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The dysfunction of descending noradrenergic (NAergic) modulation in second-order neurons has long been observed in neuropathic pain. In clinical practice, antidepressants that increase noradrenaline levels in the synaptic cleft are used as first-line agents, although adequate analgesia has not been occasionally achieved. One of the hallmarks of neuropathic pain in the orofacial regions is microglial abnormalities in the trigeminal spinal subnucleus caudalis (Vc). However, until now, the direct interaction between descending NAergic system and Vc microglia in orofacial neuropathic pain has not been explored. We found that reactive microglia ingested the dopamine-β-hydroxylase (DβH)-positive fraction, NAergic fibers, in the Vc after infraorbital nerve injury (IONI). Major histocompatibility complex class I (MHC-I) was upregulated in Vc microglia after IONI. Interferon-γ (IFNγ) was de novo induced in trigeminal ganglion (TG) neurons following IONI, especially in C-fiber neurons, which conveyed to the central terminal of TG neurons. Gene silencing of IFNγ in the TG reduced MHC-I expression in the Vc after IONI. Intracisternal administration of exosomes from IFNγ-stimulated microglia elicited mechanical allodynia and a decrease in DβH in the Vc, which did not occur when exosomal MHC-I was knocked down. Similarly, in vivo MHC-I knockdown in Vc microglia attenuated the development of mechanical allodynia and a decrease in DβH in the Vc after IONI. These results show that microglia-derived MHC-I causes a decrease in NAergic fibers, culminating in orofacial neuropathic pain.

Abstract Aim Auditory Charles Bonnet syndrome (aCBS) is characterized by musical hallucinations (MHs) that accompany acquired hearing impairments. This hallucination is the acoustic perception of music, sounds, or songs in the absence of an outside stimulus, and it may be associated with hyperactivity of the superior temporal lobes. Some studies have reported the possibility of improving MH with antiepileptics. To elucidate in detail the brain regions responsible for aCBS, we analyzed the regions that changed functionally after treatment. Methods Before and after treatment with carbamazepine (four cases), clonazepam (one case), and a hearing aid (one case), cerebral perfusion single‐photon emission computed tomography (SPECT) and the Auditory Hallucination Rating Scale (AHRS) were applied to six patients with hearing‐loss–associated MHs. Results Cerebral blood flow analysis using SPECT revealed hyperperfusion in Brodmann area (BA) 22—the posterior region of the superior temporal gyrus—in the nondominant hemisphere in all six patients in the pretreatment phase. After treatment, the hyperperfusion region improved in all patients. The area percentages with hyperperfusion in the nondominant BA22 were strongly positively correlated with the AHRS score. Conclusion The results suggest that aCBS, which was treatable with antiepileptics or hearing aids, was involved in hyperexcitement in BA22, and that MH strength was correlated with degree of excitement.

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for a pandemic affecting billions of people worldwide. Apart from the extreme global economic impact, the pandemic will likely have a lasting impact through long-term sequelae not yet fully understood. Fully understanding the mechanisms driving the various symptoms and sequelae of SARS-CoV-2 infection will allow for the eventual development of therapeutics to prevent or treat such life-altering symptoms. In this study, we developed a behavioral test of anosmia in SARS-CoV-2-infected hamsters. We find a moderately strong correlation between the level of anosmia and the score of histological damage within the olfactory epithelium. We also find a moderately strong correlation between the level of anosmia and the thickness of the olfactory epithelium, previously demonstrated to be severely damaged upon infection. Thus, this food-searching behavioral test can act as a simple and effective screening method in a hamster model for various therapeutics for SARS-CoV-2-related anosmia.

