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Our understanding of cancer metabolism has afforded the opportunity to develop therapies specific to tumor metabolic dysregulation. While molecular therapeutics targeting cancer metabolism have found success in the clinic, bioengineering approaches are nascent. Here, we describe key metabolic pathways and their genetic dysregulations in the tumor microenvironment (TME) that are ripe for intervention. We examine bioengineered biomaterial and cellular systems that harness the metabolic and immune landscape of the TME to target metabolic dependencies of tumor growth. These therapeutic strategies include, for example, preventing the uptake of essential metabolites, delivering metabolic inhibitors, and restoring an immunostimulating environment. With a focus toward clinical applications and tolerability, we identify key limitations and conclude with future directions.
Human trafficking poses a major public health challenge to the international community, with significant health and social consequences for those affected. Forced migrants are particularly vulnerable to becoming victims of human trafficking due to language barriers and migration-related hardships. These include social and economic deprivation. To better understand the lived experiences within this already vulnerable group, it is essential to examine individual cases in relation to risk factors, experiences of exploitation and exit, and resilience. Using a qualitative approach, this study examines social determinants and risk factors of forced migrants who survived human trafficking. It explores their experiences, eventual escape, and sheds light on their resilience. For this purpose, semi-structured interviews regarding the trafficking experiences were conducted with newly arrived forced migrants at a reception and registration centre in Germany. The presence of human trafficking was determined through an initial screening procedure and then confirmed in a personal interview. Additionally, we assessed the refugees' mental health burden with brief screening questionnaires for post-traumatic stress disorder, depression, anxiety, and the overall stress level (PC-PTSD-5, GAD-2, PHQ-2, RHS-15 distress thermometer). A total of 20 interviews were conducted with 14 female and 6 male participants. The participants came from 9 different countries. Most of them experienced sexual exploitation (N = 11), labour exploitation (N = 7). Few were trafficked but not exploited (N = 3). Participants reported that financial hardship was the main benefitting exploitation risk, and in many cases, they had been recruited by individuals they already knew. Spiritual rituals were sometimes used to increase pressure and control. Various forms of violence were inherent to the trafficking situations. In most cases, those affected managed to free themselves. Interpersonal connections and religious beliefs played a crucial role in coping with these experiences, however the screening for common mental disorders among refugees still indicated high levels of psychological distress. The results are discussed in relation to existing literature and implications for support and intervention are presented.
Mercury (Hg) is a global contaminant that biomagnifies in food webs, raising concerns for food safety, fisheries exploitation, and wildlife conservation. Fish, including apex predators like sharks, are the primary source of human Hg exposure, yet species-specific speciation data remain scarce. Most studies rely on total Hg (THg) as a proxy for methylmercury (MeHg), but direct MeHg measurement is essential for accurate risk assessment due to neurotoxicity and bioavailability. This study presents a comprehensive assessment, quantifying THg-MeHg in 18 species from the Mediterranean, Indian, and Atlantic Oceans, nine measured for the first time. Concentrations varied widely, with deep-sea and pelagic sharks showing highest levels. THg and MeHg strongly correlated (R2 = 0.99), but MeHg-THg ranged 65-101%, demonstrating substantial interspecific variability and challenging the assumption of near-complete methylation. Bioaccumulation increased with body size and trophic level, and biomagnification was pronounced in Mediterranean deep-sea assemblages. Nearly half of the species exceeded the 1 mg kg-1-EU Hg limit. Target Hazard Quotients exceeded 1 for deep-sea and large pelagic sharks, highlighting tangible health risks. Elevated MeHg levels in commercial fillets confirm consumer exposure. Species with the highest MeHg burdens are heavily exploited and threatened, identifying globally traded sharks as hotspots of human Hg exposure.
