bioRxiv Science⌕ Search

Biology subjects

Zhu, K.

Publications and source records attributed to Zhu, K..

At least 55 records · Page 3Linked to original sources

Genome modeling and design across all domains of life with Evo 2

All of life encodes information with DNA. While tools for sequencing, synthesis, and editing of genomic code have transformed biological research, intelligently composing new biological systems would also require a deep understanding of the immense complexity encoded by genomes. We introduce Evo 2, a biological foundation model trained on 9.3 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life. We train Evo 2 with 7B and 40B parameters to have an unprecedented 1 million token context window with single-nucleotide resolution. Evo 2 learns from DNA sequence alone to accurately predict the functional impacts of genetic variation--from noncoding pathogenic mutations to clinically significant BRCA1 variants--without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that Evo 2 autonomously learns a breadth of biological features, including exon-intron boundaries, transcription factor binding sites, protein structural elements, and prophage genomic regions. Beyond its predictive capabilities, Evo 2 generates mitochondrial, prokaryotic, and eukaryotic sequences at genome scale with greater naturalness and coherence than previous methods. Guiding Evo 2 via inference-time search enables controllable generation of epigenomic structure, for which we demonstrate the first inference-time scaling results in biology. We make Evo 2 fully open, including model parameters, training code, inference code, and the OpenGenome2 dataset, to accelerate the exploration and design of biological complexity.

genomics↗

Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D

Extrachromosomal DNAs (ecDNAs) are large, acentric, circular DNA molecules that occur pervasively across many human cancers. EcDNA can drive tumor formation and evolution, contribute to drug resistance, and associate with poor patient survival outcomes. Beyond mediating high copy numbers, the circular topology and dynamic conformational changes of ecDNA disrupt topological domains and rewire regulatory networks, thereby conferring an important role in the transcriptional regulation of oncogenes. Here, we develop ec3D, a computational method for reconstructing the three-dimensional structures of ecDNA and analyzing significant interactions from high-throughput chromatin capture (Hi-C) data. Given a candidate ecDNA sequence and the corresponding whole-genome Hi-C as input, ec3D reconstructs the spatial structure of ecDNA by maximizing the Poisson likelihood of observed interactions. Ec3Ds performance was validated using both simulated ecDNA structures with varying conformations and Hi-C data from previously-characterized cancer cell lines. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex ecDNA structures with duplicated genomic segments, identify multi-way interactions, and distinguish between interactions arising from direct spatial proximity and secondary interactions resulting from alternative folding patterns or intermolecular (trans) contacts of ecDNA molecules. Our findings provide insights into how the spatial organization of ecDNA may influence gene regulation and contribute to increased oncogene expression. Code availabilityhttps://github.com/AmpliconSuite/ec3D

cancer biology↗

Remote-Controlled Wireless Bioelectronics for Fluoxetine Therapy to Promote Wound Healing in a Porcine Model

Wound healing presents a significant challenge in biomedical science, requiring precise therapeutic delivery and real-time monitoring. Bioelectronic systems offer a promising solution but remain largely unexplored for wound care, particularly in large animal models that reflect human healing dynamics. This study introduces a remote controlled wireless bioelectronic platform equipped with an iontophoretic pump to deliver fluoxetine, a selective serotonin reuptake inhibitor that promotes wound repair. In vitro and ex-vivo testing validated efficient on demand fluoxetine delivery. In vivo experiments in a porcine wound model demonstrated clear therapeutic efficacy over 3-day and 7-day periods. The system enhanced healing outcomes, increasing re-epithelialization by 37% (H&E staining), reducing the M1/M2 macrophage ratio by 33%, and stimulating neuronal growth at the wound site. This bioelectronic platform delivers fluoxetine in a controlled, remotely-controlled manner while allowing for wound direct wound imaging that can be used to monitor wound healing progress. Additionally, it allows precise dose and temporal delivery of treatment to enhance the outcome of future large animal wound healing studies.

