Addressing both natural and societal challenges requires collective cooperation. Studies on collective-risk social dilemmas have shown that individual decisions are influenced by the perceived risk of collective failure. However, existing feedback evolving game models often focus on a single feedback mechanism, such as the coupling between cooperation and risk or between cooperation and cost. In many real-world scenarios, however, the level of cooperation, the cost of cooperating, and the collective risk are dynamically interlinked. Here, we present an evolutionary game model that considers the interplay of these three variables. Our analysis shows that the worst-case scenario, characterized by full defection, maximum risk, and the highest cost of cooperation, remains a stable evolutionary attractor. Nevertheless, cooperation can emerge and persist because the system also supports stable equilibria with non-zero cooperation. The system exhibits multistability, meaning that different initial conditions lead to either sustained cooperation or a tragedy of the commons. These findings highlight that initial levels of cooperation, cost, and risk collectively determine whether a population can avert a tragic outcome.
Biomolecular networks underpin emerging technologies in synthetic biology-from robust biomanufacturing and metabolic engineering to smart therapeutics and cell-based diagnostics-and also provide a mechanistic language for understanding complex dynamics in natural and ecological systems. Yet designing chemical reaction networks (CRNs) that implement a desired dynamical function remains largely manual: while a proposed network can be checked by simulation, the reverse problem of discovering a network from a behavioral specification is difficult, requiring substantial human insight to navigate a vast space of topologies and kinetic parameters with nonlinear and possibly stochastic dynamics. Here we introduce GenAI-Net, a generative AI framework that automates CRN design by coupling an agent that proposes reactions to simulation-based evaluation defined by a user-specified objective. GenAI-Net efficiently produces novel, topologically diverse solutions across multiple design tasks, including dose responses, complex logic gates, classifiers, oscillators, and robust perfect adaptation in deterministic and stochastic settings (including noise reduction). By turning specifications into families of circuit candidates and reusable motifs, GenAI-Net provides a general route to programmable biomolecular circuit design and accelerates the translation from desired function to implementable mechanisms.
Beatriz Anjo Lima, Ana Carolina Pais, Juliette Dupont
et al.
This study provides proof of principle for the therapeutic potential of splicing modulation as a strategy to rescue BRCA2 function in mutant cells. Variants in the hereditary cancer-associated BRCA1 and BRCA2 genes can alter RNA splicing, producing transcripts that encode internally truncated yet potentially functional proteins. However, few studies have quantitatively analyzed variant-specific splicing isoforms. Here, we investigated cells heterozygous and homozygous for the BRCA2 :c.681+5G>C variant. Using droplet digital RT–PCR, we identified two variant-specific mRNA isoforms. The predominant transcript is out-of-frame, contains a premature termination codon, and is degraded via the nonsense-mediated mRNA decay pathway. In addition, we detected a novel minor isoform encoding an internally truncated protein lacking non-essential domains. Homozygous mutant cells expressed low levels of BRCA2 protein and were defective in DNA repair. Using CRISPR-Cas9 gene editing, we induced the production of in-frame transcripts in mutant cells, which resulted in increased protein expression, enhanced RAD51 focus formation, and reduced chromosomal breaks after exposure to genotoxic agents. Our findings highlight the therapeutic potential of splicing modulation to restore BRCA2 function in mutant cells, offering a promising strategy to prevent cancer development.
RNAs are essential molecules that carry genetic information vital for life, with profound implications for drug development and biotechnology. Despite this importance, RNA research is often hindered by the vast literature available on the topic. To streamline this process, we introduce RNA-GPT, a multi-modal RNA chat model designed to simplify RNA discovery by leveraging extensive RNA literature. RNA-GPT integrates RNA sequence encoders with linear projection layers and state-of-the-art large language models (LLMs) for precise representation alignment, enabling it to process user-uploaded RNA sequences and deliver concise, accurate responses. Built on a scalable training pipeline, RNA-GPT utilizes RNA-QA, an automated system that gathers RNA annotations from RNACentral using a divide-and-conquer approach with GPT-4o and latent Dirichlet allocation (LDA) to efficiently handle large datasets and generate instruction-tuning samples. Our experiments indicate that RNA-GPT effectively addresses complex RNA queries, thereby facilitating RNA research. Additionally, we present RNA-QA, a dataset of 407,616 RNA samples for modality alignment and instruction tuning, further advancing the potential of RNA research tools.
