Natural Sciences

The traditional view of aging as a gradual, progressive process is increasingly being challenged. A growing body of evidence suggests the existence of abrupt transitions in the aging process, marked by sudden molecular shifts. Interestingly, the data indicates that such transitions occur not only in late life but also throughout the entire lifespan. Further research on the nature of such events could enhance our understanding of aging and pave the way for novel therapeutic strategies, including personalized medicine. We propose that (...) these abrupt molecular shifts could serve as biomarkers, dividing the lifespan into distinct stages and providing the foundation for a much‐needed staging system for aging. Furthermore, we argue that the sudden changes may be the hallmarks of aging tipping points, that is, points in time where aging processes are quickly amplified after surpassing critical biological thresholds. (shrink)

Abstract -/- The Recursive-Collapse-Recombination (RCR) Model is a metastable, autopoietic, non-hierarchical, non-binary, and non-linear framework that defines reality as a continuously generative process. It describes how recursion (self-reinforcing structures), collapse (destabilization and phase shifts), and recombination (adaptive restructuring) interact to produce emergent, dynamic systems. Unlike equilibrium-based models, RCR establishes metastability as the core condition of reality, ensuring ongoing transformation rather than static resolution. The model is mathematically formalized to apply across domains, from physics and cognitive science to social structures and (...) AI systems. By framing reality as an interplay of recursion, collapse, and recombination, RCR reveals why deterministic reductionism fails and why reality remains an open-ended generative structure rather than a closed, finite system. -/- Keywords -/- Recursive-Collapse-Recombination (RCR) -/- Metastability -/- Phase Transitions -/- Nonlinear Systems -/- Emergence -/- Self-Organization -/- Autopoiesis -/- Indeterminacy -/- Reality Structuring -/- Generative Systems -/- --- -/- License (CC BY 4.0) -/- This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). -/- ✔ Share — Copy and redistribute the material in any medium or format. ✔ Adapt — Remix, transform, and build upon the material for any purpose, even commercially. -/- Attribution Requirement: You must give appropriate credit, provide a link to the license, and indicate if changes were made. This must be done in a reasonable manner, but not in any way that suggests endorsement by the original author. -/- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits. (shrink)

Bacterial pathogens deliver effector proteins into host cells by deploying sophisticated secretion systems. This effector translocation during host‐pathogen interactions is a prerequisite for the manipulation of host cells and organisms and is important for pathogenesis. Analyses of dynamics and kinetics of translocation, subcellular localization, and cellular targets of effector proteins lead to understanding the mode of action and function of effector proteins in host‐pathogen interplay. This review provides an overview of biochemical and genetic tools that have been developed to study (...) protein effector translocation qualitatively or quantitatively. After introducing the challenges of analyses of effector translocation during host‐pathogen interaction, we describe various methods ranging from static visualization in fixed cells to dynamic live‐cell imaging of effector protein translocation. We show the main findings enabled by the approaches, emphasize the advantages and limitations of the methods, describe recent approaches that allow real‐time tracking of effector proteins in living cells on a single molecule level, and highlight open questions in the field to be addressed by application of new methods. (shrink)

Intra‐strand base pairing is possible when double‐stranded DNA contains inverted repeats, but vanishingly improbable without so‐called negative superhelicity. This superhelicity itself is conditional upon whether the molecule can retain torsional stress—a question of “topology.” This principle has been uncontroversial to biophysicists since the 1980s but has proven challenging for outsiders to grasp and retain. For those in AAV research, this constitutes a decades‐long missed connection. AAV is one of a multitude of viruses bearing secondary‐structure‐forming elements on their termini. Its “inverted (...) terminal repeats” (ITRs) can self‐anneal into relatively large hammerhead structures on both ends of the dynamically structured genome and are central to numerous host interactions that drive the viral lifecycle. A standalone article such as this is therefore warranted to promote an understanding of these ideas in the AAV research community and highlight their significance in the basic biology of the virus and its vector gene delivery system. (shrink)

