Roles and Mechanisms of miRNAs in Abdominal Aortic Aneurysm: Signaling Pathways and Clinical Insights.

PURPOSE OF REVIEW: Abdominal aortic aneurysm refers to a serious medical condition that can cause the irreversible expansion of the abdominal aorta, which can lead to ruptures that are associated with up to 80% mortality. Currently, surgical and interventional procedures are the only treatment options available for treating abdominal aortic aneurysm patients. In this review, we focus on the upstream and downstream molecules of the microRNA-related signaling pathways and discuss the roles, mechanisms, and targets of microRNAs in abdominal aortic aneurysm modulation to provide novel insights for precise and targeted drug therapy for the vast number of abdominal aortic aneurysm patients. RECENT FINDINGS: Recent studies have highlighted that microRNAs, which are emerging as novel regulators of gene expression, are involved in the biological activities of regulating abdominal aortic aneurysms. Accumulating studies suggested that microRNAs modulate abdominal aortic aneurysm development through various signaling pathways that are yet to be comprehensively summarized. A total of six signaling pathways (NF-κB signaling pathway, PI3K/AKT signaling pathway, MAPK signaling pathway, TGF-ß signaling pathway, Wnt signaling pathway, and P53/P21 signaling pathway), and a total of 19 miRNAs are intimately associated with the biological properties of abdominal aortic aneurysm through targeting various essential molecules. MicroRNAs modulate the formation, progression, and rupture of abdominal aortic aneurysm by regulating smooth muscle cell proliferation and phenotype change, vascular inflammation and endothelium function, and extracellular matrix remodeling. Because of the broad crosstalk among signaling pathways, a comprehensive analysis of miRNA-mediated signaling pathways is necessary to construct a well-rounded upstream and downstream regulatory network for future basic and clinical research of AAA therapy.

Iron Oxide Nanoparticles Engineered Macrophage-Derived Exosomes for Targeted Pathological Angiogenesis Therapy.

Engineering exosomes with nanomaterials usually leads to the damage of exosomal membrane and bioactive molecules. Here, pathological angiogenesis targeting exosomes with magnetic imaging, ferroptosis inducing, and immunotherapeutic properties is fabricated using a simple coincubation method with macrophages being the bioreactor. Extremely small iron oxide nanoparticle (ESIONPs) incorporated exosomes (ESIONPs@EXO) are acquired by sorting the secreted exosomes from M1-polarized macrophages induced by ESIONPs. ESIONPs@EXO suppress pathological angiogenesis in vitro and in vivo without toxicity. Furthermore, ESIONPs@EXO target pathological angiogenesis and exhibit an excellent T1-weighted contrast property for magnetic resonance imaging. Mechanistically, ESIONPs@EXO induce ferroptosis and exhibit immunotherapeutic ability toward pathological angiogenesis. These findings demonstrate that a pure biological method engineered ESIONPs@EXO using macrophages shows potential for targeted pathological angiogenesis therapy.

Copper oxide nanoparticles suppress retinal angiogenesis via inducing endothelial cell cuproptosis.

Background: Copper oxide nanoparticles (CuO NPs) exhibit antitumor activity; however, their potential as an antiangiogenesis agent is unknown. Materials & methods: The antiangiogenesis properties of CuO NPs were evaluated in vitro and in vivo and the underlying mechanism was examined using RNA sequencing and metabolomic analyses. Results: CuO NPs inhibited endothelial cell function in vitro. They also mitigated retinal vasculature development and alleviated pathological retinal angiogenesis in vivo. RNA sequencing and metabolomic analyses revealed that CuO NPs disrupt the tricarboxylic acid cycle and induce cuproptosis, which was further supported by evaluating cuproptosis-related metabolites and proteins. Conclusion: CuO NPs may be an effective antiangiogenic agent for the treatment of retinal angiogenesis.

Gypenoside XVII attenuates renal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-triggered pyroptosis.

