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Although the concept of cancer stem cells is still controversial, previous studies have shown that blood cancers, as well as specific types of solid cancers such as colorectal cancer, rely on stem cells during the onset of tumor growth and further tumor development. Moreover, resistance to therapeutic treatment in leukemias such as acute myeloid leukemia and in colorectal cancer can be attributed to a small population of cells with stemness properties known as minimal residual disease. In this review, we look back on the discovery of cancer stem cells and the contribution of the findings in blood cancer to a parallel discovery in solid cancers. We focus on CD44 as a stem cell marker, both in blood cancers and in several types of solid cancers, particularly of the gastrointestinal tract. This review highlights newly discovered molecular mechanisms of action of CD44 which indicate that CD44 has indeed a function in stemness, stem cell maintenance, and drug resistance. We attempt here to make the link between the functions of CD44 isoforms in stemness and their involvement in specific steps of tumor growth and metastasis. [ABSTRACT FROM AUTHOR]

Already known molecules which exhibit good electrochemiluminescence (ECL) efficiencies and high photoluminescence quantum yields (PLQY) have been structurally modified in order to increase their performance. The followed strategy is to stiffen the structures to limit the rotational and vibrational freedom degrees and favour radiative decay processes once excited. Molecules under investigation consist of donor‐acceptor systems in which the acceptor fraction is a benzonitrile with an imidazole in para position, while the donor fraction consists of four diphenylamine (NPh2) or 3,6‐di(tert‐butyl)‐9H‐carbazole (t‐BuCz) groups in the remaining positions on the central benzene ring. Therefore, in order to stiffen these systems and restrict the intramolecular rotations (RIR), the imidazole in the para position has been replaced with more extended π‐systems, i. e., benzimidazole and phenanthro[9,10‐d]imidazole. The restriction of the intramolecular rotation can be clearly observed by 1H NMR analysis. We expected to observe an increase in ECL efficiency and PLQY with the rigidity. Surprisingly, we observed a generally opposite trend: molecules with the smallest imidazole fraction showed the best performance in ECL and higher PLQY. Notably, NPh2 derivatives with benzimidazole and phenanthro[9,10‐d]imidazole showed an hypsochromic shift of the emission spectra with concomitant increase of the PLQY as the solvent polarity increases. [ABSTRACT FROM AUTHOR]

Although progress has been made in the treatment of cancer, particularly for the four major types of cancers affecting the lungs, colon, breast and prostate, resistance to cancer treatment often emerges upon inhibition of major signaling pathways, which leads to the activation of additional pathways as a last-resort survival mechanism by the cancer cells. This signaling plasticity provides cancer cells with a level of operational freedom, reducing treatment efficacy. Plasticity is a characteristic of cancer cells that are not only able to switch signaling pathways but also from one cellular state (differentiated cells to stem cells or vice versa) to another. It seems implausible that the inhibition of one or a few signaling pathways of heterogeneous and plastic tumors can sustain a durable effect. We propose that inhibiting molecules with pleiotropic functions such as cell surface co-receptors can be a key to preventing therapy escape instead of targeting bona fide receptors. Therefore, we ask the question whether co-receptors often considered as "accessory molecules" are an overlooked key to control cancer cell behavior. [ABSTRACT FROM AUTHOR]

The coordinating properties of the bis(1,4‐dimethyl‐1,2,4‐triazol‐5‐ylidene) ligand (abbreviated as bitz) towards silver(I) and gold(I) centres have been explored. The bitz behaves as bridging ligand giving both dinuclear [M2(bitz)2](PF6)2 and trinuclear [M3(bitz)3](PF6)3 species, whose formation has been supported by X‐ray diffraction analysis, NMR spectroscopy and mass spectrometry evidences. The dinuclear and trinuclear gold(I) complexes present very similar luminescence properties, emitting in the blue region, at ~450 nm, when excited at 350 nm. Selected experimental aspects dealing with the synthesis of the dinuclear and trinuclear species, as well as with the absorption properties of the gold(I) complexes, have been investigated also through relativistic DFT calculations. [ABSTRACT FROM AUTHOR]

