The role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Tauopathies are neurodegenerative diseases characterized by deposits of abnormal Tau protein in the brain. Conventional tauopathies are often defined by a limited number of Tau epitopes, notably neurofibrillary tangles, but emerging evidence suggests structural heterogeneity among tauopathies. The prolyl isomerase Pin1 isomerizes cis P-tau to inhibit the development of oligomers, tangles and neurodegeneration in multiple neurodegenerative diseases such as Alzheimer's disease, traumatic brain injury, vascular contribution to cognitive impairment and dementia (VCID) and preeclampsia (PE). Thus, cis P-tau has emerged as an early etiological driver, blood marker and therapeutic target for multiple neurodegenerative diseases, with clinical trials ongoing. The discovery of cis P-tau and other tau pathologies in VCID and PE calls attention for simplistic classification of tauopathy in neurodegenerative diseases. These recent advances have revealed the exciting novel role of the Pin1-cis P-tau axis in the development and treatment of vascular contribution to cognitive impairment and dementia and preeclampsia.

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry.

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

Research progress on the functions and biosynthesis of theaflavins.

Theaflavins are beneficial to human health due to various bioactivities. Biosynthesis of theaflavins using polyphenol oxidase (PPO) is advantageous due to cost effectiveness and environmental friendliness. In this review, studies on the mechanism of theaflavins formation, the procedures to screen and prepare PPOs, optimization of reaction systems and immobilization of PPOs were described. The challenges associated with the mass biosynthesis of theaflavins, such as poor enzyme activity, undesirable subproducts and inclusion bodies of recombinant PPOs were presented. Further strategies to solve these challenges and improve theaflavins production, including enzyme engineering, immobilization enzyme technology, water-immiscible solvent-water biphasic systems and recombinant enzyme technology, were proposed.

Five-week music therapy improves overall symptoms in schizophrenia by modulating theta and gamma oscillations.

Introduction: Some clinical studies have shown that music therapy as an adjunctive therapy can improve overall symptoms in patients with schizophrenia. However, the neural mechanisms of this improvement remain unclear due to insufficient neuroimaging evidence. Methods: In this work, 17 patients with schizophrenia accepted a five-week music therapy (music group) that integrated listening, singing, and composing, and required patients to cooperate in a group to complete music therapy tasks. Meanwhile, 15 patients with schizophrenia received a five-week visual art intervention as the control group including handicraft and painting activities. We collected the Manchester Scale (MS) and Positive and Negative Symptom Scale (PANSS) scores and electroencephalography (EEG) data before and after intervention in two groups. Results: Behavioral results showed that both interventions mentioned above can effectively help patients with schizophrenia relieve their overall symptoms, while a trend-level effect was observed in favor of music therapy. The EEG results indicated that music therapy can improve abnormal neural oscillations in schizophrenia which is reflected by a decrease in theta oscillation in the parietal lobe and an increase in gamma oscillation in the prefrontal lobe. In addition, correlation analysis showed that in the music group, both reductions in theta oscillations in the parietal lobe and increases in gamma oscillations in the prefrontal lobe were positively correlated with the improvement of overall symptoms. Discussion: These findings help us to better understand the neural mechanisms by which music therapy improves overall symptoms in schizophrenia and provide more evidence for the application of music therapy in other psychiatric disorders.

Higher-order epistasis within Pol II trigger loop haplotypes.

RNA polymerase II (Pol II) has a highly conserved domain, the trigger loop (TL), that controls transcription fidelity and speed. We previously probed pairwise genetic interactions between residues within and surrounding the TL and identified widespread incompatibility between TLs of different species when placed in the Saccharomyces cerevisiae Pol II context, indicating epistasis between the TL and its surrounding context. We sought to understand the nature of this incompatibility and probe higher order epistasis internal to the TL. We have employed deep mutational scanning with selected natural TL variants ("haplotypes"), and all possible intermediate substitution combinations between them and the yeast Pol II TL. We identified both positive and negative higher-order residue interactions within example TL haplotypes. Intricate higher-order epistasis formed by TL residues was sometimes only apparent from analysis of intermediate genotypes, emphasizing complexity of epistatic interactions. Furthermore, we distinguished TL substitutions with distinct classes of epistatic patterns, suggesting specific TL residues that potentially influence TL evolution. Our examples of complex residue interactions suggest possible pathways for epistasis to facilitate Pol II evolution.

