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Journal of Virology Jul 2024Human norovirus was discovered more than five decades ago and is a widespread cause of outbreaks of acute gastroenteritis. There are no approved vaccines or antivirals...
Human norovirus was discovered more than five decades ago and is a widespread cause of outbreaks of acute gastroenteritis. There are no approved vaccines or antivirals currently available. However, norovirus inhibitors, including capsid-specific monoclonal antibodies (Mabs) and nanobodies, have recently shown promising results. Several Mabs and nanobodies were found to inhibit norovirus replication using a human intestinal enteroid (HIE) culture system and/or could block norovirus attachment to histo-blood group antigen (HBGA) co-factors. In our pursuit to develop a single broad-spectrum norovirus therapeutic, we continued our analysis and development of a cross-reactive and HBGA interfering nanobody (NB26). To improve NB26 binding capacity and therapeutic potential, we conjugated NB26 onto a human IgG Fc domain (Fc-NB26). We confirmed that Fc-NB26 cross-reacts with genetically diverse GII genotype capsid protruding (P) domains (GII.8, GII.14, GII.17, GII.24, GII.26, and GII.NA1) using a direct enzyme-linked immunosorbent assay. Furthermore, X-ray crystallography structures of these P domains and structures of other GII genotypes reveal that the NB26 binding site is largely conserved, validating its broad reactivity. We showed that Fc-NB26 has ~100-fold higher affinity toward the norovirus P domain compared to native NB26. We also found that both NB26 and Fc-NB26 neutralize human norovirus replication in the HIE culture system. Furthermore, the mode of inhibition confirmed that like NB26, Fc-NB26 caused norovirus particle disassembly and aggregation. Overall, these new findings demonstrate that structural modifications to nanobodies can improve their therapeutic potential.IMPORTANCEDeveloping vaccines and antivirals against norovirus remains a challenge, mainly due to the constant genetic and antigenic evolution. Moreover, re-infection with genetically related and/or antigenic variants is not uncommon. We further developed our leading norovirus nanobody (NB26) that indirectly interfered with norovirus binding to HBGAs, by converting NB26 into a dimeric Fc-linked Nanobody (Fc-NB26). We found that Fc-NB26 had improved binding affinity and neutralization capacity compared with native NB26. Using X-ray crystallography, we showed this nanobody engaged highly conserved capsid residues among genetically diverse noroviruses. Development of such broadly reactive potent therapeutic nanobodies delivered as a slow-releasing prophylactic could be of exceptional value for norovirus outbreaks, especially for the prevention or treatment of severe acute gastroenteritis in high-risk groups such as the young, elderly, and immunocompromised.
PubMed: 38953655
DOI: 10.1128/jvi.00707-24 -
Nature Human Behaviour Jul 2024In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of...
In societies without writing, ethnographically known rituals have rarely been tracked back archaeologically more than a few hundred years. At the invitation of GunaiKurnai Aboriginal Elders, we undertook archaeological excavations at Cloggs Cave in the foothills of the Australian Alps. In GunaiKurnai Country, caves were not used as residential places during the early colonial period (mid-nineteenth century CE), but as secluded retreats for the performance of rituals by Aboriginal medicine men and women known as 'mulla-mullung', as documented by ethnographers. Here we report the discovery of buried 11,000- and 12,000-year-old miniature fireplaces with protruding trimmed wooden artefacts made of Casuarina wood smeared with animal or human fat, matching the configuration and contents of GunaiKurnai ritual installations described in nineteenth-century ethnography. These findings represent 500 generations of cultural transmission of an ethnographically documented ritual practice that dates back to the end of the last ice age and that contains Australia's oldest known wooden artefacts.
PubMed: 38951612
DOI: 10.1038/s41562-024-01912-w -
Journal of Family Medicine and Primary... May 2024Vaginal leiomyomas, originating from the anterior vaginal wall, are exceedingly uncommon, with only around 300 reported cases documented in the literature to date. We...
Vaginal leiomyomas, originating from the anterior vaginal wall, are exceedingly uncommon, with only around 300 reported cases documented in the literature to date. We present a rare case of a 50-year-old female who visited the outpatient department with complaints of abnormal uterine bleeding, and heaviness in abdomen with mass protrusion outside introitus since one year. Ultrasonography indicated adenomyosis of the uterus, with a suspected mass protruding through the posterior bladder or anterior vaginal wall. MRI imaging was conducted large polypoidal mass lesion is seen within the vaginal cavity two assymetrical round ends with close proximity to bladder and urethra with pedunculated submucosal uterine fibroid with adenomyotic changes . The provisional diagnosis of? vaginal leiomyoma along with pedunculated submucosal uterine fibroid with Adenomyosis made. Patient planned for Hysterectomy for submucosal leiomyoma with Adenomyosis and excision of vaginal mass via vaginal route. The size of vaginal mass was around size 5 * 6cm size enucleated, redundant vaginal wall excised and same sent for histopathology examination. The cut section of the vaginal mass showed whorled appearance .The Histopathology of vaginal mass showed Vaginal leiomyoma. Postoperative period was uneventful. The patient anatomy was restored and had no complaint of difficulty in urination and symptomatically improved.
