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Abstract The KM3NeT/ARCA neutrino detector is currently under construction at 3500 m depth offshore Capo Passero, Sicily, in the Mediterranean Sea. The main science objectives are the detection of high-energy cosmic neutrinos and the discovery of their sources. Simulations were conducted for the full KM3NeT/ARCA detector, instrumenting a volume of 1 km $$^3$$ 3 , to estimate the sensitivity and discovery potential to point-like neutrino sources. This paper covers the reconstruction of track- and shower-like signatures, as well as the criteria employed for neutrino event selection. With an angular resolution below 0.1 $$^\circ $$ ∘ for tracks and under 2 $$^\circ $$ ∘ for showers, the sensitivity to point-like neutrino sources surpasses existing observed limits across the entire sky.

Abstract The measurement of the flux of muons produced in cosmic ray air showers is essential for the study of primary cosmic rays. Such measurements are important in extensive air shower detectors to assess the energy spectrum and the chemical composition of the cosmic ray flux, complementary to the information provided by fluorescence detectors. Detailed simulations of the cosmic ray air showers are carried out, using codes such as CORSIKA, to estimate the muon flux at sea level. These simulations are based on the choice of hadronic interaction models, for which improvements have been implemented in the post-LHC era. In this work, a deficit in simulations that use state-of-the-art QCD models with respect to the measurement deep underwater with the KM3NeT neutrino detectors is reported. The KM3NeT/ARCA and KM3NeT/ORCA neutrino telescopes are sensitive to TeV muons originating mostly from primary cosmic rays with energies around 10 TeV. The predictions of state-of-the-art QCD models show that the deficit with respect to the data is constant in zenith angle; no dependency on the water overburden is observed. The observed deficit at a depth of several kilometres is compatible with the deficit seen in the comparison of the simulations and measurements at sea level.

One of the greatest challenges in modern gynecological oncology is ovarian cancer. Despite the numerous studies currently being conducted, it is still sometimes detected at late clinical stages, where the prognosis is unfavorable. One significant contributing factor is the absence of sensitive and specific parameters that could aid in early diagnosis. An ideal screening test, in view of the low incidence of ovarian cancer, should have a sensitivity of greater than 75% and a specificity of at least 99.6%. To enhance sensitivity and specificity, diagnostic panels are being created by combining individual markers. The drive to develop better screening tests for ovarian cancer focuses on modern diagnostic methods based on molecular testing, which in turn aims to find increasingly effective biomarkers. Currently, researchers' efforts are focused on the search for a complementary parameter to those most commonly used that would satisfactorily enhance the sensitivity and specificity of assays. Several biomarkers, including microRNA molecules, autoantibodies, cDNA, adipocytokines, and galectins, are currently being investigated by researchers. This article reviews recent studies comparing the sensitivity and specificity of selected parameters used alone and in combination to increase detection of ovarian cancer at an early stage. [ABSTRACT FROM AUTHOR]

The Cherenkov Telescope Array and the KM3NeT neutrino telescopes are major upcoming facilities in the fields of γ -ray and neutrino astronomy, respectively. Possible simultaneous production of γ rays and neutrinos in astrophysical accelerators of cosmic-ray nuclei motivates a combination of their data. We assess the potential of a combined analysis of CTA and KM3NeT data to determine the contribution of hadronic emission processes in known Galactic γ -ray emitters, comparing this result to the cases of two separate analyses. In doing so, we demonstrate the capability of Gammapy, an open-source software package for the analysis of γ -ray data, to also process data from neutrino telescopes. For a selection of prototypical γ -ray sources within our Galaxy, we obtain models for primary proton and electron spectra in the hadronic and leptonic emission scenario, respectively, by fitting published γ -ray spectra. Using these models and instrument response functions for both detectors, we employ the Gammapy package to generate pseudo data sets, where we assume 200 h of CTA observations and 10 years of KM3NeT detector operation. We then apply a three-dimensional binned likelihood analysis to these data sets, separately for each instrument and jointly for both. We find that the largest benefit of the combined analysis lies in the possibility of a consistent modelling of the γ -ray and neutrino emission. Assuming a purely leptonic scenario as input, we obtain, for the most favourable source, an average expected 68% credible interval that constrains the contribution of hadronic processes to the observed γ -ray emission to below 15%. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs., (© 2024 Wiley-VCH GmbH.)

