N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand.

About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.

Pathological mutations promote proteolysis of mitochondrial tRNA-specific 2-thiouridylase 1 (MTU1) via mitochondrial caseinolytic peptidase (CLPP).

MTU1 controls intramitochondrial protein synthesis by catalyzing the 2-thiouridine modification of mitochondrial transfer RNAs (mt-tRNAs). Missense mutations in the MTU1 gene are associated with life-threatening reversible infantile hepatic failure. However, the molecular pathogenesis is not well understood. Here, we investigated 17 mutations associated with this disease, and our results showed that most disease-related mutations are partial loss-of-function mutations, with three mutations being particularly severe. Mutant MTU1 is rapidly degraded by mitochondrial caseinolytic peptidase (CLPP) through a direct interaction with its chaperone protein CLPX. Notably, knockdown of CLPP significantly increased mutant MTU1 protein expression and mt-tRNA 2-thiolation, suggesting that accelerated proteolysis of mutant MTU1 plays a role in disease pathogenesis. In addition, molecular dynamics simulations demonstrated that disease-associated mutations may lead to abnormal intermolecular interactions, thereby impairing MTU1 enzyme activity. Finally, clinical data analysis underscores a significant correlation between patient prognosis and residual 2-thiolation levels, which is partially consistent with the AlphaMissense predictions. These findings provide a comprehensive understanding of MTU1-related diseases, offering prospects for modification-based diagnostics and novel therapeutic strategies centered on targeting CLPP.

Involvement of interferon gamma signaling in spinal trigeminal caudal subnucleus astrocyte in orofacial neuropathic pain in rats with infraorbital nerve injury.

Background: Trigeminal nerve injury causes orofacial pain that can interfere with activities of daily life. However, the underlying mechanism remains unknown, and the appropriate treatment has not been established yet. This study aimed to examine the involvement of interferon gamma (IFN-γ) signaling in the spinal trigeminal caudal subnucleus (Vc) in orofacial neuropathic pain. Methods: Infraorbital nerve (ION) injury (IONI) was performed in rats by partial ION ligation. The head-withdrawal reflex threshold (HWT) to mechanical stimulation of the whisker pad skin was measured in IONI or sham rats, as well as following a continuous intracisterna magna administration of IFN-γ and a mixture of IFN-γ and fluorocitrate (inhibitor of astrocytes activation) in naïve rats, or an IFN-γ antagonist in IONI rats. The IFN-γ receptor immunohistochemistry and IFN-γ Western blotting were analyzed in the Vc after IONI or sham treatment. The glial fibrillary acid protein (GFAP) immunohistochemistry and Western blotting were also analyzed after administration of IFN-γ and the mixture of IFN-γ and fluorocitrate. Moreover, the change in single neuronal activity in the Vc was examined in the IONI, sham, and IONI group administered IFN-γ antagonist. Results: The HWT decreased after IONI. The IFN-γ and IFN-γ receptor were upregulated after IONI, and the IFN-γ receptor was expressed in Vc astrocytes. IFN-γ administration decreased the HWT, whereas the mixture of IFN-γ and fluorocitrate recovered the decrement of HWT. IFN-γ administration upregulated GFAP expression, while the mixture of IFN-γ and fluorocitrate recovered the upregulation of GFAP expression. IONI significantly enhanced the neuronal activity of the mechanical-evoked responses, and administration of an IFN-γ antagonist significantly inhibited these enhancements. Conclusions: IFN-γ signaling through the receptor in astrocytes is a key mechanism underlying orofacial neuropathic pain associated with trigeminal nerve injury. These findings will aid in the development of therapeutics for orofacial neuropathic pain.

Impedance Characteristics of Monolayer and Bilayer Graphene Films with Biofilm Formation and Growth.

Biofilms are the result of bacterial activity. When the number of bacteria (attached to materials' surfaces) reaches a certain threshold value, then the bacteria simultaneously excrete organic polymers (EPS: extracellular polymeric substances). These sticky polymers encase and protect the bacteria. They are called biofilms and contain about 80% water. Other components of biofilm include polymeric carbon compounds such as polysaccharides and bacteria. It is well-known that biofilms cause various medical and hygiene problems. Therefore, it is important to have a sensor that can detect biofilms to solve such problems. Graphene is a single-atom-thick sheet in which carbon atoms are connected in a hexagonal shape like a honeycomb. Carbon compounds generally bond easily to graphene. Therefore, it is highly possible that graphene could serve as a sensor to monitor biofilm formation and growth. In our previous study, monolayer graphene was prepared on a glass substrate by the chemical vapor deposition (CVD) method. Its biofilm forming ability was compared with that of graphite. As a result, the CVD graphene film had the higher sensitivity for biofilm formation. However, the monolayer graphene has a mechanical disadvantage when used as a biofilm sensor. Therefore, for this new research project, we prepared bilayer graphene with high mechanical strength by using the CVD process on copper substrates. For these specimens, we measured the capacitance component of the specimens' impedance. In addition, we have included a discussion about the possibility of applying them as future sensors for monitoring biofilm formation and growth.

