs on biofilm formation and transcriptional regulations in the gram-positive Enterococcus faecalis. Five E. faecalis strains were investigated herein. Crystal violet was employed to quantify the biomass formed, and confocal microscopy in combination with SYTO9/PI allowed the visualisation of biofilms’ structure. The differential expression of 10 genes involved in quorum-sensing, biofilm formation and stress responses was evaluated using reverse-transcription-qPCR. The AHL exposure significantly increased biofilm production in strain ATCC 29212 and two isolates from infected dental roots, UmID4 and UmID5. In strains ATCC 29212 and UmID7, AHLs up-regulated the quorum-sensing genes (fsrC, cylA), the adhesins ace, efaA and asa1, together with the glycosyltransferase epaQ. In strain UmID7, AHL exposure additionally up-regulated two membrane-stress response genes (σV, groEL) associated with increased stress-tolerance and virulence. Altogether, our results demonstrate that AHLs promote biofilm formation and up-regulate a transcriptional network involved in virulence and stress tolerance in several E. faecalis strains. These data provide yet-unreported insights into E. faecalis biofilm responses to AHLs, a family of molecules long-considered the monopole of gram-negative signalling.

Interaction of the Hemagglutinin Stalk Region with Cell Adhesion Molecule (CADM) 1 and CADM2 Mediates the Spread between Neurons and Neuropathogenicity of Measles Virus with a Hyperfusogenic Fusion Protein.

Measles virus (MeV), the causative agent of measles, is an enveloped RNA virus of the family Paramyxoviridae, which remains an important cause of childhood morbidity and mortality. MeV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. During viral entry or virus-mediated fusion between infected cells and neighboring susceptible cells, the head domain of the H protein initially binds to its receptors, signaling lymphocytic activation molecule family member 1 (SLAM) and nectin-4, and then the stalk region of the H protein transmits the fusion-triggering signal to the F protein. MeV may persist in the human brain and cause a fatal neurodegenerative disease, subacute sclerosing panencephalitis (SSPE). Recently, we showed, using in vitro cell culture, that cell adhesion molecule (CADM) 1 and CADM2 are host factors that trigger hyperfusogenic mutant F proteins, causing cell-to-cell fusion and the transfer of the MeV genome between neurons. Unlike conventional receptors, CADM1 and CADM2 interact in cis (on the same membrane) with the H protein and then trigger membrane fusion. Here, we show that alanine substitutions in part of the stalk region (positions 171-175) abolish the ability of the H protein to mediate membrane fusion triggered by CADM1 and CADM2, but not by SLAM. The recombinant hyperfusogenic MeV carrying this mutant H protein loses its ability to spread in primary mouse neurons as well as its neurovirulence in experimentally infected suckling hamsters. These results indicate that CADM1 and CADM2 are key molecules for MeV propagation in the brain and its neurovirulence in vivo. IMPORTANCE Measles is an acute febrile illness with skin rash. Despite the availability of highly effective vaccines, measles is still an important cause of childhood morbidity and mortality in many countries. The World Health Organization estimates that more than 120,000 people died from measles worldwide in 2021. Measles virus (MeV), the causative agent of measles, can also cause a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. There is currently no effective treatment for this disease. In this study, using recombinant MeVs with altered receptor usage patterns, we show that cell adhesion molecule (CADM) 1 and CADM2 are host factors critical for MeV spread in neurons and its neurovirulence. These findings further our understanding of the molecular mechanism of MeV neuropathogenicity.

Siglec cis-ligands and their roles in the immune system.

Sialic acid-binding immunoglobulin-like lectins are a family of membrane molecules primarily expressed in immune cells. Most of them are inhibitory receptors containing immunoreceptor tyrosine-based inhibition motifs in the cytoplasmic tail. On the cell surface, sialic acid-binding immunoglobulin-like lectins are mostly bound by sialylated glycans on membrane molecules expressed in the same cell (cis-ligands). Although ligands of sialic acid-binding immunoglobulin-like lectins are not efficiently identified by conventional methods such as immunoprecipitation, in situ labeling including proximity labeling is useful in identifying both cis-ligands and the sialylated ligands expressed by other cells (trans-ligands) of sialic acid-binding immunoglobulin-like lectins. Interaction of the inhibitory sialic acid-binding immunoglobulin-like lectins with cis-ligands including both those with and without signaling function modulates the inhibitory activity of sialic acid-binding immunoglobulin-like lectins by multiple different ways. This interaction also modulates signaling function of the cis-ligands. So far, little is known about the role of the interaction between sialic acid-binding immunoglobulin-like lectins and the cis-ligands. Nonetheless, recent studies showed that the inhibitory activity of CD22 (also known as Siglec-2) is regulated by endogenous ligands, most likely cis-ligands, differentially in resting B cells and those in which B-cell antigen receptor is ligated. This differential regulation plays a role in quality control of signaling-competent B cells and also partial restoration of B-cell antigen receptor signaling in immunodeficient B cells.

