The emergence of tolerance between distinct social groups is a central question in social evolution, with relevance to both nonhuman primates and early human societies. Ecological factors such as resource heterogeneity and social threats like bachelor male presence have each been proposed as drivers of intergroup proximity, but their combined effects remain unclear. We developed a spatially explicit agent-based model to examine how resource patchiness and bachelor threat jointly shape aggregation dynamics and intergroup tolerance among mixed-sex groups. In the model, groups forage across heterogeneous landscapes and expand their ranges with increasing patchiness. Bachelor groups move according to local resource gradients and generate location-dependent social pressure when in proximity to social groups, prompting groups to aggregate probabilistically according to threat intensity. Aggregation decisions follow a sigmoid response, and familiarity accumulates through repeated overlap or joint aggregation. Intergroup tolerance thus arises from encounter histories rather than being preprogrammed. Simulations show that resource heterogeneity promotes tolerance by increasing overlap and encounter frequency, while bachelor threat induces aggregation as a protective response. Tolerance can also emerge without consistent aggregation, provided that ecological conditions repeatedly bring groups together. When both heterogeneity and threat are high, aggregation and familiarity peak, indicating a synergistic effect. These outcomes are robust across the explored parameter space and do not require explicit coordination or cooperative intent. Our findings highlight how simple behavioural rules embedded in ecological and social contexts can yield complex intergroup outcomes, offering a general framework for understanding the evolution of intergroup tolerance in primates and humans.

Multiple System Atrophy (MSA) and Parkinson's Disease (PD) are neurodegenerative diseases characterized by abundant α-synuclein (αSyn) aggregation in the brain. Compared to PD patients, MSA patients have more widespread neurodegeneration and a more aggressive disease course. PD-related αSyn pathology is primarily neuronal, whereas MSA brains characteristically display oligodendroglial inclusions. The strain hypothesis poses that polymorphisms of the αSyn aggregates, so-called strains, may explain disease heterogeneity. The present study investigates the differential properties of αSyn fibrils derived from MSA and PD patients' brains using the protein misfolding cyclic amplification (PMCA) method in cultured neurons and in vivo. MSA- and PD-derived αSyn species were administered to primary murine neuronal cell cultures or injected intrastriatally into wildtype mice, along with de novo generated αSyn fibrils of the ribbon and fibril types. The potency to induce phosphorylated αSyn (pSyn) pathology, microglial reactivity, and the extent of oligodendroglial pSyn pathology were compared among the different seeding materials using immunohistochemical and immunofluorescent approaches. In summary, the various seeding materials induced pSyn pathology of distinguishable potency and morphology. PMCA-derived material from MSA brains and the fibril polymorph induced more pSyn pathology in both neuronal cultures and in mice compared to PMCA-derived material from PD brains and the ribbon polymorph. Interestingly, amplified material from MSA brains induced significantly more oligodendroglial pSyn aggregates than amplified material from PD brains. Additionally, mice injected with the fibril polymorph, showed mild changes in microglial reactivity. Our findings suggest specific properties of the MSA- and PD-derived fibrils, and overall support the strain hypothesis.

WAC is a chromatin-associated regulatory protein involved in transcriptional control and has been identified as an autism-associated gene in human genetic studies. However, its functional role in regulating behavior and synaptic processes remains incompletely understood. Using Caenorhabditis elegans, we investigated the consequences of wac deficiency on food-associated social behavior, growth-associated phenotypes, and cholinergic pathway function. wac-deficient worms showed a marked reduction in food-leaving behavior, supporting impaired behavioral responsiveness to food-associated environmental cues, while aggregation behavior was not significantly altered. PHX2587 wac deletion mutant worms also exhibited reduced body length, decreased pharyngeal pumping, and shortened lifespan, indicating broader growth and physiological impairment. Stage-resolved analysis of cholinergic pathway genes revealed stage-associated transcriptional changes, with coordinated upregulation of multiple presynaptic and postsynaptic cholinergic components (ace-1, cha-1, cho-1, lev-1, lev-10, unc-17, unc-29, unc-38, and unc-50) emerging most prominently at the young adult stage. Functional RNAi analysis further identified cho-1, which encodes the high-affinity presynaptic choline transporter, as a genotype-specific modifier of cholinergic sensitivity in PHX2587 worms. Importantly, cho-1 RNAi not only reduced aldicarb hypersensitivity but also partially suppressed the reduced body length phenotype and improved food-leaving behavior in PHX2587 worms, while having limited effects in wild-type N2. Together, these findings support a functional relationship between wac deficiency and cho-1-associated cholinergic modulation, suggesting that presynaptic choline transport contributes to selected behavioral and physiological consequences of wac loss.