Most scientific equipment gets heedlessly thrown away when it’s no longer of use. But these often beautiful and well-crafted tools deserve a better fate, if anything to remind younger generations of the technological and scientific breakthroughs that they enabled.
In individuals afflicted with hemophilia, characterized by a deficiency of coagulation factor VIII (FVIII), the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arthropathy (HA). Although clotting factor replacement therapy reduces joint bleeding clinically, clotting factors need to be injected frequently due to the rapid diffusion of the drug. Hence, a novel drug delivery approach may be developed to improve the drug therapy. Platelet-derived extracellular vesicles (PEVs) are known to possess anti-inflammatory and hemostatic properties and could be used as a potential HA therapy. In this study, we constructed a PEV-LS@FVIII nanotherapeutic system by combining thioketal (TK), liposomes (LS), and FVIII to form the LS@FVIII complexes, and then hybridizing PEV with LS@FVIII. Our results demonstrated that PEV-LS@FVIII could efficiently facilitate FVIII delivery and specifically target the injured knee joint. Both in vitro and in vivo studies showed a reduction in the M1 phenotype of macrophages and an enhancement of the M2 phenotype, compared to FVIII free control. Furthermore, PEV-LS@FVIII appeared to alleviate HA-induced cartilage damage. In conclusion, our findings demonstrate that PEV-LS@FVIII could delay the progression of HA by targeting bleeding joints, modulating macrophage polarization to suppress inflammation, and mitigating cartilage damage.
Materials of engineering and construction. Mechanics of materials, Biology (General)
Sarah Frank, Elisa Gabassi, Stephan Käseberg
et al.
Molecular and cellular phenotyping of human brain organoids carrying various MID1 mutations reveals an unexpected role of the composition of the MID1 isoform pool during early patterning processes. The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 . Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.
In this paper I raise a worry about the most extended resolutions of the problem of time of canonical quantizations of general relativity. The reason for this is that these resolutions are based on analogies with deparametrizable models for which the problem can be solved, while I argue in this paper that there are good reasons for doubting about these resolutions when the theory is not deparametrizable, which is the case of general relativity. I introduce an example of a non-deparametrizable model, a double harmonic oscillator system expressed by its Jacobi action, and argue that the problem of time for this model is not solvable, in the sense that its canonical quantization doesn't lead to the quantum theory of two harmonic oscillators and the standard resolutions of the problem of time don't work for this case. I argue that as general relativity is strongly analogous to this model, one should take seriously the view that the canonical quantization of general relativity doesn't lead to a meaningful quantum theory. Finally, I comment that this has an impact on the foundations of different approaches to quantum gravity.
Giacomo Zaccone, Alessio Alesci, Doaa M. Mokhtar
et al.
The recognition and elimination of invading pathogens are vital for host survival. Macrophages play a central role in host protection and cells functionally reminiscent of vertebrate macrophages are present in all multicellular organisms. A pattern responsible for bacterial recognition found on the surface of macrophages is CD14. These cells possess a repertoire of antimicrobial molecules stored in their granules and lysosomes. Polarization states observed in mammalian macrophages termed M1 and M2 also likely exist in fish macrophages. Markers for macrophage subtypes are slowly but definitively emerging in fish species. In the present study cell markers such as CD14, acetylcholine, alpha 7 acetylcholine nicotinic receptor (nAChR) subtype, the inducible nitric oxidase synthase (iNOS), and the antimicrobial peptide piscidin 1 are reported for the first time in the intestinal macrophages of both catfish <i>Heteropneustes fossilis</i> (Bloch, 1794) and the African bonytongue <i>Heterotis niloticus</i> (Cuvier, 1829) along the anterior and the posterior axis and the concentric muscle layers. Many antimicrobial effector responses of vertebrate macrophages including respiratory burst and NO induction are similar across the diverse animal taxa. Antibodies against calbindin coupled with ones to VAChT and tubulin revealed the localization of myenteric and submucosal plexuses, which are made up of enteric neurons, glial cells, and nerves near macrophages. Current studies allow for the elucidation of multiple roles of macrophages in disease models providing an insight into their in vivo function in fish.
