Highly stereoselective α-glycosylation with GalN3 donors enabled collective synthesis of mucin-related tumor associated carbohydrate antigens.

Mucin-related tumor-associated carbohydrate antigens (TACAs) are important and interesting targets for cancer vaccine therapy. However, efficient access to a library of mucin-related TACAs remains a challenging task. One of the key issues is the challenging construction of α-GalNAc linkages. Here, we report highly stereoselective α-glycosylation with GalN3N-phenyl trifluoroacetimidate donors, which features excellent yields, outstanding stereoselectivities, broad substrate scope and mild reaction conditions. This method is successfully applied to highly stereoselective synthesis of GalN3-α-O-Ser, which served as the common intermediate for collective synthesis of a wide range of TACAs including TN antigen, STN antigen, 2,6 STF antigen, 2,3 STF antigen, glycophorin and cores 1-8 mucin-type O-glycans. In particular, the rationale for this highly stereoselective α-glycosylation is provided for the first time using DFT calculations and mechanistic studies, highlighting the crucial roles of reagent combinations (TMSI and Ph3PO) and the H-bonding directing effect of the N3 group.

Ligand-Dominated Activation of CO2 and CS2 by the Putative Nickel Phosphiniminato Intermediates.

Room-temperature photoactivation of the first- and second-generation PN3P-pincer nickel azido complexes 1a and 1b in the presence of CO2 or CS2 afforded N-bound carbamates, dithiocarbamates, and isothiocyanates, providing insights into CO2 and CS2 activation and demonstrating how a seemingly small difference in the ligand structure significantly influences the reactivity. Theoretical calculations disclosed that the charge of the phosphorus atom plays a critical role in determining the nitrogen atom transfer to form a plausible nickel phosphiniminato intermediate.

Gut microbiome as a treatment in colorectal cancer.

BACKGROUND: The gut microbiome plays a role in the development and progression of colorectal cancer (CRC). AIM AND OBJECTIVE: This review focuses on whether the gut microbiome is involved in the development and regulation of the host immune system. METHODS: The gut microbiome can influence the production and activity of immune cells and molecules that help to maintain the integrity of the intestinal barrier and prevent inflammation. Gut microbiota modulates the anti-cancer immune response. The gut microbiota can influence the function of immune cells, like T cells, that recognize and eliminate cancer cells. Gut microbiota can affect various aspects of cancer progression and the efficacy of various anti-cancer treatments. RESULTS: Gut microbiota provide promise as a potential biomarker to identify the effect of immunotherapy and as a target for modulation to improve the efficacy of immunotherapy in CRC treatment. CONCLUSION: The potential synergistic effect between the gut microbiome and anti-cancer treatment modalities provides an interest in developing strategies to modulate the gut microbiome to improve the efficacy of anti-cancer treatment.

This review focuses on the gut microbiome in the development and regulation of the host immune system. Gut microbiota provides potential biomarkers to identify the effect of immunotherapy and as a target for modulation of immunotherapy in the treatment of CRC. This provides potential synergistic effects between the gut microbiome and anti-cancer treatment modalities.

Dodecahedral hollow multi-shelled Co3O4/Ag:ZnIn2S4 photocatalyst for enhancing solar energy utilization efficiency.

Employing semiconductor photocatalysts featuring a hollow multi-shelled (HoMs) structure to establish a heterojunction is an effective approach to addressing the issues of low light energy utilization and severe recombination of photogenerated charge carriers. To take advantage of these key factors in semiconductor photocatalysis, here, a dodecahedral HoMs Co3O4/Ag:ZnIn2S4 photocatalyst (denoted as Co3O4/AZIS) was firstly synthesized by coupling Ag+-doped ZnIn2S4 (AZIS) nanosheets with dodecahedral HoMs Co3O4. The unique HoMs structure of the photocatalyst can not only effectively promote the separation and transfer of photo-induced charge, but also improve the utilization rate of visible light, exposing rich active sites for the photocatalytic redox reaction. The photocatalytic experiment results showed that the Co3O4/90.0 wt% AZIS photocatalyst has a high hydrogen (H2) production rate (695.0 µmol h-1 g-1) and high methyl orange (MO) degradation rate (0.4243 min-1). This work provides a feasible strategy for the development of HoMs heterojunction photocatalysts with enhanced H2 production and degradation properties of organic dyes.

