A pangenome reference of 36 Chinese populations.

Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference1. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.

SVision: a deep learning approach to resolve complex structural variants.

Complex structural variants (CSVs) encompass multiple breakpoints and are often missed or misinterpreted. We developed SVision, a deep-learning-based multi-object-recognition framework, to automatically detect and haracterize CSVs from long-read sequencing data. SVision outperforms current callers at identifying the internal structure of complex events and has revealed 80 high-quality CSVs with 25 distinct structures from an individual genome. SVision directly detects CSVs without matching known structures, allowing sensitive detection of both common and previously uncharacterized complex rearrangements.

G4Atlas: a comprehensive transcriptome-wide G-quadruplex database.

RNA G-quadruplex (rG4) is a vital RNA tertiary structure motif that involves the base pairs on both Hoogsteen and Watson-Crick faces of guanines. rG4 is of great importance in the post-transcriptional regulation of gene expression. Experimental technologies have advanced to identify in vitro and in vivo rG4s across diverse transcriptomes. Building on these recent advances, here we present G4Atlas, the first transcriptome-wide G-quadruplex database, in which we have collated, classified, and visualized transcriptome rG4 experimental data, generated from rG4-seq, chemical profiling and ligand-binding methods. Our comprehensive database includes transcriptome-wide rG4s generated from 82 experimental treatments and 238 samples across ten species. In addition, we have also included RNA secondary structure prediction information across both experimentally identified and unidentified rG4s to enable users to display any potential competitive folding between rG4 and RNA secondary structures. As such, G4Atlas will enable users to explore the general functions of rG4s in diverse biological processes. In addition, G4Atlas lays the foundation for further data-driven deep learning algorithms to examine rG4 structural features.

Combined Proteomic and Phosphoproteomic Characterization of the Molecular Regulators and Functional Modules During Pancreatic Progenitor Cell Development.

Differentiated multipotent pancreatic progenitors have major advantages for both modeling pancreas development and preventing or treating diabetes. Despite significant advancements in inducing the differentiation of human pluripotent stem cells into insulin-producing cells, the complete mechanism governing proliferation and differentiation remains poorly understood. This study used large-scale mass spectrometry to characterize molecular processes at various stages of human embryonic stem cell (hESC) differentiation toward pancreatic progenitors. hESCs were induced into pancreatic progenitor cells in a five-stage differentiation protocol. A high-performance liquid chromatography-mass spectrometry platform was used to undertake comprehensive proteome and phosphoproteome profiling of cells at different stages. A series of bioinformatic explorations, including coregulated modules, gene regulatory networks, and phosphosite enrichment analysis, were then conducted. A total of 27,077 unique phosphorylated sites and 8122 proteins were detected, including several cyclin-dependent kinases at the initial stage of cell differentiation. Furthermore, we discovered that ERK1, a member of the MAPK cascade, contributed to proliferation at an early stage. Finally, Western blotting confirmed that the phosphosites from SIRT1 and CHEK1 could inhibit the corresponding substrate abundance in the late stage. Thus, this study extends our understanding of the molecular mechanism during pancreatic cell development.

Near telomere-to-telomere genome assemblies of two Chlorella species unveil the composition and evolution of centromeres in green algae.

BACKGROUND: Centromeres play a crucial and conserved role in cell division, although their composition and evolutionary history in green algae, the evolutionary ancestors of land plants, remains largely unknown. RESULTS: We constructed near telomere-to-telomere (T2T) assemblies for two Trebouxiophyceae species, Chlorella sorokiniana NS4-2 and Chlorella pyrenoidosa DBH, with chromosome numbers of 12 and 13, and genome sizes of 58.11 Mb and 53.41 Mb, respectively. We identified and validated their centromere sequences using CENH3 ChIP-seq and found that, similar to humans and higher plants, the centromeric CENH3 signals of green algae display a pattern of hypomethylation. Interestingly, the centromeres of both species largely comprised transposable elements, although they differed significantly in their composition. Species within the Chlorella genus display a more diverse centromere composition, with major constituents including members of the LTR/Copia, LINE/L1, and LINE/RTEX families. This is in contrast to green algae including Chlamydomonas reinhardtii, Coccomyxa subellipsoidea, and Chromochloris zofingiensis, in which centromere composition instead has a pronounced single-element composition. Moreover, we observed significant differences in the composition and structure of centromeres among chromosomes with strong collinearity within the Chlorella genus, suggesting that centromeric sequence evolves more rapidly than sequence in non-centromeric regions. CONCLUSIONS: This study not only provides high-quality genome data for comparative genomics of green algae but gives insight into the composition and evolutionary history of centromeres in early plants, laying an important foundation for further research on their evolution.

Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.

Priming of synaptic vesicles involves Munc13-catalyzed transition of the Munc18-1/syntaxin-1 complex to the SNARE complex in the presence of SNAP-25 and synaptobrevin-2; Munc13 drives opening of syntaxin-1 via the MUN domain while Munc18-1 primes SNARE assembly via domain 3a. However, the underlying mechanism remains unclear. In this study, we have identified a number of residues in domain 3a of Munc18-1 that are crucial for Munc13 and Munc18-1 actions in SNARE complex assembly and synaptic vesicle priming. Our results showed that two residues (Q301/K308) at the side of domain 3a mediate the interaction between the Munc18-1/syntaxin-1 complex and the MUN domain. This interaction enables the MUN domain to drive the opening of syntaxin-1 linker region, thereby leading to the extension of domain 3a and promoting synaptobrevin-2 binding. In addition, we identified two residues (K332/K333) at the bottom of domain 3a that mediate the interaction between Munc18-1 and the SNARE motif of syntaxin-1. This interaction ensures Munc18-1 to persistently associate with syntaxin-1 during the conformational change of syntaxin-1 from closed to open, which reinforces the role of Munc18-1 in templating SNARE assembly. Taken together, our data suggest a mechanism by which Munc13 activates the Munc18-1/syntaxin-1 complex and enables Munc18-1 to prime SNARE assembly.

Theory-Guided Experimental Design of Covalent Triazine Frameworks for Efficient Photocatalytic Hydrogen Production.

The high crystalline covalent triazine framework-1 (CTF-1), composed of alternating triazine and phenylene, has emerged as an efficient photocatalyst for solar-driven hydrogen evolution reaction (HER). However, it is of great challenge to further improve photocatalytic HER performance via increasing crystallinity due to its near-perfect crystallization. Herein, an alternative strategy of scaffold functionalization is employed to optimize the energy band structure of crystalline CTF-1 for boosting hydrogen-evolving activity. Guided by the computational predictions, versatile CTF-based polymer photocatalysts are prepared with different functional groups (OH, NH2, COOH) using binary polymerization for practical hydrogen production. Experiment evidence verifies that the introduction of a limited number of electron-donating groups is sufficient to maintain high crystallinity in CTF, modulate the band structure, broaden visible light absorption, and consequently enhance its photophysical properties. Notably, the functionalization with OH exhibits the most positive effect on CTF-1, delivering a photocatalytic activity with a hydrogen-producing rate exceeding 100 µmol h-1.

Real-world evidence on treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with B-cell acute lymphoblastic leukemia.

Blinatumomab is efficacious in patients with B-cell acute lymphoblastic leukemia (B-ALL), yet limited real-world data exists in this context. This retrospective study provided real-world data on the treatment pattern, effectiveness, and safety of blinatumomab in Chinese patients with newly diagnosed (ND) and relapsed/refractory (R/R) B-ALL. Patients with B-ALL who received at least one dose of blinatumomab in frontline or R/R settings between August 2021 and June 2023 were included. The primary outcome was the treatment pattern of blinatumomab. Key secondary outcomes included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity, median event-free survival (EFS), and safety. The study included 96 patients with B-ALL; 53 (55.2%) patients were in the ND group and 43 (44.8%) patients were in the R/R group. The median treatment duration was one cycle (range: 1-5). Most patients underwent chemotherapies, allo-HSCT, or experimental CAR-T following blinatumomab. The ND patients using blinatumomab induction therapy achieved 100% CR/CRi rate; 87.2% achieved MRD negativity within two cycles of blinatumomab. In R/R re-induction patients, the CR/CRi rate was 50%; MRD negativity rate was 64.2%. In R/R patients using blinatumomab for consolidation, MRD negativity rate was 90.9%. The median EFS was not reached in both ND and R/R patients; 1-year EFS rate was 90.8% (95% CI: 67%, 97%) and 55.1% (95% CI: 30%, 74%), respectively. Grade ≥ 3 adverse events were observed in 12.5% patients. Blinatumomab was found to be effective with a tolerable safety profile in real world setting.

Nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates and its mechanistic insights proposed by DFT calculations.

We have developed a nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates that gives syn-ß-cyanoalkenes. DFT calculations suggest that a favored transition state promotes Cα-H bond formation for determining regio- and stereoselectivity of the products.

Procedural Efficiencies and Clinical Outcomes for Transcatheter Device Closure of Perimembranous Ventricular Septal Defects With Different Waist-Length Occluders.

BACKGROUND: Potential differences in complications and/or long-term outcomes of perimembranous ventricular septal defect (pmVSD) closures with 3-mm waist vs. 4-mm waist double-disk symmetrical occluders are not known.Methods and Results: A total of 395 consecutive pediatric patients with pmVSD recruited between January 2017 and March 2021 underwent successful transcatheter closure using symmetrical pmVSD devices. The final analysis involved 208×3-mm and 172×4-mm cases. The median follow-up was 42 months (range: 12-62 months). A total of 175 post-procedure adverse events (AEs) were observed. Most of these AEs were temporary, and there were only 8 major AEs. Compared to the 3-mm waist group, the incidence of residual shunts was significantly higher in the 4-mm waist group (13.4% vs. 6.7%; P=0.030), whereas other AEs showed similar incidences between the 2 groups. Multivariate Cox regression analysis revealed that larger defect, higher ratio between device size and body surface area, and longer procedure time can cause an increased likelihood of AEs, and smaller defect or left disk placement within aneurysmal tissue may reduce it. CONCLUSIONS: Transcatheter closure of pmVSD using a symmetrical double-disk occluder is safe and effective. Compared with a 3-mm waist symmetrical occluder, transcatheter closure with a 4-mm waist symmetrical occluder correlated with higher incidences of residual shunts.

Transcendent thinking counteracts longitudinal effects of mid-adolescent exposure to community violence in the anterior cingulate cortex.

Adolescence involves extensive brain maturation, characterized by social sensitivity and emotional lability, that co-occurs with increased independence. Mid-adolescence is also a hallmark developmental stage when youths become motivated to reflect on the broader personal, ethical, and systems-level implications of happenings, a process we term transcendent thinking. Here, we examine the confluence of these developmental processes to ask, from a transdisciplinary perspective, how might community violence exposure (CVE) impact brain development during mid-adolescence, and how might youths' dispositions for transcendent thinking be protective? Fifty-five low-SES urban youth with no history of delinquency (32 female; 27 Latinx, 28 East Asian) reported their CVE and underwent structural MRI first at age 14-18, and again 2 years later. At the study's start, participants also discussed their feelings about 40 minidocumentaries featuring other teens' compelling situations in a 2-h private interview that was transcribed and coded for transcendent thinking. Controlling for CVE and brain structure at the start: (1) New CVE during the 2-year inter-scan interval was associated with greater gray matter volume (GMV) reduction over that interval in the anterior cingulate cortex (ACC), a central network hub whose reduced volume has been associated with posttraumatic stress disorder, and across multiple additional cortical and subcortical regions; (2) participants' transcendent thinking in the interview independently predicted greater GMV increase during the 2-year inter-scan interval in the ACC. Findings highlight the continued vulnerability of mid-adolescents to community violence and the importance of supporting teens' dispositions to reflect on the complex personal and systems-level implications and affordances of their civic landscape.

Identification of residues critical for the extension of Munc18-1 domain 3a.