AdaCS: Adaptive Compressive Sensing With Restricted Isometry Property-Based Error-Clamping.

Scene-dependent adaptive compressive sensing (CS) has been a long pursuing goal that has huge potential to significantly improve the performance of CS. However, with no access to the ground truth, how to design the scene-dependent adaptive strategy is still an open problem. In this paper, a restricted isometry property (RIP) condition-based error-clamping is proposed, which could directly predict the reconstruction error, i.e., the difference between the current-stage reconstructed image and the ground truth image, and adaptively allocate more samples to regions with larger reconstruction error at the next sampling stage. Furthermore, we propose a CS reconstruction network composed of Progressively inverse transform and Alternating Bi-directional Multi-grid Network, named PiABM-Net, that could efficiently utilize the multi-scale information for reconstructing the target image. The effectiveness of the proposed adaptive and cascaded CS method is demonstrated with extensive quantitative and qualitative experiments, compared with the state-of-the-art CS algorithms.

Thiolutin has complex effects in vivo but is a direct inhibitor of RNA polymerase II in vitro.

Thiolutin is a natural product transcription inhibitor with an unresolved mode of action. Thiolutin and the related dithiolopyrrolone holomycin chelate Zn2+ and previous studies have concluded that RNA Polymerase II (Pol II) inhibition in vivo is indirect. Here, we present chemicogenetic and biochemical approaches to investigate thiolutin's mode of action in Saccharomyces cerevisiae. We identify mutants that alter sensitivity to thiolutin. We provide genetic evidence that thiolutin causes oxidation of thioredoxins in vivo and that thiolutin both induces oxidative stress and interacts functionally with multiple metals including Mn2+ and Cu2+, and not just Zn2+. Finally, we show direct inhibition of RNA polymerase II (Pol II) transcription initiation by thiolutin in vitro in support of classical studies that thiolutin can directly inhibit transcription in vitro. Inhibition requires both Mn2+ and appropriate reduction of thiolutin as excess DTT abrogates its effects. Pause prone, defective elongation can be observed in vitro if inhibition is bypassed. Thiolutin effects on Pol II occupancy in vivo are widespread but major effects are consistent with prior observations for Tor pathway inhibition and stress induction, suggesting that thiolutin use in vivo should be restricted to studies on its modes of action and not as an experimental tool.

A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer's disease.

Many aging individuals accumulate the pathology of Alzheimer's disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid ß-protein (Aß) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with ß-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aß deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aß and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.

Structural basis of transcription: RNA Polymerase II substrate binding and metal coordination at 3.0 Å using a free-electron laser.

Catalysis and translocation of multi-subunit DNA-directed RNA polymerases underlie all cellular mRNA synthesis. RNA polymerase II (Pol II) synthesizes eukaryotic pre-mRNAs from a DNA template strand buried in its active site. Structural details of catalysis at near atomic resolution and precise arrangement of key active site components have been elusive. Here we present the free electron laser (FEL) structure of a matched ATP-bound Pol II, revealing the full active site interaction network at the highest resolution to date, including the trigger loop (TL) in the closed conformation, bonafide occupancy of both site A and B Mg2+, and a putative third (site C) Mg2+ analogous to that described for some DNA polymerases but not observed previously for cellular RNA polymerases. Molecular dynamics (MD) simulations of the structure indicate that the third Mg2+ is coordinated and stabilized at its observed position. TL residues provide half of the substrate binding pocket while multiple TL/bridge helix (BH) interactions induce conformational changes that could propel translocation upon substrate hydrolysis. Consistent with TL/BH communication, a FEL structure and MD simulations of the hyperactive Rpb1 T834P bridge helix mutant reveals rearrangement of some active site interactions supporting potential plasticity in active site function and long-distance effects on both the width of the central channel and TL conformation, likely underlying its increased elongation rate at the expense of fidelity.

