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Aim: Previous ovarian surgery for endometriosis results in decreased ovarian reserve and poor response to treatment in women with infertility. However, the impact of previous overall ovarian surgery on the incidence of infertility is unclear. Therefore the authors investigated impact of previous ovarian surgery on infertility incidence. Materials and Methods: This is a case-control study using retrospectively collected data in women who received infertility treatment (cases) or delivered babies (controls) at a tertiary center between 2003 and 2012. Results: The frequency of previous ovarian surgery was similar in both groups (p > 0.05) but it was higher in women with tubal infertility than their matched controls (p < 0.05). Also, the frequency of previous reproductive organ surgery was higher in the case group and in women with tubal or unexplained infertility (p < 0.05). Conclusion: Previous ovarian surgery is not associated with entire infertility, but may increase tubal factor infertility through adhesion formation and damage to adjacent tubes.

Bart Thaci,1 Matthew J McGirt,2 Joshua M Ammerman,3 Claudius Thomé,4 Kee D Kim,1 Jared D Ament5 1Department of Neurological Surgery, University of California, Davis, Sacramento, CA, USA; 2Department of Neurological Surgery, Carolina Neurosurgery and Spine Associates, Charlotte, NC, USA; 3Department of Surgery, Sibley Memorial Hospital, Washington DC, USA; 4Deparment of Neurosurgery, Innsbruck Medical University, Innsbruck, Austria; 5Sierra Neuroscience Institute, Los Angeles, CA, USA Purpose: Despite being an extremely successful procedure, recurrent disc herniation is one of the most common post-discectomy complications in the lumbar spine and contributes significant health care and socioeconomic costs. Patients with large annular defects are at a high risk for reherniation, but an annular closure device (ACD) has been designed to reduce reherniation risk in this population and may, in turn, help control direct health care costs after discectomy.Patients and methods: This analysis examined the 90-day post-discectomy cost estimates among ACD-treated (n=272) and control (discectomy alone; n=278) patients in a randomized controlled trial (RCT). Direct medical costs were estimated based on 2017 Humana and Medicare claims. Index discectomies were assumed to occur in an outpatient (OP) setting, whereas repeat discectomies were assumed to be 60% in OP and 40% in inpatient (IP). A sensitivity analysis was performed on this assumption. The device cost was not included in the analysis in order to focus on costs in the 90-day post-operative period.Results: Within 90 days of follow-up, post-operative complications occurred in 3.3% of the ACD patients and 8.6% of the control patients (P=0.01). The average 90-day cost to treat an ACD patient was $10,257 compared to $11,299 per control patient for a 80:20 distribution of Commercial:Medicare coverage ($1,042 difference). This difference varied from $687 with 100% Medicare to $1,132 with 100% Commercial coverage. Varying the IP vs OP distribution resulted in a cost difference range of $968 to $1,156 with the ACD.Conclusion: Augmenting discectomy with an ACD in high-risk patients with a large annular defect reduced reherniation and reoperation rates, which translated to a reduction of direct health care costs between $687 and $1,156 per patient during the 90-day post-operative period. Large annular defect patients are an easily identifiable high-risk population. Operative strategies that reduce complication risks in these patients, such as the ACD, could be advantageous from both patient care and economic perspectives. Keywords: annular closure device, value-based care, 90-day bundle, lumbar discectomy, large annular defect, recurrent herniation

Streptococcus mutans, a major etiological agent of dental caries, frequently causes systemic disease, such as subacute bacterial endocarditis, if it enters the bloodstream. In this study, the production pathways of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), induced by S. mutans in mouse macrophage were examined using a quantitative real-time polymerase chain reaction and an enzyme-linked immunosorbent assay. The S. mutans stimulated the expression of TNF-α and IL-1β mRNA at a multiplicity of infection of 1 : 100, which increased at 2 and 4 h, respectively, to 24 h. It also induced the production of high levels of the TNF-α and IL-1β proteins, which increased at 2 h and reached a peak at 4 and 24 h, respectively. Nuclear factor-κB (NF-κB) was activated and reached a maximum level 30 min after the S. mutans treatment. The expression of TNF-α and IL-1β mRNA and protein was suppressed by the treatment with pyrrolidine dithiocarbamate, an NF-κB inhibitor. The S. mutans-induced TNF-α expression was suppressed by the presence of SB203580, a p38 mitogen-activated protein (MAP) kinase inhibitor, or SP600125, a Jun N-terminal kinase (JNK) MAP kinase inhibitor. On the other hand, IL-1β expression was inhibited by extracellular signal-regulated kinase (ERK)/p38/JNK MAP kinase inhibitor pretreatment. In addition, TNF-α production was suppressed more in the Toll-like receptor 2(-/-) (TLR2(-/-)) macrophages than in the TLR4(-/-) macrophages, whereas IL-1β production was suppressed more in the TLR4(-/-) macrophages than in the TLR2(-/-) macrophages. These results show that S. mutans stimulates the production of TNF-α and IL-1β in the mouse macrophage cell line, RAW 264.7, by activating ERK/p38/JNK, and NF-κB through TLR2 and TLR4, respectively. [ABSTRACT FROM AUTHOR]

STUDY DESIGN.: A prospective, multicenter, randomized, two-arm, single-blind, investigational device exemption pivotal study. OBJECTIVE.: To assess the efficacy and the safety of a polyethylene glycol (PEG) hydrogel spinal sealant (DuraSeal Spinal Sealant) as an adjunct to sutured dural repair compared with standard of care methods (control) to obtain a watertight dural closure in patients undergoing an intentional durotomy during spinal surgery. SUMMARY OF BACKGROUND DATA.: If a watertight dural closure is not achieved, cerebrospinal fluid leak with associated complications may occur. The PEG hydrogel spinal sealant is an Food and Drug Administration (FDA)-approved adjunct to sutured dural repair in spine surgery. This synthetic, absorbable hydrogel sealant works in the presence of fluid, conforms to irregular surfaces, and demonstrates strong adherence and compliance to tissue, without interfering with underlying tissue visibility. METHODS.: A total of 158 patients were treated at 24 centers after they were randomized on the basis of an approximately 2:1 ratio (sealant:control); 102 received the PEG hydrogel spinal sealant and 56 received standard care. The primary end point was intraoperative watertight closure. Secondary end points included evaluations of postoperative cerebrospinal fluid leak, infection, and wound healing. RESULTS.: Patients treated with the PEG hydrogel spinal sealant had a significantly higher rate of watertight closure than the control (100% vs. 64.3%, P < 0.001). No statistical differences were seen in postoperative cerebrospinal fluid leak, infection, and wound healing. No neurologic deficits were seen attributable to the sealant. CONCLUSION.: The PEG hydrogel spinal sealant evaluated in this study is safe and effective for providing watertight closure when used as an adjunct to sutured dural repair during spinal surgery. This readily available tool is superior to other standard of care technologies commonly used to achieve intraoperative watertight dural closure. [ABSTRACT FROM AUTHOR]