Background and Objectives: The recently published Spine Stereotactic Radiosurgery (SSRS) ESTRO guidelines advise against treating spinal metastatic disease with a single dose equal to or smaller than 18 Gy, prioritizing local control over the potential for complications. This study aims to assess the necessity and validity of these higher dose recommendations by evaluating the outcomes and experiences with lower radiation doses. Materials and Methods: A retrospective evaluation of SSRS patients treated at a single institute was conducted. The outcomes and complications of this cohort were compared to the current literature and the data supporting the new ESTRO guidelines. Results: A total of 149 treatment sessions involving 242 spinal levels were evaluated. The overall local control rate was 91.2%. The mean radiation dose for the local control group compared to the local failure group was similar (17.5 vs. 17.6 Gy, not significant). The overall complication rate was 6%. These results are consistent with previous publications evaluating SSRS for metastatic spinal disease. Conclusions: SSRS dose escalation may increase local control efficacy but comes with a higher risk of complications. The evidence supporting the strong recommendations in the recent ESTRO guidelines is not robust enough to justify a universal application. Given the palliative nature of treatment for metastatic patients, dose determination should be individualized based on patient conditions and preferences, with a detailed discussion about the risk–benefit ratio of increased doses and the level of evidence supporting these recommendations. [ABSTRACT FROM AUTHOR]

The reactivity of Zn2+ tetrahedral complexes with H2O2 was investigated in silico, as a first step in their disruption process. The substrates were chosen to represent the cores of three different zinc finger protein motifs, i. e., a Zn2+ ion coordinated to four cysteines (CCCC), to three cysteines and one histidine (CCCH), and to two cysteines and two histidines (CCHH). The cysteine and histidine ligands were further simplified to methyl thiolate and imidazole, respectively. H2O2 was chosen as an oxidizing agent due to its biological role as a metabolic product and species involved in signaling processes. The mechanism of oxidation of a coordinated cysteinate to sulfenate‐κS and the trends for the different substrates were rationalized through activation strain analysis and energy decomposition analysis in the framework of scalar relativistic Density Functional Theory (DFT) calculations at ZORA‐M06/TZ2P ae // ZORA‐BLYP‐D3(BJ)/TZ2P. CCCC is oxidized most easily, an outcome explained considering both electrostatic and orbital interactions. The isomerization to sulfenate‐κO was attempted to assess whether this step may affect the ligand dissociation; however, it was found to introduce a kinetic barrier without improving the energetics of the dissociation. Lastly, ligand exchange with free thiolates and selenolates was investigated as a trigger for ligand dissociation, possibly leading to metal ejection; molecular docking simulations also support this hypothesis. [ABSTRACT FROM AUTHOR]

Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

The adhesion of cells to the extracellular matrix engages cell surface receptors such as integrins, proteoglycans and other types of cell adhesion molecules such as CD44. To closely examine the determinants of cell adhesion, herein we describe the generation of high-density peptide arrays and test the growth of cells on these multifunctionalized surfaces. The peptide library used consists of over 11,000 different sequences, either random or derived from existing proteins. By applying this screen to SW620 mCherry colorectal cancer cells, we select for peptides with both maximum cell adhesion and maximum cell repulsion. All of these extreme properties are based on unique combinations of amino acids. Here, we identify peptides with maximum cell repulsion on secreted frizzled- and Dickkopf-related proteins. Peptides with strong cell repulsion are found at the poles of the TNF-alpha homotrimer. The formation of cellular patterns on alternating highly repulsive and adhesive peptides are examined. Our screen allows the identification of peptides suitable for biomedical and tissue engineering applications. A screen on high-density peptide arrays identified peptides with high cell-adhesion/ repulsion properties. Peptides with high repulsive properties as those found in TNF-alpha are particularly suitable for biomedical/bioengineering applications. [ABSTRACT FROM AUTHOR]

Viruses often pose a significant threat to the host through the exploitation of cellular machineries for their own benefit. In the context of immune responses, myriad host factors are deployed to target viral RNAs and inhibit viral protein translation, ultimately hampering viral replication. Understanding how "non-self" RNAs interact with the host translation machinery and trigger immune responses would help in the development of treatment strategies for viral infections. In this review, we explore how interferon-stimulated gene products interact with viral RNA and the translation machinery in order to induce either global or targeted translation inhibition. [ABSTRACT FROM AUTHOR]