Plant cytokinesis results in the formation of the cell plate by the phragmoplast which contains dynamic microtubules serving as the track for the delivery of cell wall builders included in Golgi vesicles. During the centrifugal process of cell plate assembly, new microtubules are assembled and bundled at the leading edge to prepare for vesicle transport while older microtubules are disassembled at the lagging edge upon the completion of vesicle delivery. The turnover of phragmoplast microtubules in this process is thought to (...) be regulated by phosphorylation of the key microtubule bundling factor MAP65. A recent study revealed a surprising role of the α‐Aurora kinase, which is typically known for its role in governing the formation of the bipolar spindle apparatus, in phosphorylating the primary microtubule bundler MAP65‐3 in Arabidopsis. This phosphorylation positively contributes to the expansion of the phragmoplast. The phragmoplast midzone is also the hub for other cytokinesis‐important kinases. It is intriguing how these kinases are targeted and how they may crosstalk with each other to orchestrate the expansion of the phragmoplast. (shrink)

The Hard Problem of consciousness—explaining why and how physical processes are accompanied by subjective experience—remains one of the most challenging puzzles in modern thought. Rather than attempting to resolve this issue outright, in this paper I explore whether empirical science can be broadened to incorporate consciousness as a fundamental degree of freedom. Drawing on Russellian monism and revisiting the historical “relegation problem” (the systematic sidelining of consciousness by the scientific revolution), I propose an extension of quantum mechanics by augmenting the (...) Hilbert space with a “consciousness dimension.” This framework provides a basis for reinterpreting psi phenomena (e.g., telepathy, precognition) as natural outcomes of quantum nonlocality and suggests that advanced non– human intelligence (NHI) technology might interface with a quantum–conscious substrate. For a detailed mathematical exposition of this framework, see my preprint [3]. I demarcate the philosophical issues from the empirical ones and propose several experimental strategies— including entanglement–based psi research, quantum–enhanced neuroimaging, and quantum sensor applications—to test the model. Although this framework does not resolve the Hard Problem, it offers a rigorously formulated, historically informed, and empirically testable approach to integrating subjective experience into the scientific study of mind. (shrink)

Until, 1971, articles were not freely accessible to everyone online. Project Gutenberg made the dream a reality. Exorbitant increases in the cost of print journals have forced publishers to reduce their publications and turn them from the print to the electronic journal (e-journal) medium. Higher visibility of Open Access (OA) leads to a higher number of citations, better h-index of authors and the Impact Factor (IF) of journals, which gains the popularity of e-journals. However, authors face a problem in predatory (...) journals, Article Processing Charges (APC), etc. It is not late to write this article for in-depth understanding of e-journals and the impact of Artificial Intelligence (AI) in academic scholarships, especially for novice readers, authors, and researchers. This article also depicts what important things you need to keep in mind when publishing your article to go to a higher level in the era of electronic publication. (shrink)

Talin, a key integrin activator, is essential for cellular adhesion, signal transduction, and mechanical stability. Its transition between autoinhibited and active conformations allows dynamic regulation of adhesion in response to environmental cues. Cholesterol‐rich membrane microdomains, such as lipid rafts, organize and stabilize signaling platforms, influencing talin and integrin conformational states. Cholesterol is a switch modulating talin activation, integrin binding, and adhesion. Environmental pollutants, including heavy metals and air toxins, disrupt cholesterol homeostasis, destabilize lipid rafts, and interfere with talin–integrin interactions. These (...) disruptions impair adhesion, tissue repair, and signaling fidelity, contributing to atherosclerosis and cancer metastasis. Understanding talin's interaction with cholesterol‐rich domains offers critical insights into adhesion regulation and reveals the broader impact of environmental toxicants on cellular function. This framework emphasizes the importance of membrane composition, particularly cholesterol, in mediating the effects of environmental stressors and suggests potential therapeutic interventions. (shrink)