Highly Stereoselective Synthesis of Branched Fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with Potent Antiosteoporosis Activities.

The branched fructooligosaccharides ABW90-1 and ABW50-1 from Achyranthes bidentata with potent antiosteoporosis activities have been synthesized for the first time. The synthetic approach highlights the following features: (1) 6-O-picoloyl-directed ß-d-fructofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy for the highly stereoselective constructions of ß-(2 → 6)-d-fructofuranosidic linkages and ß-(2 → 1)-d-fructofuranosidic linkages in the internal positions under the reaction conditions (DBDMH, -20 °C, CH2Cl2) and (2) the reaction conditions (DBDMH, -78 °C to -35 °C, toluene) for highly stereoselective formations of ß-(2 → 1)-d-fructofuranosidic linkages in the terminal positions.

Hypercholesterolemia Is Associated With Dysregulation of Lipid Metabolism and Poor Prognosis in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Hypercholesterolemia is frequently diagnosed in patients with primary biliary cholangitis (PBC). However, its association with the prognosis and lipid metabolism is unknown. In this study, we aimed to investigate the prognostic value of baseline total cholesterol (TC) levels in PBC and characterized the associated lipid metabolism. METHODS: Five hundred and thirty-one patients with PBC without prior cirrhosis-related complications were randomly divided into the derivation and validation cohorts at a ratio of 7:3. Complete clinical data were obtained and analyzed. The endpoints were defined as liver-related death, liver transplantation, and cirrhosis-related complications. Lipidomics was performed in 89 patients and 28 healthy controls. RESULTS: Baseline TC was independently associated with poor liver-related outcomes, and adjusted C-statistics were 0.80 (95% confidence interval [CI]: 0.74-0.85) and 0.88 (95% CI: 0.78-0.91) in the derivation and validation cohorts, respectively. The predictive ability of TC for disease outcomes was stable over time and comparable with the Globe score. The 200 mg/dL cut-off optimally divided patients into low- and high-TC groups. A combination of TC and Globe score provided a more accurate stratification of patients into risk subgroups. Lipidomics indicated an up-regulation of lipid families in high-TC patients. Pathway analysis of 66 up-regulated lipids revealed the dysregulation of glycerophospholipid and sphingolipid metabolism in high-TC patients, which were associated with poor liver-related outcomes. CONCLUSIONS: Our results indicate that patients with PBC having baseline TC levels above 200 mg/dL have unique lipidome characteristics and are at a higher risk of poor liver-related outcomes.

One-Pot Assembly of Mannose-Capped Lipoarabinomannan Motifs up to 101-Mer from the Mycobacterium tuberculosis Cell Wall.

Lipoarabinomannan (LAM) from the Mycobacterium tuberculosis cell envelope represents important targets for the development of new therapeutic agents against tuberculosis, which is a deadly disease that has plagued mankind for a long time. However, the accessibility of long, branched, and complex lipoarabinomannan over 100-mer remains a long-standing challenge. Herein, we report the modular synthesis of mannose-capped lipoarabinomannan 101-mer from the M. tuberculosis cell wall using a one-pot assembly strategy on the basis of glycosyl ortho-(1-phenylvinyl)benzoates (PVB), which not only accelerates the modular synthesis but also precludes the potential problems associated with one-pot glycosylation with thioglycosides. Shorter sequences including 18-mer, 19-mer, and 27-mer are also synthesized for in-depth structure-activity relationship biological studies. Current synthetic routes also highlight the following features: (1) streamlined synthesis of various linear and branched glycans using one-pot orthogonal glycosylation on the combination of glycosyl N-phenyltrifluoroacetimidates, glycosyl ortho-alkynylbenzoates, and glycosyl PVB; (2) highly stereoselective construction of 10 1,2-cis-arabinofuranosyl linkages using 5-O-(2-quinolinecarbonyl)-directing 1,2-cis-arabinofuranosylation via a hydrogen-bond-mediated aglycone delivery strategy; and (3) convergent [(18 + 19) × 2 + 27] one-pot synthesis of the 101-mer LAM polysaccharide. The present work demonstrates that this orthogonal one-pot glycosylation strategy can highly streamline the chemical synthesis of long, branched, and complex polysaccharides.