Study Design: Case presentation and literature review. Objective: To review the safety of using INFUSE bone graft (recombinant human bone morphogenetic protein-2 applied to an absorbable collagen sponge) in occipitocervical (OC) fusion. Summary Of Background Data: Although INFUSE bone graft is currently approved for use in certain tibial fractures, oral maxillary procedures, and anterior lumbar interbody fusion, it has been extensively used "off-label" in posterolateral lumbar and anterior cervical fusions. INFUSE is highly effective in promoting cervical spine fusion via an anterior approach, but its potential role in promoting bony fusion in posterior cervical or OC fixation has not been studied. Methods: A 53-year-old woman with basilar invagination underwent OC fixation using INFUSE bone graft. Three days after surgery she experienced neurologic decline associated with significant tissue swelling and a large postoperative seroma under significant pressure. She made excellent recovery after reoperation and drainage. An extensive review of the literature was performed to propose a modified approach to the use of INFUSE in OC fixation. Results: Proper dosing and delivery of INFUSE for posterior cervical/OC fixation is not currently known. Previously published experience with anterior cervical fusion suggests that INFUSE can have potent inflammatory effects on paraspinal soft tissue. Conclusion: INFUSE should only be used for OC fixation in patients at elevated risk of nonunion. To prevent complications due to soft tissue swelling, consideration should be given to preventing direct exposure of INFUSE to paraspinal musculature, prolonged soft tissue drainage, and prophylactic treatment with perioperative steroid therapy. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Controversy has ensued about the prognostic relevance of the new World Health Organization (WHO) schema for the classification of thymoma. In this study, we present the clinical and histologic features of 108 thymomas and evaluate the usefulness of this histologic schema in view of the prognosis. DESIGN: Retrospective, clinicopathologic analysis of our experience and a review of recent literature. SETTING: Department of Thoracic and Cardiovascular Surgery of a university hospital. METHODS: A series of 108 thymomas were reviewed and classified by the new WHO schema. The clinical characteristics and the survival outcome were investigated in reference to the WHO subtypes. The Cox proportional hazards model was applied to determine the factors affecting the tumor-related survival. Recent literature on the prognostic relevance of the WHO schema was reviewed. RESULTS: There were 7 type A tumors, 25 type AB tumors, 12 type B1 tumors, 32 type B2 tumors, 20 type B3 tumors, and 12 type C tumors. The histologic subtype closely correlated with the Masaoka stage (p = 0.00). The tumor-related survivals at 5 years and 10 years were 88.0% and 77.9%, respectively. Stage III and IV tumors had a significantly worse prognosis than stage I or II tumors (p < 0.05). Type B3 tumors had an intermediate prognostic ranking in comparison with the carcinomas and with the other groups. On multivariate analysis, the WHO subtype (A-B2 vs B3 vs C) could predict the tumor-related survival, but the Masaoka stage was the most important prognostic factor affecting the postoperative survival (p = 0.026). CONCLUSION: The Masaoka stage is the most important determinant of survival in surgically resected cases of thymoma. To clarify the prognostic relevance and clinical usefulness of the WHO schema, consistent parameters reflecting the surgical outcome and development of the diagnostic tools that could improve the interobserver agreement within type B are needed. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: Safety using Oxiplex/SP Gel during single-level discectomy for reduction of symptoms associated with unilateral herniation of the lumbar disc was investigated by self-assessment questionnaire and magnetic resonance imaging. OBJECTIVE: To evaluate the safety and assess the efficacy parameters of Oxiplex/SP Gel. SUMMARY OF BACKGROUND DATA: Animal studies demonstrated that Oxiplex/SP Gel (CMC/PEO) reduced epidural fibrosis after lumbar surgery. METHODS: Surgeons examined spine and lower extremities of patients scheduled for discectomy to assess neurologic function and pain. Treated patients received sufficient Oxiplex/SP Gel (1-3 mL) to coat the nerve root and fill the epidural space. The control condition was surgery alone. At baseline, then 30 days, 90 days, and 6 months after surgery, patients completed self-assessment questionnaires concerning leg pain, lower extremity weakness, functional disability, daily living activities, symptoms, and radiculopathy. Magnetic resonance imaging was performed at baseline and 90 days after surgery. At 30 and 90 days after surgery, patients underwent physical examination, wound inspection, and laboratory tests. RESULTS: The surgical procedures were well tolerated by the 23 patients treated with Oxiplex/SP Gel and the 11 control patients. There were no unanticipated adverse events, no clinically significant laboratory results, and no significant differences detected by magnetic resonance imaging. Treated patients had greater reduction in outcome measures at 30 days. The differences in scores were attenuated at 90 days and 6 months. A subgroup, the patients with significant leg pain and weakness at baseline (11 patients treated with Oxiplex/SP Gel and 7 control patients), had greater reduction in outcome measures than the control patients throughout the study. CONCLUSIONS: Oxiplex/SP Gel was easy to use and safe for patients undergoing unilateral discectomy. Greater benefit in clinical outcome measures was seen in gel-treated patients, especially those with severe leg pain and weakness at baseline. [ABSTRACT FROM AUTHOR]

RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3. Two distinct degron motifs, PETST and SPTST, were identified within the linker domain of RIPK3 for SPOP. RIPK3 phosphorylations at Thr403 by PIM2 and at Thr412/Ser413 by ERK2 are essential to facilitate its interaction with SPOP. Computational docking studies and immunoprecipitation analyses showed that these PIM2 and ERK2 phosphorylations bolster the stability of the RIPK3-SPOP interaction. In particular, mutations of RIPK3 at the degron motifs extended the half-life of RIPK3 by preventing its phosphorylation and subsequent ubiquitination. The deletion of SPOP, which led to increased stability of the RIPK3 protein, intensified LPS/sMAC/zVAD-induced necroptotic cell death in colon cancer cells. These findings underscore the critical role of the SPOP-mediated RIPK3 stability regulation pathway in controlling necroptotic cell death., Competing Interests: Declarations Consent for publication All authors read and approved the submission and final publication. Conflict of interest The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Aluminum scandium nitride (AlScN) has emerged as a promising candidate for next-generation ferroelectric memories, offering a much higher remanent charge density than other materials with a stable ferroelectric phase. However, the inherently high coercive field requires a substantial decrease in film thickness to lower the operating voltage. Significant leakage currents present a severe challenge during the thickness scaling, especially when maintaining compatibility with complementary-metal-oxide-semiconductor (CMOS) fabrication standards. This study adopts a HfN 0.4 bottom electrode, which minimizes lattice mismatch with Al 0.7 Sc 0.3 N (ASN), forming a coherent bottom interface that effectively reduces leakage currents even at thickness < 5 nm. CMOS-compatible HfN 0.4 /ASN/TiN stack, deposited without vacuum break between each layer, demonstrates exceptional scalability, confirming the ferroelectricity of ASN films at thicknesses down to 3 nm. The coercive voltage is decreased to 4.35 V, significantly advancing low-voltage AlScN devices that align with CMOS standards., (© 2024 Wiley‐VCH GmbH.)

Foamy virus (FV) is a retrovirus with a safer integration profile than other retroviruses, rendering it appealing for gene therapy. Prototype FV (PFV) vector systems have been devised to yield high-titer vectors carrying large transgenes. Subsequent iterations of PFV vectors have been engineered to be replication-incompetent, enhancing their safety. A third generation PFV vector system, composed of four plasmids, has been adapted to accommodate large transgenes. Additionally, a novel dual-vector system shows promise for convenient and efficient gene delivery, particularly with the forthcoming development of stable producer cell lines expressing PFV Env. FVs exhibit a broad host spectrum due to the ubiquitous presence of the host factor, heparan sulfate (HS), on their surface. The receptor-binding domain (RBD) of FV Env proteins plays a crucial role in binding to the host cell HS. The FV vector system has been employed in hematopoietic stem cell (HSC) gene therapy to address monogenic diseases in dog and mouse models. In addition, FV vectors safely and efficiently deliver anti-HIV transgenes to HSCs, and vectors carrying HIV epitopes successfully induce antibodies against HIV, offering the promise of anti-HIV gene therapy and vaccine development. In this review, we delve into the development and utilization of FV vector systems, emphasizing their unique advantages in gene therapy, including their non-pathogenic nature, broad host tropism, large transgene capacity, and persistence in resting cells. Furthermore, we discuss the potential of FV vectors in tackling current challenges in gene therapy and their viability as valuable tools for treating genetic diseases., 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 © 2024 Elsevier Inc. All rights reserved.)

Cyclic guanosine-adenosine monophosphate synthase (cGAS) is a key cytosolic DNA sensor that plays a pivotal role in the innate immune response. Although a decade of research on the cGAS has advanced our understanding of inflammasome formation, cytokine production, and signaling pathways, the role of cGAS in the nucleus remains unclear. In this study, we found that the nuclear localization of endogenous and stably expressed cGAS differed from transiently expressed cGAS, which mainly localized in the cytosol. In the nucleus, cGAS is tightly bound to chromatin DNA. The chromatin DNA binding of cGAS was dependent on RSK2. Our molecular mechanism study indicated that the N-lobe of RSK2 harboring 1-323 interacted with the NTase domain of cGAS harboring residues 213-330. This interaction increased RSK2-induced cGAS phosphorylation at Ser120 and Thr130, resulting in the tightly binding of cGAS to chromatin. Importantly, epidermal growth factor (EGF)-induced cell transformation and anchorage-independent colony growth showed an increase in growth factors, such as EGF or bFGF, in cGAS stable expression compared to mock expression. Notably, the cGAS-S120A/T130A mutant abolished the increasing effect of cell transformation of JB6 Cl41 cells and colony growth of SK-MEL-2 malignant melanoma cells. The results suggested that cGAS's chromatin DNA binding, which is indispensable to RSK2-dependent phosphorylation of cGAS at Ser120/Thr130, provides the first clue to how cGAS may participate in chromatin remodeling in the nucleus., (© 2024. The Author(s).)

Study Design: Retrospective cohort study of prospectively accrued data., Objective: To evaluate a large, prospective, multicentre dataset of surgically treated degenerative cervical myelopathy (DCM) cases on the contemporary risk of C5 palsy with surgical approach., Summary of Background Data: The influence of surgical technique on postoperative C5 palsy after decompression for DCM is intensely debated. Comprehensive, covariate-adjusted analyses are needed using contemporary data., Methods: Patients with moderate to severe DCM were prospectively enrolled in the multicenter, randomized, Phase III CSM-Protect clinical trial and underwent either anterior or posterior decompression between Jan 31, 2012 and May 16, 2017. The primary outcome was the incidence of postoperative C5 palsy, defined as the onset of muscle weakness by at least one grade in manual muscle test at the C5 myotome with slight or absent sensory disruption after cervical surgery. Two comparative cohorts were made based on the anterior or posterior surgical approach. Multivariate hierarchical mixed-effects logistic regression was used to estimate odds ratios (OR) with 95% confidence intervals (CI) for C5 palsy., Results: A total of 283 patients were included, and 53.4% underwent posterior decompression. The total incidence of postoperative C5 palsy was 7.4% and was significantly higher in patients who underwent posterior decompression compared with anterior decompression (11.26% vs. 3.03%, P =0.008). After multivariable regression, the posterior approach was independently associated with greater than four times the likelihood of postoperative C5 palsy ( P =0.017). Rates of C5 palsy recovery were comparable between the two surgical approaches., Conclusion: The odds of postoperative C5 palsy are significantly higher after posterior decompression compared to anterior decompression for DCM. This may influence surgical decision-making when there is equipoise in deciding between anterior and posterior treatment options for DCM., Level of Evidence: Therapeutic Level-II., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Breast cancer remains a significant health concern, with triple-negative breast cancer (TNBC) being an aggressive subtype with poor prognosis. Epithelial-mesenchymal transition (EMT) is important in early-stage tumor to invasive malignancy progression. Snail, a central EMT component, is tightly regulated and may be subjected to proteasomal degradation. We report a novel proteasomal independent pathway involving chaperone-mediated autophagy (CMA) in Snail degradation, mediated via its cytosolic interaction with HSC70 and lysosomal targeting, which prevented its accumulation in luminal-type breast cancer cells. Conversely, Snail predominantly localized to the nucleus, thus evading CMA-mediated degradation in TNBC cells. Starvation-induced CMA activation downregulated Snail in TNBC cells by promoting cytoplasmic translocation. Evasion of CMA-mediated Snail degradation induced EMT, and enhanced metastatic potential of luminal-type breast cancer cells. Our findings elucidate a previously unrecognized role of CMA in Snail regulation, highlight its significance in breast cancer, and provide a potential therapeutic target for clinical interventions., (© 2024. The Author(s).)