Climate change and biodiversity loss are interconnected crises that demand integrated solutions. While mitigation strategies such as reforestation and afforestation, renewable energy development, and Bioenergy with Carbon Capture and Storage (BECCS) are essential for reducing greenhouse gas emissions, they also pose risks to ecosystems, specifically biodiversity. This review examines the biodiversity impacts of these key mitigation strategies, identifying potential trade-offs and opportunities for synergy. Large-scale forest plantations can sequester carbon but often reduce biodiversity when implemented as monocultures. Renewable energy expansion, (...) particularly wind and solar farms, contributes to decarbonization but can disrupt habitats and wildlife migration. BECCS, though promoted for negative emissions, requires extensive land conversion, threatening biodiversity and food security. To balance climate action with ecological integrity, this study advocates for an eco-surplus culture, where mitigation strategies not only minimize harm but actively enhance biodiversity. Nature-based solutions, such as restoring native forests and integrating biodiversity-conscious renewable energy planning, offer pathways to maximize co-benefits. Policy frameworks must prioritize biodiversity safeguards, promote sustainable land use, and ensure community participation. Addressing climate and biodiversity goals together through holistic, long-term planning is essential for fostering environmental resilience and achieving genuinely sustainable climate solutions. (shrink)

Animals comprise hundreds of cell types, each with specialized biological functions. However, many genes expressed in each cell type belong to widely conserved gene families with ancestrally ubiquitous expression. This raises a paradox: how have these genes evolved to shape cell type‐specific traits without compromising their ancestral function in all other cells? This can be achieved through gene duplication and the origin of regulated, alternatively spliced exons, which generate new related proteins in the form of paralogous genes and alternative isoforms, (...) respectively. Here, we explore how such new related proteins can contribute to the evolution of specific cell types while preserving broader ancestral roles. Specifically, we separately classify possible expression and functional fates for new related proteins and discuss their interplays and evolutionary likelihood. Our primary hypothesis is that expression specialization, mostly coupled with functional specialization, is the predominant fate for both paralogous genes and alternative isoforms throughout animal evolution. (shrink)

This thesis uses a biosocial anthropological approach to explore the wide variety of human-environmental interactions exhibited by the Shuar of the Ecuadorian Amazon. Based on 10 months of ethnographic inquiry and deploying a comparative and evolutionary perspective, this thesis focuses primarily on the holistic nature of ancient subsistence patterns. I delve into the adaptive strategies exhibited by the contemporary Shuar and attempt to delineate the socio-ecological, ritual and cosmological significance of these patterns of behaviour. I suggest how subsistence adaptations, like (...) hunting, which have been greatly diminished in the Shuar communities, nevertheless reveal particular forms of cross-species interactions likely deeply rooted in coevolutionary processes. As clearly indicated by informants' oral histories, hunting patterns and meat-eating behaviour show complex trophic, socio-structural and ritual associations between humans and animal taxa. I then hypothesise that food taboos against eating particular animals (mostly large mammals) may have functioned as mechanisms for the preservation of prey and likely arose from ancient relationships with extinct megafauna. Further, concerning horticulture, a subsistence strategy still practised by the Shuar, I reveal how specific forms of human-plant interactions, such as those with Manihot esculenta Crantz and Guadua spp., inform patterns of patterns of growth, fertility and reproduction. This Amazonian form of human-plant coevolution exhibited by traditional horticulture underscores, in principle, basic and higher-order relational processes exemplified by the biosocial, ritual, ontological, and myth-cosmological associations between organismic kingdoms. Concerning the use of medicinal and psychoactive plants, I show how these kinds of botanical knowledge frequently intersect, thus representing adaptive behaviours highly dependent on embodied and cognitive engagements with plant materials. Both conceived as elementary forms of cure and primary triggers of metaphysical formulations, relationships with these elements of the plant kingdom are likely to be well-embedded in our evolutionary history. Lastly, the thesis' attempt at cross-species comparisons linked to different evolutionary periods (i.e., archaic hominins, extant forager-horticulturalists and non-human primates) may shed new light on the nature of complex adaptive patterns exhibited by Indigenous peoples in general and the Shuar in particular. (shrink)

Obesity paradoxically advances cancer progression while enhancing certain immunotherapies, like anti‐PD‐1/PD‐L1. Bader et al. discovered that obesity‐driven factors increase PD‐1 on tumor‐associated macrophages (TAMs), suppressing anti‐tumor responses. Remarkably, anti‐PD‐1 therapy reverses this metabolic dysfunction, boosting immune checkpoint blockade (ICB) effectiveness by reactivating PD‐1+ TAMs.