A missense GDF5 variant causes brachydactyly type A1 and multiple-synostoses syndrome 2.

Objective: This study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple-synostoses syndrome 2 (SYNS2). Methods: A Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole-exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I-TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins. Results: The family was found to have an autosomal-dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue. Conclusions: A single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist- and receptor-binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.

Association of a novel frameshift variant and a known deleterious variant in MMR genes with Lynch syndrome in Chinese families.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This condition is characterized by germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. In this study, we analyzed the molecular defects and clinical manifestations of two families affected with CRC and proposed appropriate individual preventive strategies for all carriers of the variant. METHODS: We recruited two families diagnosed with CRC and combined their family history and immunohistochemical results to analyze the variants of probands and those of other family members by using whole exome sequencing. Subsequently, gene variants in each family were screened by comparing them with the variants available in the public database. Sanger sequencing was performed to verify the variant sites. An online platform ( https://www.uniprot.org ) was used to analyze the functional domains of mutant proteins. RESULTS: A novel frameshift variant (NM_001281492, c.1129_1130del, p.R377fs) in MSH6 and a known deleterious variant (NM_000249.4:c.1731G > A, p.S577S) in MLH1 were identified in the two families with CRC. Using bioinformatics tools, we noted that the frameshift variant reduced the number of amino acids in the MSH6 protein from 1230 to 383, thereby leading to no MSH6 protein expression. The silent variant caused splicing defects and was strongly associated with LS. 5-Fluorouracil-based adjuvant chemotherapy is not recommended for patients with LS. CONCLUSIONS: The novel frameshift variant (MSH6, c.1129_1130del, p.R377fs) is likely pathogenic to LS, and the variant (MLH1, c.1731G > A, p.S577S) has been further confirmed to be pathogenic to LS. Our findings underscore the significance of genetic testing for LS and recommend that genetic consultation and regular follow-ups be conducted to guide individualized treatment for cancer-afflicted families, especially those with a deficiency in MMR expression.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Modular and Stereoselective One-Pot Total Synthesis of Icosasaccharide Motif from Cordyceps sinensis EPS-1A Glycan.

The first stereoselective one-pot synthesis of the icosasaccharide motif of EPS-1A glycan from Cordyceps sinensis has been achieved. The synthetic approach highlights the following features: (1) merging reagent modulation and remote anchimeric assistance α-glycosylation strategy for the highly stereoselective formation of five and ten continuous 1,2-cis glucosidic bonds; (2) the strategic employment of glycosyl N-phenyltrifluoroacetimidates and glycosyl o-(1-phenylvinyl)benzoates as the matched pair for efficient orthogonal one-pot synthesis; and (3) [11 + 8 + 1] orthogonal one-pot glycosylation for the efficient assembly of the target icosasaccharide.

Collaborative Camouflaged Object Detection: A Large-Scale Dataset and Benchmark.