PubMed: 38948554
DOI: 10.4103/jfmpc.jfmpc_1229_23 -
World Journal of Gastrointestinal... Jun 2024Duodenal Brunner's gland hyperplasia (BGH) is a therapeutic target when complications such as bleeding or gastrointestinal obstruction occur or when malignancy cannot be...
BACKGROUND
Duodenal Brunner's gland hyperplasia (BGH) is a therapeutic target when complications such as bleeding or gastrointestinal obstruction occur or when malignancy cannot be ruled out. Herein, we present a case of large BGH treated with endoscopic mucosal resection (EMR).
CASE SUMMARY
An 83-year-old woman presented at our hospital with dizziness. Blood tests revealed severe anemia, esophagogastroduodenoscopy showed a 6.5 cm lesion protruding from the anterior wall of the duodenal bulb, and biopsy revealed the presence of glandular epithelium. Endoscopic ultrasonography (EUS) demonstrated relatively high echogenicity with a cystic component. The muscularis propria was slightly elevated at the base of the lesion. EMR was performed without complications. The formalin-fixed lesion size was 6 cm × 3.5 cm × 3 cm, showing nodular proliferation of non-dysplastic Brunner's glands compartmentalized by fibrous septa, confirming the diagnosis of BGH. Reports of EMR or hot snare polypectomy are rare for duodenal BGH > 6 cm. In this case, the choice of EMR was made by obtaining information on the base of the lesion as well as on the internal characteristics through EUS.
CONCLUSION
Large duodenal lesions with good endoscopic maneuverability and no evident muscular layer involvement on EUS may be resectable EMR.
PubMed: 38946860
DOI: 10.4253/wjge.v16.i6.368 -
Journal of Neurochemistry Jul 2024A growth cone is a highly motile tip of an extending axon that is crucial for neural network formation. Three-dimensional-structured illumination microscopy, a type of...
A growth cone is a highly motile tip of an extending axon that is crucial for neural network formation. Three-dimensional-structured illumination microscopy, a type of super-resolution light microscopy with a resolution that overcomes the optical diffraction limitation (ca. 200 nm) of conventional light microscopy, is well suited for studying the molecular dynamics of intracellular events. Using this technique, we discovered a novel type of filopodia distributed along the z-axis ("z-filopodia") within the growth cone. Z-filopodia were typically oriented in the direction of axon growth, not attached to the substratum, protruded spontaneously without microtubule invasion, and had a lifetime that was considerably shorter than that of conventional filopodia. Z-filopodia formation and dynamics were regulated by actin-regulatory proteins, such as vasodilator-stimulated phosphoprotein, fascin, and cofilin. Chromophore-assisted laser inactivation of cofilin induced the rapid turnover of z-filopodia. An axon guidance receptor, neuropilin-1, was concentrated in z-filopodia and was transported together with them, whereas its ligand, semaphorin-3A, was selectively bound to them. Membrane domains associated with z-filopodia were also specialized and resembled those of lipid rafts, and their behaviors were closely related to those of neuropilin-1. The results suggest that z-filopodia have unique turnover properties, and unlike xy-filopodia, do not function as force-generating structures for axon extension.
PubMed: 38946488
DOI: 10.1111/jnc.16162 -
Annals of Coloproctology Jun 2024Neoadjuvant imatinib treatment, followed by complete transvaginal removal, presents a feasible option for large rectal gastrointestinal tumors located on the anterior...
Neoadjuvant imatinib treatment, followed by complete transvaginal removal, presents a feasible option for large rectal gastrointestinal tumors located on the anterior wall of the rectum and protruding into the vagina. The use of Martius flap interposition is convenient and can be employed to prevent rectovaginal fistula.
PubMed: 38946097
DOI: 10.3393/ac.2023.00556.0079 -
The American Journal of Surgical... Jul 2024A type of cholangiocarcinoma (CCA) characterized by peculiar histologic patterns and underlying adenofibromatous lesions has been reported in the literature mostly as...
A type of cholangiocarcinoma (CCA) characterized by peculiar histologic patterns and underlying adenofibromatous lesions has been reported in the literature mostly as individual case reports. This study aims to further clarify the defining characteristics of this spectrum of lesions. Clinicopathologic analysis of 8 biliary tumors with tubulocystic architecture arising in the background of adenofibroma-type lesions was performed. Three of these were also investigated with next-generation sequencing with a 174 genes panel. The patients were 5 males and 3 females, with a mean age of 64.6. All tumors were intrahepatic except for one perihilar that protruded into soft tissues. The mean size was 4.4 cm. At histology, all cases showed a peculiar and cytologically bland tubulocystic pattern that closely resembled tubulocystic-type kidney cancers, including back-to-back microcystic units that formed relatively demarcated nodules, and occurring in the background of adenofibromatous lesions. One case showed perineural invasion by otherwise deceptively benign-appearing microcystic structures, one had areas transitioning to intraductal tubulopapillary neoplasm, and 3 cases harbored more conventional small-duct CCA foci. In those 3 cases, both the tubulocystic and conventional CCA components were investigated by next-generation sequencing separately, and they shared the molecular alterations, including recurrent mutations in chromatin remodeling genes, such as ARID1A, BAP1, and PBRM1, and the actionable FGFR2-MCU fusion gene. In the limited follow-up, all but one were alive and free of disease after surgical resection. In conclusion, we described a distinct entity of CCA with specific histo-molecular features, for which we propose the designation of tubulocystic carcinoma of bile ducts.
