Nature Communications最新文献

Despite vast data support in DNA methylation (DNAm) biomarker discovery to facilitate health-care research, this field faces huge resource barriers due to preliminary unreliable candidates and the consequent compensations using expensive experiments. The underlying challenges lie in the confounding factors, especially measurement noise and individual characteristics. To achieve reliable identification of a candidate pool for DNAm biomarker discovery, we propose a Causality-driven Deep Regularization framework to reinforce correlations that are suggestive of causality with disease. It integrates causal thinking, deep learning, and biological priors to handle non-causal confounding factors, through a contrastive scheme and a spatial-relation regularization that reduces interferences from individual characteristics and noises, respectively. The comprehensive reliability of the proposed method was verified by simulations and applications involving various human diseases, sample origins, and sequencing technologies, highlighting its universal biomedical significance. Overall, this study offers a causal-deep-learning-based perspective with a compatible tool to identify reliable DNAm biomarker candidates, promoting resource-efficient biomarker discovery.

Direct conversion of dinitrogen (N₂) into N-containing compounds beyond ammonia under ambient conditions remains a longstanding challenge. Herein, we present a Lewis acid-promoted strategy for diverse nitrogen-element bonds formation from N₂ using chromium dinitrogen complex [Cp*(IⁱPr₂Me₂)Cr(N₂)₂]K (1). With the help of Lewis acids AlMe₃ and BF₃, we successfully trap a series of fleeting diazenido intermediates and synthesize value-added compounds containing N−B, N−Ge, and N−P bonds with 3 d metals, offering a method for isolating unstable intermediates. Furthermore, the formation of N−C bonds is realized under more accessible conditions that avoid undesired side reactions. DFT calculations reveal that Lewis acids enhance the participation of dinitrogen units in the frontier orbitals, thereby promoting electrophilic functionalization. Moreover, Lewis acid replacement and a base-induced end-on to side-on switch of [NNMe] unit in [(Cp*(IⁱPr₂Me₂)CrNN(BEt₃)(Me)] (8) are achieved.

Cyclic nucleotide-gated channel 5 (CNGC5), CNGC6, and CNGC9 (CNGC5/6/9 for simplicity) control Arabidopsis root hair (RH) growth by mediating the influx of external Ca²⁺ to establish and maintain a sharp cytosolic Ca²⁺ gradient at RH tips. However, the underlying mechanisms for the regulation of CNGCs remain unknown. We report here that calcium dependent protein kinase 1 (CPK1) directly activates CNGC5/6/9 to promote Arabidopsis RH growth. The loss-of-function mutants cpk1-1, cpk1-2, cngc5-1 cngc6-2 cngc9-1 (shrh1/short root hair 1), and cpk1 shrh1 show similar RH phenotypes, including shorter RHs, more RH branching, and dramatically attenuated cytosolic Ca²⁺ gradients at RH tips. The main CPK1-target sites are identified as Ser20, Ser27, and Ser26 for CNGC5/6/9, respectively, and the corresponding alanine substitution mutants fail to rescue RH growth in shrh1 and cpk1-1, while phospho-mimic versions restore the cytosolic Ca²⁺ gradient at RH apex and rescue the RH phenotypes in the same Arabidopsis mutants. Thus we discover the CPK1-CNGC modules essential for the Ca²⁺ signaling regulation and RH growth in Arabidopsis.

Overheating remains a major barrier to chip miniaturization, leading to device malfunction. Addressing the urgent need for thermal management promotes the development of solid-state electrocaloric cooling. However, enhancing passive heat dissipation through two-dimensional materials in electrocaloric polymers typically compromises the electrocaloric effect. In this work, we utilize two-dimensional polyamide with porous structure and hydrogen bonding to achieve multiple polar conformations with short-range order in the electrocaloric composite polymers. The structure minimizes intermolecular interactions while reducing energy barriers for field-driven polar-nonpolar conformational transitions. The electrocaloric polymer exhibits doubled cooling efficiency at electric fields as low as 40 MV m⁻¹. Additionally, the electrode design achieves a vertical deformation of 2 millimeters, demonstrating the feasibility of self-driven electric refrigeration devices. This porous organic two-dimensional material resolves cooling efficiency limitations from spatial confinement, advancing the integration of two-dimensional materials in flexible electronics.

Phosphorus in crucial for all living organisms. In vertebrate, cellular phosphate homeostasis is partly controlled by XPR1, a poorly characterized inositol pyrophosphate-dependent phosphate exporter. Here, we report the cryo-EM structure of human XPR1, which forms a loose dimer with 10 transmembrane helices (TM) in each protomer. The structure consists of a scaffold domain (TM1, TM3-4) and a core domain (TM2, TM5-10) structurally related to ion-translocating rhodopsins. Bound phosphate is observed in a tunnel within the core domain at a narrow point that separates the tunnel into intracellular and extracellular vestibules. This site contains a cluster of basic residues that coordinate phosphate and a conserved W573 essential for export function. Loss of inositol pyrophosphate binding is accompanied by structural movements in TM9 and the W573 sidechain, closing the extracellular vestibule and blocking phosphate export. These findings provide insight into XPR1 mechanism and pave the way for further in-depth XPR1 studies.