In this article, we provide a comprehensive study of a new task called collaborative camouflaged object detection (CoCOD), which aims to simultaneously detect camouflaged objects with the same properties from a group of relevant images. To this end, we meticulously construct the first large-scale dataset, termed CoCOD8K, which consists of 8528 high-quality and elaborately selected images with object mask annotations, covering five superclasses and 70 subclasses. The dataset spans a wide range of natural and artificial camouflage scenes with diverse object appearances and backgrounds, making it a very challenging dataset for CoCOD. Besides, we propose the first baseline model for CoCOD, named bilateral-branch network (BBNet), which explores and aggregates co-camouflaged cues within a single image and between images within a group, respectively, for accurate camouflaged object detection (COD) in given images. This is implemented by an interimage collaborative feature exploration (CFE) module, an intraimage object feature search (OFS) module, and a local-global refinement (LGR) module. We benchmark 18 state-of-the-art (SOTA) models, including 12 COD algorithms and six CoSOD algorithms, on the proposed CoCOD8K dataset under five widely used evaluation metrics. Extensive experiments demonstrate the effectiveness of the proposed method and the significantly superior performance compared to other competitors. We hope that our proposed dataset and model will boost growth in the COD community. The dataset, model, and results will be available at: https://github.com/zc199823/BBNet-CoCOD.

Recent Advances in Chemical Synthesis of Structural Domains of Lipopolysaccharides from the Commensal Gut-Associated Microbiota.

Lipopolysaccharides from the commensal gut-associated microbiota are interesting biomolecules for the treatment of various inflammatory diseases. Different from pathogenic lipopolysaccharides, commensal lipopolysaccharides have distinct chemical structures and mediate beneficial homeostasis with the immune system of the host. However, the accessibility issues of homogenous and pure commensal lipopolysaccharides hampered the in-depth studies of their functions. In this concept article, we highlight the recent synthesis of lipopolysaccharides from gut-associated lymphoid-tissue-resident Alcaligenes faecalis and Bacteroides vulgatus, which hopes to inspire the more efforts devoting to these fantastic biomolecules.

Recent chemical synthesis of plant polysaccharides.

Here, chemical syntheses of long, branched and complex glycans over 10-mer from plants are summarized, which highlights amylopectin 20-mer from starch, 17-mer from carthamus tinctorius, α-glucan 30-mer from Longan, 19-mer from psidium guajava and 11-mer from dendrobium huoshanense. The glycans assembly strategies, protecting groups utilization and glycosylation methods discussed here will inspire the efficient synthesis of diverse complex glycans with many 1,2-cis glycosidic linkages.

Corrigendum: A heterozygous mutation in NOTCH3 in a Chinese family with CADASIL.

[This corrects the article DOI: 10.3389/fgene.2022.943117.].

Identification of a novel CNV at the APC gene in a Chinese family with familial adenomatous polyposis.

Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed. Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676-112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product. Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.

Prognostic Value of Systemic Inflammation Score for Esophageal Cancer Patients Undergoing Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: The link between inflammation and cancer survival has been the subject of substantial research. The goal of this review is to summarize the evidence on the prognostic value of systemic inflammation score (SIS) in esophageal cancer patients undergoing surgical intervention. METHODS: PubMed, Scopus, Embase, and Web of Science were searched for relevant articles published until 30th June 2022. We pooled adjusted data on overall survival (OS) and disease-free survival (DFS) using a random-effects meta-analysis model. The review was pre-registered on PROSPER (No. CRD42022340717). RESULTS: Eight studies were included. All studies were conducted either in China or Japan. Six studies showed that patients with SIS of 1-2 had poor OS as compared to those with scores of 0 (HR:1.42 95% CI: 1.24, 1.62 I2=25%). SIS of 1 (HR:1.45 95% CI: 1.18, 1.78 I2=0%) and 2 (HR:1.94 95% CI: 1.49, 2.53 I2=0%) were also associated with poor OS. Two studies compared the SIS score of 2 vs 0-1. Meta-analysis indicated that poor OS was associated with SIS of 2 (HR:1.80 95% CI: 1.25, 2.58). Data from three studies showed that the SIS score did not predict DFS (HR:1.40 95% CI: 0.82, 2.39 I2=91%). CONCLUSION: SIS can be a novel prognostic indicator for esophageal cancer patients undergoing surgical intervention. Higher SIS is associated with a poor OS, but it does not predict DFS. Future studies are needed to strengthen the current evidence.

