PNAS nexus最新文献

Parental environmental exposures can induce transgenerational effects through epigenetic modifications in germ cells. Although paternal immune activation is implicated in transgenerational metabolic and neuropsychiatric disorders, the germline-encoded molecular vectors mediating this inheritance remain poorly understood. Here, we demonstrated that lipopolysaccharide-induced immune activation dynamically upregulated the abundance of 28S ribosomal RNA-derived small RNAs (28S-rsRNAs) in mouse sperm in a time-dependent manner. Furthermore, epididymal sperm maturation exhibited heightened susceptibility to acute immune perturbations compared with spermatogenic processes, and 28S-rsRNAs were selectively incorporated during their transit through the caput epididymis. Strikingly, zygotic microinjection of synthetic 28S-rsRNAs recapitulated paternal immune activation phenotypes, resulting in offspring exhibiting metabolic syndrome-like phenotypes, including obesity and impaired insulin sensitivity. Concurrently, these manipulated offspring displayed neurobehavioral abnormalities characterized by heightened anxiety-like and aggressive behaviors, accompanied by hippocampal transcriptomic alterations. Taken together, our findings demonstrate that sperm 28S-rsRNAs contribute to paternal immune activation-mediated programming of offspring behavioral and metabolic phenotypes and provide mechanistic insights into environment-germline interactions.

We propose a simple and practical machine learning-based desktop solution for analyzing biologically relevant protein motions. We termed our technology reinforced molecular dynamics (rMD) combining MD trajectory data and free-energy (FE) map data to train a dual loss function autoencoder network that can explore conformational space retroactively with no need for additional simulations. The key insight of rMD is that it replaces the latent space with an FE map for structure prediction, thus infusing the autoencoder network with physical context. The FE map is computed from a biased MD simulation over a low-dimensional collective variable (CV) space that captures some biological function. In the proposed rMD framework, the FE map can then be used directly to generate more protein structures in poorly sampled regions or to follow alternative paths in CV space to explore multiple conformational transitions. The rMD technology is entirely self-contained, does not rely on any pretrained model, and can be run on a GPU desktop computer. We present our rMD computations in a key area of molecular-glue degraders aimed at a deeper understanding of the structural transition from open to closed conformations of CRBN.

Sandy beaches act as buffers against various coastal hazards but are vulnerable to episodic (seasonal) and chronic (interannual) erosion. Understanding the variation of shoreline position, a key metric in coastal morphology, over a spectrum of time scales is therefore crucial in assessing hazard vulnerability. Long-standing research has investigated the role of El Niño-Southern Oscillation (ENSO), the dominant mode of climate variability in the Pacific Basin, in seasonal shoreline variability. Yet, ENSO's chronic influence-and that of another Pacific climate mode, the Pacific Decadal Oscillation (PDO)-on shoreline anomalies remains poorly understood. Here, we examine the variability of sandy beaches in the US Pacific Northwest, a ∼750 km long coastal region on the US West Coast. We leverage 40 years (1984-2024) of shoreline data from publicly available Earth-observing (Landsat) satellite imagery at a high spatial resolution (>10,000 shore-normal transects at 50-m alongshore spacing) and employ Convergent Cross Mapping (CCM), a methodology for inferring causality in dynamical systems. We discover that strong El Niño years are signified by erosion (75.1% of transects), and strong La Niña years exhibit accretional behavior (73.4% of transects). Furthermore, we establish, for the first time, that both ENSO and PDO exert a statistically significant control on interannual shoreline variability, particularly on the alongshore component (in 95 and 100% of littoral cells, respectively), with water level fluctuations playing a critical role. This effort advances our understanding of the seasonal-to-interannual interactions between Pacific Basin climate variability and the PNW's coastal morphodynamics, with implications for sediment management and coastal adaptation.