Iron is essential for cellular metabolism, redox balance, and proliferation, yet its redox activity generates reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Cancer cells exploit iron homeostasis mechanisms, including iron regulatory proteins, ferritinophagy, and hypoxia-inducible factors to maintain high intracellular iron, supporting metabolic reprogramming, antioxidant defenses, and therapy resistance. Iron-dependent lipid peroxidation drives ferroptosis, a regulated form of cell death uniquely dependent on iron. Ferroptosis is tightly controlled by metabolic and antioxidant pathways and mitochondrial ROS, as well as by lipid composition and polyunsaturated fatty acid availability. Ferroptosis also intersects with apoptosis and necroptosis, highlighting the central role of iron in cell fate and survival. Dysregulation of these pathways in cancer can sensitize cells to ferroptosis, creating a therapeutic vulnerability. Exploiting ferroptosis through modulation of iron availability, redox defenses, or lipid metabolism offers a promising anticancer strategy. However, tissue-specific iron dynamics, tumor heterogeneity, and interactions within the tumor microenvironment complicate clinical translation. Integrative approaches combining metabolic profiling, genetic analysis, and ferroptosis-targeted interventions will be critical to harness iron-dependent cell death while minimizing systemic toxicity. In this review, we explore the mechanisms through which cancer cells sustain high iron, evading associated toxicities and possible implications for integrating ferroptosis based therapies in clinical oncology.
Reservoir computing is a bio-inspired machine learning paradigm that exploits the intrinsic dynamics of nonlinear systems with fading memory for efficient temporal information processing. Microelectromechanical resonators offer a promising platform for reservoir computing as they inherently possess the requisite nonlinear and temporal properties while also facilitating the integration of sensing and computing within a single platform. In this work, we experimentally demonstrate a physical reservoir computing platform based on two capacitively coupled drum resonators, operating in the MHz frequency regime. Taking advantage of the concept of phonon-cavity electromechanics, a pump tone is applied at the sideband of the phonon cavity while probing one of the coupled modes, analogous to optomechanical systems, thereby creating nonlinear dynamics in energy transfer between the two resonators. Reservoir computing is implemented by exploiting the nonlinear response generated through pump amplitude modulation in combination with a time-delay feedback loop, and the performance is evaluated using both parity and Normalized Auto-Regressive Moving Average benchmarks. This work demonstrates a compact microelectromechanical platform for integrated sensing and reservoir computing and shows that the sideband pumping scheme provides a pathway for extending conventional single-resonator reservoir computing toward multimode architectures.
Understanding the genomic architecture of species of conservation concern is essential for fostering effective conservation initiatives. Current biodiversity assessment approaches increasingly incorporate genetic metrics to evaluate the status of species and populations of conservation interest. However, due to the limited availability of conspecific genomes for most non-model species, previous studies have often depended on heterospecific genomes. This approach has been shown to significantly impact the precision of genetic metrics, resulting in inaccurate measurements and insights. However, it is currently unknown what the impact of using non-species-specific genomes is for the determination of genetic indicators in vulnerable marine fishes, such as red roman (Chrysoblephus laticeps). Red roman is a southern African endemic species, which, due to overexploitation, is currently considered Near Threatened on the International Union for Conservation of Nature (IUCN) Red List. Recent studies have shown significant life history and physiological differences between exploited and protected populations. Here, we present the first high-quality scaffold-level genome assembly and annotations for the red roman, using a combination of Oxford Nanopore and Illumina sequencing, and compared key genetic indicators (diversity, population structure and effective population size) obtained from reads mapped to the genomes of other Sparidae species, with well-established genomic resources. The final assembly had 1263 scaffolds, a total length of 758 Mb, with a scaffold N50 of 5.89 Mb and Benchmarking Universal Single-Copy Orthologs (BUSCO) completeness of 99.30%. As expected, comparative analyses with genomes of different sparid species revealed enhanced read alignment, genotyping accuracy and single nucleotide polymorphism (SNP) retention after filtering. Furthermore, there were significant overall differences across the genomes for the measures of observed heterozygosity (H O), nucleotide diversity (π), Tajima's D, F ST and estimates of effective population size (N e), with different genomes presenting different (and sometimes contrasting) genetic indicators metrics and, consequently, demographic histories for red roman. Our study not only significantly improved genomic resources for genomic conservation analyses in C. laticeps, but most importantly highlighted the importance of species-specific reference genomes for accurate evolutionary and conservation inference in highly variable marine fishes.