Ibuki Arizono, Naoki Fujita, Chihiro Tsukahara
et al.
Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD<sup>+</sup>), has been studied to support human health against metabolic stress, cardiovascular disease, and neurodegenerative disease. In the present study, we investigated the effects of oral NR on axonal damage in a rat ocular hypertension model. Intraocular pressure (IOP) elevation was induced by laser irradiation and then the rats received oral NR of 1000 mg/kg/day daily. IOP elevation was seen 7, 14, and 21 days after laser irradiation compared with the controls. We confirmed that oral NR administration significantly increased NAD<sup>+</sup> levels in the retina. After 3-week oral administration of NR, morphometric analysis of optic nerve cross-sections showed that the number of axons was protected compared with that in the untreated ocular hypertension group. Oral NR administration significantly prevented retinal ganglion cell (RGC) fiber loss in retinal flat mounts, as shown by neurofilament immunostaining. Immunoblotting samples from the optic nerves showed that oral NR administration augmented the phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) level in rats with and without ocular hypertension induction. Immunohistochemical analysis showed that some p-AMPK-immunopositive fibers were colocalized with neurofilament immunoreactivity in the control group, and oral NR administration enhanced p-AMPK immunopositivity. Our findings suggest that oral NR administration protects against glaucomatous RGC axonal degeneration with the possible upregulation of p-AMPK.
BACKGROUND Water quality security and human health are important to ensure rural revitalization of old liberated areas. The continuous development and utilization of ion-adsorption type REE deposits in northern Ganzhou aggravate trace elements from ores and tailings to the water cycle, thereby endangering the sanitation and safety of drinking water. OBJECTIVES To investigate and evaluate health risk and water quality on the watershed scale of rare earth ore concentration area in the Huangpi River Basin. METHODS The contents of manganese, cadmium and other elements were determined by inductively coupled plasma-optical emission spectrometry/mass spectrometry(ICP-OES/MS). By choosing "standards for drinking water quality" (GB 5749—2006) as the evaluation basis, the water quality index (WQI), hazard quotient (HQ), and cancer risk (CR)were adopted to evaluate water quality and human health risks through analyzing 9 indices including Pb and Mn. RESULTS NH3-N and Mn were anomaly indices whether in surface water or groundwater. The average values of NH3-N were 750μg/L and 4533μg/L in surface water and groundwater, respectively. Index values of Mn were 207μg/L and 4009μg/L in surface water and groundwater, respectively. Arsenic, class I carcinogen published by the World Health Organization, had no abnormality in surface water and groundwater. Moreover, 85.7% of surface water and groundwater was found to be suitable for drinking upon analyzing the WQI values. The HQ average value of NH3-N was less than 1 in surface water and groundwater so it had no harmful effects on human health. However, the HQ average value of Mn was more than 1, which may be harmful to human health. CR values of As varying from 10-6 to 10-4 were also calculated, and the risk of cancer was acceptable. CONCLUSIONS It is suggested that relevant departments should pay attention to the status of NH3-N and heavy metal elements in water during the reclamation evaluation of rare earth mines. The research detailed in this paper confirms that the groundwater monitoring system of manganese should be improved.
Yoichiro Fujioka, Sayaka Kashiwagi, Aiko Yoshida
et al.
