Reconstitution of RNA cap methylation reveals different features of SARS-CoV-2 and SARS-CoV methyltransferases.

Cap RNA methylations play important roles in the replication, evasion of host RNA sensor recognition, and pathogenesis. Coronaviruses possess both guanine N7- and 2'-O-ribose methyltransferases (N7-MTase and 2'-O-MTase) encoded by nonstructural protein (nsp) 14 and nsp16/10 complex, respectively. In this study, we reconstituted the two-step RNA methylations of N7-MTase and 2'-O-MTase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and demonstrated its common and different features in comparison with that of SARS-CoV. We revealed that the nsp16/10 2'-O-MTase of SARS-CoV-2 has a broader substrate selectivity than the counterpart of SARS-CoV and can accommodate both unmethylated and uncapped RNA substrates in a sequence-independent manner. Most intriguingly, the substrate selectivity of nsp16/10 complex is not determined by the apoenzyme of nsp16 MTase but by its cofactor nsp10. These results provide insight into the unique features of SARS-CoV-2 MTases and may help develop strategies to precisely intervene in the methylation pathway and pathogenesis of SARS-CoV-2.

CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3.

The NLRP3-directed inflammasome complex is crucial for the host to resist microbial infection and monitor cellular damage. However, the hyperactivation of NLRP3 inflammasome is implicated in pathogenesis of inflammatory diseases, including inflammatory bowel disease (IBD). Autophagy and autophagy-related genes are closely linked to NLRP3-mediated inflammation in these inflammatory disorders. Here, we report that CCDC50, a novel autophagy cargo receptor, negatively regulates NLRP3 inflammasome assembly and suppresses the cleavage of pro-caspase-1 and interleukin 1ß (IL-1ß) release by delivering NLRP3 for autophagic degradation. Transcriptome analysis showed that knockdown of CCDC50 results in upregulation of signaling pathways associated with autoinflammatory diseases. CCDC50 deficiency leads to enhanced proinflammatory cytokine response triggered by a wide range of endogenous and exogenous NLRP3 stimuli. Ccdc50-deficient mice are more susceptible to dextran sulfate (DSS)-induced colitis and exhibit more severe gut inflammation with elevated NLRP3 inflammasome activity. These results illustrate the physiological significance of CCDC50 in the pathogenicity of inflammatory diseases, suggesting protective roles of CCDC50 in keeping gut inflammation under control.

A Content Analysis of Problematic Gambling Prevention Interventions in the United States.

Gambling revenue in the United States is at all-time highs while recent and forthcoming legislation relaxes constraints on casino gaming, sports betting, and fantasy sports betting. Increased gambling will result in increased problematic gambling, highlighting the need to study the impact of our problematic gambling prevention interventions. To address this, we conducted a content analysis of problematic gambling prevention messages in the U.S. Results reveal that although there is overlap between theoretically-based messaging appeals recommended by research and those used in actual prevention interventions, health behavior theory is inconsistently applied and there are numerous examples of potential backfire effects. Results are discussed in terms of their impact on theory development and their noteworthy practical application.

Hsp70-Targeting and Size-Tunable Nanoparticles Combine with PD-1 Checkpoint Blockade to Treat Glioma.

Invasive glioma usually disrupts the integrity of the blood-brain barrier (BBB), making the delivery of nanodrugs across the BBB possible, but sufficient targeting ability is still avidly needed to improve drug accumulation in glioma. Membrane-bound heat shock protein 70 (Hsp70) is expressed on the membrane of glioma cells rather than adjacent normal cells, therefore it can serve as a specific glioma target. Meanwhile, prolonging the retention in tumors is important for active-targeting nanoparticles to overcome receptor-binding barriers. Herein, the Hsp70-targeting and acid-triggered self-assembled gold nanoparticles (D-A-DA/TPP) are proposed to realize selective delivery of doxorubicin (DOX) to glioma. In the weakly acidic glioma matrix, D-A-DA/TPP formed aggregates to prolong retention, improve receptor-binding efficiency and facilitate acid-responsive DOX release. DOX accumulation in glioma induced immunogenic cell death (ICD) to promote antigen presentation. Meanwhile, combination with the PD-1 checkpoint blockade further activate T cells and provokes robust anti-tumor immunity. The results showed that D-A-DA/TPP can induce more glioma apoptosis. Furthermore, in vivo studies indicated D-A-DA/TPP plus PD-1 checkpoint blockade significantly improved median survival time. This study offeres a potential nanocarrier combining size-tunable strategy with active targeting ability to increase drug enrichment in glioma and synergizes with PD-1 checkpoint blockade to achieve chemo-immunotherapy.