Completely non-invasive cell manipulation in lens-integrated microfluidic devices by single-fiber optical tweezers.

In a fiber-based optical tweezer system, it is a common practice to insert the fiber probe into the sample solution to perform the tweezer function. Such a configuration of the fiber probe may lead to unwanted contamination and/or damage to the sample system and is thus potentially invasive. Here, we propose a completely non-invasive method for cell manipulation by combining a microcapillary microfluidic device and an optical fiber tweezer. We demonstrate that Chlorella cells inside the microcapillary channel can be successfully trapped and manipulated by an optical fiber probe located outside of the microcapillary, thus making the process completely non-invasive. The fiber does not even invade the sample solution. To our knowledge, this is the first report of such a method. The speed of stable manipulation can reach the 7 µm/s scale. We found that the curved walls of the microcapillaries worked like a lens, which helped to boost the light focusing and trapping efficiency. Numerical simulation of optical forces under medium settings reveals that the optical forces can be enhanced by up to 1.44 times, and the optical forces can change direction under certain conditions.

Modular Synthesis of a Tridecasaccharide Motif of Bacteroides vulgatus Lipopolysaccharides against Inflammatory Bowel Diseases through an Orthogonal One-Pot Glycosylation Strategy.

Lipopolysaccharides from Bacteroides vulgatus represent interesting targets for the treatment of inflammatory bowel diseases. However, efficient access to long, branched and complex lipopolysaccharides remains challenging. Herein, we report the modular synthesis of a tridecasaccharide from Bacteroides vulgates through an orthogonal one-pot glycosylation strategy based on glycosyl ortho-(1-phenylvinyl)benzoates, which avoids the issues of thioglycoside-based one-pot synthesis. Our approach also features: 1) 5,7-O-di-tert-butylsilylene-directed glycosylation for stereoselective construction of the α-Kdo linkage; 2) hydrogen-bond-mediated aglycone delivery for the stereoselective formation of ß-mannosidic bonds; 3) remote anchimeric assistance for stereoselective assembly of the α-fucosyl linkage; 4) several orthogonal one-pot synthetic steps and strategic use of orthogonal protecting groups to streamline oligosaccharide assembly; 5) convergent [1+6+6] one-pot synthesis of the target.

Delivery of Methoprene-Tolerant dsRNA to Improve RNAi Efficiency by Modified Liposomes for Pest Control.

The application of RNA interference (RNAi) technology for pest control is environmentally friendly and accurate. However, the efficiency of RNAi is often inconsistent and unreliable, and finding a suitable carrier element is considered critical to success in overcoming biotic and abiotic barriers to reach the target site. The fall armyworm, Spodoptera frugiperda (FAW), which is one of most important global agricultural pests, has recently spread rapidly to other parts of the world. In this study, a method to improve the stability and RNAi efficiency of the dsRNA carrier complex was reported. Methoprene-tolerant gene (Met) was selected as a target, a gene which is critical to the growth and development of FAW. Biomaterials nanoliposomes (LNPs) were modified with polyethylenimine (PEI) to deliver the dsRNA of Met. The synthesized Met3@PEI@LNPs reached a size of 385 nm and were found to load dsRNA effectively. Through stability and protection assays, it was found that LNPs provided reliable protection. In addition, the release curve also demonstrated that LNPs were able to prevent premature release under alkaline condition of the insect midgut but accelerate the release after entering the acidic environment of the target cells. The cell transfection efficiency of the prepared LNPs reached 96.4%. Toxicity tests showed that the use of LNPs could significantly improve the interference efficiency, with 91.7% interference efficiency achieved when the concentration of dsRNA in LNPs was only 25% of that of the control. Successful interference of Met demonstrated it could significantly shorten the larval period and make the larvae pupate earlier, thus achieving the purpose of control. In this study, we have demonstrated the use of nanotechnology to provide a novel RNAi delivery method for pest control.