An Unprecedented CeO2/C Non-Noble Metal Electrocatalyst for Direct Ascorbic Acid Fuel Cells.

Direct ascorbic acid fuel cells (DAAFCs) employ biocompatible ascorbic acid (AA) as fuel, allowing convenient storage, transportation, and fueling as well as avoiding fuel crossover. The AA oxidation reaction (AAOR) largely governs the performance of DAAFCs. However, AAOR electrocatalysts currently have low activity, and state-of-the-art ones are limited to carbon black. Herein, we report the synthesis of an unprecedented AAOR electrocatalyst comprising 3.9 ± 1.1 nm CeO2 nanoparticles evenly distributed on carbon black simply by the wet chemical precipitation of Ce(OH)3 and a subsequent heat treatment. The resultant CeO2/C shows a remarkable AAOR activity with a peak current density of 13.1 mA cm-2, which is 1.7 times of that of carbon black (7.67 mA cm-2). According to X-ray photoelectron spectroscopy (XPS), the surface Ce3+ of CeO2 appears to contribute to the AAOR activity. Furthermore, our density functional theory (DFT) calculation reveals that that the proton of the hydroxyl group of AA can easily migrate to the bridging O sites of CeO2, resulting in a faster AAOR with respect to the pristine carbon, -COOH, and -C=O sites of carbon. After an i-t test, CeO2/C loses 17.8% of its initial current density, which is much superior to that of carbon black. CeO2 can capture the electrons generated by the AAOR to protect the -COOH and -C=O sites from being reduced. Finally, DAAFCs fabricated with CeO2/C exhibit a remarkable power density of 41.3 mW cm-2, which is the highest among proton-exchange-membrane-based DAAFCs in the literature.

Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia.

Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer's and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing. Here we find significant cis P-tau in the placenta and serum of PE patients, and in primary human trophoblasts exposed to hypoxia or sera from PE patients due to Pin1 inactivation. Depletion of cis P-tau from PE patient sera by the antibody prevents their ability to disrupt trophoblast invasion and endovascular activity and to cause the PE-like pathological and clinical features in pregnant humanized tau mice. Our studies uncover that cis P-tau is a central circulating etiological driver and its stereo-specific antibody is valuable for early PE diagnosis and treatment.

On-Chip Compressive Sensing with a Single-Photon Avalanche Diode Array.

Single-photon avalanche diodes (SPADs) are novel image sensors that record photons at extremely high sensitivity. To reduce both the required sensor area for readout circuits and the data throughput for SPAD array, in this paper, we propose a snapshot compressive sensing single-photon avalanche diode (CS-SPAD) sensor which can realize on-chip snapshot-type spatial compressive imaging in a compact form. Taking advantage of the digital counting nature of SPAD sensing, we propose to design the circuit connection between the sensing unit and the readout electronics for compressive sensing. To process the compressively sensed data, we propose a convolution neural-network-based algorithm dubbed CSSPAD-Net which could realize both high-fidelity scene reconstruction and classification. To demonstrate our method, we design and fabricate a CS-SPAD sensor chip, build a prototype imaging system, and demonstrate the proposed on-chip snapshot compressive sensing method on the MINIST dataset and real handwritten digital images, with both qualitative and quantitative results.

Widespread epistasis shapes RNA Polymerase II active site function and evolution.