Transthyretin (TTR) amyloidosis is a progressive disease characterized by the destabilization of TTR tetramers, leading to monomer dissociation, oligomer formation, and fibril deposition in cardiac tissue. This study presents a mathematical model that captures the kinetics of TTR aggregation and deposition, integrating clinically relevant parameters to distinguish between scenarios of TTR aggregation in blood plasma and cardiac tissue. The governing equations are derived by applying conservation principles to the number of TTR tetramers, monomers, and oligomers within defined control volumes, such as the blood plasma or heart. The model predicts that the scenario with fibril accumulation within cardiac tissue better reflects the clinical progression of wild-type TTR amyloidosis, aligning with observed patient survival times and measured tetramer concentrations. In this scenario, the model successfully recapitulates published physiological data, accurately predicting a total plasma TTR concentration of approximately 25 mg/dL. Sensitivity analyses reveal that the rate of tetramer dissociation and the half-deposition time of TTR oligomers are key regulators of disease progression. Lower tetramer dissociation rates, mimicking the stabilizing effect of tafamidis, reduce fibril accumulation and biological aging. Conversely, faster oligomer deposition into fibrils leads to reduced oligomer concentrations but accelerated tissue fibril accumulation. The model predicts that, after five years of disease progression, the volumetric ratio of deposited TTR fibrils to baseline myocardial volume may reach 58% in the tissue aggregation scenario, compared to 10% when aggregation occurs in plasma. These predictions are consistent with clinical observations that link higher amyloid burden to increased mortality. Overall, the findings support a pathogenic mechanism in which TTR aggregation predominantly occurs in cardiac tissue, highlighting potential therapeutic targets to modulate disease progression. A correlation is proposed for estimating biological age in humans, which incorporates both calendar age and the volumetric ratio of deposited TTR fibrils to baseline myocardial volume.

Hemolymph coagulation is a vital component of insect immunity, rapidly reducing fluid loss and limiting pathogen spread after injury. In Manduca sexta larvae, paralytic peptide (PP) is a fast-acting cytokine activated by an unknown serine protease, and its influence on hemolymph mechanics remains largely unexplored. Here, we examine how PP exposure alters the extensional and surface rheological properties of larval hemolymph, providing insight into physical manifestation of the immune activation. Hemolymph collected from fifth-instar larvae exhibited weak viscoelastic behavior in 84% of extensional rheology experiments, with a mean characteristic relaxation time of 1.9±1.5ms. Treatment with 10 μM PP resulted in a pronounced shift toward a more Newtonian-like behavior: only 63% of samples remained viscoelastic, and the mean relaxation time (0.7±0.6ms) (p<0.001) was reduced by >2-fold. In samples subjected to repeated measurements, PP exposure caused a rapid loss of viscoelasticity on the timescale of seconds. Surface rheology was probed using magnetic rotational spectroscopy with magnetic microrods. In hemolymphs aged for > 10 minutes, the surface layer of untreated and PP-treated hemolymphs behaved as a Maxwellian viscoelastic fluid. The relaxation time of the viscoelastic reaction is measured in seconds, i.e., it is three orders of magnitude larger than that in the bulk. The surface drag coefficients of the microrods on PP-treated hemolymph are about twofold smaller than those of untreated ones. As the hemocyte aggregation ceased in ∼10 minutes after hemolymph extraction, these rheological signatures suggest that PP-stimulated coagulation initiates within the bulk hemolymph. STATEMENT OF SIGNIFICANCE: Hemolymph coagulation is essential for insect survival, preventing fluid loss, pathogen invasion, and loss of mechanical support following injury. While molecular components of insect immune responses have been extensively studied, physical transformations of hemolymph during early wound responses remain poorly understood. Using extensional rheology and magnetic rotational spectroscopy, we show that a cytokine named paralytic peptide (PP), which is proteolytically activated after wounding, rapidly alters the viscoelastic properties of the hornworm Manduca sexta hemolymph. PP reduces bulk viscoelasticity within seconds and modifies interfacial rheological behavior, revealing a direct link between immune signaling and hemolymph mechanics. These findings provide new insight into how proteolytic enzyme(s) convert hemolymph into a mechanically protective material during wound healing.

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.

Mussel foot proteins (Mfps) are a class of specialized adhesive proteins synthesized by marine mussels. Among these, type 3 mussel foot protein (Mfp-3) has tremendous application potential as a cosmetic and medical raw material, owing to its excellent antioxidant and anti-inflammatory properties. However, the low efficiency of the natural extraction method (only 1 mg of protein can be obtained from 10,000 mussels) has hindered the industrial application. Heterologous expression via genetic recombination offers a reliable alternative. However, a major challenge is that recombinant expression frequently results in misfolded, biologically inactive protein aggregates. In this study, we identified endogenous molecular chaperones in Mytilus galloprovincialis and successfully constructed a strain that co-expresses Mfp-3 and these chaperone proteins, thereby achieving the soluble expression of Mfp-3. Furthermore, through optimization of fermentation conditions, the soluble yield of Mfp-3 in high-density fermentation using a 5-l fermenter reached 713 mg/L. Meanwhile, following in vitro tyrosinase modification, the L-3,4-dihydroxyphenylalanine (DOPA) content of Mfp-3 reached 4.45%, corresponding to a modification rate of 22.26%. On this basis, this study also demonstrated that soluble Mfp-3 possesses excellent cell migration-promoting ability. Moreover, it exhibited superior biological activity in the treatment of atopic dermatitis by reducing levels of pro-inflammatory cytokines and immunoglobulins. This research provides a new strategy for the production of soluble Mfp-3 in Escherichia coli and offers a reference for the large-scale production of soluble Mfps.