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has threatened human health and the global economy. Development of additional vaccines and therapeutics is urgently required, but such development with live virus must be conducted with biosafety level 3 confinement. Pseudotyped viruses have been widely adopted for studies of virus entry and pharmaceutical development to overcome this restriction. Here we describe a modified protocol to generate vesicular stomatitis virus (VSV) pseudotyped with SARS-CoV or SARS-CoV-2 spike protein in high yield. We found that a large proportion of pseudovirions produced with the conventional transient expression system lacked coronavirus spike protein at their surface as a result of inhibition of parental VSV infection by overexpression of this protein. Establishment of stable cell lines with an optimal expression level of coronavirus spike protein allowed the efficient production of progeny pseudoviruses decorated with spike protein. This improved VSV pseudovirus production method should facilitate studies of coronavirus entry and development of antiviral agents. Key words: severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, pseudovirus, vesicular stomatitis virus (VSV), spike protein
Sugar-based molecules such as heparins or natural heparan sulfate polysaccharides have been developed and widely studied for controlling heparanase (HPSE) enzymatic activity, a key player in extracellular matrix remodelling during cancer pathogenesis. However, non-enzymatic functions of HPSE have also been described in tumour mechanisms. Given their versatile properties, we hypothesized that sugar-based inhibitors may interfere with enzymatic but also non-enzymatic HPSE activities. In this work, we assessed the effects of an original marine λ-carrageenan derived oligosaccharide (λ-CO) we previously described, along with those of its native counterpart and heparins, on cell viability, proliferation, migration, and invasion of MDA-MB-231 breast cancer cells but also of sh-MDA-MB-231 cells, in which the expression of HPSE was selectively downregulated. We observed no cytotoxic and no anti-proliferative effects of our compounds but surprisingly λ-CO was the most efficient to reduce cell migration and invasion compared with heparins, and in a HPSE-dependent manner. We provided evidence that λ-CO tightly controlled a HPSE/MMP-14/MMP-2 axis, leading to reduced MMP-2 activity. Altogether, this study highlights λ-CO as a potent HPSE “modulator” capable of reducing not only the enzymatic activity of HPSE but also the functions controlled by the HPSE levels.
Let k be an algebraically closed field of characteristic p>0. We compute the Weyl filtration multiplicities in indecomposable tilting modules and the decomposition numbers for the general linear group over k in terms of cap diagrams under the assumption that p is bigger than the greatest hook length in the partitions involved. Then we introduce and study the rational Schur functor from a category of GL_n-modules to the category of modules for the walled Brauer algebra. As a corollary we obtain the decomposition numbers for the walled Brauer algebra when p is bigger than the greatest hook length in the partitions involved. This is a sequel to an earlier paper on the symplectic group and the Brauer algebra.
The payload performance of conventional computing systems, from single processors to supercomputers, reached its limits the nature enables. Both the growing demand to cope with "big data" (based on, or assisted by, artificial intelligence) and the interest in understanding the operation of our brain more completely, stimulated the efforts to build biology-mimicking computing systems from inexpensive conventional components and build different ("neuromorphic") computing systems. On one side, those systems require an unusually large number of processors, which introduces performance limitations and nonlinear scaling. On the other side, the neuronal operation drastically differs from the conventional workloads. The conventional computing (including both its mathematical background and physical implementation) is based on assuming instant interaction, while the biological neuronal systems have a "spatiotemporal" behavior. This difference alone makes imitating biological behavior in technical implementation hard. Besides, the recent issues in computing called the attention to that the temporal behavior is a general feature of computing systems, too. Some of their effects in both biological and technical systems were already noticed. Nevertheless, handling of those issues is incomplete/improper. Introducing temporal logic, based on the Minkowski transform, gives quantitative insight into the operation of both kinds of computing systems, furthermore provides a natural explanation of decades-old empirical phenomena. Without considering their temporal behavior correctly, neither effective implementation nor a true imitation of biological neural systems are possible.