Allometric wing growth links parental care to pterosaur giantism.

Pterosaurs evolved a broad range of body sizes, from small-bodied early forms with wingspans of mostly 1-2 m to the last-surviving giants with sizes of small airplanes. Since all pterosaurs began life as small hatchlings, giant forms must have attained large adult sizes through new growth strategies, which remain largely unknown. Here we assess wing ontogeny and performance in the giant Pteranodon and the smaller-bodied anurognathids Rhamphorhynchus, Pterodactylus and Sinopterus. We show that most smaller-bodied pterosaurs shared negative allometry or isometry in the proximal elements of the fore- and hindlimbs, which were critical elements for powering both flight and terrestrial locomotion, whereas these show positive allometry in Pteranodon. Such divergent growth allometry typically signals different strategies in the precocial-altricial spectrum, suggesting more altricial development in Pteranodon. Using a biophysical model of powered and gliding flight, we test and reject the hypothesis that an aerodynamically superior wing planform could have enabled Pteranodon to attain its larger body size. We therefore propose that a shift from a plesiomorphic precocial state towards a derived state of enhanced parental care may have relaxed the constraints of small body sizes and allowed the evolution of derived flight anatomies critical for the flying giants.

How we do it? Performing a protective superficial temporal artery-middle cerebral artery bypass with endoscopic transnasal cavernous sinus lesion operation.

BACKGROUND: To describe the concept of a protective superficial temporal artery-middle cerebral artery (STA-MCA) bypass performed prior to endoscopic transnasal cavernous sinus (CS) lesion resection in order to reduce the risk of perioperative cerebral ischemia due to internal carotid artery (ICA) vasospasm, occlusion, and even injury. METHOD: We illustrated the procedure of a 14-year-old female accepting a protective STA-MCA bypass with endoscopic transnasal CS lesion resection. CONCLUSION: A protective bypass may be a prophylactic strategy in selected endoscopic transnasal CS surgery cases, particularly where the diagnosis is uncertain, or the risk of ICA injury or occlusion is high.

How I do it? Basilar bifurcation and left anterior choroidal artery aneurysms clipping.

BACKGROUND: Despite advancements in endovascular techniques, microsurgical treatment for posterior circulation aneurysms remains challenging. METHOD: This report highlights the successful clipping surgery of a 17-year-old female patient with an aneurysm located at the basilar artery (BA) bifurcation and left anterior choroidal artery (AChoA). To improve exposure, the posterior communicating artery was transected. A straight fenestrated clip was then placed to repair the BA bifurcation aneurysm, followed by a curved mini clip for the AChoA aneurysm. CONCLUSION: This report demonstrates the nuances of microsurgery in the treatment of select complex cases, which can benefit from microsurgery to achieve optimal treatment outcomes.

How I do it? Surgical removal of a corpus callosum arteriovenous malformation using a robotic digital microscope.

BACKGROUND: This report described the surgical nuance of a challenging deep-seated corpus callosum arteriovenous malformation (AVM) using a novel robotic digital microscope. METHOD: A 64-year-old male was admitted to treat a ruptured corpus callosum AVM. In order to facilitate surgical manipulation under the robotic digital microscope, a gravity-assisted supine position was utilized. Intraoperatively, identifying and preserving the transit and bystander artery is important while skeletonizing the anterior cerebral artery. The nidus was totally resected and the patient was discharged without sequella. CONCLUSION: It is feasible to perform complicated AVM resection under the robotic digital microscope with a rigorous surgical plan.

How I do it? Preoperative Microsoft HoloLens 2 planning-assisted surgical clipping of a fetal posterior cerebral artery aneurysm.