bioengineering↗

Wireless bioelectronic device for wound healing

Wireless bioelectronic actuators have been developed to deliver targeted treatments over multiple days while continuously monitoring delivery, thereby improving wound healing. Specifically, these devices can deliver charged biomolecules such as fluoxetine cations (Flx+) and electric field (EF) in freely moving pigs. Treatments can be controlled and monitored in real time via WiFi, with options for both user-specified delivery rates and durations, as well as automated closed-loop (CL) control. The devices are engineered to handle various failure scenarios that may arise in dynamic, real-world experiments--such as communication or power interruptions--ensuring that valuable experimental data is collected with minimal disruption. The ion pump features eight drug reservoirs and channels arranged around a 20 mm diameter-wound, with a central ground electrode (0 V). When voltages above 0 V are applied to the outer channels, currents flow from the reservoirs and channels into the wound, delivering Flx+ and/or EF depending on the reservoir solution. The device records applied voltages and currents locally to a microSD card at a high sampling rate, while simultaneously transmitting real-time measurements via a local WiFi network to a wound healing algorithm running on a nearby laptop. CL control of current/delivery rate is performed by an onboard microcontroller unit (MCU) and current-source microchips, based on instructions received from the wound healing algorithm. A graphical user interface (GUI) provides intuitive user control and real-time data visualization, with support for multiple devices. In vivo studies over seven days showed that Flx+-treated wounds had a 20% lower M1/M2 macrophage ratio and 41.67% greater re-epithelialization compared to controls (standard-of-care), demonstrating the actuators potential to enhance wound healing.

biochemistry↗

Ecological synchrony in human-modified landscapes under a changing climate

Different aspects of ecological systems, biotic or abiotic, often fluctuate in coordinated patterns over space and time. Such high concordance between ecological processes is often referred to as ecological synchrony. Anthropogenic activities, including and beyond climate change, have the potential to alter ecological synchrony by disrupting or enhancing existing synchrony. Despite many local studies, we have a limited systematic understanding of how ecological synchrony is shaped by management in human-dominated landscapes at regional to continental scales. From a macrosystems perspective, we review how anthropogenic activities, particularly beyond climate change, alter ecological synchrony across levels of ecological organization, from the ecosystem level to the population level. For each level, we use a large-scale case study to demonstrate ways to quantify the impacts of human modifications on synchrony using big data from remote sensing, surveys, and observatory networks. For example, we detected possible homogenization of population dynamics of bird species in North America. These changes in ecological synchrony, although in different forms, often represent challenges to ecological and social systems. Collaborative research efforts that integrate emerging open data streams moving forward will be able to provide insights into the effects of different anthropogenic drivers and the consequences of changes in synchrony.

ecology↗

Architecture of a pentameric assembly of the tail tube protein in SPR phages

The majority of phages, viruses that infect prokaryotes, deliver their genomic material into host cells via a tail structure. Previous research has established that the central tube of these phages, composed of tail tube protein (TTP), is structurally conserved, typically forming either hexameric or trimeric rings. In this study, we revealed a novel pentameric assembly of TTP and present two cryo-EM structures at resolutions of 3.5 [A] and 3.7 [A], respectively. Our detailed structural analysis demonstrates that the inner surface of the pentameric tube is highly negatively charged. Critical residues located on the loop between {beta}3 and {beta}4 play pivotal roles in the formation of the pentameric rings, and mismatches of the interactions between the stacked layers can induce the curvature of the tube. The cryo-EM structure of the TTP polymer at the tubes end uncovered that the {beta}-strands that span amino acids 27-65 move towards the central tunnel, potentially blocking the tunnel through which the phage genome is released. Our study provides new structural insights into a novel assembly of TTP, which will extend the understanding of phage assembly.

biophysics↗

Substrate tunnel regulates substrate specificity switching in hyaluronan synthase

