Efficacy of Polyethylene Glycol Electrolyte Powder Combined with Linaclotide for Colon Cleansing in Patients with Chronic Constipation undergoing colonoscopy: a Multi-centre, single-blinded, Randomized-Controlled Trial.

BACKGROUND AND AIMS: Constipation is an independent risk factor for poor bowel preparation. This study aimed to evaluate the bowel-cleansing efficacy and safety of polyethylene glycol (PEG) combined with linaclotide (lin) for colonoscopy in patients with chronic constipation. METHODS: This single-blinded, randomized, controlled and multicenter study was conducted from July 2021 to December 2022 at seven hospitals. Patients with chronic constipation who underwent colonoscopies were enrolled and randomly assigned to 4 groups with split -PEG regimens: 4L-PEG group, 4L-PEG+1d-Lin group, 3L-PEG+1d-Lin group, and 3L-PEG+3d-Lin group. The primary outcome was rates of adequate bowel preparation, defined as a total BBPS score ≥6 and a score ≥2 for each segment. Secondary outcomes were adverse effects, sleep quality, willingness to repeat the colonoscopy, adenoma detection rate, and polyp detection rate. RESULTS: 502 patients were enrolled. The rates of adequate bowel preparation (80.0% vs. 60.3%, P<0.001; 84.4% vs. 60.3%, P<0.001) and the total BBPS scores (6.90±1.28 vs. 6.00±1.61, P<0.001; 7.03±1.24 vs. 6.00±1.61, P<0.01) in 4L-PEG+1d-Lin group and 3L-PEG+3d-Lin group were superior to that in 4L-PEG group. Compared with 4L-PEG group, 4L-PEG+1d-Lin group (66.7% vs. 81.7%, P=0.008) and 3L-PEG+3d-Lin group (75.0% vs. 81.7%, P=0.224) had a lower percentage of mild adverse events. No statistically significant difference in willingness to repeat the colonoscopy, sleep quality, polyp detection rate, or adenoma detection rate was observed among groups. CONCLUSIONS: PEG combined with linaclotide might be an effective method for bowel preparation before colonoscopy in patients with chronic constipation.

MOODv2: Masked Image Modeling for Out-of-Distribution Detection.

The crux of effective out-of-distribution (OOD) detection lies in acquiring a robust in-distribution (ID) representation, distinct from OOD samples. While previous methods predominantly leaned on recognition-based techniques for this purpose, they often resulted in shortcut learning, lacking comprehensive representations. In our study, we conducted a comprehensive analysis, exploring distinct pretraining tasks and employing various OOD score functions. The results highlight that the feature representations pre-trained through reconstruction yield a notable enhancement and narrow the performance gap among various score functions. This suggests that even simple score functions can rival complex ones when leveraging reconstruction-based pretext tasks. Reconstruction-based pretext tasks adapt well to various score functions. As such, it holds promising potential for further expansion. Our OOD detection framework, MOODv2, employs the masked image modeling pretext task. Without bells and whistles, MOODv2 impressively enhances 14.30% AUROC to 95.68% on ImageNet and achieves 99.98% on CIFAR-10.

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

3D/1D Fe3O4@TiO2/TC-TiO2/SiO2 Magnetic Inorganic-Framework Molecularly Imprinted Fibers for Targeted Photodegradation.

To achieve a selective degradation of pollutants in a water body, 3D/1D magnetic molecularly imprinted fibers Fe3O4@TiO2/TC-TiO2/SiO2 were fabricated by an electrospinning method. The molecularly imprinted layer was successfully prepared by a direct imprinting method using TiO2 as a functional monomer. Fe3O4 facilitates the catalyst recovery and light utilization. The as-prepared fibrous photocatalyst has a large specific surface area of 132.4 m2/g. The successful generation of imprinted sites was proven by various characterizations. The weak interaction between the inorganic functional monomer and tetracycline (TC) was determined to be van der Waals force and hydrogen bonds by the IGMH isosurface theory. The construction of the 3D/1D homojunction of molecularly imprinted materials is beneficial to charge transfer. The as-prepared photocatalyst exhibits a high selectivity coefficient α = 737.38 competing with RhB. The TC removal efficiency reached 100% within only 20 min. In addition, the possible degradation pathway and the degradation mechanism are reasonably proposed. This work not only provides an in-depth mechanism of the weak interaction between the inorganic molecularly imprinted functional monomer and pollutant molecules but also offers new thoughts on the fabrication of photocatalysts for the effective and selective treatment of pollutants in water bodies.