BACKGROUND: The treatment of intracranial aneurysms has predominantly shifted towards endovascular strategies, but complex cases still necessitate microsurgery. Preoperative stimulation can be beneficial for inexperienced young neurosurgeons in preparing for safe microsurgery. METHOD: A 72-year-old female with a left irregular fetal posterior cerebral artery (PCA) aneurysm underwent clipping repair. Microsoft HoloLens 2, utilizing mixed reality technology, was employed for preoperative stimulation and anatomical study. During the operation, we successfully identified the planned relationship between the aneurysm and the fetal PCA. The patient was cured without any complications. CONCLUSION: We hope that this report will highlight the significance of Microsoft HoloLens 2 in microsurgical planning and education.

How I do it? A multimodality-guided awake hybrid operation for a language-area brain arteriovenous malformation and multiple intracranial aneurysms.

BACKGROUND: The cure of an eloquent brain arteriovenous malformation (BAVM) and multiple intracranial aneurysms with preservation of neurological function and the minimal procedures is challenging. METHOD: A 53-year-old male was admitted to treat a left frontal language-area BAVM and concomitant five bilateral intracranial aneurysms. After repairing the ruptured right middle cerebral artery (MCA) bifurcation aneurysms and the other two unruptured ones, at the second-stage multimodality-guided awake hybrid operation, we successfully obliterated the left frontal BAVM and two other left MCA aneurysms. CONCLUSION: The multimodality-guided awake hybrid operation may be a promising technique to treat complicated cerebrovascular disease.

How I Do It: endoscope-assisted resection of a large dumbbell-shaped cervical schwannoma.

BACKGROUND: Cervical dumbbell-shaped schwannomas are often challenging in terms of complete resection. There are few reports on the use of endoscope-assisted surgery for foraminal schwannomas. METHOD: We used the wide-angle endoscope to assist in resecting a large cervical 3-4 dumbbell-shaped schwannoma. The well-designed set-up allowed the surgeon to achieve easier manipulation ins a straight surgical trajectory with minimal intraoperative adjustment. The endoscope allowed surgeons to visualize and operate in regions beyond the straight line of sight, without the need for facetectomy and subdural inspection. CONCLUSION: We believe that this case demonstrates the feasibility of applying endoscope-assisted surgery for large cervical dumbbell-shaped schwannomas.

How I do it: Surgical Resection of a Recurrent Chondromyxoid Fibroma by Micro-Endoscopic Combination Technique.

BACKGROUND: The surgical resection of the tumor spreading into the cavernous sinus (CS) is complicated and challenging. METHOD: We report a left recurrent CS chondromyxoid fibroma occupying the clival-petrous apex-parasellar-suprasellar area, which was totally removed by the micro-endo combination technique via the middle cranial fossa extradural approach. CONCLUSION: This case demonstrates the value of the micro-endoscopic combination technique for complicated skull base surgery.

How I do it: surgical resection of a subcallosal gyrus cavernous malformation by a contralateral anterior interhemispheric approach.

BACKGROUND: Cavernous malformation (CM) of the subcallosal gyrus is extremely rare, and due to its close relationship with the lateral ventricle's frontal horn, it may be misdiagnosed as caudate head or ventricle CM. METHOD: This video shows a rare case of subcallosal gyrus CM successfully cured by a contralateral anterior interhemispheric approach. CONCLUSION: We hope this case provides new insights into anatomical knowledge and surgical approach techniques for subcallosal lesions.

How I do it: surgical resection of ventrolateral pontomesencephalic junction glioma via oculomotor-tentorial triangle.

BACKGROUND: The surgical resection of the pontomesencephalic junction (PMJ) glioma is difficult because the access is challenging due to nearby complicated neurovascular structures. METHOD: We report a left ventrolateral PMJ glioma successfully resected via the oculomotor-tentorial triangle (OTT), with improved right extremity weakness postoperatively while preserving the pyramidal tract, which resided laterally and posteriorly to the lesion. CONCLUSION: This case demonstrates the value of the OTT in brainstem surgery.

How I do it: the surgical resection of a middle third parasagittal meningioma with venous preservation strategy.

BACKGROUND: The surgical resection of the middle third parasagittal meningioma (PSM) is difficult, where the challenge is to systematically protect the eloquent parenchyma and collateral venous drainage. METHOD: We report a case of PSM that eroded the skull, wholly occluded the superior sagittal sinus at the middle third segment, underwent radical resection with evaluation and preservation of the collateral venous drainage by preoperative venography, and intraoperative indocyanine green videoangiography (ICGVA) that aimed to avoid postoperative complications. CONCLUSION: This case demonstrates the importance of venous preservation strategy and the value of ICGVA in the intraoperative assessment of collateral venous drainage function.

