Recent Findings Research Articles

Electrochemically Gated Frustrated Lewis Pair Chemistry in Electric Double Layer

The recent discovery of frustrated Lewis pairs (FLPs) during the activation of small molecules has inspired extensive research across the full span of chemical science. Owing to the nature of weak interactions, it is experimentally challenging to directly observe and modulate FLP at the molecular scale. Here we design a boron cluster anion building block (B10H82‐) and organic amine cations ([NR4]+, R= ‐CH3, ‐C2H5) as the FLP to prove the feasibility of controlling their interaction in the electric double layer (EDL) via an electrochemical strategy. In situ single‐molecule electrical measurements and Raman monitoring of B10H82‐–[NR4]+ FLP formed at the positively charged Au(111) electrode surface, in contrast to the free‐standing B10H82‐ near or below the potential of zero charge (PZC). Furthermore, this FLP chemistry leads to a shift in the local density of states of boron clusters towards the EF for enhancing electron transport, providing a new prototype of a reversible single‐cluster switch that digitally switches upon controlling FLP chemistry in the electric double layer.

Emerging Nanoparticle-Based Herbal Drug Delivery Systems for Colon Targeting Therapy

Abstract: Herbal medications hold a dominant position in the pharmaceutical sector due to their well-established therapeutic effects and extremely low negative effects. Besides, herbal remedies are easily available and highly economical. However, to circumvent the issue of poor bioavailability, the combinatorial strategy of incorporating herbal medicines and nano-technology is useful. The phytoconstituents molded in novel nanocarriers such as polymeric nanoparticles, polymeric micelles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, gold nanoparticles, etc., have been extensively investigated as they are the most promising approach for colon-targeting drug delivery systems. Although plant-based medicines have been developed for decades, there is enormous research interest in the development of an effective plant-derived delivery system for the incorporation of phytocon-stituents into various nanomaterials to overcome potential challenges related to solubility, bioavailability, and stability issues. The encapsulation of phytoconstituents in a novel nanocarrier is a promising approach to improving the bioavailability, stability, and therapeutic efficacy of herbal medicines. The herbal nanomedicines are used as a promising tool for tar-geted delivery to the colon, with potentially effective outcomes for the treatment of colonic diseases, viz., ulcerative colitis, diverticulitis, Crohn's disease, shigellosis, constipation, co-lonic polyps, colon cancer, etc. This article presents a comprehensive survey of recent find-ings and patents by innovators working exclusively on nanoparticles for the delivery of phy-tomedicines for colon targeting.

Corpi sofferenti d’amore. L’Ingénu di Voltaire tra intêret e sensibilité

In his conte philosophique L’Ingénu (1767), Voltaire engages in his philosophical battle through an original analysis of the love affair between the naïve protagonist Huron and Mademoiselle de Saint-Yves, a young Breton girl with a strict Catholic upbringing. The conflict between their desire to marry and the religious and political institutions is represented here by means of stylistic grafts belonging to the tradition of the genre of the sentimental novel, which in the middle of the 18th century was on the rise in France and the rest of Europe. Making the most recent discoveries in the medical-psychological field his own, Voltaire thus aims to establish the empathic bond on which the moral background of sentimental rhetoric was based through the representation of the psychological and physical suffering of the young protagonists. Distancing himself from the traditional concept of moral ‘virtue’ that was at the basis of the English sentimental novel, Voltaire thus instituted a reflection on amorous sentiment, now conceived not only as the main expression of the passion of individuals, but as a critical device to try to elaborate in an alternative way that reunion between private and public virtues that was at the basis of the Enlightenment mission.