Young female cancer patients can develop chemotherapy-induced primary ovarian insufficiency (POI). Cyclophosphamide (Cy) is one of the most widely used chemotherapies and has the highest risk of damaging the ovaries. Recent studies elucidated the pivotal roles of cellular senescence, which is characterized by permanent cell growth arrest, in the pathologies of various diseases. Moreover, several promising senolytics, including dasatinib and quercetin (DQ), which remove senescent cells, are being developed. In the present study, we investigated whether cellular senescence is involved in Cy-induced POI and whether DQ treatment rescues Cy-induced ovarian damage. Expression of the cellular senescence markers p16, p21, p53, and γH2AX was upregulated in granulosa cells of POI mice and in human granulosa cells treated with Cy, which was abrogated by DQ treatment. The administration of Cy decreased the numbers of primordial and primary follicles, with a concomitant increase in the ratio of growing to dormant follicles, which was partially rescued by DQ. Moreover, DQ treatment significantly improved the response to ovulation induction and fertility in POI mice by extending reproductive life. Thus, cellular senescence plays critical roles in Cy-induced POI, and targeting senescent cells with senolytics, such as DQ, might be a promising strategy to protect against Cy-induced ovarian damage.

PIP3-dependent Rac exchanger 1 (P-Rex1) is activated downstream of G protein-coupled receptors to promote neutrophil migration and metastasis. The structure of more than half of the enzyme and its regulatory G protein binding site are unknown. Our 3.2 Å cryo-EM structure of the P-Rex1-Gβγ complex reveals that the carboxyl-terminal half of P-Rex1 adopts a complex fold most similar to those of Legionella phosphoinositide phosphatases. Although catalytically inert, the domain coalesces with a DEP domain and two PDZ domains to form an extensive docking site for Gβγ. Hydrogen-deuterium exchange mass spectrometry suggests that Gβγ binding induces allosteric changes in P-Rex1, but functional assays indicate that membrane localization is also required for full activation. Thus, a multidomain assembly is key to the regulation of P-Rex1 by Gβγ and the formation of a membrane-localized scaffold optimized for recruitment of other signaling proteins such as PKA and PTEN.

BackgroundUse of smokeless tobacco (ST, moist snuff and chewing tobacco) is elevated among male rural youth, particularly participants in certain sports, including baseball.ObjectivesThis study aimed to assess factors associated with adolescent male athletes' ST-related behaviors over time, including: baseline use, initiation, and progression in use intensity in a school-based longitudinal cohort.MethodsBaseline and one-year follow-up questionnaires assessed sociodemographic characteristics, environmental factors, and tobacco-related perceptions and behaviors among 9- to12th-grade interscholastic baseball players in 36 rural California schools. Population characteristics were compared among ST use categories (never, experimental, and experienced users). Multivariable models using generalized estimating equations were estimated for outcomes among baseline ST never-users (ST susceptibility and future initiation) and experimenters (ST expectations and progression in ST use).ResultsOf 594 participants, over half (57%) had ever tried a tobacco product and the most common products tried were ST (36%) and electronic cigarettes (36%). Being older, perceiving less ST harm, being Non-Hispanic White, using alcohol or other tobacco products, having family or friends who use ST, and being receptive to advertising were associated with greater baseline ST use. Baseline alcohol consumption, lower perceived ST harm, peer use, and susceptibility and expectations were predictive of ST initiation and/or progression at one-year follow-up. Conclusion/Importance: Certain environmental, socio-demographic, cognitive, and behavioral factors predict ST susceptibility and later initiation and progression in use. Interventions addressing these factors have potential to prevent ST uptake and continued use within this high-risk adolescent population.

Abstract The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are associated with the establishment and progression of peritoneal metastasis. This study investigated the efficacy of replicative oncolytic adenovirus-mediated p53 gene therapy (OBP-702) against CAFs and peritoneal metastasis of gastric cancer (GC). Higher CAF expression in the primary tumor was associated with poor prognosis of GC, and higher CAF expression was also observed with peritoneal metastasis in immunohistochemical analysis of clinical samples. And, we found transcriptional alteration of p53 in CAFs relative to normal gastric fibroblasts (NGFs). CAFs increased the secretion of cancer-promoting cytokines, including interleukin-6, and gained resistance to chemotherapy relative to NGFs. OBP-702 showed cytotoxicity to both GC cells and CAFs but not to NGFs. Overexpression of wild-type p53 by OBP-702 infection caused apoptosis and autophagy of CAFs and decreased the secretion of cancer-promoting cytokines by CAFs. Combination therapy using intraperitoneal administration of OBP-702 and paclitaxel synergistically inhibited the tumor growth of peritoneal metastases and decreased CAFs in peritoneal metastases. OBP-702, a replicative oncolytic adenovirus-mediated p53 gene therapy, offers a promising biological therapeutic strategy for peritoneal metastasis, modulating CAFs in addition to achieving tumor lysis.