BACKGROUND: Renal ischemia-reperfusion (I/R) is one of the main causes of acute kidney injury (AKI), for which there is currently no effective treatment. Recently, the interaction between endoplasmic reticulum (ER) stress and pyroptosis during AKI has been investigated. AIM: The purpose of this study was to investigate the protective effects of Gypenoside XVII (GP-17) against I/R-induced renal injury. METHODS: In this study, mice were divided into 6 groups, sham group, I/R group, GP-17 low-, medium-, high-dose group, and positive control 4-PBA group. The renal I/R was performed in mice by clamping the bilateral renal pedicles for 40 min, and then reperfusing for 24 h. Blood and kidney samples were collected for analysis. RESULTS: The results showed that GP-17 improved renal function and alleviated renal histopathological abnormalities caused by I/R. In addition, GP-17 pretreatment significantly decreased the expression or phosphorylation of ER stress response proteins including BIP, p-PERK, and CHOP. Besides, GP-17 inhibited the expression of pyroptosis proteins including caspase-1, GSDMD, and apoptotic protein BAX. The inflammatory factor IL-1ß in these GP-17 pretreatment groups was also significantly reduced. CONCLUSION: GP-17 blocked NLRP3 inflammasome activation by inhibiting ERS, thereby inhibiting renal tubular cell pyroptosis and apoptosis, and prevented renal I/R injury.

Aurora kinase B disruption suppresses pathological retinal angiogenesis by affecting cell cycle progression.

PURPOSE: The detrimental effects of pathological angiogenesis on the visual function are indisputable. Within a prominent role in chromosome segregation and tumor progression, aurora kinase B (AURKB) assumes a prominent role. However, its role in pathological retinal angiogenesis remains unclear. This study explores this latent mechanism. METHODS: To inhibit AURKB expression, we designed specific small interfering RNAs targeting AURKB and transfected them into vascular endothelial cells. Barasertib was selected as the AURKB inhibitor. The anti-angiogenic effects of both AURKB siRNA and barasertib were assessed in vitro by cell proliferation, transwell migration, and tube formation. To evaluate the angiogentic effects of AURKB in vivo, neonatal mice were exposed to 75% oxygen followed by normoxic repositioning to establish an oxygen-induced retinopathy (OIR) model. Subsequently, phosphate-buffered saline and barasertib were administered into OIR mice via intravitreal injection. The effects of AURKB on cell cycle proteins were determined by western blot analysis. RESULTS: We found that AURKB was overexpressed during pathological angiogenesis. AURKB siRNA and barasertib significantly inhibited endothelial cell proliferation, migration, and tube formation in vitro. Furthermore, AURKB inhibition attenuated retinal angiogenesis in the OIR model. A possible mechanism is the disruption of cell cycle by AURKB inhibition. CONCLUSION: In conclusion, AURKB significantly influenced pathological retinal angiogenesis, thereby presenting a promising therapeutic target in ocular neovascular diseases.

Quantitative label-free mass spectrometry reveals content and signaling differences between neonatal and adult platelets.

BACKGROUND: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. OBJECTIVES: This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. METHODS: We isolated resting umbilical cord blood-derived platelets from healthy full-term neonates (n = 8) and resting blood platelets from healthy adults (n = 6) and compared protein and phosphoprotein contents using data-independent acquisition mass spectrometry. RESULTS: We identified 4770 platelet proteins with high confidence across all samples. Adult and neonatal platelets were clustered separately by principal component analysis. Adult platelets were significantly enriched in immunomodulatory proteins, including ß2 microglobulin and CXCL12, whereas neonatal platelets were enriched in ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched in phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched in phosphorylated proteins involved in insulin growth factor signaling. CONCLUSION: Using label-free data-independent acquisition mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation between neonatal and adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.

Roles and mechanisms of umbilical cord mesenchymal stem cells in the treatment of diabetic foot: A review of preclinical and clinical studies.

AIMS: Growing preclinical and clinical evidence has suggested the potential method of umbilical cord mesenchymal stem cell (UCMSC) therapy for diabetic foot. Thus, the authors provided an outline of the application of UCMSCs in the treatment of diabetic foot and further summarized the roles and mechanisms of this therapy. DATA SYNTHESIS: With no time limitations, the authors searched the Web of Science, Cochrane Central Register of Controlled Trials, and PubMed (MEDLINE) databases. 14 studies were included, including 9 preclinical experiments and 5 clinical trials (3 RCTs and 2 single-arm trials). CONCLUSIONS: The UCMSCs are of great efficacy and safety, and function mainly by reducing inflammation, regulating immunity, promoting growth factors, and enhancing the functions of vascular endothelial cells, fibroblasts, and keratinocytes. As a result, ulcer healing-related biological processes ensue, which finally lead to diabetic foot ulcer healing and clinical symptom improvement. UCMSC treatment enhances diabetic foot ulcer healing and has a safety profile. They function mainly by modulating immunity, promoting growth factor secretion, and enhancing cellular functions. More well-designed preclinical and clinical studies are needed to provide the most optimal protocol, the comprehensive molecular mechanisms, as well as to further evaluate the efficiency and safety profile of UCMSC treatment in diabetic foot patients.