Impact of Estrogen Therapy on BRCA1-Associated Breast Cancer Progression in Transgender Women

The combination of hormone treatment and genetic liabilities in transgender women leads to a complicated situation for breast cancer growth particularly linked to BRCA1 mutations. Gender-affirming treatment relies heavily on estrogen and causes intense cell growth and differentiation in breast tissue driven by estrogen receptor mechanisms. Mutations in BRCA1 lead to weak DNA repair processes which enhance an individual's vulnerability to cancerous changes. Rodestrogens enhance the functioning of proliferative pathways like PI3K/AKT and MAPK pathways in cells with dysfunctional BRCA1. This collaborative action elevates the threats posed by benign growths such as fibroadenomas leading to invasive breast cancer. By affecting the expression of vital regulatory proteins linked to cell proliferation estrogen further compromises the genomic integrity in cells harboring BRCA1 mutations. The hormone environment influenced by exogenous estrogen therapy can shape the tumor microenvironment for better cancer progression and metastasis. Comprehending the relationship between estrogen signaling and pathways related to BRCA1 is important for identifying the enhanced risk of cancer in transgender women using hormone therapy. This detailed study aligns recent discoveries regarding genetic vulnerability and hormonal impacts with cell mechanisms to reveal a detailed insight into breast cancer progression in these individuals. The study emphasizes the necessity for custom-designed cancer screening methods and targeted treatments to help mitigate risks and support transgender care. Understanding these pathways greatly enriches our knowledge of hormone-induced carcinogenesis among those who carry certain genetic markers while also guiding the creation of personalized care for transgender women at enhanced risk of breast cancer.

Epigenetic Regulation in Insect-Microbe Interactions.

Insects have evolved diverse interactions with a variety of microbes, such as pathogenic fungi, bacteria, and viruses. The immune responses of insect hosts, along with the dynamic infection process of microbes in response to the changing host environment and defenses, require rapid and fine-tuned regulation of gene expression programs. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNA regulation, play important roles in regulating the expression of genes involved in insect immunity and microbial pathogenicity. This review highlights recent discoveries and insights into epigenetic regulatory mechanisms that modulate insect-microbe interactions. A deeper understanding of these regulatory mechanisms underlying insect-microbe interactions holds promise for the development of novel strategies for biological control of insect pests and mitigation of vector-borne diseases.

8627 Viral Hormones: The Role Of Viral Insulin/IGF-1 Like Peptides In Host-Pathogen Interactions

Abstract Disclosure: A. Chuard: None. Viruses, encode proteins that are similar to host proteins to manipulate the host. Until our recent discovery of viral hormones, examples of viral mimicry were limited to immunomodulatory proteins and growth factors. We recently showed that six viruses in Iridoviridae family encode genes mimicking human insulin and IGF-1. We previously chemically synthesizing these viral insulin/IGF-1 like peptides (VILPs) and showed that VILPs can bind to human insulin and IGF-1 receptor and further stimulate post-receptor signaling. VILPs also stimulate glucose uptake and proliferation in mammalian cells and lower the blood glucose in mice. Originally, VILP-carrying viruses were isolated from fish; however, the role of VILPs in viral pathogenesis is not studied in depth. Here, we examined the effects of Grouper Iridovirus (GIV, one of the VILP carrying viruses) infection and GIV-VILP on host insulin/IGF signaling system using fish cells.To this end, we chemically synthesized GIV-VILP in its single chain (sc, IGF-1 like) and double chain (dc, insulin-like) forms. Stimulation of grouper kidney (GK) and AB9 zebrafish cells with these peptides, insulin and IGF-1, showed that IGF-1 was the most potent ligand in these cells indicating an abundance of IGF-1 receptor (IGF1R). Further, both forms of the VILPs were as potent as insulin in its activity on receptor phosphorylation and post-receptor signaling. Examining the viral kinetics, we also showed that GIV32 gene (encoding GIV VILP) is an early viral gene in both cell types. Virion analysis through mass spectrometry indicated that VILPs are not viral structural proteins. On the other hand, analysis of the supernatant from infected cells indicated that VILPs are secreted peptides during the viral cycle. Our results with supernatant transfer experiments from infected cells to uninfected cells support the same conclusion that VILPs are secreted. The secreted VILPs initiate autophosphorylation of IGF1R and/or insulin receptor (IR), consequently triggering downstream cellular signaling and metabolism. Through the use of specific inhibitors for each receptor, we illustrated that IR signaling is crucial for GIV viral replication. Surprisingly, inhibition of IGF1R increased viral replication and we are currently examining potential inhibitory effects of GIV VILP. Furthermore, VILPs appear to exert a biased effect on the AKT pathway compared to the Erk pathway. Furthermore, the inhibition of the AKT pathway significantly reduces GIV viral replication. In summary, our findings reveal that GIV-VILP is actively produced during infection and contributes to the viral replication. To our knowledge, VILPs are the first hormone-mimics characterized in viral replication. Elucidating the role of VILPs in host-pathogen interactions, we propose a novel viral pathogenesis mechanism where viruses mimic host hormones to manipulate the host's endocrine system. Presentation: 6/3/2024