Genetic diversity of viral populations is almost unanimously attributed to the build‐up of random mutations along with accidental recombination events. This passive role of viruses in the selection of viable genotypes is widely acknowledged. According to the hypothesis presented here, populations of steady‐state error copies of a master viral sequence would have a dominant mutant rather than a random pool of heterogeneous viral genomes with changes scattered uniformly without any preferential distribution. It would let viruses face the selection stage of (...) host surveillance having a preceding set of potential survivors or “guard” genomes among an ordinary cloud of random quasispecies. (shrink)

The major global challenges of our time, like climate and environmental crises, rising inequality, the emergence of disruptive technologies, etc., demand interdisciplinary research for effective solutions. A clear understanding of value is essential for guiding socio-cultural and economic transitions to address these issues. Despite numerous attempts to define value, existing approaches remain inconsistent across disciplines and lack a comprehensive framework. This paper introduces a novel perspective on value through the lens of granular interaction thinking theory, proposing an informational entropy-based notion (...) of value. Grounded on quantum mechanics, Shannon’s information theory, and the mindsponge theory, this framework integrates both subjective and objective considerations and is highly compatible with interdisciplinary research. The informational entropy-based notion of value effectively bridges diverse concepts of value, including use and exchange value in economics, personal values in psychology, and cultural, moral, ethical, and aesthetic values in society. By offering a unifying perspective, granular interaction thinking theory provides a valuable framework for translating insights from quantum mechanics into socio-cultural, economic, and psychological contexts, enriching theoretical discourse and enhancing analytical effectiveness. (shrink)

Trong bối cảnh cạnh tranh toàn cầu ngày càng gay gắt, khoa học đứng trước thách thức lớn trong việc tối ưu hóa nguồn lực hữu hạn. Các trung tâm quyền lực khoa học hàng đầu như Liên minh châu Âu (EU), Hoa Kỳ và châu Á đang chạy đua để củng cố vị thế dẫn đầu. Trước áp lực đó, các nền kinh tế mới nổi cần tập trung nâng cao hiệu suất đầu tư khoa học. Quan trọng hơn, (...) vấn đề không chỉ nằm ở mức ngân sách dành cho khoa học mà ở cách sử dụng nguồn lực sao cho hiệu quả nhất. Để đạt được những mục tiêu này, việc phát triển khoa học xã hội và nhân văn đóng vai trò cốt lõi trong việc giúp định hình các thước đo giá trị và thế giới quan khoa học. Cuối cùng, khoa học phải khẳng định giá trị của mình thông qua đổi mới sáng tạo và giải quyết các thách thức toàn cầu, góp phần thúc đẩy phát triển bền vững. (shrink)

Để hiện thực hóa các mục tiêu của phát triển kinh tế bền vững, TP. Hà Nội đã từng bước có những bước tiến chuyển đổi từ ngành nông nghiệp thâm dụng nhiều tài nguyên, thiên nhiên làm đầu vào cho quá trình sản xuất hàng hóa sang tích cực ứng dụng công nghệ cao vào quá trình sản xuất nông nghiệp để hình thành các mô hình sản xuất nông nghiệp theo hướng xanh hóa, bền vững, hữu cơ, tuần (...) hoàn và sinh thái thích ứng với biến đổi khí hậu toàn cầu. Bài viết phân tích thực trạng phát triển nông nghiệp xanh trên địa bàn Hà Nội, từ đó đề xuất giải pháp đẩy mạnh mô hình này trong thời gian tới. (shrink)

Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo‐transmission electron microscopy, and advancements in high‐resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms (...) of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP‐43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD. (shrink)

ABSTRACT This study evaluated the effects of postpartum diseases and body condition score (BCS) on the reproductive performance of dairy herds. Cows were monitored during the postpartum to diagnose diseases and changes in BCS. The cows were divided into those with no disease and those with one or more diseases. The incidence of diseases, pregnancy rate (PR) at the first postpartum service, number of days open, percentage of pregnant cows at 150d, and gestational loss were analyzed. No difference was observed (...) between healthy and diseased cows in the PR at the first service or for days open. Diseased cows showed greater gestational loss and the percentage of pregnant cows at 150d postpartum was higher among healthy cows. Cows with a BCS ≥ 3.0 at prepartum had a lower PR at the first service and shorter days open. In conclusion, dairy herds affected by diseases during postpartum show impaired reproductive efficiency Keywords: dairy cattle, postpartum diseases, transition period, pregnancy rate. (shrink)

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth”.