CD244 loss on monocytes promotes differentiation into M1 macrophages and potentiates PD-L1 blockade in melanoma

Abstract Accumulating data have highlighted the role of monocytes/macrophages in immune escape by generating immunologically “cold” tumors that do not respond to immunotherapy. CD244 (SLAMF4, 2B4), a member of the signaling lymphocyte activation molecule family, is expressed on myeloid cells, but its precise role has not been elucidated. Using monocyte lineage-specific CD244-deficient micechallenged with B16F10 melanoma, we report for the first time that CD244 negatively regulates tumor immunity by inhibiting the differentiation and functional maturation of monocytes into macrophageswithin the tumor microenvironment. CD244-deficient macrophages more effectively activated antigen-specific T cell responsescompared to WT macrophages, thus delaying tumor growth in the B16F10 melanoma model. Moreover, combinatorial intervention of anti-PD-L1 antibodies with CD244-KO BMDM markedly improved tumor rejectioncompared to the anti-PD-L1 antibody alone or in combination with WT BMDM. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset, revealed DEGs of CD244 −monocytes and macrophages were associated with phagocytosis, antigen presentation, and autophagy. Additionally, cell type deconvolution analysis within melanoma patients bulk RNA-seq datasets from TCGA database, revealed presence of CD244-monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Hence, we proposed that CD244 serve as a critical immunoregulatory receptor on macrophages, and CD244-deficient macrophages may represent a novel therapeutic modality, which can function synergistically with checkpoint blockade therapies. Supported by grants from National Research Foundation of Korea (NRF-2020R1A2C2103061, NRF-2018M3A9D3079288, NRF-2016M3A9B6948342)

Integrins and the Metastasis-like Dissemination of Acute Lymphoblastic Leukemia to the Central Nervous System.

Acute lymphoblastic leukemia (ALL) disseminates with high prevalence to the central nervous system (CNS) in a process resembling aspects of the CNS surveillance of normal immune cells as well as aspects of brain metastasis from solid cancers. Importantly, inside the CNS, the ALL blasts are typically confined within the cerebrospinal fluid (CSF)-filled cavities of the subarachnoid space, which they use as a sanctuary protected from both chemotherapy and immune cells. At present, high cumulative doses of intrathecal chemotherapy are administered to patients, but this is associated with neurotoxicity and CNS relapse still occurs. Thus, it is imperative to identify markers and novel therapy targets specific to CNS ALL. Integrins represent a family of adhesion molecules involved in cell-cell and cell-matrix interactions, implicated in the adhesion and migration of metastatic cancer cells, normal immune cells, and leukemic blasts. The ability of integrins to also facilitate cell-adhesion mediated drug resistance, combined with recent discoveries of integrin-dependent routes of leukemic cells into the CNS, have sparked a renewed interest in integrins as markers and therapeutic targets in CNS leukemia. Here, we review the roles of integrins in CNS surveillance by normal lymphocytes, dissemination to the CNS by ALL cells, and brain metastasis from solid cancers. Furthermore, we discuss whether ALL dissemination to the CNS abides by known hallmarks of metastasis, and the potential roles of integrins in this context.

The Use of Specialized Pro-Resolving Mediators in Biomaterial-Based Immunomodulation.