Fisheries management agencies in the U.S. Caribbean are currently taking steps into transitioning from a single species approach to one that includes Ecosystem Based Fisheries Management (EBFM) considerations. In this study, we developed and analyzed stakeholder-driven conceptual models with seven different stakeholder groups in Puerto Rico and the US Virgin Islands to assess and compare their perceptions of the fishery ecosystem. Conceptual models were developed for each stakeholder group during 29 separate workshops involving a total of 236 participants representing Commercial Fishers, Managers, Academics, Local Businesses, Environmental NGOs, and the Caribbean Fishery Management Council (CFMC) District Advisory Panels (DAPs) and Scientific and Statistical Committee (SSC). Non-Metric Multidimensional Scaling (nMDS) and two-mode social network analysis were used to investigate differences and similarities between stakeholder groups as well as to identify priority ecosystem elements and threats. Results show important variations between stakeholders and islands in terms of their perceived importance of ecosystem components and relationships, which supports the need for collaborative approaches and co-production of knowledge in the United States (U.S.) Caribbean region. Despite this variation, important areas of common concern among stakeholders were identified such as: habitat integrity (e.g., coral reefs), water quality, and influence of recreational fisheries and tourism on marine ecosystems. Findings of this study support the use of stakeholder-driven conceptual models as effective tools to guide decision-making, aid prioritization of data collection, and increase collaboration and cooperation among stakeholders in the context of fisheries management. [ABSTRACT FROM AUTHOR]

In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)–aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA–complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity. [ABSTRACT FROM AUTHOR]

In this work, we have prepared some common diphenyl diselenide compounds and evaluated the solvent effect on the 77Se NMR chemical shift. Thus, 77Se NMR spectra of diphenyl diselenides containing electron-withdrawing or electron-donating groups were recorded in eight different deuterated solvents with distinct polarities. The effects of temperature and concentration were also assessed and were found to play a minor role in the precise values of 77Se chemical shift. Finally, a computational study was performed to rationalize the 77Se NMR chemical shift behavior and to highlight the limits of standard approaches. [ABSTRACT FROM AUTHOR]

Various activities are systematically imposed on women in both paid and unpaid forms, generally involving care for others, sexual activity, or a combination of both. These activities have typically been studied separately, but these analytical divisions are increasingly being questioned. This article contributes to this debate by exploring empirical and theoretical connections two of the most prominent of these activities, prostitution and domestic service. Through a survey of the empirical literature on migration for domestic service, the article identifies four themes that suggest why some migrant women move between domestic service and prostitution: pre-existing structural constraints, migration conditions, working conditions, and migration policies. Subsequently, drawing on the work of French materialist feminists Colette Guillaumin and Paola Tabet and political theorist Carole Pateman, it sketches the outline of a theoretical account of the relationship between these two activities. [ABSTRACT FROM AUTHOR]

In discussing the dismantling and transport of the tabernacle and its furnishings, Numbers 4:20 prohibits any viewing of the "holy," except by Aaron, the priest, and his sons. Philo of Alexandria, as well as several modern scholars, read this as a prohibition on any non-priestly viewing of the sacred, Jewish cultic vessels, including the menorah, the shewbread table and the incense altar. Accordingly, a dominant view in research holds that during the Second Temple period these cultic utensils were concealed from the sight of non-priests. However, this view partly overlooks and partly misinterprets our main source in that respect: Josephus indicates that the Jewish holy vessels were actually displayed to the Jewish crowd gathered in the temple court during the Second Temple period. This is supported by the images on certain Hasmonean coins as well as by later texts, such as P.Oxy. 840 and rabbinic literature. [ABSTRACT FROM AUTHOR]