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.

Enhancing the Ignition and Combustion Performances of Solid Propellants Incorporating Al Particles Inside Oxidizers.

The combustion efficiency of Al plays a critical role in the combustion of high-energy aluminum-based solid propellants. For traditional formulations, the Al powders are dispersed in the binder matrix, leading to limited contact with the oxidizers and hence usually insufficient combustion and higher values of the pressure exponent. In this paper, various core-shell structural Al/oxidizer composites such as Al@HMX, Al@AP, and AP@Al have been prepared by a spray-drying technique based on which solid propellants with precise interfacial control between Al particles and oxidizers were realized. Compared to the control sample, the modified propellants have a greater heat of explosion of 5890 J g-1 (15% higher) and a reduced ignition delay time of 58 ms (65% decrease). Without changing the content of components, the burn rates of propellants can be easily modulated by tuning the interfacial contact of Al and oxidizers, where it varies in a wide range of 4.56-5.79 mm s-1 at the same pressure of 1 MPa. After introducing Al/oxidizer composites, the lowest pressure exponent of 0.19 within 1-15 MPa could be achieved by using Al@HMX and AP@Al composites. The agglomeration of Al was also inhibited by using Al/oxidizer composites, and the mechanism can be interpreted by using a classical "pocket" model. Moreover, the improved combustion efficiency of the solid propellants was verified by a noticeable reduction in the unreacted Al content.

Uncovering the System Vulnerability and Criticality of Human Brain Under Dynamical Neuropathological Events in Alzheimer's Disease.

BACKGROUND: Despite the striking efforts in investigating neurobiological factors behind the acquisition of amyloid-ß (A), protein tau (T), and neurodegeneration ([N]) biomarkers, the mechanistic pathways of how AT[N] biomarkers spreading throughout the brain remain elusive. OBJECTIVE: To disentangle the massive heterogeneities in Alzheimer's disease (AD) progressions and identify vulnerable/critical brain regions to AD pathology. METHODS: In this work, we characterized the interaction of AT[N] biomarkers and their propagation across brain networks using a novel bistable reaction-diffusion model, which allows us to establish a new systems biology underpinning of AD progression. We applied our model to large-scale longitudinal neuroimages from the ADNI database and studied the systematic vulnerability and criticality of brains. RESULTS: Our model yields long term prediction that is statistically significant linear correlated with temporal imaging data, produces clinically consistent risk prediction, and captures the Braak-like spreading pattern of AT[N] biomarkers in AD development. CONCLUSIONS: Our major findings include (i) tau is a stronger indicator of regional risk compared to amyloid, (ii) temporal lobe exhibits higher vulnerability to AD-related pathologies, (iii) proposed critical brain regions outperform hub nodes in transmitting disease factors across the brain, and (iv) comparing the spread of neuropathological burdens caused by amyloid-ß and tau diffusions, disruption of metabolic balance is the most determinant factor contributing to the initiation and progression of AD.

Phosphoproteomics reveals content and signaling differences between neonatal and adult platelets.

Background and Objective: Recent clinical studies have shown that transfusions of adult platelets increase morbidity and mortality in preterm infants. Neonatal platelets are hyporesponsive to agonist stimulation, and emerging evidence suggests developmental differences in platelet immune functions. This study was designed to compare the proteome and phosphoproteome of resting adult and neonatal platelets. Methods: We isolated resting umbilical cord blood-derived platelets from healthy full term neonates (n=9) and resting blood platelets from healthy adults (n=7), and compared protein and phosphoprotein contents using data independent acquisition mass spectrometry. Results: We identified 4745 platelet proteins with high confidence across all samples. Adult and neonatal platelets clustered separately by principal component analysis. Adult platelets were significantly enriched for immunomodulatory proteins, including ß2 microglobulin and CXCL12, whereas neonatal platelets were enriched for ribosomal components and proteins involved in metabolic activities. Adult platelets were enriched for phosphorylated GTPase regulatory enzymes and proteins participating in trafficking, which may help prime them for activation and degranulation. Neonatal platelets were enriched for phosphorylated proteins involved in insulin growth factor signaling. Conclusions: Using state-of-the-art mass spectrometry, our findings expanded the known neonatal platelet proteome and identified important differences in protein content and phosphorylation compared with adult platelets. These developmental differences suggested enhanced immune functions for adult platelets and presence of a molecular machinery related to platelet activation. These findings are important to understanding mechanisms underlying key platelet functions as well as the harmful effects of adult platelet transfusions given to preterm infants.