Reading m6A marks in mRNA: A potent mechanism of gene regulation in plants.

Modifications to RNA have recently been recognized as a pivotal regulator of gene expression in living organisms. More than 170 chemical modifications have been identified in RNAs, with N6-methyladenosine (m6A) being the most abundant modification in eukaryotic mRNAs. The addition and removal of m6A marks are catalyzed by methyltransferases (referred to as "writers") and demethylases (referred to as "erasers"), respectively. In addition, the m6A marks in mRNAs are recognized and interpreted by m6A-binding proteins (referred to as "readers"), which regulate the fate of mRNAs, including stability, splicing, transport, and translation. Therefore, exploring the mechanism underlying the m6A reader-mediated modulation of RNA metabolism is essential for a much deeper understanding of the epigenetic role of RNA modification in plants. Recent discoveries have improved our understanding of the functions of m6A readers in plant growth and development, stress response, and disease resistance. This review highlights the latest developments in m6A reader research, emphasizing the diverse RNA-binding domains crucial for m6A reader function and the biological and cellular roles of m6A readers in the plant response to developmental and environmental signals. Moreover, we propose and discuss the potential future research directions and challenges in identifying novel m6A readers and elucidating the cellular and mechanistic role of m6A readers in plants.

Deciphering visceral instincts: a scientific quest to unravel food choices from molecules to mind.

The study of biological mechanisms, while crucial, cannot fully explain complex phenomena like the instinct to eat. The mind-body connection, as exemplified by the concept of "voodoo death," highlights the profound influence of belief and cultural context on physiology. Indigenous knowledge systems further emphasize the interconnectedness of humans with their environment. Recent discoveries in gut-brain communication reveal the intricate neural circuits that drive our visceral desires, but a holistic approach that integrates both physiological mechanisms and the subjective experience of life, informed by diverse cultural perspectives, will be essential to truly understand what it means to be alive.

B-001 Serum 25-hydroxyvitamin D and C-3 epimer concentrations throughout gestation in a bovine dairy herd

Abstract Background Serum 25-hydroxyvitamin D (25(OH)D) serves as an indicator of vitamin D status in most animal species. The recent identification of its C-3 epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3) remains diagnostically confounding. The appearance of this epimer in blood serum has been reported for both pregnant women and infants; however, because of its recent discovery, its physiologic role, biochemical regulation, and overall biologic importance have yet to be fully elucidated. Given its prevalence in pregnant women, it was hypothesized that 3-epi-25(OH)D3 may serve as a novel predictive biomarker of pregnancy in animals. Methods In the current study, we validated an LC-MS/MS method to measure the mono-hydroxyvitamin D metabolites 25-hydroxyvitamin D2 (25(OH)D2), 25-hydroxyvitamin D3 (25(OH)D3), and 3-epi-25(OH)D3, in bovine serum. Serum was collected from dairy cows at six stages of pregnancy (n=60 (10 per group), pre-breeding heifers, 30-40 days pregnant, 70-90 days, 120-180 days, 210-260 days, and 30-45 days post-calving). The 25(OH)D metabolites were extracted from serum by supported liquid extraction (SLE) and the eluate was derivatized with 2-Nitrosopyridine. Derivatized samples were introduced to the LC-MS/MS, ionized by electrospray ionization in positive-ion mode, and detected and quantified by multiple-reaction monitoring. Results The LC-MS/MS method was linear in the concentration range of 0.25 ng/mL to 100 ng/mL with an r2 > 0.99 for each analyte. 3-epi-25(OH)D3 and total serum 25(OH)D concentrations were calculated for each stage of pregnancy. Pre-bred heifers had serum 25(OH)D concentrations ranging from 65 - 85 ng/mL with trends toward non-significant increases with mean values approaching 100 ng/mL during pregnancy. Interestingly, 3-epi-25(OH)D3 remained near baseline (1.3 - 1.9 ng/mL) for the first 90 days and elevated 3- to 4-fold thereafter. Conclusions This study confirms that epimerization of 25(OH)D3 is a conserved biochemical process across species. While not predictive of pregnancy itself, the increase in circulating 3-epi-25(OH)D3 concentrations was consistent with mid- to late-gestational increases in estrogen concentration observed for dairy cattle. Future studies will explore the potential link between increases in gestational estrogen and epimerization.