With the development of digital technologies and their increasing application in government, digital transformation is a wave rolling up the world. Previous studies had investigated some factors that affect digital transformation. But there is little research on the impact of organizational agility on digital transformation in government. To fill this gap, based on the dynamic capabilities view, this study aims to investigate how organizational agility affects digital transformation and dynamic capabilities as antecedents and factors impacting organizational agility. A survey study was conducted to empirically test the model. The data were collected from 313 government employees in government departments. The findings suggest that (1) organizational agility significantly influences digital transformation and (2) dynamic capabilities are important predictors of organizational agility. [ABSTRACT FROM AUTHOR]

Alpha‐Synuclein (α‐Synuclein) is a 140 amino acid protein implicated in neurodegenerative disorders known as synucleinopathies, where it accumulates in proteinaceous inclusions in the brain. The normal physiological function of α‐Synuclein remains obscure, as it exists in several non‐neuronal cells in which its function has not been studied. Given the tremendous interest in studying α‐Synuclein, and the existing limitations in the production of modified forms of the protein, we developed a method for the chemical synthesis of α‐Synuclein by combining peptide fragment synthesis via automated microwave‐assisted solid‐phase peptide synthesis and ligation strategies. Our synthetic pathway enables the synthesis of protein variants of interest, carrying either mutations or posttranslational modifications, for further investigations of the effects on the structure and aggregation behavior of the protein. Ultimately, our study forms the foundation for future syntheses and studies of other custom‐made α‐Synuclein variants with a single or several modifications, as necessary. [ABSTRACT FROM AUTHOR]

Autoimmunity and allergies affect a large number of people across the globe. Current approaches to these diseases target cell types and pathways that drive disease, but these approaches are not cures and cannot differentiate between healthy cells and disease-causing cells. New immunotherapies that induce potent and selective antigen-specific tolerance is a transformative goal of emerging treatments for autoimmunity and serious allergies. These approaches offer the potential of halting -- or even reversing -- disease, without immunosuppressive side effects. However, translating successful induction of tolerance to patients is unsuccessful. Biomaterials offer strategies to direct and maximize immunological mechanisms of tolerance through unique capabilities such as codelivery of small molecules or signaling molecules, controlling signal density in key immune tissues, and targeting. While a growing body of work in this area demonstrates success in preclinical animal models, these therapies are only recently being evaluated in human trials. This review will highlight the most recent advances in the use of materials to achieve antigen-specific tolerance and provide commentary on the current state of the clinical development of these technologies. [ABSTRACT FROM AUTHOR]

Galectins are animal lectins with specific affinity for galactosides via the conserved carbohydrate recognition domains. Increasing studies recently have identified critical roles of galectin family members in tumor progression. Abnormal expression of galectins contributes to the proliferation, metastasis, epithelial-mesenchymal transformation (EMT), immunosuppression, radio-resistance and chemoresistance in various cancers, which has attracted cumulative clinical interest in galectin-based cancer treatment. Galectin family members have been reported to participate in autophagy regulation under physiological conditions and in non-tumoral diseases, and implication of galectins in multiple processes of carcinogenesis also involves regulation of autophagy, however, the relationship between galectins, autophagy and cancer remains largely unclear. In this review, we introduce the structure and function of galectins at the molecular level, summarize their engagements in autophagy and cancer progression, and also highlight the regulation of autophagy by galectins in cancer as well as the therapeutic potentials of galectin and autophagy-based strategies. Elaborating on the mechanism of galectin-regulated autophagy in cancers will accelerate the exploitation of galectins-autophagy targeted therapies in treatment for cancer. [ABSTRACT FROM AUTHOR]