Potential roles of the IL-6 family in conjunctival fibrosis.

Elevated intraocular pressure (IOP) is a significant risk factor for vision loss due to glaucoma, which is a major cause of blindness worldwide. Glaucoma filtration surgery (GFS) is an important method to reduce IOP by guidance of aqueous humor into a newly built filtration bleb in the conjunctiva; management of the wound healing mechanism is essential for the success of GFS. Here, we investigated the roles of interleukin (IL)-6 family members during the wound healing process after GFS. At the surgical site, the expression levels of genes encoding IL-6, oncostatin M (OSM), their receptors, and collagen I were elevated at 3 h after GFS, whereas the levels of genes encoding transforming growth factor (TGF)-ß, α-smooth muscle actin (SMA), type IV collagen, and fibronectin were elevated at 3 days after GFS. IL-6 trans-signaling and OSM signaling suppressed TGF-ß-induced expression of α-SMA and collagen IV, as well as activation of the non-canonical TGF-ß pathway, suggesting that IL-6 and OSM may aid in controlling the phase transition from inflammation to proliferation and remodeling. The suppressive effects of OSM were accompanied by STAT3 activation, such that STAT1 function was complementary to STAT3. Taken together, these observations indicated that IL-6 family members constitute early response genes after GFS, which can suppress TGF-ß-induced expression of late response genes at the surgical site after GFS.

Investigation of Biofilms Formed on Steelmaking Slags in Marine Environments for Water Depuration.

Steelmaking slags are a promising resource as artificial seaweed beds for the reconstitution of marine environments. To grow seaweed well, the formation of biofilms is an essential process in biofouling. This study focused on the formation of initial biofilms on steelmaking slag samples and analyzed the resulting bacterial communities using the next-generation sequencing technique. Three types of steelmaking slag were submerged in an area of Ise Bay in Mie Prefecture, Japan, for 3 and 7 days in the summer and winter seasons to allow the formation of biofilms. The bacterial communities of these biofilms were richer in sulfur-oxidizing bacteria compared to the biofilms formed on polyurethane sponges. It was found that Helicobacteraceae dominantly grew on the biofilms formed on the slag samples. This shows that steelmaking slags have potential to be used as artificial seaweed beds and marine water purifiers.

Microglia-Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury.

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia-astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

An updated review on pathophysiology and management of burning mouth syndrome with endocrinological, psychological and neuropathic perspectives.

Burning mouth syndrome (BMS) is a chronic oro-facial pain disorder of unknown cause. It is more common in peri- and post-menopausal women, and sex hormone dysregulation is believed to be an important causative factor. Psychosocial events often trigger or exacerbate symptoms, and persons with BMS appear to be predisposed towards anxiety and depression. Atrophy of small nerve fibres in the tongue epithelium has been reported, and potential neuropathic mechanisms for BMS are now widely investigated. Historically, BMS was thought to comprise endocrinological, psychosocial and neuropathic components. Neuroprotective steroids and glial cell line-derived neurotrophic factor family ligands may have pivotal roles in the peripheral mechanisms associated with atrophy of small nerve fibres. Denervation of chorda tympani nerve fibres that innervate fungiform buds leads to alternative trigeminal innervation, which results in dysgeusia and burning pain when eating hot foods. With regard to the central mechanism of BMS, depletion of neuroprotective steroids alters the brain network-related mood and pain modulation. Peripheral mechanistic studies support the use of topical clonazepam and capsaicin for the management of BMS, and some evidence supports the use of cognitive behavioural therapy. Hormone replacement therapy may address the causes of BMS, although adverse effects prevent its use as a first-line treatment. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) may have important benefits, and well-designed controlled studies are expected. Other treatment options to be investigated include brain stimulation and TSPO (translocator protein 18 kDa) ligands.

Epilithic and endolithic microorganisms and deterioration on stone church facades subject to urban pollution in a sub-tropical climate.