Transparent amorphous oxide semiconductors (TAOSs) are essential materials and ushering in information and communications technologies. The performance of TAOS depends on the microstructures relating to the defects and dopants. Density functional theory (DFT) is a powerful tool to understand the structure–property relationship relating to electronic state; however, the computation of DFT is expensive, which often hinders appropriate structural modeling of amorphous materials. This study, thus, applied machine-learning potential (MLP) to reproduce the DFT level of accuracy with enhanced efficiency, to model amorphous In 2 O 3 (a-In 2 O 3), instead of expensive molecular dynamics (MD) simulations with DFT. MLP-MD could reproduce a-In 2 O 3 structure closer to the experimental data in comparison with DFT-MD and classical MD simulations with an analytical force field. Using the relatively large models obtained by the MLP-MD simulations, it was unraveled that the anionic hydrogen atoms bonding to indium atoms attract electrons instead of the missing oxygen and remedy the optical transparency of the oxygen deficient a-In 2 O 3. The preferential formation of metal–H bonding through the reaction of oxygen vacancy was demonstrated as analogous to InGaZnO x thin films [Joonho et al., Appl. Phys. Lett. 110, 232105 (2017)]. The present simulation suggests that the same mechanism works in a-In 2 O 3 , and our finding on the structure–property relationship is informative to clarify the factors affecting the optical transparency of In-based TAOS thin films. [ABSTRACT FROM AUTHOR]

We present 2 cases that both developed infective endocarditis and underwent mitral valve replacement. In addition to positive blood culture and echocardiographic findings, such as vegetation or mitral valve perforation, the 16S ribosomal RNA gene amplicon sequence approach used was helpful for disease diagnosis. (Level of Difficulty: Intermediate.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus first identified in China in 2011 and later reported in other Asian countries. Significant efforts have been made to develop anti-SFTSV compounds; however, there are no approved vaccines or antivirals against SFTSV infections. Marine organisms provide nearly unlimited biological resources to produce therapeutic drugs for the treatment and control of disease. In this study, we aimed to identify anti-SFTSV chemical compounds from the culture broth extracts of marine microbes collected from the coasts of the Nagasaki Prefecture, Japan. Of the 80 extracts, two showed an anti-SFTSV effect. One of them, which exhibited low cell toxicity, was used for further characterization. Chemical analysis combined with the anti-SFTSV effect identified surfactin as one of the main components of the selected extract. Our study showed a proof-of-concept to identify novel antiviral compounds from marine microbes against the virus of interest. Further analysis showed that surfactin affected the integrity of the virion membrane and inhibited SFTSV infection-induced membrane fusion at low pH conditions. Furthermore, surfactin inhibits the post-entry step of viral replication in the cell, which is a novel mode of antiviral action of surfactin. These results indicate that surfactin can target multiple steps of SFTSV replication in cells.

Abstract Background and Aim Obstructive jaundice induced by pancreatic adenocarcinoma is typically treated with biliary drainage with endoscopic retrograde cholangiopancreatography (ERCP)‐guided biliary drainage (ERCP‐BD). Recently, endoscopic ultrasonography‐guided biliary drainage (EUS‐BD) was employed as an alternative method after ERCP‐BD failed. We aimed to determine the efficacy and safety of EUS‐BD for primary biliary drainage. Methods Between December 2011 and February 2019, at Kawasaki General Medical Center, we retrospectively enrolled 33 patients who had undergone endoscopic biliary drainage with a metal stent, in a first attempt to relieve obstructive jaundice caused by unresectable pancreatic adenocarcinoma. We compared the technical and clinical outcomes between ERCP‐BD and EUS‐BD. Results Twenty‐three patients underwent ERCP‐BD and 10 underwent EUS‐BD. Both groups achieved 100% technical success. The clinical success rates were similar between the groups: 91% (21/23 patients) for ERCP‐BD and 100% (10/10 patients) for EUS‐BD (P = 0.48). Biliary obstruction recurred in 6/23 patients (26%) treated with ERCP‐BD and 1/10 patients (10%) treated with EUS‐BD (P = 0.40). Other adverse events occurred in 4/23 patients (17%) in the ERCP‐BD group and 1/10 patients (10%) in the EUS‐BD group (P = 0.99). Conclusion We suggest that EUS‐BD could be employed for primary biliary drainage in patients with obstructive jaundice caused by unresectable pancreatic adenocarcinoma.