Starter molds and multi-enzyme catalysis in koji fermentation of soy sauce brewing: A review.

Soy sauce is a traditional fermented food produced from soybean and wheat under the action of microorganisms. The soy sauce brewing process mainly involves two steps, namely koji fermentation and moromi fermentation. In the koji fermentation process, enzymes from starter molds, such as protease, aminopeptidase, carboxypeptidase, l-glutaminase, amylase, and cellulase, hydrolyze the protein and starch in the raw ingredients to produce short-chain substances. However, the enzymatic reactions may be diminished after being subjected to moromi fermentation due to its high NaCl concentration. These enzymatically hydrolyzed products are further metabolized by lactic acid bacteria and yeasts during the moromi fermentation process into organic acids and aromatic compounds, giving soy sauce a unique flavor. Thus, the starter molds, such as Aspergillus oryzae, Aspergillus sojae, and Aspergillus niger, and their secreted enzymes play crucial roles in soy sauce brewing. This review comprehensively covers the characteristics of the starter molds mainly used in soy sauce brewing, the enzymes produced by starter molds, and the roles of enzymes in the degradation of raw material. We also enumerate current problems in the production of soy sauce, aiming to offer some directions for the improvement of soy sauce taste.

Understanding the two-stage degradation process of peach gum polysaccharide within ultrasonic field.

This study investigated the dynamic degradation process of peach gum polysaccharide (PGPS) within ultrasonic field. The results show that the molecular weight, intrinsic viscosity, and polydispersity of PGPS were rapidly reduced within the initial 30 min and then gradually decreased. The solubility of PGPS was drastically improved from 3.0% to 40.0-42.0% (w/w) after 120 min. The conformation of PGPS changed from an extended chain to a flexible random coil within initial time of ultrasound, and gradually tended to be compact spheres. The apparent viscosity of PGPS significantly decreased after 30 min, and PGPS solution exhibited a near-Newtonian fluid behavior. It is possible that these above changes are a result of random cleavage of the decrosslinking and the backbone of PGPS, resulting in the preservation of its primary structure. The results will provide a fundamental basis for orientation design and process control of ultrasonic degradation of PGPS.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

The structural characterization of a novel Chinese yam polysaccharide and its hypolipidemic activity in HFD-induced obese C57BL/6J mice.

Obesity was considered as a rapidly growing chronic disease that influences human health worldwide. In this study, we investigated the primary structure characteristics of Chinese yam polysaccharide (CYP) and its role in regulating lipid metabolism in a high-fat diet (HFD)-fed obese mice. The molecular weight of CYP was determined to be 3.16 × 103 kDa. Periodic acid oxidation & smith degradation and nuclear magnetic resonance results suggested that CYP consists of 1 → 2, 1 â†’ 2, 6, 1 â†’ 4, 1 â†’ 4, 6, 1→, or 1 â†’ 6 glycoside bonds. The in vivo experiment results suggested that the biochemical indices, tissue sections, and protein regulation associated with lipid metabolism were changed after administering CYP in obese mice. In addition, the abundances of short-chain fatty acid (SCFA)-producing bacteria Lachnospiraceae, Lachnospiraceae_NK4A136_group, and Ruminococcaceae_UCG-014 were increased, and the abundances of bacteria Desulfovibrionaceae and Ruminococcus and metabolites of arginine, propionylcarnitine, and alloisoleucine were decreased after CYP intervention in obese mice. Spearman's correlation analysis of intestinal flora, metabolites, and lipid metabolism parameters showed that CYP may affect lipid metabolism in obese mice by regulating the intestinal environment. Therefore, CYP may be used as a promising nutritional intervention agent for lipid metabolism.

An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

First complete mitochondrial genome of the Alashan ground squirrel (Spermophilus alashanicus) (Rodentia: Sciuridae) from Ningxia, China.

The Alashan ground squirrel (Spermophilus alashanicus) is primarily distributed in the regions of Inner Mongolia and Ningxia, China. In this study, we present the first complete mitochondrial genome of S. alashanicus. The genome spans 16,464 base pairs and comprises 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a single control region with a marked AT bias. The overall GC content is 35.4%. Phylogenetic analyses indicate that S. alashanicus clusters are closely associated with S. dauricus. This comprehensive characterization of the S. alashanicus mitochondrial genome serves as a foundational resource for future studies on mitochondrial evolution, species identification, population genomics, and phylogenetics.