Glial Control of Cortical Neuronal Circuit Maturation and Plasticity.

The brain is a highly adaptable organ that is molded by experience throughout life. Although the field of neuroscience has historically focused on intrinsic neuronal mechanisms of plasticity, there is growing evidence that multiple glial populations regulate the timing and extent of neuronal plasticity, particularly over the course of development. This review highlights recent discoveries on the role of glial cells in the establishment of cortical circuits and the regulation of experience-dependent neuronal plasticity during critical periods of neurodevelopment. These studies provide strong evidence that neuronal circuit maturation and plasticity are non-cell autonomous processes that require both glial-neuronal and glial-glial cross talk to proceed. We conclude by discussing open questions that will continue to guide research in this nascent field.

The effect of ionizing radiation on hydrated fungal cells: Implications for planetary protection and mars habitability

Liquid water is one of the essential conditions for life as we know it. Its presence has been currently reported beyond Earth. Geological and mineralogical evidence indicates that water once flowed on Mars. The recent discovery of present ice-water on the planet's surface is one of the driving factors for life-detection missions. The highly radiative Martian surface, combined with aqueous thin layers, is prohibitive for the presence of hypothetical forms of terrestrial-like life on the planet. In this context, we examined the survival of hydrated colonies of the Antarctic black fungus Cryomyces antarcticus, which thrives in the extreme environment of McMurdo Dry Valleys in Antarctica, after the exposure to increasing doses of space relevant γ-rays. Results suggest that water significantly reduces the number of survivors at the lowest doses, while at the higher dose (117 kGy) the cumulative damage caused by radiation could no longer be counteracted by dehydration.

Ferroptosis and myocardial ischemia-reperfusion: mechanistic insights and new therapeutic perspectives.

Myocardial ischemia-reperfusion injury (MIRI) is a significant factor in the development of cardiac dysfunction following a myocardial infarction. Ferroptosis, a type of regulated cell death driven by iron and marked by lipid peroxidation, has garnered growing interest for its crucial involvement in the pathogenesis of MIRI.This review comprehensively examines the mechanisms of ferroptosis, focusing on its regulation through iron metabolism, lipid peroxidation, VDAC signaling, and antioxidant system dysregulation. We also compare ferroptosis with other forms of cell death to highlight its distinct characteristics. Furthermore, the involvement of ferroptosis in MIRI is examined with a focus on recent discoveries concerning ROS generation, mitochondrial impairment, autophagic processes, ER stress, and non-coding RNA regulation. Lastly, emerging therapeutic strategies that inhibit ferroptosis to mitigate MIRI are reviewed, providing new insights into potential clinical applications.

Leveraging metabolism for better outcomes in heart failure.

Whilst metabolic inflexibility and substrate constraint have been observed in heart failure for many years, their exact causal role remains controversial. In parallel, many of our fundamental assumptions about cardiac fuel use are now being challenged like never before. For example, the emergence of sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy as one of the four "pillars" of heart failure therapy is causing a revisit of metabolism as a key mechanism and therapeutic target in heart failure. Improvements in the field of cardiac metabolomics will lead to a far more granular understanding of the mechanisms underpinning normal and abnormal human cardiac fuel use, an appreciation of drug action, and novel therapeutic strategies. Technological advances and expanding biorepositories offer exciting opportunities to elucidate the novel aspects of these metabolic mechanisms. Methodologic advances include comprehensive and accurate substrate quantitation such as metabolomics and stable-isotope fluxomics, improved access to arterio-venous blood samples across the heart to determine fuel consumption and energy conversion, high quality cardiac tissue biopsies, biochemical analytics, and informatics. Pairing these technologies with recent discoveries in epigenetic regulation, mitochondrial dynamics, and organ-microbiome metabolic crosstalk will garner critical mechanistic insights in heart failure. In this state-of-the-art review, we focus on new metabolic insights, with an eye on emerging metabolic strategies for heart failure. Our synthesis of the field will be valuable for a diverse audience with an interest in cardiac metabolism.