While the social benefits of AI often outweigh its trade-offs, what about its environmental impact? To what extent can AI counterbalance the ecological burdens it creates? Can the Earth sustain itself until AI is successfully developed in the era of climate change and environmental degradation? -/- As Nguyen suggests, humanity must seek wisdom by confronting the foolishness that they are doing in environmental matters. Such wisdom urges us to reevaluate our thoughts, choices, and behaviors to minimize environmental harm and promote (...) ecological sustainability. A critical first step in using AI responsibly for the environment lies in ensuring its effective and efficient utilization. (shrink)

Amazon Book Review Series of “Better Economics for the Earth: A Lesson from Quantum and Information Theories”.

Amazon Book Review Series of “Better Economics for the Earth”.

Amazon Book Review Series of “Better Economics for the Earth: A Lesson from Quantum and Information Theories”.

Amazon Book Review Series of “Better Economics for the Earth: A Lesson from Quantum and Information Theories”.

Amazon Book Review Series of “Better Economics for the Earth: A Lesson from Quantum and Information Theories”.

Transfer RNA (tRNA) modifications play an important role in regulating mRNA translation at the codon level. tRNA modifications can influence codon selection and optimality, thus shifting translation toward specific sets of mRNAs in a dynamic manner. Queuosine (Q) is a tRNA modification occurring at the wobble position. In eukaryotes, queuosine is synthesized by the tRNA‐guanine trans‐glycosylase (TGT) complex, which incorporates the nucleobase queuine (or Qbase) into guanine of the GUN anticodons. Queuine is sourced from gut bacteria and dietary intake. Q (...) was recently shown to be critical for cellular responses to oxidative and mitochondrial stresses, as well as its potential role in neurodegenerative diseases and brain health. These unique features of Q provide an interesting insight into the regulation of mRNA translation by gut bacteria, and the potential health implications. In this review, Q biology is examined in the light of recent literature and nearly 4 decades of research. Q's role in neuropsychiatric diseases and cancer is highlighted and discussed. Given the recent interest in Q, and the new findings, more research is needed to fully comprehend its biological function and disease relevance, especially in neurobiology. (shrink)

Targeted protein degradation (TPD) has emerged as a highly promising approach for eliminating disease‐associated proteins in the field of drug discovery. Among the most advanced TPD technologies, PROteolysis TArgeting Chimera (PROTAC), functions by bringing a protein of interest (POI) into proximity with an E3 ubiquitin ligase, leading to ubiquitin (Ub)‐dependent proteasomal degradation. However, the designs of most PROTACs are based on the utilization of a limited number of available E3 ligases, which significantly restricts their potential. Recent studies have shown that (...) phytoplasmas, a group of bacterial plant pathogens, have developed several E3‐ and ubiquitin‐independent proteasomal degradation (UbInPD) mechanisms for breaking down host targets. This suggests an alternative approach for substrate recruitment and TPD. Here, we present existing evidence that supports the feasibility of UbInPD in eukaryotic cells and propose candidate proteins that can serve as docking sites for the development of E3‐independent PROTACs. (shrink)

Endothermic animals expend significant energy to maintain high body temperatures, which offers adaptability to varying environmental conditions. However, this high metabolic rate requires increased food intake. In conditions of low environmental temperature and scarce food resources, some endothermic animals enter a hypometabolic state known as torpor to conserve energy. Torpor involves a marked reduction in body temperature, heart rate, respiratory rate, and locomotor activity, enabling energy conservation. Despite their biological significance and potential medical applications, the neuronal mechanisms regulating torpor still (...) need to be fully understood. Recent studies have focused on fasting‐induced daily torpor in mice due to their suitability for advanced neuroscientific techniques. In this review, we highlight recent advances that extend our understanding of neuronal mechanisms regulating torpor. We also discuss unresolved issues in this research field and future directions. (shrink)