The virulence of Xanthomonas oryzae pv. oryzae, the causal agent of bacterial blight (BB) of rice, critically depends on the activation of SWEET sucrose uniporters of the host. To date, the role of SWEET-released sucrose for virulence remains unclear. We here identified the sux locus of Xoo consisting of a LacI-type repressor (SuxR), an outer membrane TonB-like porin (SuxA), an inner membrane MFS H⁺-symporter (SuxC), and a cytosolic sucrose hydrolase (SuxB). Structural and functional analyses demonstrate that SuxB has exclusive sucrose hydrolase activity. Mutant analyses show that the transporter SuxC and the sucrose hydrolase are necessary for growth of bacteria on sucrose, while SuxA is not essential, likely due to the ability of other porins to transport sucrose across the outer membrane. Consistent with a role of SuxR as a sucrose repressor, transcriptome studies show sucrose-dependent regulation of the suxA/suxB genes. Besides a role of sucrose for reproduction, we found that sucrose promotes motility, extracellular polysaccharides production, biofilm formation, and virulence. Notably, the SuxC sucrose H⁺-symporter and the sucrose hydrolase SuxB were required for full virulence of Xoo on indica and japonica rice varieties. Our findings indicate that pathogen-induced sucrose efflux via SWEETs provides sucrose to Xoo, that Xoo uses the sux gene cluster to acquire and utilize sucrose, and that sucrose promotes bacterial fitness and xylem colonization.

Glioblastoma is a highly aggressive brain cancer with significant mortality, primarily due to CD8⁺ T cell deficiency, which obstructs effective treatment outcomes. The dysfunction and exhaustion of CD8⁺ T cells are strongly linked to tumor-associated macrophages (TAMs), which, when exhibiting heightened glycolysis, secrete interleukin-10 and express programmed death ligand 1, both of which suppress CD8⁺ T cell function. This is under the control of cytokines and growth factors in the glioblastoma tumor microenvironment which activate multiple signaling pathways in TAMs. Moreover, TAMs can increase the aggressiveness of cancer cells by enhancing the activation of oncogenic signaling pathways. Understanding the mechanisms of the roles of glycolysis in TAM development and function as well as the regulation of glycolysis by various signaling pathways has substantial therapeutic implications. In this review, we summarize the most recent progress in TAMs, focusing on glycolysis and examine their interactions with both CD8⁺ T cells and cancer cells, and their control by signaling pathways. We also discuss in detail the potential therapeutic strategies prompted by new discoveries regarding glycolysis and signaling pathways in TAMs.

Helices are the quintessential geometric motif of the microscale, from α-helices in proteins to double helices in DNA. Assembly of the helical biopolymers is a foundational step in a hierarchy of structure that leads to biological activity. By simulating folding in a simplified setting, we probe the role of the solvent in the collaborative processes governing biomaterials. Using the morphometric approach to solvation as a simulation technique, we performed computer experiments in which a short, flexible tube, which models a biopolymer in an aqueous environment, folds solely based on the interaction of the tube with the solvent. Our findings reveal a variety of helical structures that assemble depending on solvent conditions, including overhand knots and symmetric double helices. By differentiating the role of solvation, our work illuminates the environment of all soluble biomolecules, demonstrating that the solvent can drive fundamental rearrangements, even up to tying a simple overhand knot.

The Association of Southeast Asian Nations (ASEAN) is at a turning point to drive an energy transition toward a low-carbon future. Investigating ASEAN's decarbonization strategies is timely. We present a capacity expansion model with hourly resolution for ASEAN to meet net-zero emissions by 2050, integrating electricity generation and hydrogen production. The results show two "bookend" pathways. ASEAN can decarbonize its power sector through an accelerated expansion in renewables and battery storage (up to 95% and battery charge up to 28% in 2050) or an expansion in carbon capture and storage (CCS) and hydrogen (up to 46 and 15%, respectively). CCS is found to play a key role in hydrogen production. For power system operation, grid connectivity can lower battery storage demand and power reserves but requires higher power system flexibility. Our findings can help decision-makers identify the roles of key decarbonization strategies in ASEAN and navigate between various scenarios.