The yin and yang of pioneer transcription factors: Dual roles in repression and activation.

Pioneer transcription factors, by virtue of their ability to target nucleosomal DNA in silent chromatin, play crucial roles in eliciting cell fate decisions during development and cellular reprogramming. In addition to their well-established role in chromatin opening to activate gene expression programs, recent studies have demonstrated that pioneer factors have the complementary function of being able to silence the starting cell identity through targeted chromatin repression. Given recent discoveries regarding the repressive aspect of pioneer function, we discuss the basis by which pioneer factors can suppress alternative lineage programs in the context of cell fate control.

From small to tall: breed-varied household pet dogs can be trained to detect Parkinson’s Disease

Parkinson’s Disease (PD) is a clinically diagnosed disease that carries a reported misdiagnosis rate of 10–20%. Recent scientific discoveries have provided evidence of volatile organic compounds in sebum that are unique to patients with PD. The primary objective of this study was to determine if companion dogs could be trained to distinguish between sebum samples provided by PD-positive patients and PD-negative human controls. This was a randomized, handler-blind, controlled study. Twenty-three canines of varying breeds, ages, and environmental backgrounds were included. The study period encompassed 200 total working days from 2021 to 2022. Factors investigated included donor gender and levodopa drug affectivity, as well as canine breed, age, and duration of training time. The findings in this study were compiled from data collected during the final two years of a seven-year research program. For this two-year reporting period, when averaged as a group, the 23 dogs were 89% sensitive and 87% specific to olfactory distinction between PD-positive and PD-negative human donor samples. Ten of the twenty-three dogs averaged 90% or higher in both sensitivity and specificity. In 161 separate trials, a dog was presented with both novel PD-positive and PD-negative samples. For these novel exposures, the dogs collectively averaged 86% sensitivity and 89% specificity. PD medication was also investigated and was found to have no discernible impact on canine sensitivity or specificity results. Study findings support the application of companion dogs, trained with force-free, reward-based methodologies, for the detection of PD-positive and PD-negative samples under controlled conditions.

Factors influencing wildmeat trade in Guyana and expected changes in the context of the oil-related development prospects

The recent offshore oil discovery in the Guiana Shield is expected to bring about significant changes to the area, such as increased GDP per capita, infrastructure development, and urbanization. The potential impact on the wild meat trade depends on factors influencing its demand and provision. Through interviews and group discussions with trade chain stakeholders in all towns of Guyana, we evaluate wildmeat trade sector and explored predicted changes on it in 2033 with the prospects for short term oil-related development. The most traded species in Guyana included paca, white-lipped peccary, deer, tapir and capybara and a total of 38.46 % (5 out of 13) of the taxa being traded is classified as threatened of extinction. Regions with higher population size and GDP per capita, are the main trade hubs for wildmeat. Access to improved preservation methods (e.g. freezers) and motorized transportation options (eg.: boat with engines and vehicles) significantly influence higher volumes of wildmeat traded. The economic growth anticipated in Guyana is expected to boost population growth and, by the same time, wildmeat demand in urban areas. Concomitantly, with improved infrastructure and increased access to electricity, wildmeat provision will be facilitated across a wider catchment area. Based on the assumption that cultural patterns shaping wildmeat demand and environmental regulations will likely not change at the same rapid path as economic growth in the next ten years, we predict wildmeat trade volumes to increase to 10,280 tons/year by 2033. We identify three main opportunities to ensure a sustainable wildmeat sector in the context of the economic boom: First, the sector requires to be well regulated through a licensing and a quota system that can be adequately enforced. Second, efforts to curve demand on the Coast need to be strengthened based on well designed and culturally adapted behaviour change campaigns. Third, local communities and indigenous people need to be empowered to protect and conserve their territories and wildlife resources, in particular with the authority to exclude illegal hunters.