Due to various intracellular and external cues, cellular organelles are frequently stressed in both physiological and pathological conditions. Sensing these stresses initiates various signaling pathways which may lead to adaptation of the stressed cells or trigger its their death. At the unicellular level, this stress signaling involves a crosstalk between different organelles. At the multicellular level, such pathways can contribute to indicate the presence of a stressed cell to its neighboring cells. Here, we highlight the crucial and diverse roles played (...) by Ubiquitin and Ubiquitin‐like modification in organelle stress signaling. (shrink)

Most chelicerates operate the world with two kinds of visual organs, the median and lateral eyes of the arthropod ground plan. In harvestmen (Opiliones), however, members of the small and withdrawn suborder Cyphophthalmi lack eyes except for two genera with lateral eyes. In the other suborders (Eupnoi, Dyspnoi, and Laniatores), lateral eyes are absent but median eyes pronounced. To resolve the phylogenetic history of these contrasting trait states and the taxonomic position of a four‐eyed harvestmen fossil, visual system development was (...) recently studied in the daddy longleg Phalangium opilio (Eupnoi). This effort uncovered not only a highly regressed and internalized pair of lateral eyes but also a similarly cryptic pair of additional median eyes. After recounting the evo‐devo discovery journey of uncompromising harvestmen taxonomists, this review explores comparative evidence that the enigmatic P. opilio relict eyes might serve the multichannel zeitgeber system of the biological clock. (shrink)

Recently, we identified myeloid‐derived growth factor (MYDGF) as a blood flow‐induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported (...) to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano‐elastic properties and flow‐mediated alterations in the organ‐specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal. (shrink)

Bacterial conjugation, wherein DNA is transferred between cells through direct contact, is highly prevalent in complex microbial communities and is responsible for spreading myriad genes related to human and environmental health. Despite their importance, much remains unknown regarding the mechanisms driving the spread and persistence of these plasmids in situ. Studies have demonstrated that transferring, acquiring, and maintaining a plasmid imposes a significant metabolic burden on the host. Simultaneously, emerging evidence suggests that the presence of a conjugative plasmid can also (...) provide both obvious and unexpected benefits to their host and local community. Combined, this highlights a continuous cost‐benefit tradeoff at the population level, likely contributing to overall plasmid abundance and long‐term persistence. Yet, while the metabolic burdens of plasmid conjugation, and their causes, are widely studied, their attendant potential advantages are less clear. Here, we summarize current perspectives on conjugative plasmids’ metabolic burden and then highlight the lesser‐appreciated yet critical benefits that plasmid‐mediated metabolic burdens may provide. We argue that this largely unexplored tradeoff is critical to both a fundamental theory of microbial populations and engineering applications and therefore warrants further detailed study. (shrink)

Signaling through the Wnt/β‐catenin pathway is relayed through three multiprotein complexes: (1) the membrane‐associated signalosome, which includes the activated Wnt receptors, (2) the cytoplasmic destruction complex that regulates turnover of the transcriptional coactivator β‐catenin, and (3) the nuclear enhanceosome that mediates pathway‐specific transcription. Recent discoveries have revealed that Wnt receptor activities are tightly regulated to maintain proper tissue homeostasis and that aberrant receptor upregulation enhances Wnt signaling to drive tumorigenesis, highlighting the importance of signalosome control. These studies have focused on (...) the detailed process by which Wnt ligands engage their coreceptors, LRP5/6 and Frizzled. However, the components that constitute the signalosome and the regulation of their assembly remain undefined. In this review, we discuss Wnt/β‐catenin signalosome composition and the mechanisms that regulate signalosome assembly, including the role of biomolecular condensates and ubiquitylation. We also summarize the evidence for the presence of Wnt ligand‐independent signalosome formation. (shrink)