Hyaluronic acid (HA), a ubiquitous linear polysaccharide in the extracellular matrix of vertebrates and the capsule of certain pathogenic bacteria, is characterized by its unique structure of alternating {beta}-1,3-N-acetylglucosamine and {beta}-1,4-glucuronic acid units. HA is synthesized by Class I hyaluronan synthase (HAS) in the majority of organisms, but the molecular mechanisms determining the alternating sequence of HA remain unclear. Here, we demonstrated that HA synthesized in vitro using Streptococcus equisimilis HAS maintained its alternating sequence, regardless of substrate ratios and concentrations. While the active pocket lacks intrinsic selectivity, a distal allosteric regulation from the transmembrane tunnel is revealed. The lingering HA terminals in the active pocket ensure lower binding energies for alternating substrates through Coulombic repulsion and competitive binding. Moreover, the dynamic C-terminal loop at the substrate tunnel entrance reduces transport distance for alternating substrates. Our findings indicate that HA-substrate interactions and enzyme dynamics in the substrate tunnel collectively govern the alternating substrate specificity of HAS. This study provides the first molecular insight into precise substrate specificity control within a single active pocket during template-independent polymer synthesis.

biophysics↗

Fungal spore seasons advanced across the US over two decades of climate change

Phenological shifts due to climate change have been extensively studied in plants and animals. Yet, the responses of fungal spores--crucial organisms that play important roles in ecosystems and act as airborne allergens--remain understudied. This knowledge gap in global change biology hinders our understanding of its ecological and public health implications. To bridge this gap, we acquired a long-term (2003 [~] 2022), large-scale (the continental US) dataset of airborne fungal spores collected by the US National Allergy Bureau. We first pre-processed the spore data by gap-filling and smoothing. Afterward, we extracted ten metrics describing the phenology (e.g., start and end of season) and intensity (e.g., peak concentration and integral) of fungal spore seasons. These metrics were derived using two complementary but not mutually exclusive approaches--ecological and public health approaches, defined as percentiles of total spore concentration and allergenic thresholds of spore concentration, respectively. Using linear mixed effects models, we quantified annual temporal shifts in these metrics across the continental US. We revealed a significant advancement in the onset of the spore seasons defined in both ecological (11 days, 95% confidence interval: 0.4 [~] 23 days) and public health (22 days, 6 [~] 38 days) approaches over two decades. Nevertheless, the total spore concentration in an annual cycle and in a spore allergy season tended to decrease over time. The earlier start of the spore season was significantly correlated with climatic variables, such as warmer temperatures and altered precipitations. Overall, our findings suggest possible climate-driven advanced fungal spore seasons, highlighting the importance of climate change mitigation and adaptation in public health decision-making.

ecology↗

Learning-Augmented Sketching Offers Improved Performance for Privacy Preserving and Secure GWAS

The introduction of trusted execution environments (TEEs), such as secure enclaves provided by the Intel SGX technology has enabled secure and privacy-preserving computation on the cloud. The stringent resource limitations, such as memory constraints, required by some TEEs necessitates the development of computational approaches with reduced memory usage, such as sketching. One example is the SkSES method for GWAS on a cohort of case and control samples from multiple institutions, which identifies the most significant SNPs in a privacy-preserving manner without disclosing sensitive genotype information to other institutions or the cloud service provider. Here we show how to improve the performance of SkSES on large datasets by augmenting it with a learning-augmented approach. Specifically, we show how individual institutions can perform smaller scale GWAS on their own datasets and identify two sets of variants according to certain criteria, which are then used to guide the sketching process to more accurately identify significant variants over the collective dataset. The new method achieves up to 40% accuracy gain compared to the original SkSES method under the same memory constraints on datasets we tested on. The code is available at https://github.com/alreadydone/sgx-genome-variants-search. Contactcenk.sahinalp@nih.gov

