Inducing Long Lasting B cell and T cell Immunity against Multiple Variants of SARS-CoV-2 through Mutant Bacteriophage Qß - Receptor Binding Domain Conjugate.

More than three years into the global pandemic, SARS-CoV-2 remains a significant threat to public health. Immunities acquired from infection or current vaccines fail to provide long term protection against subsequent infections, mainly due to their fast-waning nature and the emergence of variants of concerns (VOCs) such as Omicron. To overcome these limitations, SARS-CoV-2 Spike protein receptor binding domain (RBD)-based epitopes were investigated as conjugates with a powerful carrier, the mutant bacteriophage Qß (mQß). The epitope design was critical to eliciting potent antibody responses with the full length RBD being superior to peptide and glycopeptide antigens. The full length RBD conjugated with mQß activated both humoral and cellular immune systems in vivo, inducing broad spectrum, persistent and comprehensive immune responses effective against multiple VOCs including Delta and Omicron variants, rendering it a promising vaccine candidate. This article is protected by copyright. All rights reserved.

Recent advances in the synthesis of extensive libraries of heparan sulfate oligosaccharides for structure-activity relationship studies.

Heparan sulfate (HS) is a linear, sulfated and highly negatively-charged polysaccharide that plays important roles in many biological events. As a member of the glycosaminoglycan (GAG) family, HS is commonly found on mammalian cell surfaces and within the extracellular matrix. The structural complexities of natural HS polysaccharides have hampered the comprehension of their biological functions and structure-activity relationships (SARs). Although the sulfation patterns and backbone structures of HS can be major determinants of their biological activities, obtaining significant amounts of pure HS from natural sources for comprehensive SAR studies is challenging. Chemical and enzyme-based synthesis can aid in the production of structurally well-defined HS oligosaccharides. In this review, we discuss recent innovations enabling the syntheses of large libraries of HS and how these libraries can provide insights into the structural preferences of various HS binding proteins.

Investigation of Microstructure and Mechanical Properties of Extruded Mg-6Bi and Mg-6Bi-1Ag Alloys.

The extruded Mg-6Bi alloy and Mg-6Bi-1Ag alloy subjected to extrusion at 300 °C with the extrusion ratio of 25:1 and die-exit speed of 2 m/min were used to investigate microstructure characteristics and mechanical behavior. The experimental results demonstrate that the bimodal microstructure, composed of coarse dynamic unrecrystallized (unDRXed) grains and fine dynamic recrystallized (DRXed) grains, was obtained after extrusion. The Ag addition can obviously promote dynamic recrystallization and average grain size. It also indicates that the dynamic precipitation is significantly promoted by Ag addition during extrusion, obtaining more fraction of the Mg3Bi2 precipitates. Moreover, the extruded Mg-6Bi-1Ag alloy has a high tensile yield strength of 304 ± 2.0 MPa, which is increased by 19% compared to the extruded Mg-6Bi alloy, and elongation of 11.0 ± 1.7%, almost the same as 11.9 ± 0.9% of the extruded Mg-6Bi alloy. This result also shows that the extruded Mg-6Bi-1Ag alloy exhibits better strain hardening capacity. Therefore, Ag exhibits an effective role in promoting dynamic recrystallization and dynamic precipitation, resulting in the enhancement of strength and strain hardening capacity of the extruded Mg-6Bi-1Ag alloy, as well as keeping high ductility.

A comprehensive synthetic library of poly-N-acetyl glucosamines enabled vaccine against lethal challenges of Staphylococcus aureus.

Poly-ß-(1-6)-N-acetylglucosamine (PNAG) is an important vaccine target, expressed on many pathogens. A critical hurdle in developing PNAG based vaccine is that the impacts of the number and the position of free amine vs N-acetylation on its antigenicity are not well understood. In this work, a divergent strategy is developed to synthesize a comprehensive library of 32 PNAG pentasaccharides. This library enables the identification of PNAG sequences with specific patterns of free amines as epitopes for vaccines against Staphylococcus aureus (S. aureus), an important human pathogen. Active vaccination with the conjugate of discovered PNAG epitope with mutant bacteriophage Qß as a vaccine carrier as well as passive vaccination with diluted rabbit antisera provides mice with near complete protection against infections by S. aureus including methicillin-resistant S. aureus (MRSA). Thus, the comprehensive PNAG pentasaccharide library is an exciting tool to empower the design of next generation vaccines.