Transposable elements (TEs) are mobile genomic elements constituting a big fraction of eukaryotic genomes. They ignite an evolutionary arms race with host genomes, which in turn evolve strategies to restrict their activity. Despite being tightly repressed, TEs display precisely regulated expression patterns during specific stages of mammalian development, suggesting potential benefits for the host. Among TEs, the long interspersed nuclear element (LINE‐1 or L1) has been found to be active in neurons. This activity prompted extensive research into its possible role (...) in cognition. So far, no specific cause‐effect relationship between L1 retrotransposition and brain functions has been conclusively identified. Nevertheless, accumulating evidence suggests that interactions between L1 RNAs and RNA/DNA binding proteins encode specific messages that cells utilize to activate or repress entire transcriptional programs. We summarize recent findings highlighting the activity of L1 RNAs at the non‐coding level during early embryonic and brain development. We propose a hypothesis suggesting a mutualistic relationship between L1 mRNAs and the host cell. In this scenario, cells tolerate a certain rate of retrotransposition to leverage the regulatory effects of L1s as non‐coding RNAs on potentiating their mitotic potential. In turn, L1s benefit from the cell's proliferative state to increase their chance to mobilize. (shrink)

The global obesity epidemic results from a complex interplay of genetic and environmental factors, with diet being a prominent modifiable element driving weight gain and adiposity. Although excess intake of energetic macronutrients is implicated in causing obesity, ongoing debate centers on whether sugar or fat or both are driving the rising obesity rates. This has led to competing models of obesity such as the “Carbohydrate Insulin Model”, the “Energy Balance Model”, and the “Fructose Survival Hypothesis”. Conflicting evidence from studies designed (...) to focus on individual energetic macronutrients or energy rather than macronutrient mixtures underlies this disagreement. Recent research in humans and animals employing the nutritional geometry framework (NGF) emphasizes the importance of considering interactions among dietary components. Protein interacts with carbohydrates, fats, and dietary energy density to influence both calorie intake (“protein leverage”) and, directly and indirectly, metabolic physiology and adiposity. Consideration of these interactions can help to reconcile different models of obesity, and potentially cast new light on obesity interventions. (shrink)

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the (...) bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo‐SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies. (shrink)

As life extended into eukaryota, a great host of strategies emerged in the pursuit of cellular life. Some cells have been successful in solitude, some moved into cooperatives (i.e., multicellular organisms), but one additional strategy emerged. Throughout eukaryotes, many of the diverse multicellular cooperatives took life in partnership one step further. These cells came together and lost their singularity in the expanse of syncytial life. Recently in our search for this elusive “how”, we discovered the intriguing peculiarity of a nuclear, (...) RNA‐binding protein living a second life as a fusion manager at the surface of developing osteoclasts, ushering them into syncytia 1. It is from here that we will develop several thoughts about the advantages of multinucleated cells and discuss how these fusing cells pass through several hallmarks of cell death. We will propose that cell fusion shares much with cell death because cell fusion is a death of sorts for the cells that undergo it – a death of the life that was and the beginning of new life in a community without borders. (shrink)

Cancer cells exploit mechanisms to evade immune detection triggered by aberrant self‐nucleic acids (NA). PARP7, a key player in this immune evasion strategy, has emerged as a potential target for cancer therapy. PARP7 inhibitors reactivate NA sensing, resulting in type I interferon (IFN) signaling, programmed cell death, anti‐tumor immunity, and tumor regression. Cancer cells with elevated IFN‐stimulated gene (ISG) scores, representing a viral mimicry‐primed state, are particularly sensitive to PARP7 inhibition. This review focuses on the endogenous sources of NA in (...) cancer and the potential to exploit elevated aberrant self‐NA in cancer therapy. We describe strategies to increase cytoplamic NA levels, including targeting epigenetic control, DNA damage response, and mitochondrial function. We also discuss targeting RNA processing pathways, such as splicing and RNA editing, to enhance the immunostimulatory potential of existing NA. Combining PARP7 inhibitors with NA elevating strategies may improve cancer immunotherapy, especially for tumors with high ISG scores. (shrink)