PubMed: 38946053
DOI: 10.1097/PAS.0000000000002278 -
Case Reports in Otolaryngology 2024Absence or aplasia of the major salivary glands is an uncommon diagnosis and is often associated with other congenital abnormalities. Agenesis of a single submandibular...
BACKGROUND
Absence or aplasia of the major salivary glands is an uncommon diagnosis and is often associated with other congenital abnormalities. Agenesis of a single submandibular gland, however, is an even more rare phenomenon and can be associated with hypertrophy of other salivary glands.
METHODS
A 48-year-old female presented to the clinic with a left-sided neck mass below her mandible. Workup including a CT scan showed an absent left-sided submandibular gland and an enlarged sublingual gland protruding through the mylohyoid muscle.
RESULTS
The patient underwent a transoral resection of the mass with subsequent resolution of the mass. The pathology returned as normal salivary gland tissue.
CONCLUSIONS
Sublingual gland hypertrophy is a very uncommon presentation for a patient with a neck mass. This situation can arise in the setting of submandibular gland aplasia and compensatory hypertrophy of other salivary glands.
PubMed: 38939733
DOI: 10.1155/2024/8610465 -
Macromolecular Bioscience Jun 2024When a tooth is diseased or damaged through caries, bioactive molecules are liberated from the pulp and dentin as part of the natural response to injury and these are...
When a tooth is diseased or damaged through caries, bioactive molecules are liberated from the pulp and dentin as part of the natural response to injury and these are key molecules for stimulating stem cell responses for tissue repair. Incorporation of these extracellular matrix (ECM) derived molecules into a hydrogel model can mimic in vivo conditions to enable dentin-pulp complex regeneration. In this study, a chitosan/alginate (C/A) hydrogel was developed to sequester bovine ECM extracts. Human dental pulp cells (hDPCs) were cultured with these constructs and proliferation and cytotoxicity assays confirmed that these C/A hydrogels were bioactive. Sequential z-axis fluorescent imaging visualized hDPCs protruding into the hydrogel as it degraded. Alizarin red S staining showed hDPCs cultured with the hydrogels displayed increased calcium ion deposition, with dentin ECM stimulating the highest levels. Alkaline phosphatase activity was increased, as was expression of transforming growth factor-beta (TGF-β) as demonstrated using immunocytochemistry. Directional analysis following phase contrast kinetic image capture demonstrated that both dentin and pulp ECM molecules acted as chemoattractants for hDPCs. Data from this study demonstrated that purified ECM from dental pulp and dentin when delivered in a C/A hydrogel stimulated dental tissue repair processes in vitro. This article is protected by copyright. All rights reserved.
PubMed: 38938070
DOI: 10.1002/mabi.202400254 -
Parasitology International Jun 2024A new genus, Cordicestus, is proposed to accommodate proteocephalid tapeworms parasitising gars (Lepisosteiformes: Lepisosteidae) in North and Central America that were...
A new genus, Cordicestus, is proposed to accommodate proteocephalid tapeworms parasitising gars (Lepisosteiformes: Lepisosteidae) in North and Central America that were previously placed in the polyphyletic genus Proteocephalus Weinland, 1858. The new genus differs from other proteocephalid genera by the particular morphology of the scolex, which is small, protrudes apically but has no apical organ, and bears flat, heart-shaped (= cordis) suckers. In addition, the species of the new genus have an elongated cirrus sac with an almost straight internal vas deferens, and wide, sinuous ventral osmoregulatory canals with secondary canals directed outwards. The type species of the new genus, Cordicestus singularis (La Rue, 1911) n. comb., is redescribed based on new material from the shortnose gar, Lepisosteus platostomus Rafinesque (type host), and the spotted gar, L. oculatus Winchell, in the United States. Cordicestus rafaeli n. sp. is described from the tropical gar, Atractosteus tropicus Gill, in Mexico. The new species differs from its relatives primarily by the presence of craspedote proglottids (acraspedote in other species) and some biometric features. The species of Cordicestus are discussed, including unidentified specimens from A. tropicus and the Cuban gar A. tristoechus (Bloch and Schneider) in Nicaragua and Cuba, respectively, which may be new species, and a key to identification of these taxa is provided. Molecular data available for two nominal species of the new genus indicate the possible existence of another species of Cordicestus in Lepisosteus in the USA.
PubMed: 38936764
DOI: 10.1016/j.parint.2024.102916