Engineered nanomaterials enhance drug delivery strategies for the treatment of osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor in adolescents, and the clinical treatment of OS mainly includes surgery, radiotherapy, and chemotherapy. However, the side effects of chemotherapy drugs are an issue that clinicians cannot ignore. Nanomedicine and drug delivery technologies play an important role in modern medicine. The development of nanomedicine has ushered in a new turning point in tumor treatment. With the emergence and development of nanoparticles, nanoparticle energy surfaces can be designed with different targeting effects. Not only that, nanoparticles have unique advantages in drug delivery. Nanoparticle delivery drugs can not only reduce the toxic side effects of chemotherapy drugs, but due to the enhanced permeability retention (EPR) properties of tumor cells, nanoparticles can survive longer in the tumor microenvironment and continuously release carriers to tumor cells. Preclinical studies have confirmed that nanoparticles can effectively delay tumor growth and improve the survival rate of OS patients. In this manuscript, we present the role of nanoparticles with different functions in the treatment of OS and look forward to the future treatment of improved nanoparticles in OS.

BTB protein family and human breast cancer: signaling pathways and clinical progress.

BACKGROUND: Breast cancer is considered the number one killer of women both in China and abroad, and the leading cause of cancer death. It severely affects female health-related quality of life. Broad-complex, tramtrack, bric à brac (BTB) protein family was first discovered in drosophila as early as in 1993 by Godt D and peers, since then, more family members and their critical biological functions were uncovered. Moreover, researchers around the world have recently demonstrated that numerous signaling pathways connect BTB family members and human breast cancer. PURPOSE: In this review, we critically discuss these findings regarding the essential mechanisms and functions of the BTB protein family in mediating the organic processes of human breast cancer. Meanwhile, we summarize the signaling pathways the BTB protein family participates in. And we address that BTB proteins regulate the growth, apoptosis, and other behaviors of breast cancer cells. We also point out the future directions for further studies in this field. METHODS: The relevant online literatures have been reviewed for this article. CONCLUSION: This review could offer an update on novel molecular targets for treating human breast cancer and new insights into BTB protein family research.

Bimetal MOFs catalyzed Fenton-like reaction for dual-mode detection of thiamphenicol.

In this work, we used a simple ultrasonic stripping method to synthesize a bimetal MOFs at room temperature as a nanoenzyme with peroxidase-like (POD-like) activity. Through bimetal MOFs catalytic Fenton-like competitive reaction, thiamphenicol can be quantitatively dual-mode detected by fluorescence and colorimetry. It realized the sensitive detection of thiamphenicol in water, and the limits of detection (LOD) were 0.030 nM and 0.031 nM, and the liner ranges were 0.1-150 nM and 0.1-100 nM, respectively. The methods were applied to river water, lake water and tap water samples, and with satisfactory recoveries between 97.67% and 105.54%.

Exosomes incorporated with black phosphorus quantum dots attenuate retinal angiogenesis via disrupting glucose metabolism.

Black phosphorus quantum dots (BPQDs) have shown potential in tumor therapy, however, their anti-angiogenic functions have not been studied. Although BPQDs are easily degraded to non-toxic phosphrous, the reported toxicity, poor stability, and non-selectivity largely limit their further application in medicine. In this study, a vascular targeting, biocompatible, and cell metabolism-disrupting nanoplatform is engineered by incorporating BPQDs into exosomes modified with the Arg-Gly-Asp (RGD) peptide (BPQDs@RGD-EXO nanospheres, BREs). BREs inhibit endothelial cells (ECs) proliferation, migration, tube formation, and sprouting in vitro. The anti-angiogenic role of BREs in vivo is evaluated using mouse retinal vascular development model and oxygen-induced retinopathy model. Combined RNA-seq and metabolomic analysis reveal that BREs disrupt glucose metabolism, which is further confirmed by evaluating metabolites, ATP production and the c-MYC/Hexokinase 2 pathway. These BREs are promising anti-angiogenic platforms for the treatment of pathological retinal angiogenesis with minimal side effects.

Enhanced biohydrogen yield and light conversion efficiency during photo-fermentation using immobilized photo-catalytic nano-particles.