Colorectal cancer (CRC) harboring KRAS mutations remains a major therapeutic challenge, as resistance to EGFR directed signaling inhibitors persists despite receptor expression. We aimed to establish a delivery-based therapeutic strategy that bypasses EGFR signaling inhibition by exploiting the receptor as an internalization gate. We report the development of a peptide-drug conjugate (PDC) that exploits non-canonical EGFR engagement to enable tumor selective delivery of the cytotoxic payload SN38. Computational modeling demonstrates stable binding of the P6 peptide within a non-canonical extracellular cavity between domains I and III of EGFR, distinct from the classical EGF binding site, supporting a potential allosteric interaction mechanism. The resulting PDC exhibits preferential cellular uptake and cytotoxicity in KRAS mutant CRC cells compared with normal colon epithelial cells, despite EGFR expression in both, demonstrating tumor selective internalization driven by cellular context and receptor density. P6-SN38 significantly inhibits cancer cell migration in vitro, further supporting its anti-tumor activity beyond cytotoxicity. PDC treatment significantly suppresses tumor growth in in vivo KRAS mutant xenograft model, demonstrating superior efficacy compared with cetuximab-based regimens and controls, without observable body weight loss. This strategy uses EGFR as a delivery portal instead of a signaling target, enabling KRAS independent anti-tumor activity. These findings indicate a non-canonical EGFR mediated delivery approach with potential translational relevance for the treatment of therapy resistant CRC.
There is a common misconception among ocean scientists and policy makers that mesopelagic (200-1000 m) food webs are an unexploited "final frontier" of living marine resources. It is true that there are currently no substantial fisheries for the small-bodied fish species that are typically caught in the nets used in research studies. However, midwater ecosystems contain a rich biodiversity of larger fishes, including mesopredators, that largely evade scientific sampling and are absent from biogeochemical and socio-economic models of the open ocean. Drawing on studies from around the world and decades of detailed catch data from a longline fishery, we demonstrate that this "dark web" of mid-trophic fish species has already been exploited by industrial-scale fisheries in plain sight for decades. The ongoing effects of these activities on a suite of critical ecosystem services, from regulating the oceanic carbon cycle to sustaining food webs, remain unquantified and largely ignored by ocean scientists and policy makers. From a policy perspective, we recommend leveraging the Biodiversity Beyond National Jurisdiction agreement and promoting cooperation among Regional Fisheries Management Organizations to standardize data collection and strengthen environmental impact assessments under the United Nations Convention on the Law of the Sea, which could facilitate sustainable use of mesopelagic resources while balancing food security and carbon storage in a changing climate.
Higher ambient temperatures during rice cropping season reduce grain yield and quality, yet maturity group-specific responses to heat stress are largely unknown. A field trials of 36 rice varieties were conducted in Arkansas, United States, using two planting dates in a randomized complete block design with four replications under season-long conventional flood irrigation. Varieties were classified into early (n = 8), medium (n = 13), and late maturing (n = 15) based on heading dates. Cumulative heat exposure was quantified by using heat degree days (HDD) within key developmental stages. Heat stress effects were most pronounced during nighttime, suggesting that the observed yield and quality alterations were largely attributable to high nighttime temperatures (HNT). Early-maturing varieties showed greater tolerance to HNT, as evidenced by a non-significant decline in grain yield as the HDD increased. In contrast, medium- and late-maturing varieties exhibited significant yield losses per unit HDD (medium: -0.368 g plant-1 per °C·day; ∼0.9% per HDD; late: -1.024 g plant-1 per °C·day; ∼1.4% per HDD). Grain traits varied among maturity groups, with medium- and late-maturing varieties producing thinner and chalkier grains, while early-maturing varieties largely maintained grain weight. Across traits, variety and maturity group explained most variation, and significant variety × planting date interactions highlighted exploitable genotype-by-environment (G × E) effects on nighttime heat tolerance. Early-maturing varieties, including Norin 20, ZAO 402, and Geumobyeo, demonstrated strong resilience to HNT stress. Planting dates adjustments may, therefore, offer a practical adaptation strategy to mitigate heat stress under warming cropping seasons, although further investigation is needed.