The implantation of a biomaterial will lead to the immediate onset of an acute inflammatory response, which is of key importance in shaping the quality of the repair process. However, the return to homeostasis is critical to prevent a chronic inflammatory response that may impair the healing process. The resolution of the inflammatory response is now recognized as an active and highly regulated process, being described as specialized immunoresolvents that have a fundamental role in the termination of the acute inflammatory response. These mediators collectively coined as specialized pro-resolving mediators (SPMs) are a family of endogenous molecules that include lipoxins (Lx), resolvins (Rv), protectins (PD), maresins (Mar), Cysteinyl-SPMs (Cys-SPMs) and n-3 docosapentaenoic acid-derived SPMs (n-3 DPA-derived SPMs). SPMs have important anti-inflammatory and pro-resolutive actions such as decreasing the recruitment of polymorphonuclear leukocytes (PMNs), inducing the recruitment of anti-inflammatory macrophages, and increasing macrophage clearance of apoptotic cells through a process known as efferocytosis. Over the last years, the trend in biomaterials research has shifted towards the engineering of materials that are able to modulate the inflammatory response and thus stimulate appropriate immune responses, the so-called immunomodulatory biomaterials. These materials should be able to modulate the host immune response with the aim of creating a pro-regenerative microenvironment. In this review, we explore the potential of using of SPMs in the development of new immunomodulatory biomaterials and we propose insights for future research in this field.

Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody-drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development.

Multifidelity Neural Network Formulations for Prediction of Reactive Molecular Potential Energy Surfaces

This paper focuses on the development of multifidelity modeling approaches using neural network surrogates, where training data arising from multiple model forms and resolutions are integrated to predict high-fidelity response quantities of interest at lower cost. We focus on the context of quantum chemistry and the integration of information from multiple levels of theory. Important foundations include the use of symmetry function-based atomic energy vector constructions as feature vectors for representing structures across families of molecules and single-fidelity neural network training capabilities that learn the relationships needed to map feature vectors to potential energy predictions. These foundations are embedded within several multifidelity topologies that decompose the high-fidelity mapping into model-based components, including sequential formulations that admit a general nonlinear mapping across fidelities and discrepancy-based formulations that presume an additive decomposition. Methodologies are first explored and demonstrated on a pair of simple analytical test problems and then deployed for potential energy prediction for C5H5 using B2PLYP-D3/6-311++G(d,p) for high-fidelity simulation data and Hartree-Fock 6-31G for low-fidelity data. For the common case of limited access to high-fidelity data, our computational results demonstrate that multifidelity neural network potential energy surface constructions achieve roughly an order of magnitude improvement, either in terms of test error reduction for equivalent total simulation cost or reduction in total cost for equivalent error.

Studying the nomenclature of dioxins using a structure model kit based on electronic components linked with plastic tubes

Abstract Commercially available molecular models are elaborately made but generally expensive, which hinders their distribution to all classroom students. Aiming at developing an affordable molecular model, we developed a structure model kit consisting of inexpensive electronic components including transistors and colored light-emitting diodes (LEDs) with a total cost of ca. 2 USD. The structure model kit was designed for building a family of environmental pollutant molecules known as dioxins, in which transistor, white LED, red LED, and yellow LED components are used to represent sp2 carbon, hydrogen, oxygen, and chlorine atoms, respectively. Herein, we report an activity directed to nonchemistry majors studying environmental science and electronic engineering to help them gain insight into the molecular structure of dioxins using the newly developed structure model kit. The activity was well received by many students, some of whom came to understand the relationship between the structure and nomenclature of dioxins, mainly 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (2,3,7,8-TCDD) and its isomers.

Research Note: Junctional adhesion molecule A is expressed in epithelial cells of the crypt and villi whereas junctional adhesion molecule 2 is expressed in vascular cells

A functional intestinal barrier is essential for a healthy intestine. This barrier includes an apical tight junctional complex between adjacent intestinal epithelial cells. The tight junctions (TJ) are multiprotein junctional complexes that consist of a number of members of the occludin, claudin, zona occludens, and junctional adhesion molecule families. The mRNA expression of junctional adhesin molecule A (JAMA) and junctional adhesion molecule 2 (JAM2) are 2 TJ mRNAs that are often used to assess intestinal barrier integrity. The objective of this study was to use in situ hybridization to identify cells that express JAMA and JAM2 mRNA in the small intestine of chickens. In the jejunum of a 21 d old broiler, JAMA mRNA was highly expressed in the epithelial cells of the villi and crypt. By contrast, JAM2 mRNA was located in the vascular system in the center of the villi and in the lamina propria. These results demonstrate that JAMA and not JAM2 is the appropriate gene to use when assessing TJ between intestinal epithelial cells.