bioinformatics↗

TX-Phase: Secure Phasing of Private Genomes in a Trusted Execution Environment

Genotype imputation servers enable researchers with limited resources to extract valuable insights from their data with enhanced accuracy and ease. However, the utility of these services is limited for those with sensitive study cohorts or those in restrictive regulatory environments due to data privacy concerns. Although privacy-preserving analysis tools have been developed to broaden access to these servers, none of the existing methods support haplotype phasing, a critical component of the imputation workflow. The complexity of phasing algorithms poses a significant challenge in maintaining practical performance under privacy constraints. Here, we introduce TX-Phase, a secure haplotype phasing method based on the framework of Trusted Execution Environments (TEEs). TX-Phase allows users private genomic data to be phased while ensuring data confidentiality and integrity of the computation. We introduce novel data-oblivious algorithmic techniques based on compressed reference panels and dynamic fixed-point arithmetic that comprehensively mitigate side-channel leakages in TEEs to provide robust protection of users genomic data throughout the analysis. Our experiments on a range of datasets from the UK Biobank and Haplotype Reference Consortium demonstrate the state-of-the-art phasing accuracy and practical runtimes of TX-Phase. Our work enables secure phasing of private genomes, opening access to large reference genomic datasets for a broader scientific community.

bioinformatics↗

A wheat tandem kinase and NLR pair confers resistance to multiple fungal pathogens

Recently discovered tandem kinase proteins (TKPs) are pivotal to the innate immune systems of cereal plants, yet how they initiate plant immune responses remains unclear. This report identifies the wheat protein WTN1, a non-canonical NLR receptor featuring tandem NB-ARC domains, as crucial for WTK3-mediated disease resistance. Both WTK3 and its allelic variant Rwt4, known for conferring resistance to wheat powdery mildew and blast respectively, are capable of recognizing the blast effector PWT4, and activate WTN1 to form calcium-permeable channels, akin to ZAR1 and Sr35. This study unveils a unique plant defense mechanism wherein TKPs and associated NLRs operate as "sensor-executor" pairs against fungal pathogens. Additionally, evolutionary analyses reveal a co-evolutionary trajectory of the TKP-NLR module, highlighting their synergistic role in triggering plant immunity. One Sentence SummaryAn ancient synergistic TKP-NLR pair triggers innate immunity for multiple disease resistance in wheat.

plant biology↗

MYC shapes ER-mitochondria calcium transfer by directly targeting ITPR1: implications for MYC-induced safeguard mechanisms and cancer

The MYC and NMYC transcription factors (TFs) play a key role in cell proliferation and are overexpressed in most cancer cells. However, in normal cells their overexpression triggers safeguard mechanisms promoting cell death and cellular senescence, which are bypassed in cancer cells. The mechanisms of action of this TF family are only partially understood. Here, we reveal that in normal cells MYC binds to the Inositol 1,4,5-Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER-mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC/ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and/or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1 induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Collectively these data highlight a new function of MYC factors by controlling Ca2+ signaling, which could constitute an unsuspected vulnerability for some cancer cells, including high-risk MYCN-amplified neuroblastoma cells.

cancer biology↗

ARHGAP12 suppresses F-actin assembly to control epithelial tight junction mechanics and paracellular leak pathway permeability

Tight junctions (TJ) separate body compartments and control the paracellular transport of ions, solutes, and macromolecules across epithelial barriers. There is evidence that claudin-based ion transport (the pore pathway) and the paracellular transport of macromolecules (the leak pathway) are independently regulated processes. However, how leak pathway permeability is controlled is not well understood. Here we have identified the Cdc42/Rac GTPase activating protein ARHGAP12 as a novel and specific regulator of the leak pathway. ARHGAP12 is recruited to TJ via an interaction between its SH3 domain and the TJ protein ZO-2. Using a combination of biochemical and biophysical approaches, in vitro actin polymerisation assays, and permeability assays in MDCK-II cells, we show that ARHGAP12 suppresses N-WASP-mediated F-actin assembly at TJ to dampen junctional tension. This promotes paracellular leak pathway permeability without affecting ion flux. Mechanistically, we demonstrate that the ARHGAP12 tandem WW domain interacts directly and in a multivalent manner with an array of PPxR motifs in the proline-rich domain of N-WASP. This interaction is sufficient to suppress SH3 domain-mediated N-WASP oligomerisation and Arp2/3-driven F-actin assembly in vitro. Collectively our data demonstrate a critical role for ARHGAP12 in suppressing junctional F-actin assembly and tension to promote the flux of small macromolecules across the TJ.