Thrombocytopenia is a common manifestation in viperid snakebite envenomings, contributing to systemic bleeding and hemodynamic alterations. Despite its relevance, this effect is not evaluated when assessing the neutralizing ability of antivenoms. In this study we present an in vivo method in mice for the quantification of thrombocytopenic effect. Representative venoms of Costa Rican viperid snake genera (Atropoides, Bothrops, Bothriechis, Cerrophidion, Crotalus, Lachesis, Metlapilcoatlus, and Porthidium) were administered by the intramuscular route in mice and platelet counts were carried out three hours after envenoming. Only the venoms of Bothrops asper and Bothriechis lateralis induced a significant drop in platelet numbers as compared to controls receiving saline solution. The polyvalent antivenom used in Central America was effective in the neutralization of the effect, even in the case of B. lateralis venom, which is not included in the immunizing mixture. In the case of B. asper venom, a C-type lectin-like (SNACLEC), which indues platelet aggregation in the presence of plasma, is responsible for the thrombocytopenic effect. Thus, an in vitro test was designed to assess the efficacy of the antivenom, based on the neutralization of the in vitro aggregating effect of the SNACLEC and of crude venoms of B. asper and B. lateralis in which proteinase activity was inhibited to avoid the coagulation of plasma. This in vitro assay could be useful for assessing antivenom efficacy against thrombocytopenic components of venoms. It is suggested that the neutralization of thrombocytopenic effect of venoms by antivenoms be added to the list of supplementary tests used in the preclinical assessment of antivenom efficacy.

This study explores the potential of valorising excavated soft clay as a construction material through the development of novel soft clay aggregates (SCCAs) by the incorporation of a suitable side stream carbonaceous residue from methane pyrolysis. The SCCAs were developed by mixing clay, the carbonaceous residue, and cement at a ratio of 3:1:1 through a cold-bonded aggregate pelletisation process. Furthermore, SCCAs were cured under a 100% CO2 atmosphere for 8 h to precipitate mineralized CaCO3. The analytical investigation revealed that the carbonaceous residue constituted fibrous nanotube-like structures that facilitated an increase in CaCO3 precipitation by 70% with respect to the carbonated aggregates not containing the carbonaceous residue. This calcite precipitation and densification resulted in a point load compressive strength (1.3 MPa) of medium-sized (≥15 mm) SCCAs, equivalent to those of commercially used expanded glass foam aggregates. A proof-of-concept investigation of the cast concrete blocks in which SCCAs replaced 20 vol% of the natural aggregate showed a 7-day compressive strength exceeding 22 MPa, indicating their potential for use in masonry construction in accordance with Eurocode 6. Carbon footprint analysis highlighted that even considering the additional emissions related to the manufacturing steps, concrete manufactured using the aggregate formulation proposed in this study would present a 15% lower footprint, due to the carbon sequestered in the carbonaceous residue. The results of the study hence show the potential application of SCCAs as backfill materials or even for the manufacturing of medium-strength concrete products.

Currently, monkeypox virus (MPXV) treatment methods face a dilemma of potential drug resistance. They cannot simultaneously address two core pathological mechanisms driving infection: continuous viral replication and uncontrolled inflammatory storm. To overcome these challenges, we innovatively developed a dual-function therapeutic strategy with precise virus clearance and anti-inflammatory effects, constructing a dual hydrogel system synergistically combining phototherapy and immunomodulatory effects. Specifically, aggregation-induced emission (AIE) nanoparticles (NPs) are embedded in a reactive oxygen species (ROS)-degradable polyvinyl alcohol (PVA)-N1-(4-borobenzoyl)-N3-(4-borobenzoyl)-the N1, the N1, N3, N3-tetramethylpropane-1,3-diamine (tsPBA) hydrogel, while the anti-inflammatory agent is loaded in a zwitterionic hydrogel (SBMA) matrix. Under near-infrared band laser irradiation, AIE NPs efficiently generate large amounts of ROS, which, together with inflammation-produced endogenous ROS, trigger the rapid degradation of the ROS-responsive hydrogel and release of AIE NPs. The generated ROS effectively destroys the MPXV shell and strongly inactivates the virus. After virus clearance, the SBMA hydrogel continuously releases anti-inflammatory drugs (Dexamethasone, DXMS) to inhibit excessive pro-inflammatory cytokines and reduce inflammation-induced tissue damage. In mouse, rabbit, and non-human primate models with MPXV-induced skin damage, this hydrogel nanoparticle protective layer significantly inhibits viral replication and accelerates wound healing, representing a transformative, convertible platform for treating MPXV and other highly inflammatory viral infections.

Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.