PNAS nexus最新文献

Several enzymes receive functional signals from allosteric site to the active site through conformational dynamics while domain dynamics can also play a significant role. Current investigation identifies a claw-like regulatory region near the active site of dengue protease, which remains in dynamic equilibrium as active (open) and inactive (closed) forms. Enhanced sampling with metadynamics showed that the flexibility of the T[RK][SN]G loop of the claw region is crucial for the protease activity as it helps in the opening of the claw-like structure near the active site, and allows the C-terminal hydrophilic part of NS2B cofactor to enter the claw and transform the protease into its active conformation. Binding kinetics and thermodynamics studies further reveal that allosteric modulator epigallocatechin-3-gallate (EGCG) binds to the enzyme in a biphasic manner and disrupts the active/inactive conformational dynamics and locks the enzyme in an inactive conformation. The inhibitor binding in this region introduces an energy barrier in the free energy landscape of NS2B cofactor binding. In the stronger mode, EGCG could directly bind into the claw, induces conformational changes, locking the dynamic loops in a closed position, preventing NS2B binding and rendering the enzyme inactive. Whereas in the weaker mode, EGCG binds to the T[RK][SN]G loop and perturbs its flexibility driving the claw structure into a more closed conformation and maintaining the protease in an inactive state. The understanding of the mechanism, therefore, would help researchers design more potent inhibitors targeting dengue protease and homologous enzymes.

ClC-5 is a Cl-/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dent's disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523ΔVal deletion linked to Dent's disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can shed light on the origin of rare diseases and explore targets for personalized medicine.

Dengue fever, influenced by climate dynamics and human mobility in nonendemic regions, remains poorly understood. We assessed the effects of large-scale climate features on domestic dengue outbreaks using data from China (2013-2021) and projections for 2023-2028, incorporating climate, human mobility, and environmental factors. A significant positive correlation (r = 0.89, P < 0.01) was found between domestic dengue incidence and overseas imported cases. Significant associations were also noted with domestic (F _{2.96, 25.78} = 518.03, P < 0.01) and international human mobility (F _{2.77, 25.78} = 66.84, P < 0.01), the Indian Ocean Dipole (IOD) index (F _{2.98, 25.78} = 522.84), and vectorial capacity (F _{2.92, 25.78} = 338.74, P < 0.01). IOD is the most influential climate feature, with a trend of intensification over time. The Extreme Gradient Boosting (XGBoost) algorithm incorporating IOD (r ² = 0.56) predicted outbreaks in 2025, 2026, and 2028. Our findings reveal that large-scale climate phenomenon, notably the IOD, and human mobility significantly influence dengue domestic outbreaks in China through a "dislocated impact."

The "second wave" of Ediacaran evolution (∼558-548 Ma) was characterized by the appearance of macroscopic organisms in shallow marine settings, where they formed communities with high morphological and ecological diversity, including new and more complex modes of life. Based on analogy with modern marine ecosystems, these early shallow water communities could have substantially modified local hydrodynamic conditions and influenced resource availability, but we know very little about how they interacted with their fluid environment at larger spatial scales. Here, we use computational fluid dynamics to investigate the hydrodynamics of different shallow marine Ediacaran communities based on fossil surfaces from Russia and South Australia. Our results reveal considerable hydrodynamic variability among these communities, ranging from unobstructed flow, to enhanced mixing, to very low in-canopy flow. This variability represents a noticeable shift from the more conserved hydrodynamic conditions reconstructed for older Ediacaran communities from deep water settings. The variation in how shallow marine Ediacaran communities affected local hydrodynamics could have given rise to notable differences in the distribution of crucial water-borne resources such as organic carbon and oxygen. We therefore hypothesize that increasing variability in community hydrodynamics was an important source of habitat heterogeneity during the late Ediacaran. On long timescales, this heterogeneity may have helped sculpt ecological opportunity, fostering the radiation of animals.

The glycocalyx is a critical but often underappreciated modulator of cellular behavior. Its diversity across cell types within tissues remains poorly understood, but recent advances in single-cell profiling now enable more precise analysis of cell surface composition. Here, we applied single-cell glycan and RNA sequencing to profile glycocalyx diversity across human and mouse ocular surface cell types. Glycocalyx patterns effectively distinguished epithelial subtypes, with corneal epithelial cells enriched in complex and high-mannose N-glycans, conjunctival cells in fucosylated structures, and goblet cells in O-glycans. We also observed dynamic changes during epithelial maturation, marked by regulated shifts in sialic acid structures. In the mouse ocular surface, glycocalyx patterns distinguished major cell types, but the glycan profiles differed from those in humans, pointing to species-specific features. These findings demonstrate that glycocalyx composition is closely linked to cell identity and maturation and provide a foundation for exploring its roles in tissue organization and disease.