A promising therapy for fatty liver disease: PCSK9 inhibitors.

BACKGROUND: Fatty liver disease (FLD) poses a significant global health concern worldwide, with its classification into nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) contingent upon the presence or absence of chronic and excessive alcohol consumption. The absence of specific therapeutic interventions tailored to FLD at various stages of the disease renders its treatment exceptionally arduous. Despite the fact that FLD and hyperlipidemia are intimately associated, there is still debate over how lipid-lowering medications affect FLD. Proprotein Convertase Subtilisin/ Kexin type 9 (PCSK9) is a serine protease predominantly synthesized in the liver, which has a crucial impact on cholesterol homeostasis. Research has confirmed that PCSK9 inhibitors have prominent lipid-lowering properties and substantial clinical effectiveness, thereby justifying the need for additional exploration of their potential role in FLD. PURPOSE: Through a comprehensive literature search, this review is to identify the relationship and related mechanisms between PCSK9, lipid metabolism and FLD. Additionally, it will assess the pharmacological mechanism and applicability of PCSK9 inhibitors (including naturally occurring PCSK9 inhibitors, such as conventional herbal medicines) for the treatment of FLD and serve as a guide for updating the treatment protocol for such conditions. METHODS: A comprehensive literature search was conducted using several electronic databases, including Pubmed, Medline, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the database to 30 Jan 2024. Key words used in the literature search were "fatty liver", "hepatic steatosis", "PCSK9", "traditional Chinese medicine", "herb medicine", "botanical medicine", "clinical trial", "vivo", "vitro", linked with AND/OR. Most of the included studies were within five years. RESULTS: PCSK9 participates in the regulation of circulating lipids via both LDLR dependent and independent pathways, and there is a potential association with de novo lipogenesis. Major clinical studies have demonstrated a positive correlation between circulating PCSK9 levels and the severity of NAFLD, with elevated levels of circulating PCSK9 observed in individuals exposed to chronic alcohol. Numerous studies have demonstrated the potential of PCSK9 inhibitors to ameliorate non-alcoholic steatohepatitis (NASH), potentially completely alleviate liver steatosis, and diminish liver impairment. In animal experiments, PCSK9 inhibitors have exhibited efficacy in alleviating alcoholic induced liver lipid accumulation and hepatitis. Traditional Chinese medicine such as berberine, curcumin, resveratrol, piceatannol, sauchinone, lupin, quercetin, salidroside, ginkgolide, tanshinone, lunasin, Capsella bursa-pastoris, gypenosides, and Morus alba leaves are the main natural PCS9 inhibitors. Excitingly, by inhibiting transcription, reducing secretion, direct targeting and other pathways, traditional Chinese medicine exert inhibitory effects on PCSK9, thereby exerting potential FLD therapeutic effects. CONCLUSION: PCSK9 plays an important role in the development of FLD, and PCSK9 inhibitors have demonstrated beneficial effects on lipid regulation and FLD in both preclinical and clinical studies. In addition, some traditional Chinese medicines have improved the disease progression of FLD by inhibiting PCSK9 and anti-inflammatory and antioxidant effects. Consequently, the inhibition of PCSK9 appears to be a promising therapeutic strategy for FLD.

Development of NHAcGD2/NHAcGD3 conjugates of bacteriophage MX1 virus-like particles as anticancer vaccines.