Background: Graves' disease has been associated with adverse pregnancy, labor and delivery, and neonatal outcomes. Thyroid function levels, assessed during newborn screening (NBS), can serve as indicators of the adaptation in the hypothalamic–pituitary–thyroid axis. We utilized data from the national thyroid NBS program to investigate the characteristics of the mother–infant dyad of term infants born to mothers with past or active Graves' disease. Methods: The dataset of the Israeli NBS for thyroid function was linked with the electronic records of a tertiary medical center to generate a unified database of mothers and their term infants born between 2011 and 2021. The MDClone big data platform extracted maternal, pregnancy, disease course, labor and delivery, and neonatal characteristics of the mother-infant dyads. Results: Out of 103,899 registered mother–infant dyads, 292 (0.3%) mothers had past or active Graves' disease. A forward multivariate linear regression demonstrated that Graves' disease did not significantly affect NBS total thyroxine (tT4) levels (p = 0.252). NBS tT4 levels in infants born to mothers with active Graves' disease were higher than those observed in the general Israeli population (p < 0.001). Mothers with Graves' disease more frequently used assisted reproductive technology (12.7% vs. 9.0%, respectively, p = 0.012; odds ratio [OR] = 1.46 [CI 1.03–2.07], p = 0.031), and had more gestational hypertension (3.9% vs. 1.1%, p < 0.001; OR = 3.53 [CI 1.92–6.47], p < 0.001), proteinuria (2.5% vs. 0.9%, p < 0.001; OR = 3.03 [CI 1.43–6.45], p = 0.004), cesarean sections (26.4% vs. 19.7%, p = 0.029; OR = 1.46 [CI 1.13–1.90], p = 0.004), prelabor rupture of membranes (15.4% vs. 4.1%, p < 0.001; OR = 4.3 [CI 3.13–5.91], p < 0.001), and placental abnormalities (5.1% vs. 2.0%, p < 0.001; OR = 2.64 [CI 1.57–4.44]; p < 0.001). Their infants had lower adjusted birthweight z-scores (−0.18 ± 0.94 vs. −0.03 ± 0.90, p = 0.007) and were more likely to be small for gestational age (12.0% vs. 8.1%, p = 0.005; OR = 1.54 [CI 1.08–2.19], p = 0.018). Conclusions: Neonatal thyroid function levels were affected by maternal Graves' disease only when the disease was active during gestation. Moreover, maternal Graves' disease was also associated with an increased risk of adverse outcomes for the mother–infant dyad. [ABSTRACT FROM AUTHOR]

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC. Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses. [ABSTRACT FROM AUTHOR]

Recent decades have witnessed significant progress in understanding mechanisms driving neurodegeneration and disease progression in multiple sclerosis (MS), but with a focus on the cerebrum. In contrast, there have been limited studies of cerebellar disease, despite the common occurrence of cerebellar symptoms in this disorder. These rare studies, however, highlight the early cerebellar involvement in disease development and an association between the early occurrence of cerebellar lesions and risk of worse prognosis. In parallel developments, it has become evident that far from being a region specialized in movement control, the cerebellum plays a crucial role in cognitive function, via circuitry connecting the cerebellum to association areas of the cerebrum. This complexity, coupled with challenges in imaging of the cerebellum have been major obstacles in the appreciation of the spatio-temporal evolution of cerebellar damage in MS and correlation with disability and progression. MS studies based on animal models have relied on an induced neuroinflammatory disease known as experimental autoimmune encephalomyelitis (EAE), in rodents and non-human primates (NHP). EAE has played a critical role in elucidating mechanisms underpinning tissue damage and been validated for the generation of proof-of-concept for cerebellar pathological processes relevant to MS. Additionally, rodent and NHP studies have formed the cornerstone of current knowledge of functional anatomy and cognitive processes. Here, we propose that improved insight into consequences of cerebellar damage in MS at the functional, cellular and molecular levels would be gained by more extensive characterization of EAE cerebellar pathology combined with the power of experimental paradigms in the field of cognition. Such combinatorial approaches would lead to improved potential for the development of MS sensitive markers and evaluation of candidate therapeutics. [ABSTRACT FROM AUTHOR]

The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism. A systems-wide study of mice infected with SARS-CoV2 under ketogenic diet shows that this diet reprograms the transcriptional and metabolic response in animals following infection with improved health, reduced inflammation, and restored metabolism. [ABSTRACT FROM AUTHOR]