Homeobox (HOX) genes are essential regulators of embryonic development and cellular differentiation under physiological conditions. Among this gene family, HOXA10 has emerged as a pivotal factor in gastrointestinal (GI) cancers, influencing tumor growth, metastasis, disease progression, and resistance to therapy. HOXA10 functions as a transcription factor and plays key roles not only in embryogenesis but also in immunomodulation. HOXA10 and its transcriptional targets play a crucial role in cancer development, promoting cell growth, invasion, migration, metastasis, and resistance to cell death. Recent studies have explored the influence of HOXA10 on the tumor immune microenvironment, particularly its role in modulating immune cell recruitment and signaling pathways that enable tumor immune evasion. Our recent research identified a HOXA10-regulated five-gene signature that distinguishes long-term from short-term survivors of pancreatic cancer, with HOXA10 expression correlating with increased regulatory T cell (Treg) infiltration. HOXA10 impacts genes and pathways involving macrophages, Tregs, and other immune cells, potentially creating an immunosuppressive niche that promotes metastasis and diminishes the effectiveness of immunotherapies. In this review, we examine the diverse functions of HOXA10 in GI cancers, offering a comprehensive comparison with other HOX family proteins to elucidate their overlapping and distinct roles in malignancy. Our goal is to provide a thorough overview of how HOXA10 contributes to tumor development and its microenvironment. We highlight its critical role in facilitating cancer progression and metastasis, supported by data from cell lines, patient tumor samples, and clinical studies. Recognizing existing gaps in the understanding of HOXA10's role in cancer, we also explore potential strategies to target this gene, with an emphasis on synergistic approaches that combine HOXA10 inhibition and immunotherapy. Ultimately, these insights aim to identify vulnerabilities within GI cancers that could be exploited through novel therapeutic agents and combination treatments, paving the way for improved clinical outcomes.
Ferroptosis, an iron-dependent programmed cell death pathway driven by lipid peroxidation, offers a transformative approach to cancer therapy by exploiting unique cellular vulnerabilities. This comprehensive review elucidates the intricate molecular mechanisms of ferroptosis and their modulation by genetic mutations across diverse malignancies, including lung, hematological, liver, colorectal, breast, glioma, renal, pancreatic, thyroid, prostate, cervical, gastric, and melanoma. We delineate the critical functions of ferroptosis regulators, such as GPX4, system Xc⁻, and iron metabolism proteins, in orchestrating the delicate balance between oxidative damage and antioxidant protection. The study further examines how oncogenic mutations in genes like EGFR, KRAS, TP53, KEAP1, and IDH1 reshape ferroptosis susceptibility or resistance through alterations in metabolic pathways, redox homeostasis, and tumor microenvironment interactions. By highlighting mutation-specific sensitivities, this work underscores the potential of ferroptosis-targeted strategies to surmount therapeutic resistance, synergize with conventional treatments like chemotherapy and immunotherapy, and drive precision oncology forward, paving the way for enhanced clinical outcomes across a broad spectrum of cancers.
The design of implantable biomaterials often aims to guide local cell behavior to control immune response. Non-chemical routes exploit the effect of mechanical properties and structure morphology on cell behavior. A class of substrates known as bicontinuous interfacially jammed emulsion gel (bijel)-templated materials (BTMs) exhibit characteristically uniform pore size and surface curvature. Existing research on these materials in vivo demonstrates their ability to modulate the inflammatory response in the anti-inflammatory direction. We investigate a subset of the contributing components to that effect by examining the behavior and phenotype of macrophages within BTMs in vitro. The comparative substrate, the particle-templated material (PTM), has an equivalent chemical composition, but has variable pore size and surface curvature. Macrophages within these two materials take on notably different cell shapes and phenotypes. Macrophages interacting with the BTM exhibit less circular cell shapes and a lower state of inflammation. This effect is significant enough to induce lower pro-fibrotic activation in fibroblasts, without direct BTM-fibroblast contact. These results suggest that microscale curvature and pore size have a direct effect on macrophages, and that this effect can cause phenotypic changes in other cells. Findings reaffirm the significance of targeting macrophages in biomaterials design and support further investigation of the immune signaling cascade that occurs within BTMs. Our contributions to the fundamental knowledge of cell behaviors in these porous materials provide new insights applicable to advancing biomaterials design.