Background and Objectives: Traumatic spinal cord injury (SCI) remains a devastating condition with no proven effective treatment options available. In a prior single-arm study of patients with thoracic complete SCI (INSPIRE; ClinicalTrials.gov, NCT02138110), acute implantation of an investigational bioresorbable polymer scaffold (Neuro-Spinal Scaffold [NSS]) appeared to be safe through 24 months postimplantation and was associated with an American Spinal Injury Association Impairment Scale (AIS) conversion rate that exceeded historical controls. Here, we evaluated whether NSS implantation demonstrates probable benefit for safety and neurological recovery in patients with thoracic complete SCI vs standard-of-care spine surgery., Methods: INSPIRE 2.0 was a randomized, controlled, parallel, multicenter study conducted at Level I trauma centers in the United States (ClinicalTrials.gov, NCT03762655; funded by InVivo Therapeutics Corporation). Patients with AIS grade A, thoracic (T2-T12), nonpenetrating SCI requiring spine surgery ≤7 days postinjury were randomized (1:1, computer-generated allocation) to undergo NSS implantation or spine surgery alone (control group). Patients and follow-up International Standards for Neurological Classification of SCI assessors were blinded. A predefined study success criterion required the proportion of patients with improvement of ≥1 AIS grade at 6 months postsurgery (primary endpoint) to be ≥20% higher in the NSS group than in the control group., Results: Target enrollment was reached (N = 20) with 10 patients randomized and analyzed in each group. At 6 months postsurgery, an improvement in the AIS grade was reported in 2 NSS patients (20%; both to AIS C) and 3 control group patients (30%; to AIS B [n = 2] or AIS C [n = 1]). No serious or unanticipated adverse device effects were reported. The study was closed to further follow-up because of not meeting its primary endpoint., Conclusion: In this small group of patients with thoracic complete (AIS A) SCI, implantation of an intraparenchymal bioresorbable scaffold did not produce probable clinical benefit. However, this study provides evidence that surgical intervention in an injured spinal cord parenchyma may be performed safely., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Dysregulation of melanin homeostasis is implicated in causing skin pigmentation disorders, such as melasma due to hyperpigmentation and vitiligo due to hypopigmentation. Although the synthesis of melanin has been well studied, the removal of the formed skin pigment requires more research. We determined that β-mangostin, a plant-derived metabolite, induces the degradation of already-formed melanin in the mouse B16F10 cell line. The whitening effect of β-mangostin is mediated by macroautophagy/autophagy, as it was abolished by the knockdown of ATG5 or RB1CC1/FIP200, and by treatment with 3-methyladenine, a phosphatidylinositol 3-kinase complex inhibitor. However, the exact autophagy mechanism of melanosome degradation remains unknown. Selective autophagy for a specific cellular organelle requires specific E3-ligases and autophagic receptors for the target organelle. In this study, an E3-ligase, RCHY1, and an autophagy receptor, OPTN (optineurin), were identified as being essential for melanophagy in the β-mangostin-treated B16F10 cell line. As per our knowledge, this is the first report of a specific mechanism for the degradation of melanosomes, the target organelle of melanophagy. These findings are expected to broaden the scope of melanin homeostasis research and can be exploited for the development of therapeutics for skin pigmentation disorders.

Objectives: To predict tumor recurrence in patients who underwent surgical resection of ampullary adenocarcinoma using preoperative magnetic resonance (MR) imaging findings combined with clinical findings., Methods: In this multicenter study, a total of 113 patients (mean age, 62.9 ± 9.8 years; 58 men and 55 women) with ampullary adenocarcinoma who underwent preoperative MR imaging and surgery with margin-negative resection between 2006 and 2017 were retrospectively included. The MR imaging findings were evaluated by two radiologists. Preoperative clinical findings were obtained. Cox proportional regression analyses were used to identify the independent prognostic factors for recurrence-free survival (RFS). A nomogram was created based on the multivariable analysis and was internally validated., Results: Multivariable analysis revealed that presence of infiltrative tumor margin (hazard ratio [HR]: 2.18, p = 0.019), adjacent organ invasion (HR: 3.31, p = 0.006), adjacent vessel invasion (HR: 5.42, p = 0.041), peripancreatic lymph node enlargement (HR: 2.1, p = 0.019), and jaundice (HR: 1.93, p = 0.043) were significantly associated with worse RFS of ampullary adenocarcinoma after surgical resection. These MR imaging and clinical findings were used to construct a nomogram. On internal validation, the calibration plots showed excellent agreement between the predicted probabilities and the actual rates of tumor recurrence, with Harrell's c-index of 0.746., Conclusions: Combination of preoperative MR imaging and clinical findings can be useful for predicting tumor recurrence after surgical resection of ampullary adenocarcinoma. Identifying these features before surgery may aid in better treatment planning and management of these patients., Clinical Relevance Statement: A predictive nomogram using preoperative MR imaging and clinical findings can be useful in estimating the recurrence-free survival after surgical resection of ampullary adenocarcinoma., Key Points: • Presently, tumor size on imaging is the only non-invasive factor that correlates with recurrence-free survival from ampullary adenocarcinoma; other factors are obtained postoperatively. • Infiltrative tumor margin, adjacent organ invasion, adjacent vessel invasion, peripancreatic lymph node enlargement on MRI, and jaundice are significant predictors for recurrence. • A nomogram incorporating significant MR imaging and clinical findings showed good performance in predicting recurrence-free survival, which can help in treatment planning., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: To investigate the added value of using contrast-enhanced magnetic resonance imaging (MRI) in conjunction with contrast-enhanced computed tomography (CT) for differentiating malignant and benign ampullary strictures., Materials and Methods: The present retrospective study included 90 patients with ampullary strictures who underwent preoperative contrast-enhanced CT and contrast-enhanced MRI at two tertiary institutions. The image sets (i.e., CT alone vs. combined CT and MRI) were evaluated by three abdominal radiologists, who used a five-point Likert scale to score their confidence for diagnosing malignancy in patients with ampullary strictures. Diagnostic accuracy was calculated using receiver-operating characteristic (ROC) curve analysis, sensitivity, specificity, and accuracy. Additionally, interobserver agreement regarding the scoring of potential malignancies of the ampullary strictures was assessed., Results: The addition of contrast-enhanced MRI to contrast-enhanced CT showed a significant improvement in predicting malignant ampullary strictures in all three observers (p = 0.007, 0.001, and 0.002) using ROC curve analysis, and a significant improvement was observed in diagnostic sensitivity and accuracy for predicting malignancy (p = 0.016 and 0.029 for observer 1; p = 0.023 and 0.010 for observer 2; and p = 0.010 and 0.011 for observer 3). The interobserver agreement for the five-point scale in determining malignancies of the ampullary strictures was 0.86 for CT alone and 0.93 for the combined set of CT and MRI., Conclusion: The addition of contrast-enhanced MRI to CT provided added value for differentiating malignant from benign ampullary strictures., (© 2024. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: Lumbar disc herniation (LDH) occurs when the central disc material, primarily the nucleus pulposus, is displaced beyond the outer annulus, compressing the spinal nerve roots. LDH symptoms, including radicular leg pain, radiculopathy, and low back pain, are associated with considerable disease burden and the significant utilization of health care resources., Objectives: Provide overview of the current treatment landscape for LDH, identify unmet needs, and describe emerging treatments., Study Design: Narrative literature review., Methods: A review of literature concerning available LDH treatments and associated outcomes was conducted in PubMed to identify areas of unmet need. Some key words included "lumbar disc herniation," "radicular leg pain," "sciatica," "treatment," "therapy," and "burden.", Results: For patients who do not respond to conservative therapy, epidural steroid injections (ESIs) are widely used for persistent LDH symptoms. While ESIs provide short-term improvements in radicular pain, evidence that ESIs bestow sustained benefits is limited. ESIs are not approved by the US Food and Drug Administration (FDA) and, in rare cases, carry risks of infection and neurological injury, as well as the potential for long-term systemic effects of glucocorticoids. In cases when nonsurgical treatment fails to relieve symptoms, lumbar discectomy can provide rapid pain relief; however, in addition to the risk of intraoperative complications, the long-term consequences of lumbar discectomy may include recurrent pain or herniation, revision discectomy, loss of disc height, and Modic changes. Treatments for LDH in late-stage clinical development include sustained-release ESI formulations and a novel agent for chemonucleolysis, a nonsurgical method of minimizing the volume of the displaced nucleus pulposus. Emerging minimally invasive therapies that address the underlying pathophysiology of the disease have the potential to bridge the gap between symptomatic treatments and surgery., Limitations: Because this paper was a narrative review, literature search and selection processes were not systematic in nature. The evidence regarding the long-term efficacy of some treatments, such as discectomy, was limited by the high rates of crossover between the treatment groups., Conclusions: The lack of sustained benefits associated with ESIs and the risks associated with surgery underscore the unmet need for novel, minimally invasive interventional therapies able to address the underlying nerve root compression in LDH.

Purpose: The evolution of splenomegaly in patients with liver cirrhosis remains largely unknown. In this study, we followed the changes in splenic volume and established the natural course of splenomegaly. We developed an electronic circuit that simulated splenoportal circulation and identified the underlying hemodynamic mechanisms., Materials and Methods: This retrospective observational study included 93 patients with cirrhosis. Splenic volumes were measured in imaging studies at 6-month intervals and normalized by the ratio of each patient's maximum volume during follow-up (%Vmax). An electronic simulation model was constructed using software and realized on a breadboard., Results: Overall, the %Vmax increased from 0.77 ​± ​0.21 to a maximum of 1.00 ​± ​0.00 (p ​< ​0.001) during a median follow-up of 23 (3-162) months and then decreased to 0.84 ​± ​0.18 (p ​< ​0.001) during the next 9 (3-132) months. No interventional radiology procedure was performed to improve hepatic fibrosis and portal hypertension. The evolution of %Vmax showed single-peaked symmetry. An electronic simulation model showed that the upslope of the evolution curve was dependent on the increased intrahepatic vascular resistance and portal hypertension, whereas the downslope was dependent on the decreased portosystemic shunt (PSS) resistance., Conclusions: Splenomegaly in cirrhotic patients aggravated over a period of 23 months and then regressed spontaneously to its initial volume. Electronic simulation of splenoportal circulation showed that splenic enlargement was due to the advancement of liver cirrhosis and portal hypertension, whereas its regression was due to the development of a PSS., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To diagnose diabetes early or to maintain stable blood glucose levels in diabetics, blood glucose levels should be frequently checked. However, the only way to check blood glucose levels regularly is to use invasive methods, such as pricking the fingertip or using a minimally invasive patch. These invasive methods pose several problems, including being painful and potentially causing secondary infections. This study focuses on noninvasively measuring glycated hemoglobin (HbA1c) using PPG signals. In particular, the study relates to a method and a hardware design technology for removing noise that may be present in a PPG signal due to skin contact with a noninvasive HbA1c measurement device. The proposed HbA1c measurement device consists of the first sensor (PPG sensor) module including an optical barrier and the second sensor (cylindrical sensor) module for removing the skin effect. We have developed a Monte Carlo method to implement accurate, noninvasive HbA1c measurement by considering different skin properties among different subjects. Implementing this model in wearable devices will allow end users to not only monitor their glycated hemoglobin levels but also control diabetes with higher accuracy without needing any blood samples. This will be a groundbreaking advancement in modern wearable medical devices.

Background Context: SI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH., Purpose: The Discover 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH., Study Design/setting: A randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States., Patient Sample: Male and female participants (N=352; aged 30-70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks., Outcome Measures: The primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings., Methods: Participants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery., Results: Of the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: -41.7) compared with sham injection (-34.2; LSM difference: -7.5; 95% confidence interval [CI]: -14.1, -0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred., Conclusions: Condoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aconitase-2 (Aco2) is present in the mitochondria, cytosol, and nucleus of fission yeast. To explore its function beyond the well-known role in the mitochondrial tricarboxylic acid (TCA) cycle, we conducted genome-wide profiling using the aco2ΔNLS mutant, which lacks a nuclear localization signal (NLS). The RNA sequencing (RNA-seq) data showed a general downregulation of electron transport chain (ETC) genes in the aco2ΔNLS mutant, except for those in the complex II, leading to a growth defect in respiratory-prone media. Complementation analysis with non-catalytic Aco2 [aco2ΔNLS + aco2(3CS)], where three cysteines were substituted with serine, restored normal growth and typical ETC gene expression. This suggests that Aco2's catalytic activity is not essential for its role in ETC gene regulation. Our mRNA decay assay indicated that the decrease in ETC gene expression was due to transcriptional regulation rather than changes in mRNA stability. Additionally, we investigated the Php complex's role in ETC gene regulation and found that ETC genes, except those within complex II, were downregulated in php3Δ and php5Δ strains, similar to the aco2ΔNLS mutant. These findings highlight a novel role for nuclear aconitase in ETC gene regulation and suggest a potential connection between the Php complex and Aco2., (© 2024. The Author(s), under exclusive licence to Microbiological Society of Korea.)

Plant growth must be regulated throughout the plant life cycle. The myeloblastosis (MYB) transcription factor (TF) family is one of the largest TF families and is involved in metabolism, lignin biosynthesis, and developmental processes. Here, we showed that OsMYB14, a rice R2R3-MYB TF, was expressed in leaves and roots, especially in rice culm and panicles, and that it localized to the nucleus. Overexpression of OsMYB14 (OsMYB14-ox) in rice resulted in a 30% reduction in plant height compared to that of the wild type (WT), while the height of the osmyb14-knockout (osmyb14-ko) mutant generated using the CRISPR/Cas9 system was not significantly different. Microscopic observations of the first internode revealed that the cell size did not differ significantly among the lines. RNA sequencing analysis revealed that genes associated with plant development, regulation, lipid metabolism, carbohydrate metabolism, and gibberellin (GA) and auxin metabolic processes were downregulated in the OsMYB14-ox line. Hormone quantitation revealed that inactive GA19 accumulated in OsMYB14-ox but not in the WT or knockout plants, suggesting that GA20 generation was repressed. Indole-3-acetic acid (IAA) and IAA-aspartate accumulated in OsMYB14-ox and osmyb14-ko, respectively. Indeed, real-time PCR analysis revealed that the expression of OsGA20ox1, encoding GA20 oxidase 1, and OsGH3-2, encoding IAA-amido synthetase, was downregulated in OsMYB14-ox and upregulated in osmyb14-ko. A protein-binding microarray revealed the presence of a consensus DNA-binding sequence, the ACCTACC-like motif, in the promoters of the OsGA20ox1 and GA20ox2 genes. These results suggest that OsMYB14 may act as a negative regulator of biological processes affecting plant height in rice by regulating GA biosynthesis and auxin metabolism., Competing Interests: Declaration of Competing Interests The authors declare that they have no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent advances in contrastive learning have significantly improved the performance of deep learning models. In contrastive learning of medical images, dealing with positive representation is sometimes difficult because some strong augmentation techniques can disrupt contrastive learning owing to the subtle differences between other standardized CXRs compared to augmented positive pairs; therefore, additional efforts are required. In this study, we propose intermediate feature approximation (IFA) loss, which improves the performance of contrastive convolutional neural networks by focusing more on positive representations of CXRs without additional augmentations. The IFA loss encourages the feature maps of a query image and its positive pair to resemble each other by maximizing the cosine similarity between the intermediate feature outputs of the original data and the positive pairs. Therefore, we used the InfoNCE loss, which is commonly used loss to address negative representations, and the IFA loss, which addresses positive representations, together to improve the contrastive network. We evaluated the performance of the network using various downstream tasks, including classification, object detection, and a generative adversarial network (GAN) inversion task. The downstream task results demonstrated that IFA loss can improve the performance of effectively overcoming data imbalance and data scarcity; furthermore, it can serve as a perceptual loss encoder for GAN inversion. In addition, we have made our model publicly available to facilitate access and encourage further research and collaboration in the field., (© 2024. The Author(s).)

Potato ( Solanum tuberosum L.) is one of the most important food crops in Korea. In July 2021 and 2022, dark black-rot symptoms with pink tinges were observed on field-grown potato tubers in Hongsung and Chuncheon, Korea, respectively. We obtained four isolates (HSv05 and HSv10 from Hongsung, and CCp03 and CCp05 from Chuncheon) from diseased tubers and identified these isolates as Pythium aphanidermatum by analyzing the sequences of internal transcribed spacer rDNA region and mitochondrial cytochrome c oxidase subunit II ( COX2 ) mtDNA gene. Additionally, we compared the cultural and morphological characteristics of these four isolates with those of the reference isolate KACC 48066 of P. aphanidermatum and the literature. Further, we tested the pathogenicity of all these isolates against potato tubers. The cultural and morphological characteristics of the four test isolates were similar to those of the reference isolate and the literature; all four test isolates proved pathogenic to potato tubers. Therefore, we concluded that P. aphanidermatum is the causal agent of potato leak and this is the first report of the disease on potato in Korea., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Korean Society of Mycology.)

While mixed methods research is increasingly used to examine determinants of unwarranted variability in healthcare delivery and outcomes, novel integrative approaches are required to meet the needs of mixed methods healthcare delivery research. This article describes novel refining strategies that enhance the linkage between qualitative and quantitative dimensions of a mixed methods healthcare delivery research study. Leveraging our study experiences, this paper demonstrates several refining strategies: (1) using mediated allocation concealment to facilitate qualitative sampling; (2) informing qualitative inquiry through quantitative analytics; and (3) training and immersing multidisciplinary researchers in qualitative data collection and analysis. Developing and implementing strategies in mixed methods healthcare delivery research could advance methodological rigor and strengthen multidisciplinary collaboration.

Importance: The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery., Objective: To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM., Design, Setting, and Participants: This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical trial conducted from January 2012 to May 2017. Adult surgical patients with DCM with moderate to severe myelopathy (mJOA scale score of 8-14) were randomized to receive either riluzole or placebo. The present study was conducted from July to December 2023., Intervention: Riluzole (50 mg twice daily) or placebo for a total of 6 weeks, including 2 weeks prior to surgery and 4 weeks following surgery., Main Outcomes and Measures: The primary outcome measure was a difference in clinical improvement from baseline to 1-year follow-up, assessed using a global statistical test (GST). The 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS), arm and neck pain numeric rating scale (NRS) scores, American Spinal Injury Association (ASIA) motor score, and Nurick grade were combined into a single summary statistic known as the global treatment effect (GTE)., Results: Overall, 290 patients (riluzole group, 141; placebo group, 149; mean [SD] age, 59 [10.1] years; 161 [56%] male) were included. Riluzole showed a significantly higher probability of global improvement compared with placebo at 1-year follow-up (GTE, 0.08; 95% CI, 0.00-0.16; P = .02). A similar favorable global response was seen at 35 days and 6 months (GTE for both, 0.07; 95% CI, -0.01 to 0.15; P = .04), although the results were not statistically significant. Riluzole-treated patients had at least a 54% likelihood of achieving better outcomes at 1 year compared with the placebo group. The ASIA motor score and neck and arm pain NRS combination at 1 year provided the best-fit parsimonious model for detecting a benefit of riluzole (GTE, 0.11; 95% CI, 0.02-0.16; P = .007)., Conclusions and Relevance: In this secondary analysis of the CSM-PROTECT trial using a global outcome technique, riluzole was associated with improved clinical outcomes in patients with DCM. The GST offered probability-based results capable of representing diverse outcome scales and should be considered in future studies assessing spine surgery outcomes.

Laparoscopic liver resection (LLR) remains controversial in the treatment of intrahepatic cholangiocarcinoma (ICC). The aim of the present study is to investigate the outcomes of LLR for ICC compared to open liver resection (OLR). We retrospectively reviewed patients who underwent surgery for ICC between January 2013 and February 2020. OLR and LLR were compared after propensity score matching (PSM). Overall survival (OS) and recurrence-free survival (RFS) were compared between the matched groups. During the study period, 219 patients met the inclusion criteria (OLR = 170 patients, 77.6%; LLR = 49 patients, 22.4%). Two groups of 43 patients each were analyzed after PSM. The 5-year RFS and OS were 44.6% and 47.9% in the OLR group and 50.9% and 39.8% in the LLR group, respectively. Hospital stay and intensive care unit care were significantly shorter and lower in the LLR group than in the OLR group, respectively. Total postoperative complications and complication rates for those Clavien-Dindo grade 3 or higher were similar between the OLR group and the LLR group. Multiple tumors and lymph node metastases were predisposing factors for tumor recurrence and death in multivariate analysis. The present study suggests that LLR should be considered in selective ICC because of short hospitalization and similar oncologic outcome and overall survival., (© 2024. Italian Society of Surgery (SIC).)

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019., (© 2024. The Author(s).)

Introduction: The purposes of this study were to evaluate the effect of the combined use of object detection for the classification of the C-shaped canal anatomy of the mandibular second molar in panoramic radiographs and to perform an external validation on a multicenter dataset., Methods: The panoramic radiographs of 805 patients were collected from 4 institutes across two countries. The CBCT data of the same patients were used as "Ground-truth". Five datasets were generated: one for training and validation, and 4 as external validation datasets. Workflow 1 used manual cropping to prepare the image patches of mandibular second molars, and then classification was performed using EfficientNet. Workflow 2 used two combined methods with a preceding object detection (YOLOv7) performed for automated image patch formation, followed by classification using EfficientNet. Workflow 3 directly classified the root canal anatomy from the panoramic radiographs using the YOLOv7 prediction outcomes. The classification performance of the 3 workflows was evaluated and compared across 4 external validation datasets., Results: For Workflows 1, 2, and 3, the area under the receiver operating characteristic curve (AUC) values were 0.863, 0.861, and 0.876, respectively, for the AGU dataset; 0.935, 0.945, and 0.863, respectively, for the ASU dataset; 0.854, 0.857, and 0.849, respectively, for the ODU dataset; and 0.821, 0.797, and 0.831, respectively, for the ODU low-resolution dataset. No significant differences existed between the AUC values of Workflows 1, 2, and 3 across the 4 datasets., Conclusions: The deep learning systems of the 3 workflows achieved significant accuracy in predicting the C-shaped canal in mandibular second molars across all test datasets., (Copyright © 2024 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Foamy viruses (FVs) are generally recognized as non-pathogenic, often causing asymptomatic or mild symptoms in infections. Leveraging these unique characteristics, FV vectors hold significant promise for applications in gene therapy. This study introduces a novel platform technology using a pseudo-virus with single-round infectivity. In contrast to previous vector approaches, we developed a technique employing only two vectors, pcHFV lacking Env and pCMV-Env, to introduce the desired genes into target cells. Our investigation demonstrated the efficacy of the prototype foamy virus (PFV) dual-vector system in producing viruses and delivering transgenes into host cells. To optimize viral production, we incorporated the codon-optimized Env (optEnv) gene in pCMV-Env and the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE) at the 3' end of the transgene in the transfer vector. Consequently, the use of optEnv led to a significant enhancement in transgene expression in host cells. Additionally, the WPRE exhibited an enhancing effect. Furthermore, the introduced EGFP transgene was present in host cells for a month. In an effort to expand transgene capacity, we further streamlined the viral vector, anticipating the delivery of approximately 4.3 kbp of genes through our PFV dual-vector system. This study underscores the potential of PFVs as an alternative to lentiviruses or other retroviruses in the realm of gene therapy.

Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4's transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis., (© 2024. The Author(s).)

Silybum marianum (L.) Gaertn., commonly known as milk thistle, is a medicinal plant belonging to the Asteraceae family. This plant has been recognized for its medicinal properties for over 2,000 years. However, the genome of this plant remains largely undiscovered, having no reference genome at a chromosomal level. Here, we assembled the chromosome-level genome of S. marianum, allowing for the annotation of 53,552 genes and the identification of transposable elements comprising 58% of the genome. The genome assembly from this study showed 99.1% completeness as determined by BUSCO assessment, while the previous assembly (ASM154182v1) showed 36.7%. Functional annotation of the predicted genes showed 50,329 genes (94% of total genes) with known protein functions in public databases. Comparative genome analysis among Asteraceae plants revealed a striking conservation of collinearity between S. marianum and C. cardunculus. The genomic information generated from this study will be a valuable resource for milk thistle breeding and for use by the larger research community., (© 2024. The Author(s).)

Melanosomes are specific organelles dedicated to melanin synthesis and accumulation in melanocytes. Autophagy is suggestively involved in melanosome degradation, although the potential underlying molecular mechanisms remain elusive. In selective autophagy, autophagy receptors and E3-ligases are the key factors conferring cargo selectivity. In B16F10 cells, β-mangostin efficiently induced melanosome degradation without affecting other organelles such as mitochondria, peroxisomes, and the endoplasmic reticulum. Among various autophagy receptors, optineurin (OPTN) contributes TANK-binding kinase 1 (TBK1)-dependently to melanosome degradation and its knockdown inhibited β-mangostin-mediated melanosome degradation. OPTN translocation to melanosomes was dependent on its ubiquitin-binding domain. Moreover, OPTN-mediated TBK1 activation and subsequent TBK1-mediated S187 OPTN phosphorylation were essential for melanosome degradation. β-mangostin increased K63-linked melanosome ubiquitination. Finally, the E3-ligase RCHY1 knockdown inhibited the melanosome ubiquitination required for OPTN- and TBK1-phosphorylation as well as melanosome degradation. This study suggests that melanophagy, melanosome-selective autophagy, contributes to melanosome degradation, and OPTN and RCHY1 are an essential autophagy receptor and a E3-ligase, respectively, conferring cargo selectivity in melanophagy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objectives: This systematic review on generative adversarial network (GAN) architectures for dental image analysis provides a comprehensive overview to readers regarding current GAN trends in dental imagery and potential future applications., Methods: Electronic databases (PubMed/MEDLINE, Scopus, Embase, and Cochrane Library) were searched to identify studies involving GANs for dental image analysis. Eighteen full-text articles describing the applications of GANs in dental imagery were reviewed. Risk of bias and applicability concerns were assessed using the QUADAS-2 tool., Results: GANs were used for various imaging modalities, including two-dimensional and three-dimensional images. In dental imaging, GANs were utilized for tasks such as artifact reduction, denoising, and super-resolution, domain transfer, image generation for augmentation, outcome prediction, and identification. The generated images were incorporated into tasks such as landmark detection, object detection and classification. Because of heterogeneity among the studies, a meta-analysis could not be conducted. Most studies (72%) had a low risk of bias in all four domains. However, only three (17%) studies had a low risk of applicability concerns., Conclusions: This extensive analysis of GANs in dental imaging highlighted their broad application potential within the dental field. Future studies should address limitations related to the stability, repeatability, and overall interpretability of GAN architectures. By overcoming these challenges, the applicability of GANs in dentistry can be enhanced, ultimately benefiting the dental field in its use of GANs and artificial intelligence., (© 2023. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

The dynamic spatial organization of genomes across time, referred to as the four-dimensional nucleome (4DN), is a key component of gene regulation and biological fate. Viral infections can lead to a reconfiguration of viral and host genomes, impacting gene expression, replication, latency, and oncogenic transformation. This review provides a summary of recent research employing three-dimensional genomic methods such as Hi-C, 4C, ChIA-PET, and HiChIP in virology. We review how viruses induce changes in gene loop formation between regulatory elements, modify chromatin accessibility, and trigger shifts between A and B compartments in the host genome. We highlight the central role of cellular chromatin organizing factors, such as CTCF and cohesin, that reshape the 3D structure of both viral and cellular genomes. We consider how viral episomes, viral proteins, and viral integration sites can alter the host epigenome and how host cell type and conditions determine viral epigenomes. This review consolidates current knowledge of the diverse host-viral interactions that impact the 4DN., (© 2024. The Author(s).)

Nanodevice oscillators (nano-oscillators) have received considerable attention to implement in neuromorphic computing as hardware because they can significantly improve the device integration density and energy efficiency compared to complementary metal oxide semiconductor circuit-based oscillators. This work demonstrates vertically stackable nano-oscillators using an ovonic threshold switch (OTS) for high-density neuromorphic hardware. A vertically stackable Ge 0.6 Se 0.4 OTS-oscillator (VOTS-OSC) is fabricated with a vertical crossbar array structure by growing Ge 0.6 Se 0.4 film conformally on a contact hole structure using atomic layer deposition. The VOTS-OSC can be vertically integrated onto peripheral circuits without causing thermal damage because the fabrication temperature is <400 °C. The fabricated device exhibits oscillation characteristics, which can serve as leaky integrate-and-fire neurons in spiking neural networks (SNNs) and coupled oscillators in oscillatory neural networks (ONNs). For practical applications, pattern recognition and vertex coloring are demonstrated with SNNs and ONNs, respectively, using semiempirical simulations. This structure increases the oscillator integration density significantly, enabling complex tasks with a large number of oscillators. Moreover, it can enhance the computational speed of neural networks due to its rapid switching speed.

Acetylcholinesterase (AChE) inhibitors cause insect death by preventing the hydrolysis of the neurotransmitter acetylcholine, which overstimulates the nervous system. In this study, isorhapontin, isolated from E. globulus leaves, was evaluated as a natural insecticide with AChE inhibition at 12.5 μM. Using kinetic analyses, we found that isorhapontin acted as a competitive inhibitor that binds to the active site of AChE. The inhibition constant (K i ) was 6.1 μM. Furthermore, isorhapontin and resveratrol, which have basic skeletons, were predicted to bind to the active site of AChE via molecular docking. A comparison of the hydrogen bonding between the two stilbenes revealed characteristic differences in their interactions with amino acids. In isorhapontin, Trp83, Gly149, Tyr162, Tyr324, and Tyr370 interacted with the sugar moiety. These results suggest that with further development, isorhapontin can be used as an insecticide alternative., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis., (© 2024. The Author(s).)

Diabetes is the leading cause of kidney disease that progresses to kidney failure. However, the key molecular and cellular pathways involved in diabetic kidney disease (DKD) pathogenesis are largely unknown. Here, we performed a comparative analysis of adult human kidneys by examining cell type-specific chromatin accessibility by single-nucleus ATAC-seq (snATAC-seq) and analyzing three-dimensional chromatin architecture via high-throughput chromosome conformation capture (Hi-C method) of paired samples. We mapped the cell type-specific and DKD-specific open chromatin landscape and found that genetic variants associated with kidney diseases were significantly enriched in the proximal tubule- (PT) and injured PT-specific open chromatin regions in samples from patients with DKD. BACH1 was identified as a core transcription factor of injured PT cells; its binding target genes were highly associated with fibrosis and inflammation, which were also key features of injured PT cells. Additionally, Hi-C analysis revealed global chromatin architectural changes in DKD, accompanied by changes in local open chromatin patterns. Combining the snATAC-seq and Hi-C data identified direct target genes of BACH1, and indicated that BACH1 binding regions showed increased chromatin contact frequency with promoters of their target genes in DKD. Thus, our multi-omics analysis revealed BACH1 target genes in injured PTs and highlighted the role of BACH1 as a novel regulator of tubular inflammation and fibrosis., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)