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Abstract Background Cystic echinococcosis (CE) is prevalent in livestock farming regions around the world. However, it remains relatively rare compared to other infectious diseases. CE typically affects the liver, lungs, brain, and kidneys. Spinal and pleural wall involvement is exceedingly rare. We report a unique case of intradural and pleural wall CE in a young male, successfully treated with surgery and postoperative medication. Case presentation A 19-year-old Tibetan male from the Qinghai-Tibet Plateau was diagnosed with intradural and pleural wall CE through imaging, serology, and surgical pathology. According to the Dew/Braithwaite & Lees (BL) classification, his condition was an exceptionally rare form of spinal echinococcosis, compounded by an even rarer pleural wall involvement. Prompt surgical intervention and postoperative medication resulted in significant improvement in spinal cord compression symptoms. Conclusions This case highlights the diagnostic and therapeutic challenges of rare CE locations. MRI proved superior to CT in diagnosing bony cystic echinococcosis. Early surgical intervention combined with medication facilitates spinal cord function recovery, providing valuable insights for managing similar cases.

Abstract Background The oncogenic protein HOXA9 plays a critical role in leukemia transformation and maintenance, and its aberrant expression is a hallmark of most aggressive acute leukemia. Although inhibiting the upstream regulators of HOXA9 has been proven as a significant therapeutic intervention, the comprehensive regulation network controlling HOXA9 expression in leukemia has not been systematically investigated. Results Here, we perform genome-wide CRISPR/Cas9 screening in the HOXA9-driven reporter acute leukemia cells. We identify a poorly characterized RNA-binding protein, RBM5, as the top candidate gene required to maintain leukemia cell fitness. RBM5 is highly overexpressed in acute myeloid leukemia (AML) patients compared to healthy individuals. RBM5 loss triggered by CRISPR knockout and shRNA knockdown significantly impairs leukemia maintenance in vitro and in vivo. Through domain CRISPR screening, we reveal that RBM5 functions through a noncanonical transcriptional regulation circuitry rather than RNA splicing, such an effect depending on DNA-binding domains. By integrative analysis and functional assays, we identify HOXA9 as the downstream target of RBM5. Ectopic expression of HOXA9 rescues impaired leukemia cell proliferation upon RBM5 loss. Importantly, acute protein degradation of RBM5 through auxin-inducible degron system immediately reduces HOXA9 transcription. Conclusions We identify RBM5 as a new upstream regulator of HOXA9 and reveal its essential role in controlling the survival of AML. These functional and molecular mechanisms further support RBM5 as a promising therapeutic target for myeloid leukemia treatment.

Abstract Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.

In this study, the molecular dynamics (MD) method was used to study the tensile deformation of polycrystalline γ-TiAl with complex and random grain orientations. Firstly, the tensile deformation was simulated with different average grain sizes (8.60 nm, 6.18 nm, and 4.50 nm) and strain rates (1 × 108 s−1, 5 × 108 s−1, and 1 × 109 s−1). The results show that the peak stress increases with an increase in tensile strain rate, and the peak stress decreases as the grain size decreases, showing an inverse Hall–Petch effect. Upon observing atomic configuration evolution during tensile deformation, it is found that the grain boundary is seriously distorted, which indicates obvious grain boundary sliding occurring. With a further increase in the loading, some dislocations nucleate at the grain boundaries and propagate towards the interior of the grains along the grain boundaries, which demonstrates that dislocation motion is the primary coordination of the mechanical process of the grain boundaries. The dislocation density near the grain boundaries continues to increase, leading to the generation of micro-cracks and eventually causing material failure. Another interesting phenomenon is that the grains rotate, and the specific rotation angle values of each grain are quantitatively calculated. Grain rotation relaxes the stress concentration near the grain boundaries and plays a toughening role. Consequently, the plastic deformation behaviors of polycrystalline γ-TiAl are achieved through the grain boundary mechanical process, that is, grain boundary sliding and grain rotation.