Multi-subunit RNA Polymerases (msRNAPs) are responsible for transcription in all kingdoms of life. At the heart of these msRNAPs is an ultra-conserved active site domain, the trigger loop (TL), coordinating transcription speed and fidelity by critical conformational changes impacting multiple steps in substrate selection, catalysis, and translocation. Previous studies have observed several different types of genetic interactions between eukaryotic RNA polymerase II (Pol II) TL residues, suggesting that the TL's function is shaped by functional interactions of residues within and around the TL. The extent of these interaction networks and how they control msRNAP function and evolution remain to be determined. Here we have dissected the Pol II TL interaction landscape by deep mutational scanning in Saccharomyces cerevisiae Pol II. Through analysis of over 15000 alleles, representing all single mutants, a rationally designed subset of double mutants, and evolutionarily observed TL haplotypes, we identify interaction networks controlling TL function. Substituting residues creates allele-specific networks and propagates epistatic effects across the Pol II active site. Furthermore, the interaction landscape further distinguishes alleles with similar growth phenotypes, suggesting increased resolution over the previously reported single mutant phenotypic landscape. Finally, co-evolutionary analyses reveal groups of co-evolving residues across Pol II converge onto the active site, where evolutionary constraints interface with pervasive epistasis. Our studies provide a powerful system to understand the plasticity of RNA polymerase mechanism and evolution, and provide the first example of pervasive epistatic landscape in a highly conserved and constrained domain within an essential enzyme.

Characterization of RNA polymerase II trigger loop mutations using molecular dynamics simulations and machine learning.

Catalysis and fidelity of multisubunit RNA polymerases rely on a highly conserved active site domain called the trigger loop (TL), which achieves roles in transcription through conformational changes and interaction with NTP substrates. The mutations of TL residues cause distinct effects on catalysis including hypo- and hyperactivity and altered fidelity. We applied molecular dynamics simulation (MD) and machine learning (ML) techniques to characterize TL mutations in the Saccharomyces cerevisiae RNA Polymerase II (Pol II) system. We did so to determine relationships between individual mutations and phenotypes and to associate phenotypes with MD simulated structural alterations. Using fitness values of mutants under various stress conditions, we modeled phenotypes along a spectrum of continual values. We found that ML could predict the phenotypes with 0.68 R2 correlation from amino acid sequences alone. It was more difficult to incorporate MD data to improve predictions from machine learning, presumably because MD data is too noisy and possibly incomplete to directly infer functional phenotypes. However, a variational auto-encoder model based on the MD data allowed the clustering of mutants with different phenotypes based on structural details. Overall, we found that a subset of loss-of-function (LOF) and lethal mutations tended to increase distances of TL residues to the NTP substrate, while another subset of LOF and lethal substitutions tended to confer an increase in distances between TL and bridge helix (BH). In contrast, some of the gain-of-function (GOF) mutants appear to cause disruption of hydrophobic contacts among TL and nearby helices.

Reciprocal inhibition of PIN1 and APC/CCDH1 controls timely G1/S transition and creates therapeutic vulnerability.

Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/CCDH1), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/CCDH1 regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/CCDH1 E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/CCDH1 itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/CCDH1 inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/CCDH1 resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/CCDH1 is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy.

Dynamic-tuning yeast storage carbohydrate improves the production of acetyl-CoA-derived chemicals.

Acetyl-coenzyme A (Acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) are important precursors for producing various chemicals, and their availability affects the production of their downstream chemicals. Storage carbohydrates are considered important carbon and energy reservoirs. Herein, we find that regulating the storage carbohydrate synthesis improves metabolic fluxes toward malonyl-CoA. Interestingly, not only directly decreasing storage carbohydrate accumulation improved malonyl-CoA availability but also increasing the storage carbohydrate by UGP1 overexpression enables an even higher production of acetyl-CoA- and malonyl-CoA-derived chemicals. We find that Ugp1p overexpression dynamically regulates the carbon flux to storage carbohydrate synthesis. In early exponential phases, Ugp1 overexpression causes more storage carbohydrate accumulation, while the carbon flux is then redirected toward acetyl-CoA and malonyl-CoA in later phases, thereby contributing to the synthesis of their derived products. Our study demonstrates the importance of storage carbohydrates rearrangement for the availability of acetyl-CoA and malonyl-CoA and therefore will facilitate the synthesis of their derived chemicals.

Ultrafine PtCoRh nanorods for highly efficient hydrogen evolution reaction in acid.

PtCoRh nanorods with an average width of 1.6 ± 0.2 nm show an overpotential of 6.1 mV at 10 mA cm-2 toward acidic HER. The exceptional activity originates from a high electrochemically active surface area of 130.1 m2 gPt-1 and a unique Pt-H bond strength appropriately tuned by Co and Rh.