Oxidative phosphorylation and glycolysis are the dominant ATP‐generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell‐specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady‐state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions. Synopsis: This manuscript details a method to calculate ATP production rates using OCR and ECAR data obtained from the Seahorse XF Analyzer. This generates a single readout measuring real‐time rates of ATP produced from oxidative phosphorylation and glycolysis in live cells. ECAR can quantitatively reflect lactate efflux after adjusting for buffering power of the experimental medium, respiratory acidification, and sensor coverage of the measurement well.The approach quantifies changes in ATP produced from oxidative phosphorylation and glycolysis in response to physiologically relevant stimuli.Real‐time ATP production rates capture changes in ATP utilization that steady‐state ATP levels do not.Examples are given for acute activation of neurons, adipocytes, macrophages, and T cells. [ABSTRACT FROM AUTHOR]

Focusing on the success of Florina Ilis' novel The children's crusade, this article explores its potential as a literary contribution in a broader global discourse, as it could be considered "literary Romanian capital" in a discussion about world literature. While the book draws on clichéd stereotypes of Romanian society from the early 2000s, including the Ceauşescu era and the challenging transition from communism to democracy, the author uses a universal language of trauma. This allows for a wider audience to engage with the themes presented in the novel. Thus, her story becomes part of a global collection of works exploring the theme of the "children's crusade" (including George Zabriskie Gray, Marcel Schwob, Lucian Blaga, Jerzy Andrzejewski, Thea Beckman, Gregory J. Rinaldi, Karleen Bradford, Kathleen McDonnell, Bryce Courtenay, Mario Vargas Llosa, Tullio Avoledo, amongst others). Considering the connection between continuity and innovation in Romanian literature, 75 years following Lucian Blaga's play, with the same title, Florina Ilis employs a plot with medieval roots in her novel, which has fascinated writers worldwide, to deliver a unique perspective, in a new discourse. [ABSTRACT FROM AUTHOR]

Many natural substances and drugs are radical scavengers that prevent the oxidative damage to fundamental cell components. This process may occur via different mechanisms, among which, one of the most important, is hydrogen atom transfer. The feasibility of this process can be assessed in silico using quantum mechanics to compute Δ G HAT ○ . This approach is accurate, but time consuming. The use of machine learning (ML) allows us to reduce tremendously the computational cost of the assessment of the scavenging properties of a potential antioxidant, almost without affecting the quality of the results. However, in many ML implementations, the description of the relevant features of a molecule in a machine-friendly language is still the most challenging aspect. In this work, we present a newly developed machine-readable molecular representation aimed at the application of automatized ML algorithms. In particular, we show an application on the calculation of Δ G HAT ○ . [ABSTRACT FROM AUTHOR]

The nature of the photoexcited triplet state of free-base 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (H2TPPS4−) has been investigated by advanced Electron Paramagnetic Resonance (EPR) techniques combined with quantum chemical calculations. The zero-field splitting (ZFS) parameters, D and E, the orientation of the transition dipole moment in the ZFS tensor frame, and the proton hyperfine couplings have been determined by magnetophotoselection-EPR and pulse electron-nuclear double resonance spectroscopy. Both time-resolved and pulse experiments exploit the electron spin polarization of the photoexcited triplet state. Comparison of the magnetic observables with computational results, including CASSCF calculations of the ZFS interaction tensor, provides an accurate picture of the triplet-state electronic structure. The theoretical investigation has been integrated with a systematic analysis on the parent free-base porphyrin molecule to assess the effect of the sulfonatophenyl substituents on the magnetic tensors. Additionally, the magnetophotoselection effects are discussed in terms of tautomerization in the excited singlet state of H2TPPS4−. [ABSTRACT FROM AUTHOR]

Due to its endogenously high oxygen consumption, the central nervous system (CNS) is vulnerable to oxidative stress conditions. Notably, the activity of several CNS-targeting compounds, such as antidepressant and hypnotic drugs, or endogenous mediators, such as melatonin, is indeed linked to their ability of mitigating oxidative stress. In this work, we report the synthesis of two organoselenium compounds of which the structure was inspired by CNS-targeting psychotropic drugs (zolpidem and fluoxetine) and an endogenous mediator (melatonin). The molecules were designed with the aim of combining the ROS-scavenging properties, which were already assessed for the parent compounds, with a secondary antioxidant action, a glutathione peroxidase (GPx) mimic role empowered by the presence of selenium. The compounds were obtained through a facile three-step synthesis and were predicted by computational tools to passively permeate through the blood–brain barrier and to efficiently bind to the GABA A receptor, the macromolecular target of zolpidem. Of note, the designed synthetic pathway enables the production of several other derivatives through minor modifications of the scheme, paving the way for structure–activity relationship studies. [ABSTRACT FROM AUTHOR]