A 33-year-old woman visited our hospital due to visual loss. Her BP was 280/150 mm Hg and pulse rate was 111 beats per minute. A urinalysis showed protein in urine, suggesting kidney injury. A transthoracic echocardiography showed left ventricular hypertrophy. A Cardiac magnetic resonance imaging suggested left ventricular endocardial edema or inflammation. Ophthalmoscopy showed optic disc edema and hard exudates in both eyes. A brain MRI showed multiple high-intensity areas at the pons and white matter of the cerebrum and cerebellum. Although the patient had malignant hypertension, she was successfully treated by medication.

Alkylsilane-derived hybrid films exhibiting excellent dynamic dewetting behaviors toward various liquids are promising, since they are smooth, highly transparent, and a low environmental burden. However, the detailed mechanism of their unique dynamic dewetting behaviors and its relation to the surface segregation of alkylsilanes during the film formation have not yet been clearly identified. In this study, we prepared various hybrid films by varying the mixing ratios of tetraethoxysilane (TEOS) and n-dodecyltriethoxysilane (C12TES) and investigated the changes in the s-CH2/s-CH3 peak strength ratios of the resulting hybrid films under dry and wet conditions by sum-frequency generation (SFG) spectroscopy. When the static/dynamic water contact angles significantly changed, it was clearly observed that the s-CH2/s-CH3 ratio of each hybrid film under dry and wet condition also changed markedly. With increasing TEOS concentration, the static contact angles became smaller, while the contact angle hysteresis tended to increase because of the increase in gauche defects at the air interface and hydrogen bonds. This finding suggests that the concentration and conformation of the alkyl chains derived from surface-segregated C12TES molecules play an important role in determining the final dewetting behaviors of the hybrid films to water.

Background/Aims Difficult biliary cannulation is an important risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Therefore, this study aimed to identify the factors that predict difficult cannulation for common bile duct stones (CBDS) to reduce the risk for PEP. Methods This multicenter retrospective study included 1,406 consecutive patients with native papillae who underwent ERCP for CBDS. Factors predicting difficult cannulation for CBDS were identified using univariate and multivariate analyses. Results Univariate analysis showed that six factors significantly predicted difficult cannulation: ERCP performed by non-expert endoscopists, low-volume center, absence of acute cholangitis, normal serum bilirubin, intradiverticular papilla, and type of major duodenal papilla. Multivariate analysis identified ERCP performed by non-expert endoscopists (odds ratio [OR], 2.5; p

Afferent-loop syndrome (ALS) is known as a rare complication of partial or total gastrectomy and also occurs after pancreatoduodenectomy. The symptoms of ALS vary with the location of the mechanical obstruction, and the choice of therapeutic method should reflect the patient’s condition and disease state. Herein, we report the use of endoscopic ultrasound (EUS)-guided afferent loop drainage with a plastic stent and its reintervention for malignant ALS. An 80-year-old man was admitted to our hospital with abdominal pain. Thirty-two months before, the patient underwent left hepatectomy with choledochojejunostomy and Roux-en-Y reconstruction for hilar biliary adenocarcinoma. An abdominal CT scan showed a dilated afferent loop and a low-density lesion in the peritoneum that suggested recurrence of hilar biliary adenocarcinoma and malignant ALS due to mechanical obstruction of the afferent loop caused by peritoneal dissemination. The recurrence site did not include the choledochojejunostomy anastomosis and was far distal to it. We employed a convex EUS scope and directly punctured the afferent loop from the stomach. We inserted one double pig-tail stent, and the ALS immediately improved. Five months later, ALS recurred, and we exchanged a plastic stent through the fistula. After reintervention, ALS did not recur before the patient’s death due to cancer progression.