LncRNA TUG1 functions as a ceRNA for miR-6321 to promote endothelial progenitor cell migration and differentiation.

Endothelial progenitor cell (EPC) recruitment and angiogenesis play crucial roles in aneurysm neck endothelialization, but the mechanisms of EPC recruitment and angiogenesis are still unclear. Recent studies have shown that long noncoding RNAs (lncRNAs) can regulate the function and differentiation of cells in various ways. LncRNA TUG1 is involved in liver cancer and glioma-mediated angiogenesis. The aim of this study was to investigate the role of lncRNA TUG1 in regulating EPC migration and differentiation. Overexpression and knockdown of lncRNA TUG1 with lentivirus, scratch assays, Transwell assays and tube formation assays using EPCs isolated from rat bone marrow showed that lncRNA TUG1 overexpression promoted EPC migration, invasion and differentiation. Moreover, ELISAs showed that lncRNA TUG1 overexpression increased VEGF expression. Bioinformatics prediction, luciferase assays, Western blots and RIP assays indicated that lncRNA TUG1 functions as a ceRNA (competing endogenous RNA) for miR-6321 and that miR-6321 inhibits EPC migration and differentiation through its target, ATF2. As a potential therapeutic target, lncRNA TUG1 may play a vital role in the pathogenesis of aneurysms.

How I do it? Posterior inferior cerebellar artery-intracranial vertebral artery reimplantation bypass and trapping of dissecting aneurysm involving the proximal posterior inferior cerebellar artery.

BACKGROUND: Proximal posterior inferior cerebellar artery (PICA) aneurysms are surgically challenging due to the high variability in the anatomy of the PICA origin, their deep-seated nature, and their entanglement with the lower cranial nerves. Direct or reconstructive clipping may not be achievable if the aneurysm is large, or dissecting, or exhibits atherosclerosis or calcification. METHOD: We present a case of a proximal PICA lateral medullary segment (P2) aneurysm that was successfully cured by trapping the aneurysm and reconstructing the PICA using the PICA-intracranial vertebral artery (PICA-V4) via end-to-side reimplantation bypass with the far lateral approach. CONCLUSION: This case demonstrates the feasibility and safety of PICA-V4 reimplantation bypass, especially if the origin of the PICA is highly seated and the intracranial VA, or V4 segment, is long enough and well-exposed supra or under hypoglossal nerves.

How I do it: anatomical resection of a large diffusive recurrent high-grade glioma for preservation of the central core.

BACKGROUND: Maximal safe surgical treatment of diffusive glioma without a clear boundary between the tumor and central core is challenging. METHOD: We present a case of a large, diffusive, recurrent high-grade glioma with preservation of the central core following an anatomical resection protocol that aimed to maintain quality of life. CONCLUSION: Knowing the key anatomical landmarks and following the anatomical resection protocol are fundamental to surgical safety for treatment of glioma.

How I do it? Gravity-assisted endoscopic cingulate gyrus glioma resection.

BACKGROUND: The cingulate gyrus is part of the limbic system with extensive connectivity to different anatomical and functional areas. The traditional transcortical approach for a cingulate gyrus glioma contains high risk of transient or even irreversible postoperative hemiplegia. METHOD: We present a case of gravity-assisted, fully endoscopic resection of a cingulate gyrus glioma with improvement of motor dysfunction while preserving the paracentral lobule, corticospinal tracts, and supplementary motor area. CONCLUSION: This case demonstrates the value of gravity-assisted endoscopic resection in the dominant cingulate gyrus tumor which is surrounded by eloquent parenchyma.

How I do it? Anatomical multifocal high-grade glioma resection.

BACKGROUND: If an awake surgery is somehow not available for gliomas at the language area, understanding the anatomy and well-designed surgical strategy are important. METHOD: We present a case with left hemispheric multifocal high-grade gliomas located deeply at the left temporal pole, the Wernicke's area, and mesial temporal region. Because the patient could not endure the awake surgery and obtain practicable functional magnetic resonance imaging (MRI) for eloquent cortex evaluation, we removed the lesions following the anatomical resection strategy guided by diffusion tensor imaging (DTI). CONCLUSION: This case demonstrates the value of DTI and the importance of anatomical resection strategies in glioma surgeries.