Social mobility in the cultural sector is currently an important issue in government policy and public discussion, associated with perceptions of a collapse in numbers of working-class origin individuals becoming artists, actors, musicians and authors. The question of who works in creative occupations has also attracted significant sociological attention. To date, however, there have been no empirically grounded studies into the changing social composition of such occupations. This article uses the Office for National Statistics Longitudinal Study to show that, while those from more privileged social backgrounds have long dominated, there has been no change in the relative class mobility chances of gaining access to creative work. Instead, we must turn to the pattern of absolute mobility into this sector in order to understand claims that it is experiencing a 'mobility crisis'. [ABSTRACT FROM AUTHOR]

We set up an in silico experiment and designed a chimeric compound integrating molecular features from different efficient ROS (Reactive Oxygen Species) scavengers, with the purpose of investigating potential relationships between molecular structure and antioxidant activity. Furthermore, a selenium centre was inserted due to its known capacity to reduce hydroperoxides, acting as a molecular mimic of glutathione peroxidase; finally, since this organoselenide is a precursor of a N-heterocyclic carbene ligand, its Au(I) carbene complex was designed and examined. A validated protocol based on DFT (Density Functional Theory) was employed to investigate the radical scavenging activity of available sites on the organoselenide precursor ((SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)), as well as on the organometallic complex ((SMD)-M06-2X/SDD (Au), 6-311+G(d,p)//ZORA-BLYP-D3(BJ)/TZ2P), considering HAT (Hydrogen Atom Transfer) and RAF (Radical Adduct Formation) regarding five different radicals. The results of this case study suggest that the antioxidant potential of chemical motifs should not be considered as an additive property when designing a chimeric compound, but rather that the relevance of a molecular topology is derived from a chemical motif combined with an opportune chemical space of the molecule. Thus, the direct contributions of single functional groups which are generally thought of as antioxidants per se do not guarantee the efficient radical scavenging potential of a molecular species. [ABSTRACT FROM AUTHOR]

A majority of scholars view the Hasmonean-Spartan correspondence, reported in 1 Maccabees, as inauthentic, since it contains many improbabilities, including the assertion that the Jews and the Spartans are fraternal nations. However, its patent implausibility also renders it unimaginable that the correspondence was intended to be understood literally. Hence, the binary choice offered in research, whereby it is either a bizarre fabrication or an authentic correspondence, despite all its peculiarities, is problematic. The Hasmonean-Spartan correspondence thus remains a conspicuous, unresolved enigma in the research of 1 Maccabees and the early Hasmonean period. Based on a textual clue, this article proposes a solution, namely, that the correspondence is, in fact, an ingenious derision of the Jews' authentic ethnic "brothers"—the Samaritans. This suggestion provides new insights into the history of the early Hasmoneans and the literary creativity of the author of 1 Maccabees. [ABSTRACT FROM AUTHOR]

The selenium element is essential to some life forms and its biological-chemistry function is mainly performed by the selenol/selenolate moiety (–SeH/–Se–) in a few selenoproteins. Many synthetic organoselenium compounds (OSeCs) have demonstrated important therapeutic applications, with the Ebselen and diphenyl diselenide being the most studied OSeCs. They could act as "hidden selenol" molecules, where the –SeH/–Se– are responsible for the reduction of dangerous peroxides and the protection against the neurotoxic methylmercury. However, their actual mechanisms of action at atomic/molecular level are still elusive. The main conundrum about OSeCs is how they can have quite different structures and similar in vivo action and at the same time modulate quite distinct physiological functions? The question is a hard one because we know little about the metabolism of OSeCs, the in vivo studies are always typically phenomenological, OSeCs have low selectivity and non-specific interactions with thiol-containing proteins. The use of in silico and in vitro models, followed by new analytical methodologies, will give important answers about the metabolism, reactivity, and specificity of OSeCs with specific biological targets, and a real advancement in the subfield of "pharmacological applications" of OSeCs. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD. In NAFLD, high levels of fatty acids in the liver impair lysosomal acidification. Here, the authors report the synthesis of novel biodegradable acid-activated acidifying nanoparticles that re-acidify lysosomes, restore autophagy, and reverse fasting hyperglycemia and hepatic steatosis in fat mice. [ABSTRACT FROM AUTHOR]