Abstract Unfolded protein response (UPR) maintains the endoplasmic reticulum (ER) homeostasis, survival, and physiological function of mammalian cells. However, how cells adapt to ER stress under physiological or disease settings remains largely unclear. Here by a genome-wide CRISPR screen, we identified that RBBP8, an endonuclease involved in DNA damage repair, is required for ATF4 activation under ER stress in vitro. RNA-seq analysis suggested that RBBP8 deletion led to impaired cell cycle progression, retarded proliferation, attenuated ATF4 activation, and reduced global protein synthesis under ER stress. Mouse tissue analysis revealed that RBBP8 was highly expressed in the liver, and its expression is responsive to ER stress by tunicamycin intraperitoneal injection. Hepatocytes with RBBP8 inhibition by adenovirus-mediated shRNA were resistant to tunicamycin (Tm)-induced liver damage, cell death, and ER stress response. To study the pathological role of RBBP8 in regulating ATF4 activity, we illustrated that both RBBP8 and ATF4 were highly expressed in liver cancer tissues compared with healthy controls and highly expressed in Ki67-positive proliferating cells within the tumors. Interestingly, overexpression of RBBP8 in vitro promoted ATF4 activation under ER stress, and RBBP8 expression showed a positive correlation with ATF4 expression in liver cancer tissues by co-immunostaining. Our findings provide new insights into the mechanism of how cells adapt to ER stress through the crosstalk between the nucleus and ER and how tumor cells survive under chemotherapy or other anticancer treatments, which suggests potential therapeutic strategies against liver disease by targeting DNA damage repair, UPR or protein synthesis.

Abstract Background CTCF is a well-established chromatin architectural protein that also plays various roles in transcriptional regulation. While CTCF biology has been extensively studied, how the domains of CTCF function to regulate transcription remains unknown. Additionally, the original auxin-inducible degron 1 (AID1) system has limitations in investigating the function of CTCF. Results We employ an improved auxin-inducible degron technology, AID2, to facilitate the study of acute depletion of CTCF while overcoming the limitations of the previous AID system. As previously observed through the AID1 system and steady-state RNA analysis, the new AID2 system combined with SLAM-seq confirms that CTCF depletion leads to modest nascent and steady-state transcript changes. A CTCF domain sgRNA library screening identifies the zinc finger (ZF) domain as the region within CTCF with the most functional relevance, including ZFs 1 and 10. Removal of ZFs 1 and 10 reveals genomic regions that independently require these ZFs for DNA binding and transcriptional regulation. Notably, loci regulated by either ZF1 or ZF10 exhibit unique CTCF binding motifs specific to each ZF. Conclusions By extensively comparing the AID1 and AID2 systems for CTCF degradation in SEM cells, we confirm that AID2 degradation is superior for achieving miniAID-tagged protein degradation without the limitations of the AID1 system. The model we create that combines AID2 depletion of CTCF with exogenous overexpression of CTCF mutants allows us to demonstrate how peripheral ZFs intricately orchestrate transcriptional regulation in a cellular context for the first time.

Abstract Background Osteoarthritis (OA) is a chronic degenerative disease that is one of the main causes of disability in middle-aged and elderly people. Adipose stem cell (ASC)-derived exosomes (ASC-Exo) could repair cartilage damage and treat OA. MiRNA-338-3p expression was confirmed to play a role in inhibiting proinflammatory cytokines. Herein, we aimed to explore the mechanism by which exosomes derived from miR-338-3p overexpressing ASCs protects chondrocytes from interleukin (IL)-1β-induced chondrocyte change. Methods Exosomes were extracted from ASCs transfected with miR-338-3p or its antisense inhibitor. The ASC-Exos (miR-338-3p silencing/overexpression) were incubated with IL-1β-induced ATDC5 cells, followed by evaluation of the chondrocyte proliferation, degradation, and inflammation injury. Results In vitro results revealed that ASC-Exos inhibited the expression of prostaglandin E2 (PGE2), IL-6, IL-1β, and TNF-α, as well as promoted the proliferation of ATDC5 cells. Moreover, ASC-Exos inhibited inflammation injury and degradation of ATDC5 cells by transferring miR-338-3p. Luciferase reporter assays showed that RUNX2 was a target gene of miR-338-3p. Additionally, RUNX2 overexpression in ATDC5 cells reversed the protective effect of miR-338-3p on chondrocytes. Taken together, this study demonstrated that exosomes secreted from miR-338-3p-modified ASCs were effective in the repair of IL-1β-induced chondrocyte change by inhibiting RUNX2 expression. Conclusions Our result provided valuable data for understanding the mechanism of ASC-Exos in OA treatment. Graphical abstract