BACKGROUND: Neurotransmitter release depends on the fusion of synaptic vesicles with the presynaptic membrane and is mainly mediated by SNARE complex assembly. During the transition of Munc18-1/Syntaxin-1 to the SNARE complex, the opening of the Syntaxin-1 linker region catalyzed by Munc13-1 leads to the extension of the domain 3a hinge loop, which enables domain 3a to bind SNARE motifs in Synaptobrevin-2 and Syntaxin-1 and template the SNARE complex assembly. However, the exact mechanism of domain 3a extension remains elusive. RESULTS: Here, we characterized residues on the domain 3a hinge loop that are crucial for the extension of domain 3a by using biophysical and biochemical approaches and electrophysiological recordings. We showed that the mutation of residues T323/M324/R325 disrupted Munc13-1-mediated SNARE complex assembly and membrane fusion starting from Munc18-1/Syntaxin-1 in vitro and caused severe defects in the synaptic exocytosis of mouse cortex neurons in vivo. Moreover, the mutation had no effect on the binding of Synaptobrevin-2 to isolated Munc18-1 or the conformational change of the Syntaxin-1 linker region catalyzed by the Munc13-1 MUN domain. However, the extension of the domain 3a hinge loop in Munc18-1/Syntaxin-1 was completely disrupted by the mutation, leading to the failure of Synaptobrevin-2 binding to Munc18-1/Syntaxin-1. CONCLUSIONS: Together with previous results, our data further support the model that the template function of Munc18-1 in SNARE complex assembly requires the extension of domain 3a, and particular residues in the domain 3a hinge loop are crucial for the autoinhibitory release of domain 3a after the MUN domain opens the Syntaxin-1 linker region.

A Rapid Localization Method Based on Super Resolution Magnetic Array Information for Unknown Number Magnetic Sources.

A rapid method that uses super-resolution magnetic array data is proposed to localize an unknown number of magnets in a magnetic array. A magnetic data super-resolution (SR) neural network was developed to improve the resolution of a magnetic sensor array. The approximate 3D positions of multiple targets were then obtained based on the normalized source strength (NSS) and magnetic gradient tensor (MGT) inversion. Finally, refined inversion of the position and magnetic moment was performed using a trust region reflective algorithm (TRR). The effectiveness of the proposed method was examined using experimental field data collected from a magnetic sensor array. The experimental results showed that all the targets were successfully captured in multiple trials with three to five targets with an average positioning error of less than 3 mm and an average time of less than 300 ms.

A Novel Three-Point Localization Method for Bladder Volume Estimation.

The measurement of bladder volume is crucial for the diagnosis and treatment of urinary system diseases. Ultrasound imaging, with its non-invasive, radiation-free, and repeatable scanning capabilities, has become the preferred method for measuring residual urine volume. Nevertheless, it still faces some challenges, including complex imaging methods leading to longer measurement times and lower spatial resolution. Here, we propose a novel three-point localization method that does not require ultrasound imaging to calculate bladder volume. A corresponding triple-element ultrasound probe has been designed based on this method, enabling the ultrasound probe to transmit and receive ultrasound waves in three directions. Furthermore, we utilize the Hilbert Transform algorithm to extract the envelope of the ultrasound signal to enhance the efficiency of bladder volume measurements. The experiment indicates that bladder volume estimation can be completed within 5 s, with a relative error rate of less than 15%. These results demonstrate that this novel three-point localization method offers an effective approach for bladder volume measurement in patients with urological conditions.

N-Containing Porous Carbon-Based MnO Composites as Anode with High Capacity and Stability for Lithium-Ion Batteries.

MnO has attracted much attention as the anode for Li-ion batteries (LIBs) owing to its high specific capacity. However, the low conductivity limited its large application. An effective solution to solve this problem is carbon coating. Biomass carbon materials have aroused much interest for being low-cost and rich in functional groups and hetero atoms. This work designs porous N-containing MnO composites based on the chemical-activated tremella using a self-templated method. The tremella, after activation, could offer more active sites for carbon to coordinate with the Mn ions. And the as-prepared composites could also inherit the special porous nanostructures of the tremella, which is beneficial for Li+ transfer. Moreover, the pyrrolic/pyridinic N from the tremella can further improve the conductivity and the electrolyte wettability of the composites. Finally, the composites show a high reversible specific capacity of 1000 mAh g-1 with 98% capacity retention after 200 cycles at 100 mA g-1. They also displayed excellent long-cycle performance with 99% capacity retention (relative to the capacity second cycle) after long 1000 cycles under high current density, which is higher than in most reported transition metal oxide anodes. Above all, this study put forward an efficient and convenient strategy based on the low-cost biomass to construct N-containing porous composite anodes with a fast Li+ diffusion rate, high electronic conductivity, and outstanding structure stability.

ZIF-67-Derived Flexible Sulfur Cathode with Improved Redox Kinetics for High-Performance Li-S Batteries.