Abstract 6132: Impact of treatment with agents targeting different members of HER family, CDKs and downstream cell signaling molecules on growth and migration of stomach cancer cells

Abstract Stomach cancer ranks fifth and fourth for the incidence and mortality rate for cancer worldwide, respectively. In recent years, several inhibitors with specificity to one or more members of human epidermal growth factor receptor (HER) family have been approved for the treatment of patients with different cancer types. Of these, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients and with tumor heterogeneity being one contributing factor. In this study, we investigated the effect of various types of targeted agents on the growth in vitro of a panel of human stomach cancer cells (HSCCLs) and the impact of stomach cancer proliferation rate on the anti-tumor activities of these agents. Moreover, we investigated the cell surface expression of the HER family members, other biomarkers such as C-Met, Alk-7 and cancer stem cell makers CD44 and CD133 by flow cytometry and the effect various targeted agents on tumor migration using Incucyte. Of the 18 agents examined, the CDK 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at IC50 values between 1nM to 9nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual EGFR/HER2 TKI lapatinib and the EGFR specific TKI erlotinib in inhibiting the growth of HSCCLs. Interestingly, the HER-2 overexpressing cells lines NCI-N87 (Mean Fluorescence Intensity =596) was most sensitive to the HER inhibitors. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs and with the IC50 values ranging from 2nM to 7uM. Interestingly, many of these agents were more effective in inhibiting the growth of HSCCLs when proliferating at slower rate. Of the agent examined, neratinib, afatinib, dinacicilib, dasatinib, stattic and miransertib also inhibited the migration of stomach cancer cells. Finally, treatment with a combination of afatinib with dinaciclib, capmatinib, dasatinib, stattic, ponatinib or miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells. As stomach cancer cells are heterogenous in nature, our results support further research on the therapeutic potential of the CDK dinaciclib in combination with a pan-HER inhibitor in stomach cancer. Citation Format: Tina Al-Janaby, Narmin Nahi, Said A. Khelwatty, Alan Seddon, Izhar Bagwan, Helmout Modjtahedi. Impact of treatment with agents targeting different members of HER family, CDKs and downstream cell signaling molecules on growth and migration of stomach cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6132.

Characteristic Substituent Effect Model for the Infrared Intensities of the X2CY (X = H, F, Cl, Br; Y = O, S) Molecules.

Many years ago, the gas-phase infrared fundamental intensities of Cl2CS were determined within experimental error from the experimental intensities and frequencies of F2CO, Cl2CO, and F2CS. An additive characteristic substituent shift relationship between atomic polar tensors of these molecules formed the basis for these calculations. Here, QCISD/cc-pVTZ-level Quantum Theory of Atoms In Molecules (QTAIM) individual charge, charge transfer, and polarization contributions to these atomic polar tensor elements are shown to obey the same basic relationship for the extended X2CY (Y = O, S; X = H, F, Cl, Br) family of molecules. QTAIM charge and polarization contributions, as well as the total equilibrium dipole moments of the X2CY molecules, also follow this characteristic substituent shift model. The root-mean-sqaure error for the 231 estimates of these parameters is 0.14 e or only about 1% of the total 10 e range of the Atomic Polar Tensor (APT) contributions determined from the wave functions. The substituent effect APT contribution estimates were used to calculate the infrared intensities of the X2CY molecules. Although one serious discrepancy was observed for one of the CH stretching vibrations of H2CS, accurate values were within 45 km·mol-1 or about 7% of the 656 km·mol-1 intensity range predicted by the QCISD/cc-pVTZ wave functions. Hirshfeld charge, charge transfer, and polarization contributions are also found to follow this model, although their charge parameters do not follow electronegativity expectations.

L1CAM expression in human gastrointestinal tract development: From tongue to colon-rectum.

L1CAM (L1 cell adhesion molecule) is a member of the L1 family of neural adhesion molecules, involved in the development of multiple organs and tissues, including kidneys, the enteric nervous system, and adrenal glands. The aim of this study was to analyze, at the immunohistochemical level, the expression of L1CAM in the human tongue, parotid glands, and the different segments of the gastrointestinal tract during human development. Immunohistochemical analysis for L1CAM was performed in the human tongue, parotid glands, and in the different segments of the gastrointestinal tract during development, starting from the 8th up to the 32nd week of gestation. Our results were given by the expression of the L1CAM protein in different segments of the gastrointestinal tract during development, starting from the 8th week up to the 32nd week of gestation. L1CAM-reactive cells appeared aggregated in small bodies, irregular in shape, showing L1CAM storage in the cytoplasm. L1CAM expressing bodies were frequently found to be connected one to the next by thin fibers, a finding suggestive of the existence of an L1CAM network inside the developing tissue. Our study confirms that L1CAM is involved in gut development, as well as in tongue and salivary gland development. These findings confirm that the role of L1CAM in fetal development is not restricted to the central nervous system and are necessary for further studies on the role of this molecule in human development.

Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development

BackgroundLoss-of-function mutations in the contactin-associated protein-like 2 (CNTNAP2) gene are causal for neurodevelopmental disorders, including autism, schizophrenia, epilepsy, and intellectual disability. CNTNAP2 encodes CASPR2, a single-pass transmembrane protein that belongs to the neurexin family of cell adhesion molecules. These proteins have a variety of functions in developing neurons, including connecting presynaptic and postsynaptic neurons, and mediating signaling across the synapse. MethodsTo study the effect of loss of CNTNAP2 function on human cerebral cortex development, and how this contributes to the pathogenesis of neurodevelopmental disorders, we generated human induced pluripotent stem cells from one neurotypical control donor null for full-length CNTNAP2, modeling cortical development from neurogenesis through to neural network formation in vitro. ResultsCNTNAP2 is particularly highly expressed in the first two populations of early-born excitatory cortical neurons, and loss of CNTNAP2 shifted the relative proportions of these two neuronal types. Live imaging of excitatory neuronal growth showed that loss of CNTNAP2 reduced neurite branching and overall neuronal complexity. At the network level, developing cortical excitatory networks null for CNTNAP2 had complex changes in activity compared with isogenic controls: an initial period of relatively reduced activity compared with isogenic controls, followed by a lengthy period of hyperexcitability, and then a further switch to reduced activity. ConclusionsComplete loss of CNTNAP2 contributes to the pathogenesis of neurodevelopmental disorders through complex changes in several aspects of human cerebral cortex excitatory neuron development that culminate in aberrant neural network formation and function.

Potentialities of Antimicrobial Peptide Mastoparan C Isolated the European Hornet Vespa Crabro in Drug Discovery

Abstract: Exploring the potential of natural bioactive peptides is becoming more and more important for new drug discovery. First isolated from the European wasp Vespa crabro, the antimicrobial peptide Mastoparan C was found in higher content than many other molecules in the Mastoparan family. In addition to the mast cell degranulation that is similar to some components in insect venom, this compound possesses remarkable biological activities such as broad-spectrum antibacterial and antifungal, inhibiting the proliferation of many human cancer cell lines. However, unfortunately, Mastoparan C has the notable side effect of causing mammalian hemolysis. By investigating its structure-activity relationships, this review pointed out some suggestions to overcome the disadvantages of this potential peptide and thereby support further in-depth study in the drug discovery field.
 Keywords: Mastoparan C, antimicrobial peptide, biological activity, structure-activity relationships.

Resistin Contribution to Cardiovascular Risk in Chronic Kidney Disease Male Patients.

Resistin is a molecule that belongs to the Resistin-Like Molecules family (RELMs), the group of proteins taking part in inflammatory processes. Increased resistin concentrations are observed in cardiovascular complications. Resistin contributes to the onset of atherosclerosis and intensifies the atherosclerotic processes. The aim of this study was to investigate the relationship between resistin and cardiovascular (CV) risk in men with chronic kidney disease (CKD) not treated with dialysis. One hundred and forty-two men were included in the study: 99 men with eGFR lower than 60 mL/min/1.73 m2 and 43 men with eGFR ≥ 60 mL/min/1.73 m2. CV risk was assessed. Serum resistin, tumor necrosis factor-alpha (TNF-alpha) and plasminogen activator inhibitor-1 (PAI-1) were measured among other biochemical parameters. We observed that resistin concentrations were significantly higher in patients with CKD compared to individuals with eGFR ≥ 60 mL/min/1.73 m2 (p = 0.003). In CKD, after estimating the general linear model (GLM), we found that resistin is associated with CV risk (p = 0.026) and PAI-1 serum concentrations (0.012). The relationship of PAI-1 with resistin depends on the level of CV risk in CKD (p = 0.048). Resistin concentrations rise with the increase of CV risk in CKD patients and thus resistin may contribute to the progression of cardiovascular risk in this group of patients. The relationship between resistin and CV risk is modified by PAI-1 concentrations.