Exploring Phthalimide as the Acid Component in the Passerini Reaction.

Multicomponent reactions, particularly the Passerini reaction, serve as efficient tools for the synthesis of druglike molecules and the creation of compound libraries. Despite the effectiveness of the Passerini reaction, the limited alternatives to the crucial carboxylic acid component pose a structural constraint. Here, we have discovered that the phthalimide moiety and its derivatives react in the Passerini reaction as an acid component. We explored their potential in synthesizing diverse and intricate molecules. The phthalimide moiety stands out as a favorable building block due to its oxidative stability, heat-stable characteristics, and resistance to solvents. Our approach introduces a novel perspective to multicomponent reactions by incorporating NH-based acid components, addressing the ongoing need for the development of innovative molecular scaffolds.

PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release.

Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.

BAL: Balancing Diversity and Novelty for Active Learning.

The objective of Active Learning is to strategically label a subset of the dataset to maximize performance within a predetermined labeling budget. In this study, we harness features acquired through self-supervised learning. We introduce a straightforward yet potent metric, Cluster Distance Difference, to identify diverse data. Subsequently, we introduce a novel framework, Balancing Active Learning (BAL), which constructs adaptive sub-pools to balance diverse and uncertain data. Our approach outperforms all established active learning methods on widely recognized benchmarks by 1.20%. Moreover, we assess the efficacy of our proposed framework under extended settings, encompassing both larger and smaller labeling budgets. Experimental results demonstrate that, when labeling 80% of the samples, the performance of the current SOTA method declines by 0.74%, whereas our proposed BAL achieves performance comparable to the full dataset.

Genetically Engineered Protein-Based Bioadhesives with Programmable Material Properties.

Silk-amyloid-mussel foot protein (SAM) hydrogels made from recombinant fusion proteins containing ß-amyloid peptide, spider silk domain, and mussel foot protein (Mfp) are attractive bioadhesives as they display a unique combination of tunability, biocompatibility, bioabsorbability, strong cohesion, and underwater adhesion to a wide range of biological surfaces. To design tunable SAM hydrogels for tailored surgical repair applications, an understanding of the relationships between protein sequence and hydrogel properties is imperative. Here, we fabricated SAM hydrogels using fusion proteins of varying lengths of silk-amyloid repeats and Mfps to characterize their structure and properties. We found that increasing silk-amyloid repeats enhanced the hydrogel's ß-sheet content (r = 0.74), leading to higher cohesive strength and toughness. Additionally, increasing the Mfp length beyond the half-length of the full Mfp sequence (1/2 Mfp) decreased the ß-sheet content (r = -0.47), but increased hydrogel surface adhesion. Among different variants, the hydrogel made of 16xKLV-2Mfp displayed a high ultimate strength of 3.0 ± 0.3 MPa, an ultimate strain of 664 ± 119%, and an attractive underwater adhesivity of 416 ± 20 kPa to porcine skin. Collectively, the sequence-structure-property relationships learned from this study will be useful to guide the design of future protein adhesives with tunable characteristics for tailored surgical applications.

Tailored biomedical materials for wound healing.

Wound healing is a long-term, multi-stage biological process that mainly includes haemostatic, inflammatory, proliferative and tissue remodelling phases. Controlling infection and inflammation and promoting tissue regeneration can contribute well to wound healing. Smart biomaterials offer significant advantages in wound healing because of their ability to control wound healing in time and space. Understanding how biomaterials are designed for different stages of wound healing will facilitate future personalized material tailoring for different wounds, making them beneficial for wound therapy. This review summarizes the design approaches of biomaterials in the field of anti-inflammatory, antimicrobial and tissue regeneration, highlights the advanced precise control achieved by biomaterials in different stages of wound healing and outlines the clinical and practical applications of biomaterials in wound healing.

Patient Brain Organoids Identify a Link between the 16p11.2 Copy Number Variant and the RBFOX1 Gene.

Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.

Genome-wide promoter responses to CRISPR perturbations of regulators reveal regulatory networks in Escherichia coli.