Lithium-sulfur (Li-S) batteries have received much attention due to their high energy density and low price. In recent years, alleviating the volume expansion and suppressing the shuttle effect during the charge and discharge processes of Li-S batteries have been widely addressed. However, the slow conversion kinetics from polysulfide (LiPSs) to Li2S2/Li2S still limits the application of Li-S batteries. Therefore, we designed a ZIF-67 grown on cellulose (named ZIF-67@CL) as an electrocatalyst to improve the interconversion kinetics from LiPSs to Li2S2/Li2S for Li-S batteries. Based on the results of adsorption experiments of LiPSs, ZIF-67@CL and CL hosts were immersed in Li2S4 solution to adsorb LiPSs, and the UV-Vis test was conducted on the supernatant after adsorption. The results showed that the ZIF-67@CL had a stronger adsorption for LiPSs compared with the cellulose (CL). Furthermore, in the Li2S nucleation tests, the fabricated cells were galvanostatically discharged to 2.06 V at 0.112 mA and then potentiostatically discharged at 2.05 V. Based on the results of Li2S nucleation tests, the catalytic effect of ZIF-67 was further verified. As a result, the sulfur cathode used a ZIF-67 catalyst (named S/ZIF-67@CL) and delivered an initial capacity of 1346 mAh g-1 at a current density of 0.2 C. Even at a high current density of 2 C, it exhibited a high-capacity performance of 1087 mAh g-1 on the first cycle and maintained a capacity output of 462 mAh g-1 after 150 cycles, with a Coulombic efficiency of over 99.82%.

IAGS: Inferring Ancestor Genome Structure under a Wide Range of Evolutionary Scenarios.

Significant improvements in genome sequencing and assembly technology have led to increasing numbers of high-quality genomes, revealing complex evolutionary scenarios such as multiple whole-genome duplication events, which hinders ancestral genome reconstruction via the currently available computational frameworks. Here, we present the Inferring Ancestor Genome Structure (IAGS) framework, a novel block/endpoint matching optimization strategy with single-cut-or-join distance, to allow ancestral genome reconstruction under both simple (single-copy ancestor) and complex (multicopy ancestor) scenarios. We evaluated IAGS with two simulated data sets and applied it to four different real evolutionary scenarios to demonstrate its performance and general applicability. IAGS is available at https://github.com/xjtu-omics/IAGS.

Antioxidants attenuate mitochondrial oxidative damage through the Nrf2 pathway: A promising therapeutic strategy for stroke.

Stroke represents one of the leading causes of disability and death worldwide. Reactive oxygen species overproduction-induced oxidative stress in mitochondria results in mitochondrial DNA damage, mitochondrial autophagy (mitophagy), inflammation, and apoptosis during the pathologic progression of stroke. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator that induces the transcription of a wide range of antioxidant genes to attenuate mitochondrial oxidative stress. Different antioxidative compounds, including polyphenols, mitochondrial antioxidants, triterpenoids, and others, have been shown to be able to activate Nrf2 and, thus, exert neuroprotective effects on stroke by ameliorating mitochondrial oxidative damage. In this review, we briefly discussed the role of mitochondrial oxidative stress in the pathophysiology of stroke and focused on the protective effects of antioxidative compounds through attenuating mitochondrial oxidative damage by activating Nrf2 in stroke. In conclusion, these antioxidants may represent novel therapeutic strategies against stroke.

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS: We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS: Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.

Amygdala Metabotropic Glutamate Receptor 1 Influences Synaptic Transmission to Participate in Fentanyl-Induced Hyperalgesia in Rats.

The underlying mechanisms of opioid-induced hyperalgesia (OIH) remain unclear. Herein, we found that the protein expression of metabotropic glutamate receptor 1 (mGluR1) was significantly increased in the right but not in the left laterocapsular division of central nucleus of the amygdala (CeLC) in OIH rats. In CeLC neurons, the frequency and the amplitude of mini-excitatory postsynaptic currents (mEPSCs) were significantly increased in fentanyl group which were decreased by acute application of a mGluR1 antagonist, A841720. Finally, the behavioral hypersensitivity could be reversed by A841720 microinjection into the right CeLC. These results show that the right CeLC mGluR1 is an important factor associated with OIH that enhances synaptic transmission and could be a potential drug target to alleviate fentanyl-induced hyperalgesia.