The successful development of an anticancer vaccine will be a giant leap forward in cancer prevention and treatment. Herein, the bacteriophage MX1 coat protein virus-like particles (MX1 VLPs) have been conjugated with 9NHAc-GD2 (NHAcGD2) to obtain a MX1-NHAcGD2 conjugate. Intriguingly, vaccinating against this conjugate produced a robust anti-NHAcGD2 IgG response in mice, with an average IgG titer of over 3 million. More interestingly, antibodies induced by the MX1-NHAcGD2 conjugate bound well to IMR-32 neuroblastoma cells and had potent complement-dependent cytotoxic (CDC) effects on IMR-32 cells. Inspired by the superiority of the 9NHAc-GD2 antigen, we also designed another 9NHAc-modified ganglioside antigen, 9NHAc-GD3 (NHAcGD3), to overcome the hydrolytic instability of 9-O-acetylated-GD3. By coupling NHAcGD3 with MX1 VLP, the MX1-NHAcGD3 conjugate was constructed. Strikingly, vaccination of MX1-NHAcGD3 elicited high anti-NHAcGD3 IgG antibodies, which effectively recognized human malignant melanoma SK-MEL-28 cells and had a significant CDC effect against this cell line. This study provides novel MX1-NHAcGD2 and MX1-NHAcGD3 conjugates with broad clinical translational prospects as promising anticancer vaccines.

Bionanoengineered 2D monoelemental selenene for piezothrombolysis.

Thrombosis-related diseases represent the leading causes of disability or death worldwide. However, conventional thrombolytic therapies are subjected to narrow therapeutic window, short circulation half-life and bleeding. Herein, we rationally design and develop a safe and efficient nonpharmaceutical thrombolysis strategy based on a specific piezocatalytic effect arising from platelet membrane (PM)-conjugated two-dimensional (2D) piezoelectric selenene, Se-PM nanosheets (NSs). The 2D selenene is fabricated from nonlayered bulk selenium powder by a facile liquid-phase exfoliation method, and the PM conjugation confers selenene with the distinct thrombus-homing feature. Under ultrasonic activation, the piezoelectric characteristic of selenene triggers electrons and holes separation, resulting in generation of reactive oxygen species (ROS) by reacting with surrounding H2O and O2 in the thrombosis microenvironment for thrombolysis. Both systematic in vitro and in vivo assessments demonstrate that the biocompatible Se-PM NSs efficiently degrade erythrocytes, fibrin and artificial blood clots under ultrasound irradiation. Compared to the clinical thrombolytic drug urokinase plasminogen activator, the engineered Se-PM NSs possess excellent thrombolytic efficacy by single treatment in the tail thrombosis animal model without bleeding risk. The engineered Se-PM nanoplatform marks an exciting jumping-off point for research into the application of piezocatalysis in clinical treatment of thrombosis.

Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

Enhancing Protective Antibodies against Opioids through Antigen Display on Virus-like Particles.

Opioid use disorder (OUD) has become a public health crisis, with recent significant increases in the number of deaths due to overdose. Vaccination can provide an attractive complementary strategy to combat OUD. A key for high vaccine efficacy is the induction of high levels of antibodies specific to the drug of abuse. Herein, a powerful immunogenic carrier, virus-like particle mutant bacteriophage Qß (mQß), has been investigated as a carrier of a small molecule hapten 6-AmHap mimicking heroin. The mQß-6-AmHap conjugate was able to induce significantly higher levels of IgG antibodies against 6-AmHap than mice immunized with the corresponding tetanus toxoid-6-AmHap conjugate in head-to-head comparison studies in multiple strains of mice. The IgG antibody responses were persistent with high anti-6-AmHap titers 600 days after being immunized with mQß-6-AmHap. The antibodies induced exhibited strong binding toward multiple heroin/morphine derivatives that have the potential to be abused, while binding weakly to medications used for OUD treatment and pain relief. Furthermore, vaccination effectively reduced the impacts of morphine on mice in both ambulation and antinociception assays, highlighting the translational potential of the mQß-6-AmHap conjugate to mitigate the harmful effects of drugs of abuse.

Stereoselective Synthesis of Sialyl Lewisa Antigen and the Effective Anticancer Activity of Its Bacteriophage Qß Conjugate as an Anticancer Vaccine.