Elucidating genome-scale regulatory networks requires a comprehensive collection of gene expression profiles, yet measuring gene expression responses for every transcription factor (TF)-gene pair in living prokaryotic cells remains challenging. Here, we develop pooled promoter responses to TF perturbation sequencing (PPTP-seq) via CRISPR interference to address this challenge. Using PPTP-seq, we systematically measure the activity of 1372 Escherichia coli promoters under single knockdown of 183 TF genes, illustrating more than 200,000 possible TF-gene responses in one experiment. We perform PPTP-seq for E. coli growing in three different media. The PPTP-seq data reveal robust steady-state promoter activities under most single TF knockdown conditions. PPTP-seq also enables identifications of, to the best of our knowledge, previously unknown TF autoregulatory responses and complex transcriptional control on one-carbon metabolism. We further find context-dependent promoter regulation by multiple TFs whose relative binding strengths determined promoter activities. Additionally, PPTP-seq reveals different promoter responses in different growth media, suggesting condition-specific gene regulation. Overall, PPTP-seq provides a powerful method to examine genome-wide transcriptional regulatory networks and can be potentially expanded to reveal gene expression responses to other genetic elements.

Soil microbial community characteristics and the influencing factors at different elevations on the eastern slope of Helan Mountain, Northwest China.

As an important bridge connecting aboveground communities and belowground biological processes, soil microorganisms play an important role in regulating belowground ecological processes. The altitudinal changes and driving factors of soil microbial community in mountain ecosystem in arid region are still unclear. We measured soil physicochemical properties at seven altitudes in the range of 1300-2800 m in Helan Mountains, and investigated the understory community composition, soil physicochemical properties, and soil microbial community. The driving factor for soil microbial community was explored by variance partitioning analysis and redundancy analysis. The results showed that the total amount of soil microorganisms and bacterial biomass first increased and then decreased with the increases of altitude, fungi, actinomyces, arbuscular mycorrhizal fungi, Gram-positive bacteria, and Gram-negative bacteria groups showed a gradual increase. The variation of fungal-to-bacterial ratio (F/B) along the altitude showed that the cumulative ability of soil bacteria was stronger than that of fungi at low altitudes, while the pattern is opposite at high altitudes. The ratio of Gram-positive bacteria to Gram-negative bacteria (GP/GN) showed an overall decreasing trend with the increases of altitude, indicating that soil bacteria and organic carbon availability changed from "oligotrophic" to "eutrophication" and from "low" to "high" transition as the altitude increased. Vegetation properties, soil physical and chemical properties jointly accounted for 95.7% of the variation in soil microbial community. Soil organic carbon (SOC), soil water content (SWC), and total nitrogen (TN) were significantly correlated with soil microbial community composition. Our results revealed the distribution pattern and driving factors of soil microbial communities at different elevations on the eastern slope of Helan Mountain, which would provide theoretical basis and data support for further understanding the interaction between plant-soil-microorganisms in arid areas.

Protein-Based Hydrogels and Their Biomedical Applications.

Hydrogels made from proteins are attractive materials for diverse medical applications, as they are biocompatible, biodegradable, and amenable to chemical and biological modifications. Recent advances in protein engineering, synthetic biology, and material science have enabled the fine-tuning of protein sequences, hydrogel structures, and hydrogel mechanical properties, allowing for a broad range of biomedical applications using protein hydrogels. This article reviews recent progresses on protein hydrogels with special focus on those made of microbially produced proteins. We discuss different hydrogel formation strategies and their associated hydrogel properties. We also review various biomedical applications, categorized by the origin of protein sequences. Lastly, current challenges and future opportunities in engineering protein-based hydrogels are discussed. We hope this review will inspire new ideas in material innovation, leading to advanced protein hydrogels with desirable properties for a wide range of biomedical applications.

A Modular Chemistry Platform for the Development of a Cereblon E3 Ligase-Based Partial PROTAC Library.

Proteolysis targeting chimeras (PROTACs) are a promising therapeutic strategy to selectively promote the degradation of protein targets by exploiting the ubiquitin-proteasome system. Among the limited number of E3 ligase ligands discovered for the PROTAC technology, ligands of cereblon (CRBN) E3 ligase, such as pomalidomide, thalidomide, or lenalidomide, are the most frequently used for the development of PROTACs. Our group previously reported that a phenyl group could be tolerated on the C4-position of lenalidomide as the ligand of CRBN to develop PROTACs. Herein, we report a modular chemistry platform for the efficient attachment of various ortho-, meta-, and para-substituted phenyls to the C4-position of the lenalidomide via Suzuki cross-coupling reaction, which allows the systematic investigation of the linker effect for the development of PROTACs against any target. We examined the substrate scope by preparing twelve lenalidomide-derived CRBN E3 ligase ligands with different linkers.