Abstract Background The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Results Here, we systematically integrate multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, and CRISPR-Cas9 survival dropout screens, and time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewires genome-wide chromatin accessibility. Increased accessible chromatin regions are frequently located adjacent to CTCF-binding sites at promoter regions and insulator sites associated with enhanced transcription of nearby genes. In addition, we use CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners. We successfully identify 40 candidates, including multiple established partners. Interestingly, many CTCF co-regulators that have alterations of their respective downstream gene expression do not show changes of their own expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. Conclusions This study highlights that CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation.

Abstract Although genome-wide DNA methylomes have demonstrated their clinical value as reliable biomarkers for tumor detection, subtyping, and classification, their direct biological impacts at the individual gene level remain elusive. Here we present MethylationToActivity (M2A), a machine learning framework that uses convolutional neural networks to infer promoter activities based on H3K4me3 and H3K27ac enrichment, from DNA methylation patterns for individual genes. Using publicly available datasets in real-world test scenarios, we demonstrate that M2A is highly accurate and robust in revealing promoter activity landscapes in various pediatric and adult cancers, including both solid and hematologic malignant neoplasms.

Many process synthesis and design problems in engineering are actually mixed integer nonlinear programming problems (MINLP), because they contain both continuous and integer variables. These problems are generally recognized to be complex and intractable by virtue of the combinatorial characteristic. In order to effectively solve process synthesis and design problems, a global particle swarm optimization (GPSO) algorithm is proposed in this paper. GPSO algorithm makes two improvements on original particle swarm optimization (PSO) algorithm: first, it introduces a global inertia weight, which is beneficial for improving its global searching capacity during the whole optimization process; second, it adopts a mutation operation with a small probability, which enables the GPSO algorithm to get rid of the local optimum easily. Simulation results show that the GPSO algorithm has high efficiency on finding the optimal solutions, and it has stronger convergence than the other four particle swarm optimization algorithms.

In this work, an improved Jaya (IJaya) algorithm is proposed and used to solve the economic load dispatch (ELD) problem considering valve-point effect and multi-fuel options. Compared with original Jaya, the convergence rate of IJaya is accelerated by distance-varying acceleration coefficient (DVAC), and the population diversity is enlarged by a self-adaptive population mechanism (SAPM). Meanwhile, to avoid premature problem, Gaussian and Cauchy mutation (GCM) is used to help IJaya jump out of local optima. The superiorities of IJaya have been validated by solving ELD cases with 6, 10, 13, 15, 40 generators, and the results are analysed in aspects of convergence rate, solution quality and robustness. The conclusion is that, in the tested ELD cases, IJaya behaves much more competitive than Jaya under the same testing conditions.

B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.

Multi-omic profiling is a powerful approach to dissecting molecular mechanisms in disease. Here the authors generate whole proteome, phosphoproteome and transcriptome profiles from two mouse models of high-grade glioma driven by different oncogenes, and validate identified master regulators with a CRISPR screen.

The IGH@ proto-oncogene translocation is a known genomic driver in several blood cancers. Here, the authors show that IGH-DUX4 translocation occurs on the silenced IGH allele avoiding toxic high-level expression of DUX4 in B-ALL.