cell biology↗

Improving the value utilization of tuna peptide powder for the cosmetics field through ozone oxidation

To improve the utilization efficiency of small molecule peptides in marine proteins and promote their application in cosmetics, this study adopts ozone oxidation to conduct deodorization research on tuna small molecule peptides. To devise a method for the ozone oxidation and deodorization of tuna peptide powder suitable for the cosmetics field, orthogonal tests were carried out. The time, ozone concentration, and temperature were adjusted to determine the optimal conditions for ozonation and deodorization of tuna peptide powder. The results showed that at 50{degrees}C and an ozone concentration of 99.10 x 103 mg/m3, wet ozone oxidation for 40 min can also significantly reduce the fishy smell. Under these conditions, the color of tuna peptide powder treated with wet ozone was lighter. In addition, the main volatile compounds were detected by gas chromatography-mass spectrometry (GC-MS). The content of the main fishy volatile substance, hexanal, decreased by 66.4%, and two octyl aldehydes were observed. The results also showed that the protein activity of tuna peptide powder after ozonation remained unchanged. Thus, this study presents an approach to the ozone oxidation of tuna peptide powder that is suitable for cosmetics.

bioengineering↗

Galvanotactic directionality of cell groups depends on group size

Motile cells migrate directionally in the electric field in a process known as galvanotaxis, important and under-investigated phenomenon in wound healing and development. We previously reported that individual fish keratocyte cells migrate to the cathode in electric fields, that inhibition of PI3 kinase reverses single cells to the anode, and that large cohesive groups of either unperturbed or PI3K-inhibited cells migrate to the cathode. Here we find that small uninhibited cell groups move to the cathode, while small groups of PI3K-inhibited cells move to the anode. Small groups move faster than large groups, and groups of unperturbed cells move faster than PI3K-inhibited cell groups of comparable sizes. Shapes and sizes of large groups change little when they start migrating, while size and shapes of small groups change significantly, lamellipodia disappear from the rear edges of these groups, and their shapes start to resemble giant single cells. Our results are consistent with the computational model, according to which cells inside and at the edge of the groups pool their propulsive forces to move but interpret directional signals differently. Namely, cells in the group interior are directed to the cathode independently of their chemical state. Meanwhile, the edge cells behave like individual cells: they are directed to the cathode/anode in uninhibited/PI3K-inhibited groups, respectively. As a result, all cells drive uninhibited groups to the cathode, while larger PI3K-inhibited groups are directed by cell majority in the group interior to the cathode, while majority of the edge cells in small groups win the tug-of-war driving these groups to the anode. Significance statementMotile cells migrate directionally in electric fields. This behavior - galvanotaxis - is important in many physiological phenomena. Individual fish keratocytes migrate to the cathode, while inhibition of PI3K reverses single cells to the anode. Uninhibited cell groups move to the cathode. Surprisingly, groups of PI3K-inhibited cells exhibit bidirectional behavior: larger/smaller groups move to the cathode/anode, respectively. A mechanical model suggests that inner and outer cells interpret directional signals differently, and that a tug-of-war between the outer and inner cells directs the cell groups. These results shed light on general principles of collective cell migration.

cell biology↗

Predicting reproductive phenology of wind-pollinated trees via PlanetScope time series

