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Nature Communications Oct 2023Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The...
Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed a conserved epitope, away from the HBGA binding site, fully accessible only when VP1 transitions to a "raised" conformation in the capsid. Together with dynamic light scattering and electron microscopy of the GII.4 VLPs, our studies suggest a mechanism in which M4 accesses the epitope by altering the conformational dynamics of the capsid and triggering its disassembly to neutralize GII.4 infection.
Topics: Humans; Capsid Proteins; Capsid; Norovirus; Binding Sites; Epitopes; Blood Group Antigens; Caliciviridae Infections
PubMed: 37845211
DOI: 10.1038/s41467-023-42146-0 -
Trends in Cell Biology Nov 2023Primary cilia protrude from most vertebrate cell bodies and act as specialized 'signalling antennae' that can substantially lengthen or retract in minutes to hours in... (Review)
Review
Primary cilia protrude from most vertebrate cell bodies and act as specialized 'signalling antennae' that can substantially lengthen or retract in minutes to hours in response to specific stimuli. Here, we review the conditions and mechanisms responsible for regulating primary cilia length (PCL) in mammalian nonsensory neurons, and propose four models of how they could affect ciliary signalling and alter cell state and suggest experiments to distinguish between them. These models include (i) the passive indicator model, where changes in PCL have no consequence; (ii) the rheostat model, in which a longer cilium enhances signalling; (iii) the local concentration model, where ciliary shortening increases the local protein concentration to facilitate signalling; and (iv) the altered composition model where changes in PCL skew signalling.
Topics: Humans; Animals; Cilia; Signal Transduction; Vertebrates; Neurons; Mammals
PubMed: 37302961
DOI: 10.1016/j.tcb.2023.05.005 -
Acta Biomaterialia Sep 2023Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc... (Review)
Review
Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. IVD herniation manifests as the nucleus pulposus (NP) protruding beyond the boundaries of the intervertebral disc due to disruption of the annulus fibrosus (AF). With a deepening understanding of the importance of the AF structure in the pathogenesis of intervertebral disc degeneration, numerous advanced therapeutic strategies for AF based on tissue engineering, cellular regeneration, and gene therapy have emerged. However, there is still no consensus concerning the optimal approach for AF regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. STATEMENT OF SIGNIFICANCE: Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. However, there is still no consensus concerning the optimal approach for annulus fibrosus (AF) regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions.
Topics: Humans; Annulus Fibrosus; Tissue Engineering; Low Back Pain; Intervertebral Disc; Intervertebral Disc Degeneration; Intervertebral Disc Displacement; Biocompatible Materials
PubMed: 37330029
DOI: 10.1016/j.actbio.2023.06.012 -
Open Biology Dec 2023Cilia are hair-like organelles that protrude from the surface of eukaryotic cells and are present on the surface of nearly all human cells. Cilia play a crucial role in... (Review)
Review
Cilia are hair-like organelles that protrude from the surface of eukaryotic cells and are present on the surface of nearly all human cells. Cilia play a crucial role in signal transduction, organ development and tissue homeostasis. Abnormalities in the structure and function of cilia can lead to a group of human diseases known as ciliopathies. Currently, zebrafish serves as an ideal model for studying ciliary function and ciliopathies due to its relatively conserved structure and function of cilia compared to humans. In this review, we will summarize the different types of cilia that present in embryonic and adult zebrafish, and provide an overview of the advantages of using zebrafish as a vertebrate model for cilia research. We will specifically focus on the roles of cilia during zebrafish organogenesis based on recent studies. Additionally, we will highlight future prospects for ciliary research in zebrafish.
Topics: Animals; Humans; Zebrafish; Cilia; Ciliopathies; Homeostasis; Organogenesis
PubMed: 38086423
DOI: 10.1098/rsob.230228 -
Frontiers in Immunology 2023As a component of the innate immune system, there is emerging evidence to suggest that neutrophils may play a critical role in the initiation and progression of... (Review)
Review
As a component of the innate immune system, there is emerging evidence to suggest that neutrophils may play a critical role in the initiation and progression of hepatocellular carcinoma (HCC). Neutrophil extracellular traps (NETs) are web-like chromatin structures that protrude from the membranes during neutrophil activation. Recent research has shown that NETs, which are at the forefront of the renewed interest in neutrophil studies, are increasingly intertwined with HCC. By exploring the mechanisms of NETs in HCC, we aim to improve our understanding of the role of NETs and gain deeper insights into neutrophil biology. Therefore, this article provides a summary of key findings and discusses the emerging field of NETs in HCC.