Weathering of two church facades in Rio de Janeiro was caused substantially by salts, mainly halite and gypsum, detected by SEM and chemical analyses, which cause physical stresses by deposition within the rock. Biofilm populations, determined by SEM and as operational taxonomic units (OTUs), degraded stone by penetration, solubilization and redeposition of minerals on their surfaces. Endolithic cyanobacteria were associated with gypsum deposits. Microbiomes were typical for high-stress environments, high salt, intense insolation, low water and low nutrients (eg halophilic Rubrobacter, Salinicola, Sterigmatomyces). The main colonizers on the church most affected by traffic (Nossa Senhora da Candelária - CA) were Actinobacteria; Gammaproteobacteria (chiefly Pseudomonas) were predominant on the site situated in a leafy square (São Francisco de Paula - SF). Major Gammaproteobacteria on CA were halophilic Halomonas and Rhodobacteriaceae. Fungal OTUs on both churches were principally dimorphic, yeast-like basidiomycetes. Many OTUs of thermophilic microorganisms (eg the Thermomicrobia class, Chloroflexi) were present. This is the first use of next generation sequencing (NGS) to study microbial biofilm interactions with metamorphic and granite buildings in an intensely urban, sub-tropical climate.

Microbiomes of Biofilms on Decorative Siliceous Stone: Drawbacks and Advantages of Next Generation Sequencing.

Next Generation Sequencing (NGS), using the Illumina® metabarcoding system, showed differences between biofilm communities on three degraded siliceous stone church façades in central Rio de Janeiro. Two church biofilms (on granite and augen gneiss) were dominated by Actinobacteria; the third (granite), surrounded by trees and further from intense vehicular traffic, by Gammaproteobacteria. Yeast-like forms of Basidiomycetes and Ascomycetes were major fungi on all facades, but 22.8% of Operational Taxonomic Units could not be assigned to any fungal taxon after DNA amplification with ITS primers and analysis with the UNITE database, indicating the need for more fungal NGS studies. The pipeline used in analysis of the V4 region of rRNA bacterial gene sequences influenced the taxa detected, with two major classes and many genera identified only by the pipeline using the Greengenes, and not the Silva, database. Principal Components Analysis separated façade biofilms into the appropriate three groups and indicated greater dissimilarity of the tree-surrounded church biofilm from the others, confirmed by Jaccard Similarity coefficients, suggesting that local environment influences community composition more than stone type. NGS allows rapid and detailed analysis of microbiomes, but results must be carefully assessed and must not be used as the sole indication of community composition.

ERK-GluR1 phosphorylation in trigeminal spinal subnucleus caudalis neurons is involved in pain associated with dry tongue.

BACKGROUND: Dry mouth is known to cause severe pain in the intraoral structures, and many dry mouth patients have been suffering from intraoral pain. In development of an appropriate treatment, it is crucial to study the mechanisms underlying intraoral pain associated with dry mouth, yet the detailed mechanisms are not fully understood. To evaluate the mechanisms underlying pain related to dry mouth, the dry-tongue rat model was developed. Hence, the mechanical or heat nocifensive reflex, the phosphorylated extracellular signal-regulated kinase and phosphorylated GluR1-IR immunohistochemistries, and the single neuronal activity were examined in the trigeminal spinal subnucleus caudalis of dry-tongue rats. RESULTS: The head-withdrawal reflex threshold to mechanical, but not heat, stimulation of the tongue was significantly decreased on day 7 after tongue drying. The mechanical, but not heat, responses of trigeminal spinal subnucleus caudalis nociceptive neurons were significantly enhanced in dry-tongue rats compared to sham rats on day 7. The number of phosphorylated extracellular signal-regulated kinase-immunoreactive cells was also significantly increased in the trigeminal spinal subnucleus caudalis following noxious stimulation of the tongue in dry-tongue rats compared to sham rats on day 7. The decrement of the mechanical head-withdrawal reflex threshold (HWT) was reversed during intracisternal administration of the mitogen-activated protein kinase kinase 1 inhibitor, PD98059. The trigeminal spinal subnucleus caudalis neuronal activities and the number of phosphorylated extracellular signal-regulated kinase-immunoreactive cells following noxious mechanical stimulation of dried tongue were also significantly decreased following intracisternal administration of PD98059 compared to vehicle-administrated rats. Increased number of the phosphorylated GluR1-IR cells was observed in the trigeminal spinal subnucleus caudalis of dry-tongue rats, and the number of phosphorylated GluR1-IR cells was significantly reduced in PD98059-administrated rats compared to the vehicle-administrated tongue-dry rats. CONCLUSIONS: These findings suggest that the pERK-pGluR1 cascade is involved in central sensitization of trigeminal spinal subnucleus caudalis nociceptive neurons, thus resulting in tongue mechanical hyperalgesia associated with tongue drying.