Airborne pollen triggers allergic reactions which result in public health consequences. A better understanding of flowering and pollen phenology could improve airborne pollen predictions and reduce pollen exposure. Data on the timing of flowering and pollen release are needed to improve models of airborne pollen concentrations, but existing in-situ data collection efforts are expensive and spatially sparse. Satellite-based estimates of plant phenology could potentially enable large-scale data collection, but it is difficult to detect the reproductive phenology of wind-pollinated flowers from space. Here, we infer the reproductive phenology of wind-pollinated plants using PlanetScope time series with a spatial resolution of 3 m and a daily revisit cycle, complemented by in-situ flower and pollen observations, leveraging the correlation between vegetative and reproductive phenology. On the individual tree level, we extracted PlanetScope-derived green-up time and validated its correlation to flowering time using flower observations in a national-scale observatory network. Scaling up to the city level, we developed a novel approach to characterize pollen phenology from PlanetScope-derived vegetative phenology, by optimizing two tuning parameters: the threshold of green-up or green-down and the time lag between green-up/down and flowering. We applied this method to seven cities in the US and seven key wind-pollinated tree genera, calibrated by measurements of airborne pollen concentrations. Our method characterized pollen phenology accurately, not only in-sample (Spearman correlation: 0.751, nRMSE: 13.5%) but also out-of-sample (Spearman correlation: 0.691, nRMSE: 14.5%). Using the calibrated model, we further mapped the pollen phenology landscape within cities, showing intra-urban heterogeneity. Using high spatiotemporal resolution remote sensing, our novel approach enables us to infer the flowering and pollen phenology of wind-pollinated plant taxa on a large scale and a fine resolution, including areas with limited prior in-situ flower and pollen observations. The use of PlanetScope time series therefore holds promise for developing process-based pollen models and targeted public health strategies to mitigate the impact of allergenic pollen exposure.

ecology↗

Biological changes, political ideology, and scientific communication shape human perceptions of pollen seasons

Climate change is changing the timing and intensity of pollen seasons, thereby increasing human exposure to allergenic pollen. Climate-driven changes in pollen seasons present a unique opportunity to craft messaging aimed at communicating climate change impacts on public health through changes in the biological systems. However, it is unclear how pollen seasons are experienced and understood by the public, including how well we detect pollen seasons or what factors we view as responsible for changes in pollen seasons. Here, we use social media data in the United States from 2012 to 2022 to assess public perceptions of pollen seasons at large spatiotemporal scales. We show that pollen seasons detected by social media (Twitter) users align well with natural pollen seasons. Attribution of changing pollen seasons, however, varies based on political ideology: liberal users, compared to conservative users, are more likely to attribute changing pollen seasons to climate change. Mass media and scientific experts play a key role in communicating how climate change drives changing pollen seasons. Our findings reveal how changes in biological systems, political ideology, and scientific communications collectively shape public perceptions of pollen seasons under climate change. Our findings constitute a step towards more effective climate change impact communication and public health intervention design.

scientific communication and education↗

Dynamic regulation of H2A.Zub and H3K27me3 by ambient temperature in plant cell fate determination

Crucial to plant development, ambient temperature triggers intricate mechanisms enabling adaptive responses to temperature variations. The precise coordination of chromatin modifications in shaping cell fate under diverse temperatures remains elusive. Our study, integrating comprehensive transcriptome, epigenome profiling and genetics, unveils that lower ambient temperature (16{degrees}C) restores developmental defects caused by H3K27me3 loss in PRC2 mutants by specifically depositing H2A.Zub at ectopically expressed embryonic genes, such as ABI3 and LEC1. This deposition leads to re-silencing of these genes and compensates for H3K27me3 depletion. PRC1-mediated H2A.Zub and PRC2-catalyzed H3K27me3 play roles in silencing transcription of these embryonic genes for post-germination development. Low temperature decelerates H2A.Z turnover at specific loci likely by attenuating the interaction between TOE1 and H2A.Z chaperone, sustaining repression of embryonic genes and alleviating requirement for PRC2-H3K27me3 at post-germination stage. Our findings offer mechanistic insights into the cooperative epigenetic layers facilitating plants adaptation to varying environmental temperatures.

plant biology↗