The rapid increase of novel per- and polyfluoroalkyl substances (PFAS) raises concerns, while their identification remains challenging. Here, we develop a two-layer homolog network approach for PFAS nontarget screening using mass spectrometry. The first layer constructs networks between homologs, with evaluation showing that it filters 94% of false candidates. The second layer builds a network between classes to expedite the identification of PFAS. We detected 94 PFAS in twelve waterproof products and two related industrial sludges, including 36 novel PFAS not previously reported in any sample. A local dataset is constructed for retrospective analysis by re-analyzing our previous samples, revealing fifteen novel PFAS in samples collected in 2005. The retrieval of the public database MassIVE uncovers novel PFAS in samples from seven countries. Here, we reveal the historic and global presence of novel PFAS, providing guidance for the management and policy-making concerning persistent chemicals.

Particle manipulation plays a pivotal role in scientific and technological domains such as materials science, physics, and the life sciences. Here, we present a dynamically reconfigurable acoustofluidic metasurface that enables precise trapping and positioning of microscale particles in fluidic environments. By harnessing acoustic-structure interaction in a passive membrane resonator array, we generate localized standing acoustic waves that can be reconfigured in real-time. The resulting radiation force allows for subwavelength manipulation and patterning of particles on the metasurface at individual and collective scales, with actuation frequencies below 2 MHz. We further demonstrate the capabilities of the reconfigurable metasurface in trapping and enriching beads and biological cells flowing in microfluidic channels, showcasing its potential in high-throughput bioanalytical applications. Our versatile and biocompatible particle manipulation platform is suitable for applications ranging from the assembly of colloidal particles to enrichment of rare cells.

Kinetoplastids are a clade of eukaryotic protozoans that include human parasitic pathogens like trypanosomes and Leishmania species. In these organisms, protein-coding genes are transcribed as polycistronic pre-mRNAs, which need to be processed by the coupled action of trans-splicing and polyadenylation to yield monogenic mature mRNAs. During trans-splicing, a universal RNA sequence, the spliced leader RNA (SL RNA) mini-exon, is added to the 5’-end of each mRNA. The 5’-end of this mini-exon carries a hypermethylated cap structure and is bound by a trypanosomatid-specific cap-binding complex (CBC). The function of three of the kinetoplastid CBC subunits is unknown, but an essential role in cap-binding and trans-splicing has been suggested. Here, we report cryo-EM structures that reveal the molecular architecture of the Trypanosoma brucei CBC (TbCBC) complex. We find that TbCBC interacts with two distinct features of the SL RNA. The TbCBP20 subunit interacts with the m⁷G cap while TbCBP66 recognizes double-stranded portions of the SL RNA. Our findings pave the way for future research on mRNA maturation in kinetoplastids. Moreover, the observed structural similarities and differences between TbCBC and the mammalian cap-binding complex will be crucial for considering the potential of TbCBC as a target for anti-trypanosomatid drug development.

The first Neolithic farmers arrived in the Western Mediterranean area from the East. They established settlements in coastal areas and over time migrated to new environments, adapting to changing ecological and climatic conditions. While farming practices and settlements in the Western Mediterranean differ greatly from those known in the Eastern Mediterranean and central Europe, the extent to which these differences are connected to the local environment and climate is unclear. Here, we tackle this question by compiling data and proxies at a superregional and multi-scale level, including archaeobotanical information, radiocarbon dates and paleoclimatic models, then applying a machine learning approach to investigate the impact of ecological and climatic constraints on the first Neolithic humans and crops. This approach facilitates calculating the pace of spread of farming in the Western Mediterranean area, modelling and estimating the potential areas suitable for settlement location, and discriminating distinct types of crop cultivation under changing climatic conditions that characterized the period 5900 – 2300 cal. BC. The results of this study shed light onto the past climate variability and its influence on human distribution in the Western Mediterranean area, but also discriminate sensitive parameters for successful agricultural practices.

The Drosophila visual system is a powerful model to study the development of neural circuits. Lobula columnar neurons-LCNs are visual output neurons that encode visual features relevant to natural behavior. There are ~20 classes of LCNs forming non-overlapping synaptic optic glomeruli in the brain. To address their origin, we used single-cell mRNA sequencing to define the transcriptome of LCN subtypes and identified lines that are expressed throughout their development. We show that LCNs originate from stem cells in four distinct brain regions exhibiting different modes of neurogenesis, including the ventral and dorsal tips of the outer proliferation center, the ventral superficial inner proliferation center and the central brain. We show that this convergence of similar neurons illustrates the complexity of generating neuronal diversity, and likely reflects the evolutionary origin of each subtype that detects a specific visual feature and might influence behaviors specific to each species.