Aberrant HOXA9 expression is a hallmark of most aggressive acute leukemias, notably those with KMT2A (MLL) gene rearrangements. HOXA9 overexpression not only predicts poor diagnosis and outcome but also plays a critical role in leukemia transformation and maintenance. However, our current understanding of HOXA9 regulation in leukemia is limited, hindering development of therapeutic strategies. Here, we generated the HOXA9-mCherry knock-in reporter cell lines to dissect HOXA9 regulation. By utilizing the reporter and CRISPR/Cas9 screens, we identified transcription factors controlling HOXA9 expression, including a novel regulator, USF2, whose depletion significantly down-regulated HOXA9 expression and impaired MLLr leukemia cell proliferation. Ectopic expression of Hoxa9 rescued impaired leukemia cell proliferation upon USF2 loss. Cut and Run analysis revealed the direct occupancy of USF2 at HOXA9 promoter in MLLr leukemia cells. Collectively, the HOXA9 reporter facilitated the functional interrogation of the HOXA9 regulome and has advanced our understanding of the molecular regulation network in HOXA9-driven leukemia.

The mitotic deacetylase complex (MiDAC) is a recently identified histone deacetylase (HDAC) complex. While other HDAC complexes have been implicated in neurogenesis, the physiological role of MiDAC remains unknown. Here, we show that MiDAC constitutes an important regulator of neural differentiation. We demonstrate that MiDAC functions as a modulator of a neurodevelopmental gene expression program and binds to important regulators of neurite outgrowth. MiDAC upregulates gene expression of pro-neural genes such as those encoding the secreted ligands SLIT3 and NETRIN1 (NTN1) by a mechanism suggestive of H4K20ac removal on promoters and enhancers. Conversely, MiDAC inhibits gene expression by reducing H3K27ac on promoter-proximal and -distal elements of negative regulators of neurogenesis. Furthermore, loss of MiDAC results in neurite outgrowth defects that can be rescued by supplementation with SLIT3 and/or NTN1. These findings indicate a crucial role for MiDAC in regulating the ligands of the SLIT3 and NTN1 signaling axes to ensure the proper integrity of neurite development.

Summary: The p53 tumor suppressor pathway is frequently inactivated in human cancers. However, there are some cancer types without commonly recognized alterations in p53 signaling. Here we report that histone demethylase KDM5A is involved in the regulation of p53 activity. KDM5A is significantly amplified in multiple types of cancers, an event that tends to be mutually exclusive to p53 mutation. We show that KDM5A acts as a negative regulator of p53 signaling through inhibition of p53 translation via suppression of a subgroup of eukaryotic translation initiation genes. Genetic deletion of KDM5A results in upregulation of p53 in multiple lineages of cancer cells and inhibits tumor growth in a p53-dependent manner. In addition, we have identified a regulatory loop between p53, miR-34, and KDM5A, whereby the induction of miR-34 leads to suppression of KDM5A. Thus, our findings reveal a mechanism by which KDM5A inhibits p53 translation to modulate cancer progression. : Molecular Mechanism of Gene Regulation; Cancer Subject Areas: Molecular Mechanism of Gene Regulation, Cancer

The most aggressive of four medulloblastoma (MB) subgroups are cMyc-driven group 3 (G3) tumors, some of which overexpress EZH2, the histone H3K27 mono-, di-, and trimethylase of polycomb-repressive complex 2. Ezh2 has a context-dependent role in different cancers as an oncogene or tumor suppressor and retards tumor progression in a mouse model of G3 MB. Engineered deletions of Ezh2 in G3 MBs by gene editing nucleases accelerated tumorigenesis, whereas Ezh2 re-expression reversed attendant histone modifications and slowed tumor progression. Candidate oncogenic drivers suppressed by Ezh2 included Gfi1, a proto-oncogene frequently activated in human G3 MBs. Gfi1 disruption antagonized the tumor-promoting effects of Ezh2 loss; conversely, Gfi1 overexpression collaborated with Myc to bypass effects of Trp53 inactivation in driving MB progression in primary cerebellar neuronal progenitors. Although negative regulation of Gfi1 by Ezh2 may restrain MB development, Gfi1 activation can bypass these effects.