The electrochemical NO reduction reaction (NORR) has been exploited as an alternative method to scrub NO from industrial and residential effluents as well as a route for ammonia synthesis. However, the product selectivity and electroactivity are strongly affected by numerous factors, and the detailed mechanism remains elusive. In this work, the NORR on Pd, Ru, Ir, Au, Ag, and Cu in both alkaline and acidic media was studied with coupled differential electrochemical mass spectrometry and attenuated total reflection-surface-enhanced infrared absorption spectroscopy. The potential-dependent product formation in both alkaline and acidic media and surface-adsorbed species could be simultaneously monitored, enabling us to correlate the product selectivity with adsorbed species and to elucidate the NORR mechanism. At potentials >0.4 V, N2O was the dominant product on all studied metals, and the kinetics for N2O formation were enhanced in alkaline media when compared to acidic media. Cu was the most selective and effective catalyst for the NORR to NH3/NH2OH. NH3/NH2OH were also the predominant products on Pt, Ru, and Ir in both alkaline and acidic media and on Ag and Au in alkaline media at potentials of hydrogen evolution/adsorption. The NORR on Pd selectively generated N2 at 0.175 V in alkaline media but not in acidic media. These in situ experimental data provide new mechanistic insights into the NORR selectivity that could inform/guide the design of more effective and selective NORR catalysts and establish optimal operation conditions for the electrochemical synthesis of selected products.
Acid mine drainage (AMD) is a common extreme ecosystem characterized by strong acidity, oligotrophy, high sulfate, and metal ion concentrations. Despite the harsh environmental conditions that threaten the survival of microorganisms, recent studies have revealed the presence of active and complex life activities within it. Microalga play an important role in the remediation and evolution of AMD due to their unique cellular structure and ecological functions. However, the understanding of the survival adaptations of acid-tolerant microalgae in AMD remains limited. In this study, high-throughput sequencing combined with experimental omics methods were employed to isolate an acid-tolerant microalga (Parachlorella sp. MP1) from AMD and explore its adaptability mechanisms to the AMD environment. Genomic analysis revealed a substantial repertoire of genes associated with acid and metal tolerance, demonstrating broad adaptability and functionality in genetic information processing and metabolic pathways. These genetic features underpin a complex metabolic network enabling the strain to cope with concurrent acidic and metal stress in AMD. Based on the comprehensive analysis of genomic and physiological evidence, the multi-level adaptability mechanisms of Parachlorella sp. MP1 to AMD stress were inferred, which mainly include the secretion of extracellular polymeric substances (EPS), the synthesis of specific lipids, the efflux and sequestration of ions, the neutralization of intracellular H+ and metal detoxification, the activation of the antioxidant system, and the reallocation of carbon resources. By combining genomic insights with experimental validation, this study enhances the understanding of microbial adaptive mechanisms in extreme environments and provides a reference for the exploitation and utilization of extremophilic microorganisms.
Increasing antibiotic-resistant bacterial infections pose a global public health challenge that demands therapeutic strategies beyond conventional antibiotics. The cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING) pathway is crucial to innate immune defense through cytosolic DNA detection and antimicrobial response initiation. Emerging evidence suggests that antibiotic-resistant bacteria can subvert or overactivate this pathway, leading to immune evasion and excessive inflammation. Methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, and multidrug-resistant Mycobacterium tuberculosis exploit cGAS-STING signaling to suppress host immunity or trigger damaging hyperinflammatory responses. This highlights the dual nature of the cGAS-STING pathway in bacterial infections. STING agonists may enhance immune responses against persistent infections, and STING inhibitors can mitigate excessive inflammation caused by resistant pathogens. Targeting the cGAS-STING pathway represents a host-directed therapy that modulates host immunity rather than targeting pathogens. Understanding the interplay between cGAS-STING signaling and antibiotic resistance mechanisms is essential for developing next-generation immunotherapeutics to complement conventional antibacterial treatments.
Adult Protective Services (APS) is crucial in addressing reports of vulnerable adult abuse, neglect, and exploitation. APS reports have surged recently thus enhancing APS systems, is vital to effectively identifying and intervening in maltreatment cases. This qualitative evaluation utilized focus group methods to solicit caseworker and supervisor perspectives on system-level intake challenges and resources/strategies to improve APS intake/screening. Key challenges included limited federal and state resources, under-developed MIS systems, inconsistent policy guidance, and impractical risk assessment tools. Addressing these issues through enhanced resources, better training, improved policy frameworks, and collaborative efforts can significantly strengthen APS's ability to protect vulnerable adults.