The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)‐Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex‐III deficiency, we show that inhibition of CV hydrolytic activity by (+)‐Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV–ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis‐selective inhibitors of CV. Synopsis: In mitochondria, Complex V can rotate forward or reverse to either synthesize or hydrolyze ATP respectively. Here, isolated inhibition of the reverse activity of CV is sufficient to prevent ATP depletion in conditions of impaired respiration. A new assay to quantify ATP hydrolysis by ATP synthase (CV) shows that CV reverse activity occurs in coupled mitochondria.The polyphenol (+)‐Epicatechin is identified as a selective inhibitor of CV reverse activity while leaving synthesis unaffected.In cells with impaired respiratory function (+)-Epicatechin can increase cellular ATP content without restoring respiratory function.Muscle injury in a mouse model of Duchenne Muscular Dystrophy results in an increased CV reverse activity that correlates with the loss of muscle strength.(+)‐Epicatechin decreases ATP hydrolysis and improves muscle force in the Duchenne Muscular Dystrophy mouse model. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.In NAFLD, high levels of fatty acids in the liver impair lysosomal acidification. Here, the authors report the synthesis of novel biodegradable acid-activated acidifying nanoparticles that re-acidify lysosomes, restore autophagy, and reverse fasting hyperglycemia and hepatic steatosis in fat mice. [ABSTRACT FROM AUTHOR]

Sulfoxides and selenoxides oxidize thiols to disulfides while being reduced back to sulfides and selenides. While the reduction mechanism of sulfoxides to sulfides has been thoroughly explored experimentally as well as computationally, less attention has been devoted to the heavier selenoxides. In this work, we explore the reductive mechanism of dimethyl selenoxide, as an archetypal selenoxide and, for the sake of comparison, the reductive mechanism of dimethyl sulfoxide to gain insight into the role of the chalcogen on the reaction substrate. Particular attention is devoted to the key role of sulfurane and selenurane intermediates. Moreover, the capacity of these system to oxidize selenols rather than thiols, leading to the formation of selenyl sulfide bridges, is explored in silico. Notably, this analysis provides molecular insight into the role of selenocysteine in methionine sulfoxide reductase selenoenzyme. The activation strain model of chemical reactivity is employed in the studied reactions as an intuitive tool to bridge the computationally predicted effect of the chalcogen on the chalcogenoxide as well as on the chalcogenol. [ABSTRACT FROM AUTHOR]

Cancer is a devastating disease and the second leading cause of death worldwide. However, the development of resistance to current therapies is making cancer treatment more difficult. Combining the multi-omics data of individual tumors with information on their in-vitro Drug Sensitivity and Resistance Test (DSRT) can help to determine the appropriate therapy for each patient. Miniaturized high-throughput technologies, such as the droplet microarray, enable personalized oncology. We are developing a platform that incorporates DSRT profiling workflows from minute amounts of cellular material and reagents. Experimental results often rely on image-based readout techniques, where images are often constructed in grid-like structures with heterogeneous image processing targets. However, manual image analysis is time-consuming, not reproducible, and impossible for high-throughput experiments due to the amount of data generated. Therefore, automated image processing solutions are an essential component of a screening platform for personalized oncology. We present our comprehensive concept that considers assisted image annotation, algorithms for image processing of grid-like high-throughput experiments, and enhanced learning processes. In addition, the concept includes the deployment of processing pipelines. Details of the computation and implementation are presented. In particular, we outline solutions for linking automated image processing for personalized oncology with high-performance computing. Finally, we demonstrate the advantages of our proposal, using image data from heterogeneous practical experiments and challenges. [ABSTRACT FROM AUTHOR]