Successful treatment of Beauveria bassiana fungal keratitis with topical voriconazole.

We describe a 66-year-old woman who suffered from fungal keratitis after corneal transplantation. The causative organism was identified as Beauveria bassiana on the basis of morphological characteristics and the sequence of the internal transcribed spacer region of the ribosomal RNA gene. The patient was successfully treated with topical voriconazole (VRCZ) use only. We, hereby, present the first report of a case with B. bassiana fungal keratitis that responded to topical antifungal VRCZ treatment.

Clipping Surgery for Unruptured Middle Cerebral Artery Aneurysms.

Clipping surgeries for 139 consecutive unruptured middle cerebral aneurysms were performed between April 1991 and March 2014. Left hemiparesis occurred in one case (0.7 %). Transient symptoms arose in six patients due to perforator injury, arterial branch occlusion, damage to the venous system, or chronic subdural hematoma. Neither mortality nor decline in cognitive function was noted in this study. Clipping surgery for unruptured middle cerebral artery aneurysms can be done with minimal morbidity. However, meticulous management during the perioperative period as well as the use of modern technologies during the surgery, such as MEP monitoring and ICG videoangiography, are needed for safe and secure clipping surgery.

Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation.

Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freund's adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Intra-cisterna magna anti-CX3CR1 or anti-interleukin (IL)-1ß neutralizing antibody administration decreased the enhanced excitability of Vc and C1-C2 neurons in CFA-injected rats, whereas intra-cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1ß expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1-C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2-C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1-C2 or C2-C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1ß is released from the activated microglia, and the excitability of neurons in Vc and C1-C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia.

[Tuberculosis of the thyroid gland mimicking thyroid carcinoma in the elderly].

A 76-year-old woman with a 10-year history of chronic glomerulonephritis was treated at a clinic after presenting with a gradual worsening of the renal function. The patient had no history of tuberculosis. She was subsequently hospitalized for uremic symptoms and treated with internal shunt insertion and dialysis. Thyroid ultrasonography was performed to screen for secondary hyperparathyroidism, which revealed a calcified thyroid mass and cervical lymph node swelling. Fine-needle aspiration biopsy was thus conducted to assess suspected thyroid cancer. The cytological findings showed few follicular epithelial cells, without any signs of malignancy. However, a diagnosis of thyroid cancer continued to be strongly suspected based on the imaging features. Total thyroidectomy and bilateral cervical regional lymph node dissection were therefore performed, and the pathological examination of the thyroidectomy specimen disclosed scattered epithelioid granulomas with caseous necrosis in the entire right lobe as well as the cervical lymph nodes. Based on these findings, the patient was diagnosed with thyroid tuberculosis. As the symptoms and imaging findings of tuberculosis are nonspecific in elderly patients, it is necessary to consider this disease in this population. We therefore propose the inclusion of thyroid tuberculosis in the differential diagnosis of elderly patients who present with malignant thyroid tumors on aspiration biopsy cytology, regardless of whether or not they have a previous history of tuberculosis.

Contact-Killing Antibacterial Polystyrene Polymerized Using a Quaternized Cationic Initiator.

Contact-killing antibacterial materials are attracting attention owing to their ability for sustained antibacterial activity. However, contact-killing antibacterial polystyrene (PS) has not been extensively studied because its chemically stable structure impedes chemical modification. In this study, we developed an antibacterial PS sheet with a contact-killing surface using PS synthesized from 2,2'-azobis-[2-(1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium-2-yl)]propane triflate (ADIP) as a radical initiator with cationic moieties. The PS sheet synthesized with ADIP (ADIP-PS) exhibited antibacterial activity in contrast to PS synthesized with other azo radical initiators. Surface ζ-potential measurements revealed that only ADIP-PS had a cationic surface, which contributed to its contact-killing antibacterial activity. The ADIP-PS sheets also exhibited antibacterial activity after washing. In contrast, PS sheets containing silver, a typical leachable antibacterial agent, lost all antibacterial activity after the same washing treatment. The antibacterial ADIP-PS sheet demonstrated strong broad-spectrum activity against both Gram-positive and Gram-negative bacteria, including drug-resistant bacteria. Cytotoxicity tests using L929 cells showed that the ADIP-PS sheets were noncytotoxic. This contact-killing antibacterial PS synthesized with ADIP thus demonstrated good prospects as an easily producible antimicrobial material.