Bacterial immobilization is a common method in anaerobic fermentation, since of the maintenance of high bacterial activity, insurance of high density microbial during continuous fermentation, and quick adaptability to the environment. While, the bio-hydrogen production capacity of immobilized photosynthetic bacteria (I-PSB) is seriously affected by the low light transfer efficiency. Hence, in this study, photo-catalytic nano-particles (PNPs) was added into the photo-fermentative bio-hydrogen production (PFHP) system, and its enhancement effects of bio-hydrogen production performance were investigated. Results showed that the maximum cumulative hydrogen yield (CHY) of I-PSB with 100 mg/L nano-SnO2 (154.33 ± 7.33 mL) addition was 18.54% and 33.06% higher than those of I-PSB without nano-SnO2 addition and control group (free cells), and the lag time was the shortest indicating a shorter cell arrest time, more cells and faster response. Maximum energy recovery efficiency and light conversion efficiency were also found to be increased by 18.5% and 12.4%, respectively.

Diagnostic and therapeutic strategies for non-alcoholic fatty liver disease.

The global incidence rate of non-alcoholic fatty liver disease (NAFLD) is approximately 25%. With the global increase in obesity and its associated metabolic syndromes, NAFLD has become an important cause of chronic liver disease in many countries. Despite recent advances in pathogenesis, diagnosis, and therapeutics, there are still challenges in its treatment. In this review, we briefly describe diagnostic methods, therapeutic targets, and drugs related to NAFLD. In particular, we focus on evaluating carbohydrate and lipid metabolism, lipotoxicity, cell death, inflammation, and fibrosis as potential therapeutic targets for NAFLD. We also summarized the clinical research progress in terms of drug development and combination therapy, thereby providing references for NAFLD drug development.

Role of glucose metabolism in ocular angiogenesis (Review).

Glucose metabolism, the major source of energy, plays a crucial role in physiological cell function and the maintenance of homeostasis. Glucose acts as the predominant source of metabolic fuel in the generation of ATP and is involved in biosynthesis and epigenetics. Thus, glucose metabolism maintains a key role in cell function, homeostasis, energy generation, biosynthesis and epigenetics. An increasing number of studies have revealed that glucose metabolism is intricately involved in angiogenesis, with the disruption of angiogenesis contributing to several vascular diseases. Ocular vascular diseases are common ophthalmological disorders, and the prevalence of these disorders is increasing annually. Ocular vascular diseases largely occur from abnormal congenital development or acquired disturbances to the vasculature. Thus, identifying the process of occurrence and development of physiological and pathological angiogenesis is of utmost importance, and this involves understanding the inseparable role of intercellular communications between vascular cells. Although vascular endothelial growth factor (VEGF) is a well­recognized therapeutic target for the management of ocular vascular diseases, VEGF­based therapy fails to achieve the desired therapeutic effects in several cases, partly due to drug resistance and non­compliance. In the present review, current knowledge on the processes and roles of glucose metabolism in governing both physiological and pathological ocular angiogenesis are summarized, highlighting vascular glucose metabolism as a promising strategy for maintaining or restoring the physiological functions of the vasculature, thus potentially ameliorating ocular vascular diseases.

Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity.

Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer's disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.

Uncovering the dynamic effects of DEX treatment on lung cancer by integrating bioinformatic inference and multiscale modeling of scRNA-seq and proteomics data.

Lung cancer is one of the leading causes of cancer-related death, with a five-year survival rate of 18%. It is a priority for us to understand the underlying mechanisms affecting lung cancer therapeutics' implementation and effectiveness. In this study, we combine the power of Bioinformatics and Systems Biology to comprehensively uncover functional and signaling pathways of drug treatment using bioinformatics inference and multiscale modeling of both scRNA-seq data and proteomics data. Based on a time series of lung adenocarcinoma derived A549 cells after DEX treatment, we first identified the differentially expressed genes (DEGs) in those lung cancer cells. Through the interrogation of regulatory network of those DEGs, we identified key hub genes including TGFß, MYC, and SMAD3 varied underlie DEX treatment. Further gene set enrichment analysis revealed the TGFß signaling pathway as the top enriched term. Those genes involved in the TGFß pathway and their crosstalk with the ERBB pathway presented a strong survival prognosis in clinical lung cancer samples. With the basis of biological validation and literature-based curation, a multiscale model of tumor regulation centered on both TGFß-induced and ERBB-amplified signaling pathways was developed to characterize the dynamic effects of DEX therapy on lung cancer cells. Our simulation results were well matched to available data of SMAD2, FOXO3, TGFß1, and TGFßR1 over the time course. Moreover, we provided predictions of different doses to illustrate the trend and therapeutic potential of DEX treatment. The innovative and cross-disciplinary approach can be further applied to other computational studies in tumorigenesis and oncotherapy. We released the approach as a user-friendly tool named BIMM (Bioinformatic Inference and Multiscale Modeling), with all the key features available at https://github.com/chenm19/BIMM.