Biosensor-Coupled In Vivo Mutagenesis and Omics Analysis Reveals Reduced Lysine and Arginine Synthesis To Improve Malonyl-Coenzyme A Flux in Saccharomyces cerevisiae.

Malonyl-coenzyme A (malonyl-CoA) is an important precursor for producing various chemicals, but its low availability limits the synthesis of downstream products in Saccharomyces cerevisiae. Owing to the complexity of metabolism, evolutionary engineering is required for developing strains with improved malonyl-CoA synthesis. Here, using the biosensor we constructed previously, a growth-based screening system that links the availability of malonyl-CoA with cell growth is developed. Coupling this system with in vivo continuous mutagenesis enabled rapid generation of genome-scale mutation library and screening strains with improved malonyl-CoA availability. The mutant strains are analyzed by whole-genome sequencing and transcriptome analysis. The omics analysis revealed that the carbon flux rearrangement to storage carbohydrate and amino acids synthesis affected malonyl-CoA metabolism. Through reverse engineering, new processes especially reduced lysine and arginine synthesis were found to improve malonyl-CoA synthesis. Our study provides a valuable complementary tool to other high-throughput screening method for mutant strains with improved metabolite synthesis and improves our understanding of the metabolic regulation of malonyl-CoA synthesis. IMPORTANCE Malonyl-CoA is a key precursor for the production a variety of value-added chemicals. Although rational engineering has been performed to improve the synthesis of malonyl-CoA in S. cerevisiae, due to the complexity of the metabolism there is a need for evolving strains and analyzing new mechanism to improve malonyl-CoA flux. Here, we developed a growth-based screening system that linked the availability of malonyl-CoA with cell growth and manipulated DNA replication for rapid in vivo mutagenesis. The combination of growth-based screening with in vivo mutagenesis enabled quick evolution of strains with improved malonyl-CoA availability. The whole-genome sequencing, transcriptome analysis of the mutated strains, together with reverse engineering, demonstrated weakening carbon flux to lysine and arginine synthesis and storage carbohydrate can contribute to malonyl-CoA synthesis. Our work provides a guideline in simultaneous strain screening and continuous evolution for improved metabolic intermediates and identified new targets for improving malonyl-CoA downstream product synthesis.

Resolving the Tribo-catalytic reaction mechanism for biochar regulated Zinc Oxide and its application in protein transformation.

The utilization of mechanical energy to control water pollutants under dark conditions is currently a point of study focus. Herein, biochar -zinc oxide (BC-ZnO) composites with various structures were synthesized by co-pyrolysis of cotton and ZnO at different temperature and used for tribo-catalytic reaction. The introduction of BC can improve charge transmission and separation efficiency. Ultraviolet photoelectron spectra (UPS) and density functional theory (DFT) calculation prove the addition of BC can reduce work function of ZnO, and enhance its electron-donating ability. Specially, suitable adsorption amount is the key factor to improve the tribo-catalytic performance. When the pyrolysis temperature is 600 °C, BC-ZnO has the best degradation efficiency, which can degrade 90% Rhodamine B (RhB) in 75 min, while ZnO can degrade only 38%. On this basis, using bovine serum albumin (BSA) as a model, the effect of tribo-catalytic reaction on controlling proteins in water was studied by fluorescence excitation-emission matrix spectroscopy (3D EEM) and infrared microscope, and the transformation of proteins was further analyzed. This study provides a new strategy to improve the tribo-catalytic performance of ZnO, and explores its application prospects of biological wastewater control.

SEPT6_TRIM33 Gene Fusion and Mutated TP53 Pathway Associate With Unfavorable Prognosis in Patients With B-Cell Lymphomas.

BACKGROUND: Mounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma. METHODS: Circulating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups. RESULTS: We identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ, GNAS, H3F3A, DNMT3A, HLA-A, and HLA-B. These frequently mutated genes were significantly associated with negative "regulation of gene expression, epigenetic" and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2_WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6_TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6_TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions. CONCLUSIONS: SEPT6_TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients.