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Although the liver of the lamprey, a group of cyclostomes that diverged the earliest among vertebrates, has abundant bile ducts in the larval stage, which degenerate during metamorphosis, there is no comparative study on its architecture with other early diverged vertebrates in terms of the morphological evolution of vertebrate livers. The present study was undertaken to compare the characteristics of the brook lamprey liver with those of the hagfish and banded houndshark, which have the portal triad type liver architecture, and to discuss its evolution. Although the liver of the brook lamprey had two-cell cords of hepatocytes lined by sinusoids in the ammocoetes larval stage, intrahepatic bile ducts around portal veins penetrated into the liver parenchyma with convolution and gradual reduction in diameter. They also faced dilated sinusoids. The epithelial cells had characteristic intercellular spaces. These characteristics were distinct from those of bile ducts in the hagfish and banded houndshark livers. Although the liver architectures of the hagfish and banded houndshark were similar, the latter penetrated the intrahepatic bile ducts more deeply along the portal veins than the former, in which intrahepatic bile ducts were restricted near the hilum. After metamorphosis, bile ducts degenerated in brook lampreys. These data indicate that the liver architecture of the ammocoetes larva is unique in the parenchymal distribution of bile ducts, their sinusoidal facing, and morphology among extant vertebrates. The periportal distribution of intrahepatic biliary structures may have been established prior to the divergence of the cyclostomes and gnathostomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Microanastomosis presents a challenge in neurosurgical procedures, requiring specialized skills. Regular practice outside the operating room is crucial. This study aims to provide a detailed description of the side-to-side anastomosis technique and analyze its advantages in preventing failures compared with other variations., Methods: We examined the technique, characteristics, and outcomes of side-to-side bypass procedures for complex aneurysms in the anterior cerebral artery territory at our institution over the past decade. We compared our technique with those described in the literature by other groups., Results: The Far East Neurosurgical Institute (FENI) technique was used in 15 patients, with 17 side-to-side anastomoses performed. The average anastomosis time was 27.5 minutes, with 100% patency in follow-up. Our technique demonstrated safety and effectiveness in treating intracranial aneurysms, yielding satisfactory short- and long-term functionality outcomes. We highlight the importance of maintaining a curvilinear arteriotomy shape, at least 3 times the diameter of the artery, and utilizing an interrupted suturing technique on the anterior wall., Conclusions: This paper presents the first comprehensive description of the side-to-side anastomosis technique, supported with images and videos for training and replicability. Our technique enhances flow dynamics and reduces the risk of acute thrombus formation. Training in simulators and microsurgery practice centers outside the operating room is essential for acquiring and refining microsurgical skills., (Copyright © 2024. Published by Elsevier Inc.)

Background/aim: Cancer remains a major global health challenge, with an estimated 10 million cancer-related deaths in 2020, hindering efforts to extend life expectancy. Cisplatin, an effective platinum-based chemotherapeutic agent used against various malignancies, has numerous side effects. Ganoderma lucidum is a traditional Chinese medicine with extensive historical use and proven biological activity. This study investigated the effects of G. lucidum on cisplatin-induced nephrotoxicity and gastrointestinal toxicity., Materials and Methods: RAW264.7 cells were treated with cisplatin, G. lucidum, or both. Cytotoxicity and antioxidant capacity were measured. Slc:ICR (ICR) mice were treated with cisplatin, G. lucidum, or both. The survival rate and physiological data were measured., Results: G. lucidum suppressed cisplatin-induced cytotoxicity and apoptosis in RAW264.7 cells. G. lucidum suppressed cisplatin-induced nephrotoxicity and gastrointestinal toxicity via its antioxidant effects in ICR mice., Conclusion: The suppressive mechanism of G. lucidum may be mediated via its antioxidant effects. These findings indicate its potential to reduce the side effects of cisplatin., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches that promote axonal regeneration are critical to improve the outcomes for patients with peripheral nerve injuries. In this study, we investigated the effects of Ficus carica L. (fig) and Vaccinium macrocarpon Ait. (cranberry), which are rich in phytochemicals with demonstrable and diverse medicinal properties, on nerve regeneration in a mouse model of sciatic nerve crush. Our investigation revealed that fig extract, but not cranberry extract, prevented the decline in muscle weight and nerve conduction velocity induced by nerve crush. The fig extract also mitigated motor function impairment, myelin thinning, and axon diameter reduction, indicating its potential to promote nerve regeneration. Furthermore, the fig extract enhanced macrophage infiltration into the nerve tissue, suggesting that it could ameliorate nerve injury by promoting tissue repair via increased macrophage infiltration. The study provides valuable insights into the potential of the fig extract as a novel agent promoting nerve regeneration. Further investigation into the mechanisms underlying the action of fig extracts is needed to translate these findings into clinical applications for patients with peripheral nerve injuries., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The pathogenicity of Clostridioides difficile in piglets remains controversial. It is unknown whether C. difficile control helps protect piglet health. To clarify the association between C. difficile presence and piglet diarrhea, isolates were obtained from piglets with and without diarrhea. In addition, to determine the genetic relationship of C. difficile from pigs and humans, we performed whole-genome sequencing (WGS) of C. difficile isolates. Diarrheal and non-diarrheal stool samples were collected from neonatal piglets from five farms in Japan in 2021. To clarify the relationship between C. difficile derived from pigs and those from human clinical cases, WGS of C. difficile isolates was performed. Toxin-positive C. difficile were significantly more prevalent in piglets with diarrhea, although the overall frequency of C. difficile did not differ between piglets with and without diarrhea. This observation indicates an association between toxin-positive C. difficile and diarrhea in piglets. However, further studies are needed to establish a direct causal relationship and to explore other contributing factors to diarrhea in piglets. WGS results showed that C. difficile sequence type (ST) 11 including the hypervirulent PCR ribotype 078 isolates derived from Japanese pigs were closely related to ST11 of overseas strains (human clinical and animal-derived) and a Japanese human clinical strain. Toxin-positive C. difficile may cause diarrhea in piglets and hypervirulent C. difficile are spreading among pigs and human populations worldwide.

Background: Acute bacterial arthritis (ABA) is a serious, pediatric infection that can result in motor comorbidities. Normally, a joint fluid white blood cell (WBC) count of 50,000 or more cells/mm 3 is used to make a presumptive diagnosis of ABA. This study evaluated the utility of the joint fluid WBC count for diagnosing pediatric ABA confirmed by a positive culture result., Methods: Patients with ABA between March 2010 and March 2023 at Tokyo Metropolitan Children's Medical Center were included. ABA was confirmed by positive joint fluid culture results for a pathogenic organism. Patients with negative results and those without a joint fluid WBC count were excluded. Electronic medical records were retrospectively reviewed for demographic data, timing of arthrocentesis, culture results and the joint fluid WBC count., Results: Ninety-five patients with ABA were identified; of these, 22 were included. The median age was 5 years [interquartile range (IQR): 2-10 years]. Males comprised 55% of the population. The median joint fluid WBC count was 19,575 (IQR: 6806-47,388) cells/mm 3 , and 23% of the patients had 50,000 cells/mm 3 or more. The median time from symptom onset to arthrocentesis was 3 days (IQR: 2-5 days). The isolated organisms were methicillin-susceptible Staphylococcus aureus (50%), methicillin-resistant S. aureus (9%), Streptococcus pyogenes (27%), Streptococcus pneumoniae (5%), Klebsiella pneumoniae (5%) and Salmonella spp. (5%)., Conclusions: Most of the patients with ABA confirmed by positive results of a joint fluid culture had a joint fluid WBC count of less than 50,000 cells/mm 3 ., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction and Objectives: Macrophage-induced inflammation plays a key role in defense against injury and harmful pathogens. Autophagy and the inflammatory response are associated; however, the relationship between the autophagy pathway and lipopolysaccharide (LPS)- induced inflammatory responses remains unknown. We aimed to determine the effect of autophagy on the LPS-induced myeloid differentiation factor 88 (MyD88)/nuclear transcription factor kB (NF-kB) pathway-mediated inflammatory response in RAW264.7 cells., Materials and Methods: To determine the effect of autophagy on the LPS-induced inflammatory response, using various in vitro assays, we determined the effect of autophagy inhibitors and inducers on the inflammatory response in RAW264.7 cells., Results: Chloroquine (CQ), an autophagy inhibitor, suppressed pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNFα) in LPS-stimulated RAW264.7 cells. CQ also affected inflammatory mediators such as myeloid differentiation factor 88 and NF-kB in LPS-stimulated RAW264.7 cells., Conclusion: This study demonstrated that CQ regulates the LPS-induced inflammatory response in RAW264.7 cells. We propose that targeting the regulation of pro-inflammatory cytokine levels and inflammatory mediators using CQ is a promising therapeutic approach for preventing inflammatory injury. CQ serves as a potential therapeutic target for treating various inflammatory diseases., Competing Interests: The authors declare no conflict of interest.

Background  Transsylvian approach is one of the main approaches for a variety of vascular, tumor, and skull-base lesions. Sylvian fissure harbors a lot of critical structures including the middle cerebral artery and many venous structures. If not done properly, the transsylvian approach could cause several complications. Up to now, there is no simple training model for practicing Sylvian fissure dissection. In this article, we describe the technique of using microscissors for the sharp dissection of arachnoid trabeculae. We also propose a new model for practicing Sylvian arachnoid dissection using a three-dimensional (3D) brain model with cotton fiber. Materials and Method  We inserted cotton fiber into the Sylvian fissure of the brain model (aneurysm box from UpsurgeOn) and covered the Sylvian fissure with a cotton sheet, then sprayed the water over it. We dissected this model under a microscope by using Kamiyama scissors in the right hand and suction in the left hand. Result  Under the microscope, our model appears comparable with the real Sylvian fissure. We can use this model for practicing arachnoid dissection with Kamiyama scissors. Conclusion  The arachnoid dissection model by using a 3D brain model with cotton fiber is a simplified and novel approach for practicing the Sylvian fissure dissection., Competing Interests: Conflict of Interest None declared., (Asian Congress of Neurological Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Objective: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients., Methods: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology., Results: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells., Conclusion: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan., (Copyright © 2024. Published by Elsevier B.V.)

Inversin-deficient (inv) mice have anomalies in liver and pancreatic development in addition to an inverted left-right axis of the body. The present study was undertaken to unveil mechanisms of bile and pancreatic duct development from immunohistochemical analyses of anomalies in inv mice. Intrahepatic bile ducts having proximodistal polarity in size and the height of their epithelia, and ductules were formed in livers of wild-type neonates. By contrast, in inv mice, ductal plates, precursor structures of intrahepatic bile ducts and ductules, persisted without the proximodistal polarity. Their epithelial cells did not acquire planar cell polarity (PCP) in terms of expression of tight junction proteins although they expressed bile duct markers, HNF1β and SOX9. They had an apicobasal polarity from expression of basal laminar components. Enlargement of the hepatic artery and poor connective tissue development, including the abnormal deposition of the extracellular matrices, were also noted in inv mice, suggesting that bile duct development was coupled to that of the hepatic artery and portal vein. In pancreata of inv neonates, neither the main pancreatic duct was formed, nor dilated duct-like structures had the morphological polarity from the connecting point with the common bile duct. Lumina of acini was dilated, and centroacinar cells changed their position in the acini to their neck region. Immunohistochemical analyses of tight junction proteins suggested that epithelial cells of the duct-like structures did not have a PCP. Thus, Invs may be required for the establishment of the PCP of the whole duct system in the liver and pancreas., (© 2023 American Association for Anatomy.)

Global climate changes undermine the effectiveness of 'set and forget' phytosanitary regulations. Uncertainties in future greenhouse gas emission profiles render it impossible to accurately forecast future climate, thus limiting the ability to make long-term biosecurity policy decisions. Agile adaptive biosecurity frameworks are necessary to address these climatic uncertainties and to effectively manage current and emerging threats. This paper provides opinions on these issues and presents a case study focusing on the threats posed by Aleurocanthus woglumi (citrus blackfly) to Europe. It delves into the biology of the species, its preferred hosts, and how climate change could affect its spread. Utilizing a bioclimatic niche model, the paper estimates the potential distribution of A. woglumi in Europe under recent historical and medium-term future conditions, revealing a potential expansion of its range into higher elevations and more northern regions by the year 2050. The main aim is to leverage the results to showcase the system's sensitivity to likely emission scenarios, essentially stress-testing for potential emerging threats to biosecurity policies and phytosanitary regulations. The results underscore the significance of considering global change factors in pest risk assessment and phytosanitary regulations for effective risk mitigation. Consequently, adaptive biosecurity measures are essential, encompassing horizon scanning, enhanced targeted surveillance, periodic updates of risk assessments, and adjustments to regulations. For instance, biosecurity risk management could involve establishing a set of trigger conditions to prompt updates of risk assessments, such as identifying a zone where the confirmed establishment of a pest signifies a significant change in the pest risk profile. For jurisdictions containing areas modeled as being climatically suitable under historical climates or future climate scenarios, we caution against importing untreated host materials from regions that are likely to become suitable habitats for A. woglumi in the future. Moreover, it is important to consider both present and future climate change scenarios when making decisions to effectively address the threats posed by invasive species. In the case of highly impactful invasives, investing in preemptive biological control measures may prove to be a prudent choice., Competing Interests: Declaration of Competing Interest The author declares no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Accumulation of ammonia causes central and peripheral fatigue. This study aimed to investigate the synergistic effect of tea catechins and low-dose ornithine in activating the urea cycle to reduce blood ammonia levels during exercise., Methods: We used hepatocyte-like cells derived from human-induced pluripotent stem (iPS) cells to assess the effect of tea catechins combined with ornithine on urea cycle activity. The urea production and expression of key genes involved in the metabolism of urea were investigated. We then examined the synergistic improvement in ammonia metabolism by tea catechins in combination with ornithine in a human pilot study., Results: Tea catechins combined with ornithine increased urea cycle activity in hepatocyte-like cells derived from human iPS cells. Intake of 538.6 mg of tea catechins with 1592 mg of ornithine for 2 consecutive days during exercise loading suppressed the exercise-induced increase in the blood ammonia concentration as well as stabilized blood glucose levels., Conclusion: Controlling the levels of ammonia, a toxic waste produced in the body, is important in a variety of situations, including exercise. The present study suggests that a heterogeneous combination of polyphenols and amino acids efficiently suppresses elevated ammonia during exercise in humans by a mechanism that includes urea cycle activation., Trial Registration: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry (No. UMIN000035484, dated January 8, 2019)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although the liver of the hagfish, an earliest diverged lineage among vertebrates, has a histological architecture similar to that of mammals, its gene expression has not been explored yet. The present study was undertaken to comparatively characterize gene expression in the liver of the hagfish with that of the mouse, using in situ hybridization technique. Expression of alb (albumin) was detectable in all hepatocytes of the hagfish liver, but was negative in intrahepatic bile ducts. Their expression in abundant periportal ductules was weak. The expression pattern basically resembled that in mammalian livers, indicating that the differential expression of hepatocyte markers in hepatocytes and biliary cells may have been acquired in ancestral vertebrates. alb expression was almost homogeneous in the hagfish liver, whereas that in the mouse liver lobule was zonal. The glul (glutamate-ammonia ligase) expression was also homogeneously detectable in hepatocytes without zonation, and weakly so in biliary cells of the hagfish, which contrasted with its restricted pericentral expression in mouse livers. These findings indicated that the hagfish liver did not have mammalian-type zonation. Whereas tetrapods had Hnf (hepatocyte nuclear factor) 1a and Hnf1b genes encoding the transcription factors, the hagfish had a single gene of their orthologue hnf1. Although HNF1α and HNF1β were immunohistochemically detected in hepatocytes and biliary cells of the mouse, respectively, hnf1 was expressed in both hepatocytes and biliary cells of the hagfish. These data indicate that gene expression of hnf1 in the hagfish liver may be ancestral with that of alb and glul during vertebrate evolution., (© 2023 American Association for Anatomy.)

Background and Objectives: The treatment of complex intracranial aneurysms with bypass surgery using 2 branches of the superficial temporal artery (STA) proves to be an effective surgical option. However, the harvest of these 2 STA branches, combined with a pterional craniotomy, carries the potential risk of delayed wound healing of the skin flap. This study undertook a retrospective analysis to examine and identify the factors associated with this delayed wound healing., Methods: A total of 56 consecutive cases, including both ruptured and unruptured complex intracranial aneurysms, that underwent bypass surgery with 2 branches of the STA, were analyzed retrospectively., Results: Major delayed wound healing was observed in 6 (10.7%) cases. Univariate analysis demonstrated significant associations with the following factors: rupture (P = 0.023), presence of diabetes mellitus (P = 0.028), large craniotomy size (P = 0.012), and the type of skin incision (P ≤ 0.001). Age (P = 0.283), sex (P = 0.558), body mass index (P = 0.221), and other blood test parameters did not demonstrate any statistical significance. Similarly, the presence of a dominant frontal branch (P = 0.515) or a low-positioned frontal branch (P = 0.622) did not reveal statistically significant results., Conclusions: In the treatment of complex intracranial aneurysms, where harvesting of the 2 STA branches is involved with a pterional craniotomy, producing a smaller skin flap (L- or T-shaped incision) is effective in minimizing the risk of delayed wound healing. The process of harvesting the STA and closing the wound demands meticulous care, taking into consideration the normal anatomical structures and the subdermal vascular plexus of the scalp., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The species distributions migration poleward and into higher altitudes in a warming climate is especially concerning for economically important insect pest species, as their introduction can potentially occur in places previously considered unsuitable for year-round survival. We explore the expansion of the climatically suitable areas for a horticultural pest, the Mediterranean fruit fly (medfly) Ceratitis capitata (Diptera, Tephritidae), with an emphasis on Europe and California. We reviewed and refined a published CLIMEX model for C. capitata, taking into consideration new records in marginal locations, with a particular focus on Europe. To assess the model fit and to aid in interpreting the meaning of the new European distribution records, we used a time series climate dataset to explore the temporal patterns of climate suitability for C. capitata from 1970 to 2019. At selected bellwether sites in Europe, we found statistically significant trends in increasing climate suitability, as well as a substantial northward expansion in the modelled potential range. In California, we also found a significant trend of northward and altitudinal expansion of areas suitable for C. capitata establishment. These results provide further evidence of climate change impacts on species distributions and the need for innovative responses to increased invasion threats., (© 2024. The Author(s).)

Mechanical thrombectomy (MT) is the leading treatment for acute large vessel occlusion (LVO). However, surgical thrombectomy (ST) may have a role in well selected LVO patients where MT failed to re-establish flow, the endovascular route is inaccessible, or where MT is a financially prohibitive or absent option (developing and poor countries). We compared the efficacy and efficiency between ST and MT, and described our operative experience and its potential application in the developing world. Clinical outcomes, procedural times, and efficacy of treatment were compared between the MT and ST of acute LVO between 2012 and 2022. Propensity score-matched analysis was also conducted to compare MT and ST. One-hundred nine patients fulfilled the study criteria (77 MTs vs 32 STs). Factors driving outcome were age (aOR: 0.95, 95%CI, 0.91-0.98), hemisphere side (aOR: 0.38, 95%CI, 0.15-0.96), and DWI-ASPECT (aOR: 1.39, 95%CI, 1.09-1.77) at presentation by the multivariate analysis. Times from door-start of procedure (P = 0.45) and start of procedure-recanalization (P = 0.13) were similar between treatment options. Propensity score-matched analysis found no significant difference for 2 treatment methods about time of door to recanalization (P = 0.155) and outcome (P = 0.221). The prognosticators of thrombectomy for acute LVO in patients with successful recanalization were age, affected hemisphere side, and DWI-ASPECT score. Our evidence shows that the efficacy of ST is similar to that of MT. There should be a place of ST for cases of mechanical failure or tandem cervical ICA and MCA occlusion. ST may be a temporizing LVO treatment option in healthcare systems where MT is inexistent or financially prohibitive to patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Mastery of sylvian fissure dissection is essential to access lesions within the deep basal cisterns. The deep sylvian vein and its tributaries play a major role during access to and beyond the carotid cistern through the sylvian fissure and determine the complexity of microdissection. Preserving the venous outflow during sylvian fissure dissection is the best reliable strategy to prevent postoperative venous strokes or venous hypertension. The authors report the role of the basal vein of Rosenthal (BVR) in the venous outflow pattern of the deep sylvian cistern., Methods: The authors analyzed 262 consecutive surgical cases involving sylvian fissure dissection from 2015 to 2017. Inclusion criteria were complete sylvian fissure dissection for the treatment of intracranial aneurysms. Exclusion criteria were giant size (aneurysm diameter > 24 mm), meningitis, subarachnoid hemorrhage within the sylvian cistern, absence of 4D CT angiography, and previous surgery. Retrospective radiological and operative video reviews were carried out to assess the association between the superficial sylvian vein and the BVR. The authors analyzed the course of the BVR and the patterns of venous drainage of the sylvian cistern. The surgical difficulty of sylvian fissure dissection was rated by the authors to study the operative significance of the venous patterns encountered. Two clinical cases are described to illustrate the proposed BVR classification., Results: A total of 97 patients met the selection criteria. The most frequent type of BVR was immature (diameter < 0.5 mm, 68%). When the BVR was incompletely developed or absent (immature type), the deep sylvian veins drained through a middle sylvian vein in 70% of cases, requiring advanced sylvian fissure dissection techniques. However, when the BVR was completely developed (32%), the middle sylvian vein was found in a minority of cases (6%), which allowed for an unobstructed transsylvian corridor. Interrater and test-retest reliability of the surgical difficulty was greater than 0.9., Conclusions: Preoperative assessment of the BVR anatomy is key to predict the deep sylvian venous pattern. The authors provide objective evidence supporting the reciprocal relationship between the type of BVR and the presence of a middle sylvian vein and the deep sylvian venous outflow. An immature BVR should alert the neurosurgeon of the high likelihood of finding a complex deep venous pattern, which may drive surgical planning.

The purpose of this study was to examine whether 4 wk of daily ingestion of milk fat globule membrane (MFGM) combined with exercise training improves physical performance-muscle strength, agility and muscle power-in healthy young adults. The study was designed as a randomized, double-blind, and placebo-controlled trial. Twenty healthy young adults received either an MFGM powder containing 1.6 g of fat and 160 mg of sphingomyelin or an isocaloric placebo powder daily throughout 4 wk of power or agility training. Physical performance tests and body composition measurements were conducted before and after the 4-wk intervention. Ingestion of MFGM did not affect isometric or isokinetic muscle strength, but it was associated with a greater increase in vertical jump peak power compared with placebo. There were no significant changes in body weight or lean body mass during the intervention period in either group, and no significant differences between groups. We conclude that daily MFGM supplementation combined with exercise training has the potential to improve physical performance in young adults; however, further studies with larger sample sizes should be conducted to obtain more evidence supporting achievement of improved physical performance through MFGM supplementation.

Leucine (Leu), an essential amino acid, is known to stimulate protein synthesis in the skeletal muscle via mTOR complex 1 (mTORC1) activation. However, the intrinsic contribution of other amino acids to Leu-mediated activation of mTORC1 signaling remains unexplored. This study aimed to identify amino acids that can promote mTORC1 activity in combination with Leu and to assess the effectiveness of these combinations in vitro and in vivo. We found that tyrosine (Tyr) enhanced Leu-induced phosphorylation of S6 kinase (S6K), an indicator of mTORC1 activity, although it exerted no such effect individually. This booster effect was observed in C2C12 cells, isolated murine muscle, and the skeletal muscles of mice orally administered the amino acids. To explore the molecular mechanisms underlying this Tyr-mediated booster effect, the expression of the intracellular Leu sensors, Sestrin1 and 2, was suppressed, and the cells were treated with Leu and Tyr. This suppression enabled Tyr alone to induce S6K phosphorylation and enhanced the booster effect, suggesting that Tyr possibly contributes to mTORC1 activation when Sestrin-GAP activity toward Rags 2 (GATOR2) is dissociated through Sestrin knockdown or the binding of Sestrins to Leu. Collectively, these results indicate that Tyr is a key regulator of Leu-mediated protein synthesis.

The histopathologic distinction of lung adenocarcinoma (LADC) subtypes is subject to high interobserver variability, which can compromise the optimal assessment of patient prognosis. Therefore, this study developed convolutional neural networks capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the recently established LADC tumor grades. Consensus LADC histopathologic images were obtained from 17 expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained to predict eight different LADC classes. Furthermore, the trained models were tested on an independent cohort of 133 patients. The models achieved high precision, recall, and F1 scores exceeding 0.90 for most of the LADC classes. Clear stratification of the three LADC grades was reached in predicting the disease-specific survival by the two models, with both Kaplan-Meier curves showing significance (P = 0.0017 and 0.0003). Moreover, both trained models showed high stability in the segmentation of each pair of predicted grades with low variation in the hazard ratio across 200 bootstrapped samples. These findings indicate that the trained convolutional neural networks improve the diagnostic accuracy of the pathologist and refine LADC grade assessment. Thus, the trained models are promising tools that may assist in the routine evaluation of LADC subtypes and grades in clinical practice., (Copyright © 2023 American Society for Investigative Pathology. All rights reserved.)

Aim: This study aimed to evaluate the effect of ultrasound-assessed lesion morphology on the outcomes of drug-coated balloon (DCB) versus plain old balloon angioplasty (POBA) treatment for de novo dysfunctional arteriovenous fistulas (AVF) lesions., Methods: This single-center retrospective study enrolled 114 consecutive patients (mean age, 73 ± 10 years; male, 69%) with de novo dysfunctional AVF lesions who underwent percutaneous transluminal angioplasty (PTA) using DCB (n = 48) and POBA (n = 66). The morphology of the stenotic lesions, evaluated using ultrasonography, was classified into intimal hyperplasia and shrinking types. The outcome measure was 12-month primary patency. Factors associated with loss of primary patency were evaluated using Cox proportional hazards models., Results: The baseline characteristics were not significantly different between the 2 treatment groups. The 12-month primary patency rate was significantly higher in the DCB group than in the POBA group (66.8 ± 7.1% versus 35.9 ± 6.3%, P = .006). The 12-month primary patency rate in the lesions with intimal hyperplasia type was not significantly different (DCB: 70.3 ± 9.5% versus POBA: 45.9 ± 8.0%; P = .310), whereas that in the shrinking type was significantly higher in the DCB group than in the POBA group (61.9 ± 10.6% versus 15.2 ± 8.1%; P < .001). The interaction analysis demonstrated that lesion morphology had a significantly different hazard ratio (HR) for restenosis between the POBA and DCB groups (P for interaction = .031). The multivariate analysis revealed that DCB usage (adjusted hazard ratio [aHR], 0.49; 95% confidence interval [CI]: [0.28, 0.87]; P = .015), ultrasound-assessed lesion morphology (shrinking type: aHR, 1.77; 95% CI: [1.07, 2.93]; P = .026), and location of stenosis (aHR, 2.26; 95% CI: 1.15, 4.46; P = .018) were significantly associated with AVF patency after PTA., Conclusion: This study revealed that lesion morphology evaluated using ultrasonography had a differential impact on DCB and POBA outcomes. The therapeutic effect of DCB was unexpectedly confirmed in the shrinking type., Clinical Impact: The effectiveness of DCB in inhibiting smooth muscle cell proliferation in intimal hyperplasia lesions was expected based on the known mechanism of action of paclitaxel. However the therapeutic effect of DCB was unexpectedly confirmed in the shrinking type too. We may not need to hesitate usage of DCB for shrinking type., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KS received honoraria from Medtronic Japan and Boston scientific Japan. OI received honoraria from Medtronic Japan. TS, KO, NO, and MI have no competing interests.

The pathogenic bacteria Bordetella pertussis and Bordetella parapertussis cause pertussis (whooping cough) and pertussis-like disease, respectively, both of which are characterized by paroxysmal coughing. We previously reported that pertussis toxin (PTx), which inactivates heterotrimeric GTPases of the G i family through ADP-ribosylation of their α subunits, causes coughing in combination with Vag8 and lipid A in B. pertussis infection. In contrast, the mechanism of cough induced by B. parapertussis , which produces Vag8 and lipopolysaccharide (LPS) containing lipid A, but not PTx, remained to be elucidated. Here, we show that a toxin we named deacylating autotransporter toxin (DAT) of B. parapertussis inactivates heterotrimeric G i GTPases through demyristoylation of their α subunits and contributes to cough production along with Vag8 and LPS. These results indicate that DAT plays a role in B. parapertussis infection in place of PTx.

Background: The liver architecture of vertebrates can be classified into two types, the portal triad type (having periportal bile ducts) and the non-portal triad type (having bile ducts independent of the course of portal veins). The former is typically detectable in livers of tetrapods and cartilaginous fish, and its ancestral state is found in the hagfish, an earliest diverged lineage among vertebrates. Teleosts other than osteoglossomorphs have the latter. The aim of the present study is to reveal the changes of the hepatic innervation, biliary cilia and smooth muscle distribution, and extracellular matrices along vertebrate evolution with attention to the two types of liver architectures., Methods: The hepatic innervation, biliary cilia and smooth muscle distribution, and collagen deposition were immunohistochemically and histochemically compared among livers of various vertebrates, using anti-acetylated tubulin and anti-α-smooth muscle actin antibodies, and Sirius red staining. These were also ultrastructurally examined., Results: Although the hagfish liver had periportal intrahepatic bile ducts and ductules as detected in mammalian livers, it lacked smooth muscles around bile ducts and portal veins. Extracellular matrices in their connective tissues had thick collagen fibers. Its innervation was restricted to intrahepatic bile ducts and portal veins in the hilum. In livers of other vertebrates, including teleosts, the innervation was broadly detectable, especially around bile ducts, hepatic arteries and portal veins (afferent vessels), but not around central veins (efferent vessels). The chondrichthyans ultrastructurally had smooth muscle tissue around bile ducts. Cilia distribution was confirmed in intrahepatic bile ducts of tetrapods and basal actinopterygians. Teleosts other than osteoglossomorphs lacked cilia in their intrahepatic bile ducts., Conclusions: The liver architecture of the hagfish may be unique for innervation and extracellular matrices. Hepatic innervation may not have occurred in vertebrate ancestors. Hepatic innervation in bile ducts, hepatic arteries and portal veins may have been conserved among the extant jawed vertebrates. Cilia distribution in bile ducts may have changed during evolution of actinopterygians., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background/aim: Stereotactic radiosurgery (SRS)-used for brain metastases (BMs) with a tumor diameter of ≤2 cm-has a high local control rate, however, it can cause symptomatic radiation-induced brain necrosis. Hypofractionated stereotactic radiation therapy (HFSRT) is not commonly used for such lesions and its effectiveness remains unknown. Herein, the efficacy of 30 Gy 5-fraction HFSRT for treating BMs of <2 cm was retrospectively evaluated., Patients and Methods: Patients who received HFSRT and had a gross tumor volume (GTV) of ≤2 cm in maximum diameter were included in the study (49 patients; 179 BMs; median follow-up period, 11.9 months)., Results: The mean GTV Peripheral Dose (D95) was 36.2 Gy. The local control (LC) rates at 1 and 2 years were 93.0% and 81.5%, respectively, for all lesions. The 1-year LC rates were 93.6% and 92.0% for ≤1.0-cm and 1.0-2.0-cm lesions, respectively. Multivariate analysis revealed that the only significant difference was in GTV maximal tumor diameter (HR=1.961, p=0.0002). Notably, only one patient had asymptomatic radiation necrosis., Conclusion: Owing to the high toxicity of SRS, 5-fraction HFSRT can be an effective treatment strategy for BMs of <2 cm., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The crop-growing region of Western Australia characterized by a Mediterranean-type climate is projected to become warmer and drier. Appropriate selection of crop sequences will be of importance to cope with these climatic changes for this largest grain-producing region of Australia. Through linking a widely used crop model (APSIM), 26 General Circulation Models (GCMs) with one Shared Socioeconomic Pathway (SSP585) and economic analysis, we explored how the climate change would affect dryland wheat cropping and whether/how long fallow (the practice of leaving a field out of production for an entire growing season) could be integrated into wheat cropping system in Western Australia. The potential adaptation of long fallow into wheat system was assessed with four fixed rotations (fallow-wheat, fallow-wheat-wheat, fallow-wheat-wheat-wheat, and fallow-wheat-wheat-wheat-wheat) and four flexible sowing rule-based rotations (the land was fallowed if sowing rule was not met), compared with continuous wheat. The simulation results at four representing locations show that climate change would have negative impacts on both yield and economic return of continuous wheat cropping in Western Australia. Wheat after fallow out-yielded and out-profited wheat after wheat under future climate. But integrating fallow into wheat cropping systems with the above fixed rotations would lead to yield and economic loss. By contrast, cropping systems in which fallowing took place when sowing condition could not be met at a certain time would achieve comparable yield and economic return to continuous wheat, with wheat yield being only 5 % less than continuous wheat and the gross margin being $12 ha -1 more than continuous wheat averaged across locations. We highlight strategic integration of long fallow into cropping system in a dryland Mediterranean-type environment would have a great potential to cope with future climate change. These findings can be extended into other Mediterranean-type cropping regions in Australia and beyond., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Carbon-ion radiotherapy (C-ion RT) is effective for head and neck mucosal melanoma (HN-MM), including radioresistant mucosal melanoma. Melanoma also responds effectively to immune checkpoint inhibitors (ICIs). Data on the efficacy and safety of ICIs for HN-MM are insufficient., Aims: To analyze the efficacy and safety of ICI salvage therapy in patients with HN-MM recurrence after C-ion RT., Methods and Results: This retrospective study analyzed the medical records of 52 patients with HN-MM treated with C-ion RT between 2012 and 2020. A dose of 57.6 or 64.0 Gy (relative biological effectiveness) was provided in 16 fractions. The primary endpoint was 3-year overall survival (OS) rate. The median follow-up time was 26.8 months for all patients. A total of 29 patients had local recurrence or distant metastasis, and 16 patients who received ICI therapy. The 3-year OS rate in the ICI group (n = 16) and best supportive care group (n = 13) were 53.8% and 0.0%, respectively (p = 0.837); the difference was not statistically significant. There were no deaths after 1 year among patients who underwent ICI therapy. No adverse events associated with C-ion RT were related to or exacerbated by ICI., Conclusion: ICI salvage therapy is effective and safe for patients with HN-MM recurrence after C-ion RT., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

We describe an adaptative bypass at the posterior third of the superior sagittal sinus (SSS) through the parietal diploe veins related to a large falcine meningioma on a 55-year-old lady with progressive headaches and mild left hemiparesis. Cranial imaging revealed a large tumor at the posterior third of the cerebral falx, compatible with meningioma. Imaging also revealed lack of continuity of the superior sagittal sinus at that region. Large diploic veins were seen bypassing the segment of the SSS affected by the tumor. An "L"-shaped modified posterior interhemispheric craniotomy was performed to avoid traversing the diploic veins. Near-total resection of the meningioma was accomplished. Postoperative imaging revealed a small remnant invading the SSS, which was treated with adjuvant radiotherapy. The patient tolerated the procedure well and was discharged to rehabilitation unit on postoperative day 5 with no neurologic deficits., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and continues to spread worldwide. To avoid the spread of infection, it is important to control its transmission routes. However, as methods to prevent airborne infections are lacking, people are forced to take measures such as keeping distance from others or wearing masks. Here, we evaluate the antiviral activity of propylene glycol (PG), which is safe, odorless, and volatile. PG showed pronounced antiviral activity against the influenza virus (IAV) at concentrations above 55% in the liquid phase. Given its IAV inactivation mechanism, which involves increasing the fluidity of the viral membrane, PG is expected to have a broad effect on enveloped viruses. PG showed antiviral activity against SARS-CoV-2. We also developed a system to evaluate the antiviral effect of PG in spray and volatilized forms. PG was found to be effective against aerosol IAV in both forms; the effective PG concentration against IAV in the vapor phase was 87 ppmv (0.27 mg/L). These results demonstrate that PG is an effective means for viral inactivation in various situations for infection control. This technology is expected to control the spread of current and future infectious diseases capable of causing outbreaks and pandemics.

Intracranial aneurysms (IAs) are a high-risk factor for life-threatening subarachnoid hemorrhage. Their etiology, however, remains mostly unknown at present. We conducted screening for sporadic somatic mutations in 65 IA tissues (54 saccular and 11 fusiform aneurysms) and paired blood samples by whole-exome and targeted deep sequencing. We identified sporadic mutations in multiple signaling genes and examined their impact on downstream signaling pathways and gene expression in vitro and an arterial dilatation model in mice in vivo. We identified 16 genes that were mutated in at least one IA case and found that these mutations were highly prevalent (92%: 60 of 65 IAs) among all IA cases examined. In particular, mutations in six genes ( PDGFRB , AHNAK , OBSCN , RBM10 , CACNA1E , and OR5P3 ), many of which are linked to NF-κB signaling, were found in both fusiform and saccular IAs at a high prevalence (43% of all IA cases examined). We found that mutant PDGFRBs constitutively activated ERK and NF-κB signaling, enhanced cell motility, and induced inflammation-related gene expression in vitro. Spatial transcriptomics also detected similar changes in vessels from patients with IA. Furthermore, virus-mediated overexpression of a mutant PDGFRB induced a fusiform-like dilatation of the basilar artery in mice, which was blocked by systemic administration of the tyrosine kinase inhibitor sunitinib. Collectively, this study reveals a high prevalence of somatic mutations in NF-κB signaling pathway-related genes in both fusiform and saccular IAs and opens a new avenue of research for developing pharmacological interventions.

Background: IL-22 is induced by aryl hydrocarbon receptor (AhR) signaling and plays a critical role in gastrointestinal barrier function through effects on antimicrobial protein production, mucus secretion, and epithelial cell differentiation and proliferation, giving it the potential to modulate the microbiome through these direct and indirect effects. Furthermore, the microbiome can in turn influence IL-22 production through the synthesis of L-tryptophan (L-Trp)-derived AhR ligands, creating the prospect of a host-microbiome feedback loop. We evaluated the impact IL-22 may have on the gut microbiome and its ability to activate host AhR signaling by observing changes in gut microbiome composition, function, and AhR ligand production following exogenous IL-22 treatment in both mice and humans., Results: Microbiome alterations were observed across the gastrointestinal tract of IL-22-treated mice, accompanied by an increased microbial functional capacity for L-Trp metabolism. Bacterially derived indole derivatives were increased in stool from IL-22-treated mice and correlated with increased fecal AhR activity. In humans, reduced fecal concentrations of indole derivatives in ulcerative colitis (UC) patients compared to healthy volunteers were accompanied by a trend towards reduced fecal AhR activity. Following exogenous IL-22 treatment in UC patients, both fecal AhR activity and concentrations of indole derivatives increased over time compared to placebo-treated UC patients., Conclusions: Overall, our findings indicate IL-22 shapes gut microbiome composition and function, which leads to increased AhR signaling and suggests exogenous IL-22 modulation of the microbiome may have functional significance in a disease setting. Video Abstract., (© 2023. The Author(s).)

Background: Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively., Methods: A serum miRNA profile (miRNomes)-based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified., Results: Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type-specific serum miRNomes., Conclusions: This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics., (© The Author(s) 2022. Published by Oxford University Press.)

Efforts have been made to replace animal experiments in safety evaluations, including in vitro-based predictions of human internal exposures, such as predicting peak plasma concentration (Cmax) values for xenobiotics and comparing these values with in vitro-based toxicity endpoints. Herein, the authors predicted the Cmax values of food-related compounds in humans based on existing and novel in vitro techniques. In this study, 20 food-related compounds, which have been previously reported in human pharmacokinetic or toxicokinetic studies, were evaluated. Human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIEC) and Caco-2 cells, HepaRG cells, equilibrium dialysis of human plasma, and LLC-PK1 cell monolayer were used to assess intestinal absorption and availability, hepatic metabolism, unbound plasma fraction, and secretion and reabsorption in renal tubular cells, respectively. After conversion of these parameters into human kinetic parameters, the plasma concentration profiles of these compounds were predicted using in silico methods, and the obtained Cmax values were found to be between 0.017 and 183 times the reported Cmax values. When the in silico-predicted parameters were modified with in vitro data, the predicted Cmax values came within 0.1-10 times the reported values because the metabolic activities of hiPSC-SIECs, such as uridine 5’-diphospho-glucuronosyl transferase, are more similar to those of human primary enterocytes. Thus, combining in vitro test results with the plasma concentration simulations resulted in more accurate and transparent predictions of Cmax values of food-related compounds than those obtained using in silico-derived predictions alone. This method facilitates accurate safety evaluation without the need for animal experiments.

Sophisticated functions of biological tissues are supported by small biological units of cells that are localized within a region of 100 μm scale. The cells in these units secrete molecules to form their microenvironment to play a vital role in biological functions. Various microfluidic devices have been developed to analyze the microenvironment but were not designed for cells in a culture dish in a confluent condition, a typical setup for cell and tissue cultivation. This study presents a novel glass capillary-based microfluidic device for studying confluent cells in a culture dish. The multiple capillaries allow the device to confine the local flow in 100 μm or smaller scale to form two adjacent regions with different chemical properties; it can simultaneously perform local cell stimulation and collect secreted molecules from the stimulated cells. Cell removal was achieved upon trypsin stimulation from a limited area (3.8 × 10 -3 ± 1.0 × 10 -3 mm 2 ), which corresponded to 7.6 ± 2.0 cells, using the mouse skeletal myoblast cell line (C2C12 cells) in a confluent condition. Microenvironmental analysis was demonstrated by measuring the secreted tumor necrosis factor alpha (TNF-α) collected from the microenvironment of the stimulated and unstimulated mouse leukemic monocyte cell line (RAW264 cells) to track temporal changes in the TNF-α production. The TNF-α secreted from stimulated cells was approximately four-fold higher than that from unstimulated cells in 90 min. This device enables local cell stimulation and the collection of secreted molecules for cells under confluent conditions, which contributes to the analysis of the cellular microenvironment.

Background: The goal in treating patients with subarachnoid hemorrhage (SAH) is shifting to preventing early brain injury. Intracranial pressure must be controlled to manage such an injury. We retrospectively analyzed the impact of aggressive removal of cisternal subarachnoid clots with simultaneous aneurysm repair for all grades of SAH., Methods: Our study included 260 consecutive patients with SAH treated through aggressive subarachnoid clot removal with simultaneous aneurysm repair. Baseline patient characteristics, history, radiographic findings, and time of SAH onset to arrival in the operating room were retrospectively collected. Factors related to poor outcome (modified Rankin Scale score >2) were analyzed., Results: Multivariate analysis revealed several characteristics were significantly associated with poor outcome: advanced age (adjusted odds ratio [aOR] 1.07, 95% confidence interval [CI] 1.04-01.10); time of SAH onset to operating room per 1-hour increments (aOR 1.03, 95% CI 1.01-01.05; postoperative hematoma volume (aOR 1.04, 95% CI 1.01-01.06); and poorer World Federation of Neurosurgical Societies grade (aOR 2.18, 95% CI 1.63-02.92). According to a receiver operating characteristic analysis, the cut-off time of SAH onset to operating room was 6.0 hours (area under the curve 0.61, P = 0.01, 95% CI 0.52-0.69, sensitivity = 0.79, specificity = 0.43) as the threshold between modified Rankin Scale scores of 0-2 and 3-6., Conclusions: Prognostic factors of SAH in patients undergoing emergent aneurysm repair with simultaneous removal of a cisternal subarachnoid clot are advanced age, poorer World Federation of Neurosurgical Societies grade, postoperative hematoma volume, and a longer time from SAH onset to operating room. The clinical outcome may improve with emergent reduction of intracranial pressure through removal of the subarachnoid clot as soon as possible., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have significantly improved the survival of advanced non-small cell lung cancer (NSCLC). Detecting NSCLC patients with exceptional response to ICIs is necessary to improve the treatment. This case control study profiled circulating microRNA expressions of 213 NSCLC patients treated with nivolumab monotherapy to identify patients with exceptional response. Based on the response and progression-free survival, patients were divided into 3 groups: Exceptional-responder (n = 27), Resistance (n = 161), and Others (n = 25). Resistance group was further randomly partitioned into six non-overlapping sets (n = 26 or 27), while each partition was combined with Exceptional-responder and Others to make balanced datasets. We built machine learning models optimized for identifying Exceptional-responder via 3-group classification and constructed a panel of 45 microRNAs and 3 fields of clinical information. Machine learning models based on the selected panel achieved 0.81-0.89 (median 0.85) sensitivity and 0.52-0.71 (median 0.59) precision for Exceptional-responder in 3-group classification with 5-fold cross validation in all six datasets constructed, while conventional method relying on tumor PD-L1 immunohistochemistry achieved 0.44-0.44 sensitivity and 0.55-0.67 (median 0.62) precision. This study demonstrated the machine learning models achieved much higher sensitivity and accuracy in identifying Exceptional-responder to nivolumab monotherapy when comparing to conventional method only using companion PD-L1 testing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O 2 •- ), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking. Here, we present the structure of the human NOX2 core complex bound to a selective anti-NOX2 antibody fragment. The core complex reveals an intricate extracellular topology of NOX2, a four-transmembrane fold of the p22 subunit, and an extensive transmembrane interface which provides insights into NOX2 assembly and activation. Functional assays uncover an inhibitory activity of the 7G5 antibody mediated by internalization-dependent and internalization-independent mechanisms. Overall, our results provide insights into the NOX2 core complex architecture, disease-causing mutations, and potential avenues for selective NOX2 pharmacological modulation., (© 2022. The Author(s).)

It is well known that birds have great diversity in nesting strategies, but we still have limited knowledge of the variation among species that share the habitat. Here, I will report and compare the nesting strategies between the two sympatric songbirds. Blue-capped ( Uraeginthus cyanocephalus ) and red-cheeked cordon-bleus ( Uraeginthus bengalus ) are socially monogamous, biparental songbirds (family Estrildidae) that sympatrically inhabit arid landscapes with trees and bushes in East Africa. Both species build domed nests with grasses that are often located near wasp nests. They also sometimes take over old weaver (family Ploceidae) nests. While these nesting strategies are already described as common behavioral traits in both species in the literature, interspecies variation in these nesting strategies in areas of sympatry is not reported. My initial field observation during their breeding season suggested that whether these nesting strategies were adopted or not varied somewhat between the sympatric cordon-bleus. Thus, I carried out a more formal investigation to test these differences. I found that red-cheeked cordon-bleus built their nests near wasp nests more frequently than blue-capped cordon-bleus, while I did not find any other significant differences between the nesting sites of the two species, such as the use of weaver nests, the types of nesting plants, or nest heights. These results suggest that the sympatric cordon-bleus share several nest-site characteristics, but that red-cheeked cordon-bleus have an affinity for nesting near wasp nests. Further studies will be required to elucidate the costs and benefits of these nesting strategies or the role that adjacency to wasp nests might play in the sympatry of the two species., Competing Interests: I declare I have no competing interests., (© 2022 The Author. Ecology and Evolution published by John Wiley & Sons Ltd.)

Objectives: Complete atrioventricular septal defect with tetralogy of Fallot is a rare and complex heart disease. This study aimed to describe contemporary management approaches for this heart disease and the outcomes., Methods: Data were obtained from 46 domestic institutions in the Japan Cardiovascular Database (2011-2018). Patients with a fundamental diagnosis of complete atrioventricular septal defect with tetralogy of Fallot, without other complex heart diseases, were included. The primary outcome was operative mortality (30-day or in-hospital mortality)., Results: A total of 119 patients underwent initial surgery for a complete atrioventricular septal defect with tetralogy of Fallot during this study period. Primary repair was performed in 40 (34%) patients (primary repair group), and palliative procedure was performed in 79 (66%) patients as part of a planned staged approach (staged group). Forty institutions (87%) experienced at least one case of staged repair. No institution experienced more than or equal to two cases/year on average during the study period. Overall, 11 operative mortalities occurred (9.2%). Operative mortality rates in the primary and staged groups were comparable (p = 0.5). Preoperative catecholamine use, repeat palliative surgeries, and emergency admission were significant risk factors for operative mortality in multivariate analysis (odds ratio, 95% confidence interval: 8.58, [0-0.11]; 12.65, [1.28-125.15]; 8.64, [1.87-39.32, respectively])., Conclusions: Staged approach for complete atrioventricular septal defect with tetralogy of Fallot was the preferred option. The outcomes of this complex disease were favorable for patients in centers with low cases of complete atrioventricular septal defect with tetralogy of Fallot., (© 2022. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background/aim: We investigated the effects of chloroquine, an autophagy inhibitor, on doxorubicin-induced apoptosis in A549 cells., Materials and Methods: A549 cells were treated with doxorubicin, chloroquine, or both. Then, cytotoxicity was measured. The expression levels of caspases and mitogen-activated protein kinases were also quantified. In addition, the levels of doxorubicin-derived reactive oxygen species were measured., Results: Chloroquine enhanced doxorubicin-induced apoptosis and oxidative stress and suppressed the doxorubicin-induced extracellular-signal-regulated kinase activation., Conclusion: Chloroquine enhances doxorubicin-induced and oxidative stress-mediated apoptosis. This mechanism may involve the dephosphorylation of extracellular-signal-regulated kinases., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The posterior condylar emissary vein (PCEV) and posterior condylar canal (PCC) are anatomical landmarks for identifying important structures like jugular tubercle and occipital condyle in surgical approach to the foramen magnum and condylar fossa. Several anatomical variations have been described. Drainage into the jugular bulb is found to be commonest., Method: A 70-year-old patient with unruptured vertebral artery-posterior inferior cerebellar artery (PICA) junction aneurysm-underwent surgical clipping via transcondylar fossa approach., Result: Preoperative computed tomography demonstrated an abnormal communication existed between the left-sided PCC and hypoglossal canal (HC). The PCEV was identified draining into a dilated venous channel/pouch at the "hip" of sigmoid sinus (junction of sigmoid sinus and jugular bulb). Intra-operatively, an occipital artery-PICA bypass was performed. The PCEV was skeletonized, coagulated, and divided to achieve hemostasis. The lateral and cranial drilling around PCC was successful at safeguarding the underlying contents of HC (in medial and caudal extent)., Conclusion: Preoperative angiography and detailed morphometric analysis of the PCC were helpful in planning surgical approach-identifying and controlling the PCEV, and skeletonization of the PCC without compromising the hypoglossal nerve and anterior condylar emissary vein., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)