Surface matters: Decarburising wootz crucible steel ingots

Wootz, the Indian crucible steel, is a hypereutectoid iron–carbon alloy and famous for its outstanding qualities. Due to the paucity of archaeological and historical ingot finds and conservative sampling strategies, discussions of the homogeneity of such ingots and the microstructural representativeness of samples have remained generic and assumptive. Thus two major shortcomings in the study of crucible steel ingots include the determination of their absolute carbon content and its relative distribution across the ingots. The recent discovery of a large hoard of wootz ingots from Telangana (Jaikishan et al. 2021) offered a unique opportunity to study their microstructure and determine their carbon content.Reports based on traditional metallography suggest a wide carbon range, from 1 to 2 wt% carbon, for similar ingots (Scott 2013). Recent work based on image analysis (Desai and Rehren 2023) offered narrower carbon estimates (about 1.8 wt%) for several of the recently discovered ingots, with some variation in concentration towards the edge of the samples. As a collaborative effort to determine absolute carbon values and potential uneven distribution of the carbon in the Telangana ingots, traditional metallography was coupled with laser-induced breakdown spectroscopy (LIBS). Beyond documenting the microstructure across several ingots, the study provides macrostructural evidence of rim decarburisation, which we believe to be intentional. This study presents the micro- and macrostructure of two of the hypereutectoid Telangana ingots, highlighting the skill of the craftsmen in decarburising the outer surfaces of their ingots, potentially for ease of subsequent forging.

Formation of Close-in Neptunes around Low-mass Stars through Breaking Resonant Chains

Conventional planet formation theories predict a paucity of massive planets around small stars, especially very low-mass (0.1−0.3 M ⊙) mid-to-late M dwarfs. Such tiny stars are expected to form planets of terrestrial sizes but not much bigger. However, this expectation is challenged by the recent discovery of LHS 3154 b, a planet with period of 3.7 days and minimum mass of 13.2 M ⊕ orbiting a 0.11 M ⊙ star. Here, we propose that close-in Neptune-mass planets like LHS 3154 b formed through an anomalous series of mergers from a primordial compact system of super-Earths. We perform simulations within the context of the “breaking the chains” scenario, in which super-Earths initially form in tightly spaced chains of mean-motion resonances before experiencing dynamical instabilities and collisions. Planets as massive and close-in as LHS 3154 b (M p ∼ 12−20 M ⊕, P < 7 days) are produced in ∼1% of simulated systems, in broad agreement with their low observed occurrence. These results suggest that such planets do not require particularly unusual formation conditions but rather are an occasional by-product of a process that is already theorized to explain compact multiplanet systems. Interestingly, our simulated systems with LHS 3154 b-like planets also contain smaller planets at around ∼30 days, offering a possible test of this hypothesis.

Mapping Sliding Ferroelectricity in Bulk (PbS)1.11VS2 Crystals

The recent discovery of sliding ferroelectricity opens up the field of 2D ferroelectricity. However, the limitation to switching the polarization due to the topological protection of the domain walls limits the potential of these heterostructures. Here, the switching of sliding ferroelectric bulk misfit layer compound (PbS)1.11VS2 crystals is studied using switching spectroscopy piezoresponse force microscopy. A large number of measured hysteresis loops can be efficiently analyzed using unsupervised machine‐learning tools. Different switching behavior of the domains is observed on different types of domain structures, and it is shown that full domain switching can be observed for the right type of dislocation structure in the PbS layer.

Novel microbial modifications of bile acids and their functional implications.

This review outlines the recent discoveries of bile acids that have undergone novel microbial modifications, highlighting their biological roles and the profound implications for the development of innovative therapeutic strategies. The review aims to provide valuable insights and breakthroughs for future drug candidates in the expanding field of bile acid therapeutics.