Amyloid fibril formation is a highly heterogeneous process as evidenced by polymorphism in fibril structure. It has been suggested that different polymorphs are associated with different diseases or disease subtypes. Detailed characterization of this heterogeneity is a key to understanding the aggregation mechanism and, possibly, the disease mechanism. In this work, we develop Förster resonance energy transfer (FRET) imaging of amyloid fibril formation in real time and investigate the concentration-dependent heterogeneous fibril formation of amyloid β 42 (Aβ42). We incubated a mixture of unlabeled and labeled (5% donor and 5% acceptor) Aβ42, followed aggregation, and characterized individual fibrils in terms of FRET efficiency, acceptor fluorescence lifetime, and stoichiometry of the donor- and acceptor-labeled monomers incorporated into the fibrils. By FRET efficiency, we found that there are two distinct species at a relatively low concentration, 2 μM. The high FRET species appears first, but the low FRET species becomes dominant at later times. On the other hand, the high FRET species dominates throughout aggregation at 4 μM. The broad FRET efficiency distributions are consistent with those calculated from various known fibril structures. In addition to the FRET efficiencies, different acceptor lifetimes at the two concentrations and broad acceptor density distributions indicate at least three structurally distinct fibril species exist at each concentration, which also differ between the two different concentrations. The distinct heterogeneity in fibril formation pathways depending on the monomer concentration highlights the importance of understanding heterogeneity in the context of the biologically relevant aggregation environment.

The effects of using large language models (LLMs) versus traditional web search on depth of learning are explored. A theory is proposed that when individuals learn about a topic from LLM syntheses, they risk developing shallower knowledge than when they learn through standard web search, even when the core facts in the results are the same. This shallower knowledge accrues from an inherent feature of LLMs-the presentation of results as summaries of vast arrays of information rather than individual search links-which inhibits users from actively discovering and synthesizing information sources themselves, as in traditional web search. Thus, when subsequently forming advice on the topic based on their search, those who learn from LLM syntheses (vs. traditional web links) feel less invested in forming their advice, and, more importantly, create advice that is sparser, less original, and ultimately less likely to be adopted by recipients. Results from seven online and laboratory experiments (n = 10,462) lend support for these predictions, and confirm, for example, that participants reported developing shallower knowledge from LLM summaries even when the results were augmented by real-time web links. Implications of the findings for recent research on the benefits and risks of LLMs, as well as limitations of the work, are discussed.

Many of today's pressing societal challenges, such as organ shortages, low vaccination rates, and climate change, require significant changes in individual behavior. One promising intervention to encourage such behavioral change is the opt-out default, which presumes consent for a desirable action rather than requiring active opt-in. While past research focused on the impact of opt-out defaults on the targeted behavior, potential crowding out of related behaviors has been largely overlooked. Here, we investigate whether adopting opt-out policies for deceased organ donation reduces living donations, a related prosocial behavior serving the same public good. Analyzing epidemiological panel data from countries that adopted an opt-out default between 2000 and 2023, we find that the policy switch, on average, leads to a nonsignificant increase in annual deceased donor rates of +1.21 people per million population (+7%, P = 0.213) but to a significant decrease in living donor rates of -4.59 people per million population (-29%, P = 0.026). Across four additional studies, we demonstrate that this crowding-out effect is reflected in a reduced willingness for living altruistic (vs. familial) donations and is attributable to a stronger belief that the organ supply is sufficiently met with deceased donations under opt-out (vs. opt-in). Our research advances insights into the unintended consequences of default nudges and suggests ways to mitigate them.

Expression of inhibitory Siglec receptors has been described on T cells of patients with viral infection and cancer. However, the exact function and their role in T-cell activation and control of infections have not been well investigated. Here, we show that Siglec-9 levels increase on T cells in patients with acute severe acute respiratory syndrome coronavirus 2 infection relative to levels on healthy controls. T cells of these patients are inhibited by Siglec-9, and specific blocking with antibodies released this inhibition. To further test the role of Siglec-9 in acute viral infections, we characterized a murine model with T-cell intrinsic Siglec-9 overexpression. We found that Siglec-9 restricted T-cell immunity after acute infection with lymphocytic choriomeningitis virus, thereby dampening T-cell-mediated immune pathology. These results show that inhibitory Siglec receptors including Siglec-9 T cell intrinsically modulate and fine-tune antiviral T-cell activation, proliferation, and effector function.

In this work, we introduce encapsulated wine beads as a novel, edible material for unconventional and neuromorphic computing. When encapsulated in alginate beads, wine, a complex mixture of proteins, organic acids, sugars, metal ions, and volatiles, exhibits nonlinear electrical behavior and memory effects governed by ox-redox processes. These responses show plasticity-like features, allowing programmable resistance states. The wine beads can be leveraged for computing, and to demonstrate this potential, the wine bead was used as a single-node reservoir for classification tasks. Our findings indicate that the resistance is programmable, exhibits a high degree of repeatability, and can be used for reservoir computing scenarios.