Galectins are galactoside-binding proteins, exerting numerous functions inside and outside the cell, particularly conferring adaptation to stress factors. For most of them, aberrant expression profiles have been reported in the context of cancer. Albeit not being oncogenic drivers, galectins can be harnessed to exacerbate the malignant phenotype. Their impact on disease establishment and progression is not limited to making cancer cells resistant to apoptosis, but is prominent in the context of the tumor microenvironment, where it fosters angiogenesis, immune escape and exclusion. This review focuses mainly on Gal-1, Gal-3 and Gal-9 for which the involvement in cancer biology is best known. It presents the types of galectin dysregulations, attempts to explain the mechanisms behind them and analyzes the different ways in which they favor tumour growth. In an era where tumour resistance to immunotherapy appears as a major challenge, we highlight the crucial immunosuppressive roles of galectins and the potential therapeutic benefits of combinatorial approaches including galectin inhibition. [ABSTRACT FROM AUTHOR]

To achieve sustainable urban development, many countries around the world are exploring the path of smart cities. The progress and development of digital technology has paved a promising road. Digital transformation of the government is an important factor for smart cities in China. Scholars are increasingly interested in the digital transformation of government, but there is little empirical research on the driving factors of digital transformation among local governments. Based on the technology–organization–environment (TOE) framework, this study explores the driving factors of digital transformation among local governments in China. A questionnaire survey and the structural equation model were used. Technological readiness, organizational efficiency, public service delivery, citizens' expectations and superior pressure are significant driving factors. Technological readiness is the first factor affecting the government's digital transformation. Applying the identified drivers, the results of this research could be used as orientation towards, and provide concrete practical approaches for, successful digital transformation among local governments, which would lay a foundation for smart city construction. [ABSTRACT FROM AUTHOR]

Background and aim: Galectins have been recently tackled by many researchers in the field of cancer due to their role in tumorigenesis, disease progression, and metastasis. Thus, they are currently involved in biomarkers research on several types of cancer. In ovarian cancers, few studies were carried out to evaluate galectins expression profiling. Hence, our present study was executed to evaluate the mRNA expression of galectins -1, -3, -4, -8, and -9 in epithelial ovarian cancers. Methods: Fifty-six tumor samples of ovarian carcinomas were analyzed for mRNA expression using qRT-PCR, and fold-changes were calculated in comparison to tissue samples of 26 women with normal ovaries. Results: The results of the present paper emphasize the importance of galectins as predictors for targeted therapy. LGALS1, LGALS3, LGALS4, LGALS8, and LGALS9 were found to be mostly overexpressed in ovarian carcinoma patients with the following percentage: 78.6%, 92.9%, 66.1%, 87.5%, and 85.7% respectively. Moreover, galectins -3 and -9 were found to be significantly elevated with lymph node metastasis (p = 0.044 and p = 0.011). Also, upregulation of galectin-1 and -9 were statistically significant in stages IIB, IIC, and IIIB (p = 0.002) in FIGO staging. CA19.9 is positively correlated to galectin-4 expression (p = 0.039). Conclusion: Our findings strengthen the role of galectins in carcinogenesis, disease progression, and lymphnode metastasis in ovarian carcinomas. And since these galectins are mostly overexpressed, they could be promising markers for targeted therapy to reduce disease progression and metastasis process. [ABSTRACT FROM AUTHOR]

Cyclodepsipeptide are a class of natural cyclic peptides that have a wide range of biological activities, hence the potential to be developed as new drug candidates. Cyclodpesipeptides comprise a backbone of amide bonds and at least one ester moiety, thus are complex and challenging to synthesis. Generally, cyclodepsipeptides are synthesised via solid‐phase peptide synthesis, solution‐phase or a combination of solid and solution‐phase. Currently, solid‐phase peptide synthesis is more in demand, but it also has several challenges in its application especially for the cyclodepsipeptide that contains N‐methylated residues, as well as solution‐phase peptide synthesis tends to have a longer reaction step. Therefore, the combination of solid and solution‐phase peptide synthesis is a better alternative. This review discusses the synthetic strategies for cyclodepsipeptides including the preparation of precursor and macrocyclization. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are generated during incomplete combustion of organic materials. Prior research has demonstrated that BaP is a prenatal ovarian toxicant and carcinogen. However, the metabolic pathways active in the embryo and its developing gonads and the mechanisms by which prenatal exposure to BaP predisposes to ovarian tumors later in life remain to be fully elucidated. To address these data gaps, we orally dosed pregnant female mice with BaP from embryonic day (E) 6.5 to E11.5 (0, 0.2, or 2 mg/kg/day) for metabolite measurement or E9.5 to E11.5 (0 or 3.33 mg/kg/day) for embryonic gonad RNA sequencing. Embryos were harvested at E13.5 for both experiments. The sum of BaP metabolite concentrations increased significantly with dose in the embryos and placentas, and concentrations were significantly higher in female than male embryos and in embryos than placentas. RNA sequencing revealed that enzymes involved in metabolic activation of BaP are expressed at moderate to high levels in embryonic gonads and that greater transcriptomic changes occurred in the ovaries in response to BaP than in the testes. We identified 490 differentially expressed genes (DEGs) with false discovery rate P -values < 0.05 when comparing BaP-exposed to control ovaries but no statistically significant DEGs between BaP-exposed and control testes. Genes related to monocyte/macrophage recruitment and activity, prolactin family genes, and several keratin genes were among the most upregulated genes in the BaP-exposed ovaries. Results show that developing ovaries are more sensitive than testes to prenatal BaP exposure, which may be related to higher concentrations of BaP metabolites in female embryos. [ABSTRACT FROM AUTHOR]

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Alpha-Synuclein (α-Synuclein) is a 140 amino acid protein implicated in neurodegenerative disorders known as synucleinopathies, where it accumulates in proteinaceous inclusions in the brain. The normal physiological function of α-Synuclein remains obscure, as it exists in several non-neuronal cells in which its function has not been studied. Given the tremendous interest in studying α-Synuclein, and the existing limitations in the production of modified forms of the protein, we developed a method for the chemical synthesis of α-Synuclein by combining peptide fragment synthesis via automated microwave-assisted solid-phase peptide synthesis and ligation strategies. Our synthetic pathway enables the synthesis of protein variants of interest, carrying either mutations or posttranslational modifications, for further investigations of the effects on the structure and aggregation behavior of the protein. Ultimately, our study forms the foundation for future syntheses and studies of other custom-made α-Synuclein variants with a single or several modifications, as necessary., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Recently, the utilization of Software as a Service (SaaS) by public organizations for sourcing software applications has led to reduced costs and improved quality of existing operations. Many studies have investigated the influential factors for cloud computing (CC) adoption in developed countries in the extant literature. However, studies have investigated the adoption of CC-SaaS in a developing country, especially in an unstable country like Iraq is sparse. Therefore, the main objective of this study is to conduct a pilot study on the factors affecting public organization intention towards the adoption of CCSaaS in Iraq. The obtained result indicates that the normality of data in this study falls between -0.49 to 1.50, the recommended range of -/+2. Also, the reliability analysis result for the constructs is above the established benchmark of 0.60 of Cronbach's alpha, indicating that the data is reliable and normally distributed. [ABSTRACT FROM AUTHOR]