Task scheduling has become a significant research focus in cloud computing because of the growing need for efficient resource utilization. This paper explores an innovative scheduling approach harnessing Human Memory Optimization (HMO) and Fuzzy Adaptive Human Memory Optimization (FAHMO). Such techniques are inspired by human cognitive principles and employ an adaptive search strategy that maintains an effective trade-off between exploration and exploitation. By maintaining a history of successful and unsuccessful scheduling decisions, HMO enables continuous enhancement of scheduling efficiency. Integrating fuzzy logic into FAHMO improves the decision-making process by effectively managing uncertainty and ambiguity in task scheduling, thereby producing more flexible and efficient solutions. Comparative analysis demonstrates that HMO and FAHMO outperform conventional metaheuristic algorithms, including PSO-PGA, in terms of convergence speed and task completion time. The results confirm that the proposed approach significantly reduces makespan and enhances overall cloud task scheduling performance. Specifically, FAHMO achieved up to 67.46% improvement in makespan and 63.18% in convergence accuracy compared to PSO-PGA.
Listeria monocytogenes demonstrates remarkable persistence in food processing environments, particularly in areas with established biofilm communities. This communication synthesizes emerging evidence for a novel ecological strategy whereby L. monocytogenes functions as a secondary colonizer, exploiting central voids created during Gram-negative bacterial biofilm dispersal. We propose the "secondary colonizer hypothesis" - that L. monocytogenes utilizes a sophisticated temporal succession strategy, colonizing biofilm voids characterized by steep oxygen gradients and phosphatidylethanolamine-rich debris from dispersed primary colonizers. This strategy employs specialized metabolic pathways including cobalamin-dependent catabolism of ethanolamine, propylene glycol, and glycerol while simultaneously utilizing ferric iron reduction for respiration. The metabolic coupling allows each bacterial cell to accumulate iron via ferritin-like protein storage, creating competitive advantages through localized limitation. Recent evidence identifies Veillonella as a key bridging species that may facilitate this ecological succession through metabolic complementarity. Notably, while L. monocytogenes co-occurs with Gram-positive bacteria, its metabolic specialization for ethanolamine and iron scavenging suggests a preferential adaptation to the nutrient-dense voids of dispersed Gram-negative biofilms. The implications for food safety protocols, particularly cleaning chemical formulations and ecological monitoring strategies, warrant immediate attention.
Central nervous system drug delivery centers primarily on strategies aimed at crossing the blood-brain barrier. In a recent study, Gao et al.1 report that nanoparticles can bypass the blood-brain barrier by hijacking calvarial immune cells and exploiting migration through skull-meninges channels, which enables lesion-targeted, minimally invasive therapeutic delivery to the brain.
Narrative time is essential for understanding and remembering stories. Reconstructive memory theory posits that retrieving past events is not a mere reactivation of the original memory trace but involves a reorganization process informed by a combination of stored memories, general knowledge, and interpretative elements. Recent studies have shown that humans are remarkably accurate in judging the time-of-occurrence of fragments from a previously encoded narrative, but also that expectations and assumptions can compromise their performance. Here, we investigated the mechanism underlying the ability to infer the time-of-occurrence of videoclips extracted from a previously unencoded movie to elucidate the gradual integration of episodic and semantic information during the construction of narrative time. Across four experiments performed by different groups of human participants, we progressively manipulated the amount of available episodic information for the time-estimation task. Compared with the high precision observed for a known (i.e., previously encoded) movie, a robust decrease in performance was observed in the absence of prior encoding, irrespective of task repetitions. Exposing participants to additional episodic information (movie fragments) between task repetitions produced a gradual enhancement in task performance, especially when episodic cues were presented in chronological order. These results suggest that the temporal information provided by episodic cues can be exploited to gradually form a temporal scaffolding of the narrative, filling in the gaps between encoded pieces of information. This temporal representation, in turn, enables the dating of movie fragments, almost as if the movie had been encoded in its entirety.