Pheomelanin is a sulfur-containing pigment produced by melanocytes notably in individuals with red hair/fair skin and animals with orange integumentary structures. Pheomelanin is not photoprotective as the dark eumelanin, but is cytotoxic, being related to a high risk of melanoma independently of UV radiation. This questions any physiological role for the pigment. The persistence of genetic variants promoting pheomelanogenesis may be explained by a contribution to cysteine homeostasis, as the toxicity of excessive cysteine accumulation in melanocytes may be avoided when the amino acid is used to build the inert pigment. Such function remains untested. Recently, melanocortin-1 receptor (MC1R) signaling, which hinders pheomelanogenesis, has been shown to be highly dependent on its degree of palmitoylation. Finding an efficient selective inhibitor of the enzyme that catalyzes depalmitoylation (APT2), ML349, has thus opened a convenient pharmacological method to block pheomelanogenesis and thus test for its physiological role. Here, a simultaneous treatment with dietary cysteine and ML349 impaired feather pheomelanin-based pigmentation in male zebra finches Taeniopygia guttata. ML349 treatment resulted in the increase in systemic oxidative damage (malondialdehyde) when accounting for the antioxidant capacity of orange, pheomelanin-producing follicular melanocytes by means of NFE2L2 expression, but not that of black, eumelanin-producing melanocytes. Females, that do not produce pheomelanin, were not affected by ML349, but cysteine supplementation tended to increase their oxidative damage. These findings prove a role of pheomelanin in cysteine homeostasis, opening a better understanding of melanoma risk through environmental factors affecting cysteine availability, and the evolutionary predictors of animal color diversity.

DNA barcodes, which are short DNA strings, are regularly used as tags in pooled sequencing experiments to enable the identification of reads originating from the same sample. A crucial task in the subsequent analysis of pooled sequences is barcode calling, where one must identify the corresponding barcode for each read. This task is computationally challenging when the probability of synthesis and sequencing errors is high, like in photolithographic microarray synthesis. Identifying the most similar barcode for each read is a theoretically attractive solution for barcode calling. However, an all-to-all exact similarity calculation is practically infeasible for applications with millions of barcodes and billions of reads. Hence, several computational approaches for barcode calling have been proposed, but the challenge of developing an efficient and precise computational approach remains. Here, we propose a simple, yet highly effective new barcode calling approach that uses a filtering technique based on precomputed k-mer lists. We find that this approach has a slightly higher accuracy than the state-of-the-art approach, is more than 500 times faster than that, and allows barcode calling for one million barcodes and one billion reads per day on a server GPU. The same throughput can even be realized using a CPU-parallel implementation.

Myoelectric control paradigms have the potential to enable continuous volitional control of bionic limbs in various movement conditions. Although individuals with below knee amputations and an agonist-antagonist muscle interface (AMI) were proven to display a greater degree of continuous volitional control in bionic ankle-foot systems with respect to conventional socket-suspended prosthetic users, it remains unclear how myoelectric interfaces could translate to non-AMI prosthetic users with bone-anchored prostheses (BAP). This preliminary study proposes a human-machine interface (HMI) based on a neuromechanical model to enable volitional, continuous myoelectric control of a bionic leg in AMI and BAP users, walking across various speeds and ground inclinations. Differently from state of the art solutions, the proposed HMI is based on a digital twin of the intact leg, synthesizing the user's phantom limb musculoskeletal function as controlled by muscle activations measured from the residuum. When embedded in a real-time framework, it enabled the participants to achieve volitional modulation of prosthesis peak plantar-dorsiflexion torques timing and amplitude during overground walking at three speeds (between 1.6 and 3.96 km/h), with case studies provided during calf-raises (30, 45, and 60 bpm) and ramp ascent walking (3 and 5% incline). Before prosthesis control tests, the participants underwent a 2-day gait training session. Results showed that all three subjects learned how to alter initial muscle activation patterns so that an average of 87% of peak activation timing fell within target ranges. The proposed neuromechanical modeling technology opens new avenues toward generalizable HMIs for the volitional control of active prostheses beyond set conditions and amputation types.