To study the effect of the supersonic nozzle structure on the spontaneous condensation of water vapor, the wet steam model used to study the wet steam liquefaction of steam turbine was introduced into the numerical study of supersonic nozzle in supersonic cyclone separator, and the numerical results was in good agreement with the experimental data of the related literature. The supersonic nozzles, the contraction section with the Witozinsky curve and the bicubic curve, and the expansion section with conical curve and Foelsch curves, were designed. The influence of supersonic nozzle structure on water vapour liquefaction ability was investigated. And the following research results were obtained. When the structure of the supersonic nozzle was the same, the Witozinsky curve was selected for contraction section of the supersonic nozzle, and the nucleation rate of the droplet in the nozzle increased by 21.97 % and the number of droplets increased by 32.16 %, which was helpful to the gas liquefaction in the nozzle. When the contraction curve of the supersonic nozzle was consistent, and the expansion curve was Foelsch curve, the gas nucleation rate and the number of droplets in the nozzle were greatly improved. The distribution of nozzle humidity was related to the structure of expansion section, but not to the structure of contraction section. The maximum humidity in nozzle depended on the outlet diameter of nozzle. When the other structures of the nozzle were consistent, the cone angle of divergent section increased from 2° to 8°, the peak value of the nucleation rate increased by 493.15 %, the maximum of the droplet number increased by 246.12 %, the outlet humidity of the nozzle increased by 73.37 %, which greatly improved the gas liquefaction rate. In the case of gas liquefaction, increasing the cone angle of expansion section was conducive to liquefaction of water vapor.

Induced pluripotent stem (iPS) cells have attracted enormous attention due to their vast potential in regenerative medicine, pharmaceutical screening and basic research. Most prior established iPS cell lines were derived and maintained on mouse embryonic fibroblast (MEF) cells supplemented with exogenous leukemia inhibitory factor (LIF). Drawbacks of MEF cells impede optimization as well as dissection of reprogramming events and limit the usage of iPS cell derivatives in therapeutic applications. In this study, we develop a reproducible protocol for efficient reprogramming mouse neural progenitor cells (NPCs) on human foreskin fibroblast (HFF) cells via retroviral transfer of human transcriptional factors OCT4/SOX2/KLF4/C-MYC. Two independent iPS cell lines are derived without exogenous LIF. They display typical undifferentiated morphology and express pluripotency markers Oct4 and Sox2. Transgenes are inactivated and the endogenous Oct4 promoter is completely demethylated in the established iPS cell lines, indicating a fully reprogrammed state. Moreover, the iPS cells can spontaneously differentiate or be induced into various cell types of three embryonic germ layers in vitro and in vivo when they are injected into immunodeficient mice for teratoma formation. Importantly, iPS cells extensively integrate with various host tissues and contribute to the germline when injected into the blastocysts. Interestingly, these two iPS cell lines, while both pluripotent, exhibit distinctive differentiation tendencies towards different lineages. Taken together, the data describe the first genuine mouse iPS cell lines generated on human feeder cells without exogenous LIF, providing a reliable tool for understanding the molecular mechanisms of nuclear reprogramming.

Abstract Due to the existence of the evaporation duct near‐sea‐surface described as an inhomogeneous refractive index of atmosphere, microwaves can be trapped in the duct and propagate along it. To investigate wireless power transfer (WPT) over the sea surface, we utilize the two‐dimensional parabolic equation to calculate the electric field distribution and to obtain the transferred power. By analysing the propagation results with specific evaluation functions, we obtained the proper conditions for long‐distance WPT over the sea surface. When the initial field distributes uniformly on the one‐meter aperture, the frequency is 12 GHz, and the centre position is 4 m, a unique focusing spot can be obtained in the duct and nearly 5%, 8%, and 12% of the initial power remains at a distance of 10 km with a receiving aperture of 1, 2, and 3 m, respectively. The presented WPT scheme near the sea surface has potential applications in the power supply or charging for ships or small islands.