Covering: up to 2020 This short review surveys aspects of glycolipid-based natural products and their biological relevance in multiple sclerosis (MS). The role of isolated gangliosides in disease models is discussed together with an overview of ganglioside-inspired small molecule drugs and imaging probes. The discussion is extended to neurodegeneration in a more general context and addresses the need for more efficient synthetic methods to generate (glyco)structures that are of therapeutic relevance. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including protein kinase C (PKC), phospholipase C (PLC), p63RhoGEF, and Rho. Combined with G protein and b-arrestin BRET biosensors, our sensors enabled real-time monitoring of GPCR signaling at different levels in downstream pathways in both native and engineered cells. Profiling of the responses to 14 angiotensin II (AngII) type 1 receptor (AT1R) ligands enabled the clustering of compounds into different subfamilies of biased ligands and showed that, in addition to the previously reported functional selectivity between Gαq and β-arrestin, there are also biases among G protein subtypes. We also demonstrated that biases observed at the receptor and G protein levels propagated to downstream signaling pathways and that these biases could occur through the engagement of different G proteins to activate a common effector. We also used these tools to determine how naturally occurring AT1R variants affected signaling bias. This suite of BRET biosensors provides a useful resource for fingerprinting biased ligands and mutant receptors and for dissecting functional selectivity at various levels of GPCR signaling. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity toward EGFR. Peptide modifications, including D‐amino acid substitution, cyclization, and chain reversal, were investigated. In addition, to facilitate labeling of the peptide with a fluorescent dye, an additional lysine residue was introduced onto the linear (KLARLLT) and cyclic peptides cyclo(KLARLLT) (Cyclo.L1). The lysine residue was also converted into an azide group in both a linear and reversed cyclic peptide sequences cyclo(K(N3)larllt) (Cyclo.L1.1) to allow for subsequent “click” conjugation. The cyclic peptides showed enhanced binding to EGFR by SPR. NMR and molecular modeling studies suggest that the peptides acquire a β‐turn structure in solution. In vitro stability studies in human serum show that the cyclic peptide is more stable than the linear peptide. [ABSTRACT FROM AUTHOR]

Background: The effectiveness of traditional Chinese medicine (TCM) in assisting the reduction of the toxic effects of chemotherapy and enhancing the efficacy of chemotherapy is gradually being recognized. Traditional Chinese medicine injection (TCMJ) has been widely used as a promising adjuvant drug in the treatment of ovarian carcinoma. However, the exact clinical efficacy and safety of TCMJ have not been well studied due to the wide variety. This study aims to conduct a network meta-analysis of randomized controlled trials (RCTs) about comparing the effect of TCMJ combined with chemotherapy and chemotherapy alone on the treatment of ovarian cancer, thus summarizing the effects of TCMJ on the prognosis, quality of life and immune function of ovarian carcinoma patients, and providing a reference for developing therapeutic regimens for ovarian carcinoma., Methods: Randomized controlled trials reporting the effect of TCMJ combined with chemotherapy and chemotherapy alone on the prognosis, quality of life and immune function in patients with ovarian carcinoma published before September 2021 will be screened out from online databases like PubMed, Web of Science, Scopus, Cochrane Library, Embase, China Scientific Journal Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Database. Subsequently, 2 researchers will be independently responsible for literature screening, data extraction and assessment of their quality. All data will be processed by R.4.1.0., Results: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication., Conclusions: Evidence-based medicine supports the efficacy and safety of TCMJ combined with chemotherapy for the treatment of ovarian carcinoma, which is better than that of chemotherapy alone., Ethics and Dissemination: Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms., Osf Registration Number: DOI 10.17605/OSF.IO/P93VJ., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

A new transition metal-free method for the preparation of substituted imidazoles from easy-to-handle amidine hydrochlorides and bromoacetylenes has been developed. The reactions proceed in air and use inexpensive K2CO3 as base. Additions of 2,2′-bipyridine and water have beneficial effects on the product yields. Various di- and trisubstituted imidazoles have been prepared in good yields (up to 88 %). [ABSTRACT FROM AUTHOR]

Current literature demonstrates that almost every area of chemical and life sciences, as well as technology utilizes quantitative structure-activity/property relationships (QSAR/QSPR) to accelerate development and increase efficiency. The designs of pharmaceuticals, agrichemicals, and consumer products as well as the assessment of their toxicity and environmental impact have become major areas of application QSAR/QSPR; the methods of which also penetrate into relatively new applications such as materials science and nanotechnology. In terms of methodology development the new trend is the integration of QSAR/QSPR with adjacent computational methods such as virtual screening and molecular dynamics. Such synergy offers unique opportunities and heralds a new era of computer-aided molecular design. [ABSTRACT FROM AUTHOR]

A new 1,5 disubstituted imidazole AT1 Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity ( V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT1 receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension. [ABSTRACT FROM AUTHOR]

In the present study, we report the synthesis and biological evaluation of a series of new non-peptide PAR1 mimetic receptor antagonists, based on conformational analysis of the S42FLLR46 tethered ligand (TL) sequence of PAR1. These compounds incorporate the key pharmacophore groups in the TL sequence, guanidyl, amino and phenyl, which are essential for triggering receptor activity. Compounds 5 and 15 (50–100 μM) inhibited both TFLLR-amide (10 μM) and thrombin-mediated (0.5 and 1 U/ml; 5 and 10 μM) calcium signaling in a cultured human HEK cell assay. [ABSTRACT FROM AUTHOR]

Galectin-7 is a soluble unglycosylated lectin that is able to bind specifically to β-galactosides. It has been described to be involved in apoptosis, proliferation and differentiation, but also in cell adhesion and migration. Several disorders and diseases are discussed by covering the aforementioned biological processes. Structural features of galectin-7 are discussed as well as targeting the protein intracellularly or extracellularly. The exact molecular mechanisms that lie behind many biological processes involving galectin-7 are not known. It is therefore useful to come up with chemical probes or tools in order to obtain knowledge of the physiological processes. The objective of this review is to summarize the roles and functions of galectin-7 in the human body, providing reasons why it is necessary to design inhibitors for galectin-7, to give the reader structural insights and describe its current inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: This review compiles our current knowledge of one of the main pathways activated by tumors to escape immune attack. Indeed, it integrates the current understanding of how tumor-derived circulating galectins affect the elicitation of effective anti-tumor immunity. It focuses on several relevant topics: which are the main galectins produced by tumors, how soluble galectins circulate throughout biological liquids (taking a body-settled gradient concentration into account), the conditions required for the galectins' functions to be accomplished at the tumor and tumor-distant sites, and how the physicochemical properties of the microenvironment in each tissue determine their functions. These are no mere semantic definitions as they define which functions can be performed in said tissues instead. Finally, we discuss the promising future of galectins as targets in cancer immunotherapy and some outstanding questions in the field. Current data indicates that anti-tumor T cell-mediated immunity correlates with a better prognosis in cancer patients. However, it has widely been demonstrated that tumor cells negatively manage immune attack by activating several immune-suppressive mechanisms. It is, therefore, essential to fully understand how lymphocytes are activated in a tumor microenvironment and, above all, how to prevent these cells from becoming dysfunctional. Tumors produce galectins-1, -3, -7, -8, and -9 as one of the major molecular mechanisms to evade immune control of tumor development. These galectins impact different steps in the establishment of the anti-tumor immune responses. Here, we carry out a critical dissection on the mechanisms through which tumor-derived galectins can influence the production and the functionality of anti-tumor T lymphocytes. This knowledge may help us design more effective immunotherapies to treat human cancers. [ABSTRACT FROM AUTHOR]

Many autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and celiac disease (CD), arise from improper immune system recognition of self or benign peptides as threats. No autoimmune disease currently has a cure. Many treatments suppress the entire immune system to decrease symptom severity. The core molecular interaction underlying these diseases involves specific alleles of the human leukocyte antigen (HLA) receptor hosting the immunodominant peptides associated with the disease (i.e., myelin basic protein, Type II collagen, or α‐gliadin) in their binding groove. Once bound, circulating T‐cells can recognize the HLA‐antigen complex and initiate the complex cascade that forms an adaptive immune response. This initial HLA‐antigen interaction is a promising target for therapeutic intervention. Two general strategies have been pursued: altered peptide ligands (APLs) that attempt to recruit a different class of T‐cell to induce an anti‐inflammatory response to balance the pro‐inflammatory response associated with the antigen; and HLA‐blockers (HLABs), peptides that quantitatively displace the antigen to inhibit the immune response. Both approaches would benefit from improved HLA‐drug binding, but as the HLA receptors are highly promiscuous, the binding sites are not specific for any natural amino acid. Unnatural amino acids, either designed or screened through high‐throughput assays, may provide a solution. This review summarizes the nascent field of using noncanonical residues to treat MS, RA and CD, focusing on the importance of specific molecular interactions, and provides some examples of the synthesis of these unnatural residues. [ABSTRACT FROM AUTHOR]