Sialyl Lewisa (sLea ), also known as cancer antigen 19-9 (CA19-9), is a tumor-associated carbohydrate antigen. The overexpression of sLea on the surface of a variety of cancer cells makes it an attractive target for anticancer immunotherapy. However, sLea -based anticancer vaccines have been under-explored. To develop a new vaccine, efficient stereoselective synthesis of sLea with an amine-bearing linker was achieved, which was subsequently conjugated with a powerful carrier bacteriophage, Qß. Mouse immunization with the Qß-sLea conjugate generated strong and long-lasting anti-sLea IgG antibody responses, which were superior to those induced by the corresponding conjugate of sLea with the benchmark carrier keyhole limpet hemocyanin. Antibodies elicited by Qß-sLea were highly selective toward the sLea structure, could bind strongly with sLea -expressing cancer cells and human pancreatic cancer tissues, and kill tumor cells through complement-mediated cytotoxicity. Furthermore, vaccination with Qß-sLea significantly reduced tumor development in a metastatic cancer model in mice, demonstrating tumor protection for the first time by a sLea -based vaccine, thus highlighting the significant potential of sLea as a promising cancer antigen.

Risk Factor Analysis and Intervention Study for Unspecific Functional Enteropathy in a Maritime Environment: A Cross-Sectional Analytical Survey.

Background: The study aimed to investigate the risk factors and interventions for unspecific functional bowel disorders (U-FBDs) in military personnel under maritime environment. Methods: This cross-sectional analytical survey used the Rome III questionnaire for surveying 1018 military personnel involved in overseas humanitarian medical services from June 2013 to January 2016. Individuals diagnosed with U-FBDs were included in the U-FBDs group, while those without FBDs or other diseases were considered the control group. The psychological and sleep conditions of military personnel with U-FBDs were assessed using the SCL-90 scale and the Pittsburgh Sleep Quality Index scale, respectively. Health education and treatment were provided to individuals diagnosed with U-FBDs, and the improvements were evaluated after three months. Results: Among 923 qualified questionnaires, 243 subjects was included in U-FBDs group and 240 in the control group. Smoking, alcohol consumption, and multiple seafaring missions were identified as risk factors for U-FBDs in military personnel on ocean-going missions. The U-FBDs group had significantly worse sleep quality, sleep efficiency, daytime dysfunction score, and total PSQI score compared to the control group (P < 0.05). Additionally, 10 factor scores of SCL-90 and the total score in the U-FBDs group were significantly higher than those in the control group (P < 0.01). Patients with U-FBDs also reported the highest rate of somatic symptoms (P < 0.01). Conclusion: The onset of U-FBDs among military personnel on long-haul maritime may be closely related to mental, psychological, and sleep factors. Health education and treatment may help improve the symptoms of U-FBDs.

Development of a novel sialic acid-conjugated camptothecin prodrug for enhanced cancer chemotherapy.

Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.

Single-Cell B-Cell Sequencing to Generate Natively Paired scFab Yeast Surface Display Libraries.

The immune cell profiling capabilities of single-cell RNA sequencing (scRNA-seq) are powerful tools that can be applied to the design of theranostic monoclonal antibodies (mAbs). Using scRNA-seq to determine natively paired B-cell receptor (BCR) sequences of immunized mice as a starting point for design, this method outlines a simplified workflow to express single-chain antibody fragments (scFabs) on the surface of yeast for high-throughput characterization and further refinement with directed evolution experiments. While not extensively detailed in this chapter, this method easily accommodates the implementation of a growing body of in silico tools that improve affinity and stability among a range of other developability criteria (e.g., solubility and immunogenicity).

Fusion of Multi-Modal Features to Enhance Dense Video Caption.

Dense video caption is a task that aims to help computers analyze the content of a video by generating abstract captions for a sequence of video frames. However, most of the existing methods only use visual features in the video and ignore the audio features that are also essential for understanding the video. In this paper, we propose a fusion model that combines the Transformer framework to integrate both visual and audio features in the video for captioning. We use multi-head attention to deal with the variations in sequence lengths between the models involved in our approach. We also introduce a Common Pool to store the generated features and align them with the time steps, thus filtering the information and eliminating redundancy based on the confidence scores. Moreover, we use LSTM as a decoder to generate the description sentences, which reduces the memory size of the entire network. Experiments show that our method is competitive on the ActivityNet Captions dataset.