Topics: Humans; Extracellular Traps; Carcinoma, Hepatocellular; Liver Neoplasms; Neutrophils
PubMed: 38173719
DOI: 10.3389/fimmu.2023.1253964 -
ELife Aug 2023MCM8 and MCM9 form a functional helicase complex (MCM8/9) that plays an essential role in DNA homologous recombination repair for DNA double-strand break. However, the...
MCM8 and MCM9 form a functional helicase complex (MCM8/9) that plays an essential role in DNA homologous recombination repair for DNA double-strand break. However, the structural characterization of MCM8/9 for DNA binding/unwinding remains unclear. Here, we report structures of the MCM8/9 complex using cryo-electron microscopy single particle analysis. The structures reveal that MCM8/9 is arranged into a heterohexamer through a threefold symmetry axis, creating a central channel that accommodates DNA. Multiple characteristic hairpins from the N-terminal oligosaccharide/oligonucleotide (OB) domains of MCM8/9 protrude into the central channel and serve to unwind the duplex DNA. When activated by HROB, the structure of MCM8/9's N-tier ring converts its symmetry from to with a conformational change that expands the MCM8/9's trimer interface. Moreover, our structural dynamic analyses revealed that the flexible C-tier ring exhibited rotary motions relative to the N-tier ring, which is required for the unwinding ability of MCM8/9. In summary, our structural and biochemistry study provides a basis for understanding the DNA unwinding mechanism of MCM8/9 helicase in homologous recombination.
Topics: DNA-Binding Proteins; Minichromosome Maintenance Proteins; Cryoelectron Microscopy; Recombinational DNA Repair; DNA
PubMed: 37535404
DOI: 10.7554/eLife.87468 -
Endoscopic and Histopathological Characteristics of Gastrointestinal Lymphoma: A Multicentric Study.Diagnostics (Basel, Switzerland) Aug 2023: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic...
: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic characteristics of primary gastrointestinal non-Hodgkin lymphomas. : We investigated 140 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. Characteristics of the lesions were evaluated and analyzed using image-enhanced endoscopy, endoscopic ultrasound, and histopathology. : The median age was 60.5 (range: 11-99), and 59 (42.1%) were female. The most frequent complaint was abdominal pain (74.3%), followed by bloody feces (10%) and diarrhea (2.9%). B symptoms were observed in 15 (10.7%) patients. GI obstruction was the most common complication (10.0%), followed by hemorrhage (7.9%) and perforation (1.5%). Regarding endoscopic findings, the identified sites were the following: the stomach (61.4%), colon (10%), small intestine (10%), ileocecum (8.6%), rectum (6.4%), and duodenum (3.6%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most prevalent in the stomach. was identified in 46 cases (39.0%), with MALT lymphoma being the most infected subtype. Nearly all gastrointestinal non-Hodgkin lymphomas manifested as superficial type (25-59.6%) and ulcer type (15.6-50%) under endoscopy. We found that fungating type and protruding with ulcer type were more frequent types of aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) compared to the indolent types (MALT lymphoma, follicular lymphoma, duodenal-type follicular lymphoma, and small lymphocytic lymphoma) ( < 0.05). : This study showed that most subtypes of gastrointestinal non-Hodgkin lymphomas exhibited same endoscopic features (superficial type and ulcer type). Aggressive gastrointestinal non-Hodgkin lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) were highly suspected when fungating lesions and protruding with ulcer lesions were encountered under endoscopy. Endoscopists should be aware of the connection between enhanced endoscopic characteristics and histological varieties of gastrointestinal lymphoma to improve diagnosis.
PubMed: 37685305
DOI: 10.3390/diagnostics13172767