Sixth cranial nerve palsy and trigeminal neuropathic pain due to a space-occupying lesion.

Various neuropathies of the cranil nerves can accompany trigeminal neuropathic pain attributed to space-occupying lesions. In this case report, the patient presented with persistent intraoral pain and numbness on the right side of the face. Cranial nerve examination revealed dysfunctional eye movements, diplopia, and mechanical hyposensitivity in the mandibular region. The patient was diagnosed with neuropathy due to intracranial lesions and referred to the Department of Neurosurgery and Otorhinolaryngology. The patient was suspected of having malignant lymphoma and is currently undergoing neurosurgical intervention. This article discusses the importance of the examination of the cranial nerve for patients with persistent pain in the trigeminal nerve distribution.

[Fulminant type 1 diabetes in an elderly patient treated after receiving a diagnosis of type 2 diabetes].

The patient was a 76-year-old, male who was diagnosed with high blood glucose at 30 years of age. He suffered a stroke at 52 years of age. and was diagnosed with type 2 diabetes at a nearby hospital. Oral hypoglycemic medicines were administered along with diet and exercise therapy, which resulted in good glycemic control. The patient required an emergency hospital admission in December 2010 for weight loss. In addition, he suffered from frequent urination. He was diagnosed with diabetic ketoacidosis based on the following findings: blood glucose, 1,003 mg/dL; glycated hemoglobin, 7.7%; positive urine ketone bodies; and blood gas pH, 7.293. Although he had previously received medical treatment, the patient was transferred to our hospital, as he was unable to achieve stable glycemic control. At the time of admission, level of blood glucose and fasting serum C peptide were 1.002 mg/dL and 0.1 ng/mL, respectively. A glucagon loading test performed at our hospital revealed a serum C peptide level of <0.5 ng/ml. Tests for islet-cell autoantibodies were negative, and the patient's pathological conditions met the diagnostic criteria for fulminant type 1 diabetes. His human leukocyte antigen genotype was DRB1*0405 DQB1*0401, which is a disease susceptibility haplotype. In our experience, acute exacerbation of fulminant type 1 diabetes is observed in elderly patients who receive treatment following a diagnosis of type 2 diabetes. The differential diagnosis of ketoacidosis in elderly patients with type 2 diabetes should also include fulminant type 1 diabetes. Furthermore, providing an appropriate diagnosis and rapid treatment intervention is required.

Antibiofilm Property and Biocompatibility of Siloxane-Based Polymer Coatings Applied to Biomaterials.

Biofilm infections sometimes occur on biomaterials inserted into the body because biomaterials can block the attack of immune cells such as macrophages, promoting biofilm formation by invading bacteria. Owing to their use in antifouling applications, including biofilm formation, siloxane-based polymer coatings are considered a promising method to prevent biofilm formation on the surface of biomaterials. In this study, we explored the antibiofilm property and biocompatibility of siloxane-based polymer coatings. Biofilm formation and cytotoxicity tests were performed using Escherichia coli and Staphylococcus epidermidis to quantify the biofilms while U937 cells were used to measure the time course of viable cell concentration and viability, respectively. In both the biofilm formation and cytotoxicity tests, stainless steel SUS316L plates and titanium plates coated with the siloxane-based polymer and sterilized in an autoclave were used as the biomaterials. The amount of biofilm formed on the polymer-coated titanium plate was substantially higher than that on a noncoated titanium plate in the case of S. epidermidis. The viable cell concentration and viability of U937 cultured on the polymer-coated titanium plate were lower than those of U937 cultured on the noncoated titanium plate. The same trend was observed between polymer-coated and noncoated SUS316L plates. These results indicate that the siloxane-based polymer coatings need additional treatment to achieve a satisfactory antibiofilm property and that they are sensitive to autoclave treatment, resulting in cytotoxicity.

Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction.

Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor screening in combination with structural modeling and found that remdesivir is a selective, partial agonist for urotensin-II receptor (UTS2R) through the Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and impaired contractility in both neonatal and adult cardiomyocytes, all of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related cardiovascular events and that genetic variations of UTS2R gene can be a potential risk factor for cardiovascular events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.