Topological deep learning based deep mutational scanning.

High-throughput deep mutational scanning (DMS) experiments have significantly impacted protein engineering, drug discovery, immunology, cancer biology, and evolutionary biology by enabling the systematic understanding of protein functions. However, the mutational space associated with proteins is astronomically large, making it overwhelming for current experimental capabilities. Therefore, alternative methods for DMS are imperative. We propose a topological deep learning (TDL) paradigm to facilitate in silico DMS. We utilize a new topological data analysis (TDA) technique based on the persistent spectral theory, also known as persistent Laplacian, to capture both topological invariants and the homotopic shape evolution of data. To validate our TDL-DMS model, we use SARS-CoV-2 datasets and show excellent accuracy and reliability for binding interface mutations. This finding is significant for SARS-CoV-2 variant forecasting and designing effective antibodies and vaccines. Our proposed model is expected to have a significant impact on drug discovery, vaccine design, precision medicine, and protein engineering.

Recurrent and convolutional neural networks for sequential multispectral optoacoustic tomography (MSOT) imaging.

Multispectral optoacoustic tomography (MSOT) is a beneficial technique for diagnosing and analyzing biological samples since it provides meticulous details in anatomy and physiology. However, acquiring high through-plane resolution volumetric MSOT is time-consuming. Here, we propose a deep learning model based on hybrid recurrent and convolutional neural networks to generate sequential cross-sectional images for an MSOT system. This system provides three modalities (MSOT, ultrasound, and optoacoustic imaging of a specific exogenous contrast agent) in a single scan. This study used ICG-conjugated nanoworms particles (NWs-ICG) as the contrast agent. Instead of acquiring seven images with a step size of 0.1 mm, we can receive two images with a step size of 0.6 mm as input for the proposed deep learning model. The deep learning model can generate five other images with a step size of 0.1 mm between these two input images meaning we can reduce acquisition time by approximately 71%.

Efficient platform for synthesizing comprehensive heparan sulfate oligosaccharide libraries for decoding glycosaminoglycan-protein interactions.

Glycosaminoglycans (GAGs) are abundant, ubiquitous carbohydrates in biology, yet their structural complexity has limited an understanding of their biological roles and structure-function relationships. Synthetic access to large collections of well defined, structurally diverse GAG oligosaccharides would provide critical insights into this important class of biomolecules and represent a major advance in glycoscience. Here we report a new platform for synthesizing large heparan sulfate (HS) oligosaccharide libraries displaying comprehensive arrays of sulfation patterns. Library synthesis is made possible by improving the overall synthetic efficiency through universal building blocks derived from natural heparin and a traceless fluorous tagging method for rapid purification with minimal manual manipulation. Using this approach, we generated a complete library of 64 HS oligosaccharides displaying all possible 2-O-, 6-O- and N-sulfation sequences in the tetrasaccharide GlcN-IdoA-GlcN-IdoA. These diverse structures provide an unprecedented view into the sulfation code of GAGs and identify sequences for modulating the activities of important growth factors and chemokines.

Transcriptomic and Chromatin Landscape Analysis Reveals That Involvement of Pituitary Level Transcription Factors Modulate Incubation Behaviors of Magang Geese.