A combination of spectroscopic, chromatographic and computational approaches was employed to investigate the reaction of several diselenides of formula (R-PhSe)2 (R = CH3O, CH3, H, Cl, CF3) with a thiolate nucleophile, leading to the breaking of the selenium–selenium (Se–Se) bond. This process has fundamental importance in biological environments and provides a rationale to analyze the so-called thiol modifier effect of diselenides, which may be exploited in pharmacology and toxicology. Our data suggest that withdrawing substituents favor the reaction, effectively making the reaction energy more negative, but strong electron-withdrawing groups also prompt structural modification on the starting reactant, increasing the reaction barrier. Thus, the nature (electron rich or electron poor) of the diselenides can play an essential role in the reactivity and biological activity of these molecules. [ABSTRACT FROM AUTHOR]

Consumers can influence ecological patterns and processes through their trophic roles and contributions to the flow of energy through ecosystems. However, the diet and associated trophic roles of consumers commonly change during ontogeny. Despite the prevalence of ontogenetic variation in trophic roles of most animals, we lack an understanding of whether they change consistently across local populations and broad geographic gradients. We examined how the diet and trophic position of a generalist marine predator varied with ontogeny across seven broadly separated locations (~ 750 km). We observed a high degree of heterogeneity in prey consumed without evidence of spatial structuring in this variability. However, compound-specific isotope analysis of amino acids revealed remarkably consistent patterns of increasing trophic position through ontogeny across local populations, suggesting that the roles of this generalist predator scaled with its body size across space. Given the high degree of diet heterogeneity we observed, this finding suggests that even though the dietary patterns differed, the underlying food web architecture transcended variation in prey species across locations for this generalist consumer. Our research addresses a gap in empirical field work regarding the interplay between stage-structured populations and food webs, and suggests ontogenetic changes in trophic position can be consistent in generalist consumers. [ABSTRACT FROM AUTHOR]

Cross-party violence - violence between opposing partisans - is a growing concern worldwide. Understanding the predictors of the legitimization of violence against political opponents is thus becoming a vital goal. In this work, we propose two potential explanatory frameworks: affective polarization and low non-violent group efficacy. The first reflects an affective motivation to harm the out-party, while the latter reflects an instrumental motivation to deploy violence. Furthermore, while the former is frequently suggested in scholarly work as a cause for such violence, it has so far been backed only by limited empirical support. On the other hand, the latter is hardly examined in the context of interactions between opposing partisans. We tested the relationship of the two explanatory frameworks with the legitimization of cross-party violence using public opinion surveys in two real-world contexts: in 2020, in Israel (N = 500) and in the US (N = 631). Results from a regression analysis provide support for the instrumental explanation but not for the affective one. We discuss the theoretical implications of our findings for the research of affective polarization, and potential practical implications for attempts to reduce cross-party violence. [ABSTRACT FROM AUTHOR]

The reactive oxygen species (ROS) scavenging capacities of ginkgolides and bilobalide, which are the peculiar constituents of the extract of Ginkgo biloba, are investigated in silico (level of theory: (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)). Unlike other popular antioxidant natural substances, the carbon backbones of these compounds are entirely aliphatic and exclusively single C–C bonds are present. The selectivity for alkoxyl radicals via hydrogen-atom transfer (HAT) is assessed; importantly, the scavenging of peroxyl radicals is also possible from a peculiar site, here labeled C10 both for ginkgolides and bilobalide. The energetics are described in detail, and the analysis discloses that the studied compounds are powerful scavengers, with thermodynamic and kinetic properties similar to those of Trolox and melatonin, and that, in addition, they display selectivity for peroxyl radicals. These are all chemical-reactivity features contributing to the therapeutic action of the extract of G. biloba. [ABSTRACT FROM AUTHOR]

The equilibrium of copper-catalyzed atom transfer radical polymerization was investigated in silico with the aim of finding an explanation for the experimentally observed solvent effect. Various combinations of alkyl halide initiators and copper complexes in acetonitrile (MeCN) and dimethyl sulfoxide (DMSO) were taken into consideration. A continuum model for solvation, which does not account for the explicit interactions between the solvent and metal complex, is not adequate and does not allow the reproduction of the experimental trend. However, when the solvent molecules are included in the coordination sphere of the copper(I,II) species and the continuum description of the medium is still used, a solvent dependence of process thermodynamics emerges, in fair agreement with experimental trends. [ABSTRACT FROM AUTHOR]