The incubation behavior of geese seriously affects their egg production performance. Studies on incubation behavior have identified functional genes, but the regulatory architecture relationship between functional genes and chromatin accessibility remains poorly understood. Here, we present an integrated analysis of open chromatin profiles and transcriptome to identify the cis-regulatory element and their potential transcription factors involved in regulating incubation behavior in goose pituitary. Assay for transposase-accessible chromatin sequencing (ATAC-seq) revealed that open chromatin regions increased in the pituitary during the transition from incubation behavior to laying. We identified 920 significant differential accessible regions (DARs) in the pituitary. Compared to the laying stage, most DARs had higher chromatin accessibility in the brooding stage. Motif analysis of open DARs showed that the most significant transcription factor (TF) occupied sites predominantly enriched in motifs binding to the RFX family (RFX5, RFX2, and RFX1). While the majority of TF motifs enriched under sites of the nuclear receptor (NR) family (ARE, GRE, and PGR) in closed DARs at the incubation behavior stage. Footprint analysis indicated that the transcription factor RFX family exhibited higher binding on chromatin at the brooding stage. To further elucidate the effect of changes in chromatin accessibility on gene expression levels, a comparison of the transcriptome revealed 279 differentially expressed genes (DEGs). The transcriptome changes were associated with processes of steroid biosynthesis. By integrating ATAC-seq and RNA-seq, few DARs directly affect incubation behavior by regulating the transcription levels of genes. Five DAR-related DEGs were found to be closely related to maintaining the incubation behavior in geese. Footprinting analysis revealed a set of transcription factors (RFX1, RFX2, RFX3, RFX5, BHLHA15, SIX1, and DUX) which displayed the highest activity at the brooding stage. SREBF2 was predicted to be the unique differentially expressed transcription factor whose mRNA level was down-regulated and enriched in hyper-accessible regions of PRL in the broody stage. In the present study, we comprehensively profiled the transcriptome and chromatin accessibility in the pituitary related to incubation behavior. Our findings provided insight into the identification and analysis of regulatory elements in goose incubation behavior. The epigenetic alterations profiled here can help decipher the epigenetic mechanisms that contribute to the regulation of incubation behavior in birds.

Super-resolution and segmentation deep learning for breast cancer histopathology image analysis.

Traditionally, a high-performance microscope with a large numerical aperture is required to acquire high-resolution images. However, the images' size is typically tremendous. Therefore, they are not conveniently managed and transferred across a computer network or stored in a limited computer storage system. As a result, image compression is commonly used to reduce image size resulting in poor image resolution. Here, we demonstrate custom convolution neural networks (CNNs) for both super-resolution image enhancement from low-resolution images and characterization of both cells and nuclei from hematoxylin and eosin (H&E) stained breast cancer histopathological images by using a combination of generator and discriminator networks so-called super-resolution generative adversarial network-based on aggregated residual transformation (SRGAN-ResNeXt) to facilitate cancer diagnosis in low resource settings. The results provide high enhancement in image quality where the peak signal-to-noise ratio and structural similarity of our network results are over 30 dB and 0.93, respectively. The derived performance is superior to the results obtained from both the bicubic interpolation and the well-known SRGAN deep-learning methods. In addition, another custom CNN is used to perform image segmentation from the generated high-resolution breast cancer images derived with our model with an average Intersection over Union of 0.869 and an average dice similarity coefficient of 0.893 for the H&E image segmentation results. Finally, we propose the jointly trained SRGAN-ResNeXt and Inception U-net Models, which applied the weights from the individually trained SRGAN-ResNeXt and inception U-net models as the pre-trained weights for transfer learning. The jointly trained model's results are progressively improved and promising. We anticipate these custom CNNs can help resolve the inaccessibility of advanced microscopes or whole slide imaging (WSI) systems to acquire high-resolution images from low-performance microscopes located in remote-constraint settings.

Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases.

Phosphatidylinositol phosphate kinases (PIPKs) produce lipid signaling molecules and have been attracting increasing attention as drug targets for cancer, neurodegenerative diseases, and viral infection. Given the potential cross-inhibition of kinases and other ATP-utilizing enzymes by ATP-competitive inhibitors, targeting the unique lipid substrate binding site represents a superior strategy for PIPK inhibition. Here, by taking advantage of the nearly identical stereochemistry between myo-inositol and D-galactose, we designed and synthesized a panel of D-galactosyl lysophospholipids, one of which was found to be a selective substrate of phosphatidylinositol 4-phosphate 5-kinase. Derivatization of this compound led to the discovery of a human PIKfyve inhibitor with an apparent IC50 of 6.2 µM, which significantly potentiated the inhibitory effect of Apilimod, an ATP-competitive PIKfyve inhibitor under clinical trials against SARS-CoV-2 infection and amyotrophic lateral sclerosis. Our results provide the proof of concept that D-galactose-based phosphoinositide mimetics can be developed into artificial substrates and new inhibitors of PIPKs.