Therapeutic potential of SOX9 dysruption in Combined Hepatocellular Carcinoma-Cholangiocarcinoma.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) represents a challenging subtype of primary liver cancer with limited treatment options and a poor prognosis. Recently, we and others have highlighted the context-dependent roles of the biliary-specific transcription factor SOX9 in the pathogenesis of liver cancers using various Cre applications in Sox9 (flox/flox) strains, to achieve elimination for exon 2 and 3 of the Sox9 gene locus as a preventive manner. Here, we reveal the contrasting responses of developmental Sox9 elimination using Alb-Cre;Sox9 (flox/flox) ( Sox9 LKO) versus CRISPR/Cas9 -based tumor specific acute Sox9 CKO in SB-HDTVI-based Akt-YAP1 and Akt-NRAS cHCC-CCA formation. Sox9 LKO specifically abrogates the Akt-YAP1 CCA region while robustly stimulating the proliferation of remaining poorly differentiated HCC pertaining liver progenitor cell characteristics, whereas Sox9 CKO potently prevents Akt-YAP1 and Akt-NRAS cHCC-CCA development irrespective of fate of tumor cells compared to respective controls. Additionally, we find that Akt-NRAS , but not Akt-YAP1 , tumor formation is partially dependent on the Sox9-Dnmt1 cascade. Pathologically, SOX9 is indispensable for Akt-YAP1 -mediated HC-to-BEC/CCA reprogramming but required for the maintenance of CCA nodules. Lastly, therapeutic elimination of Sox9 using the OPN-CreERT2 strain combined with an inducible CRISPR/Cas9 -based Sox9 iKO significantly reduces Akt-YAP1 cHCC-CCA tumor burden, similar to Sox9 CKO. Thus, we contrast the outcomes of acute Sox9 deletion with developmental Sox9 knockout models, emphasizing the importance of considering adaptation mechanisms in therapeutic strategies. This necessitates the careful consideration of genetic liver cancer studies using developmental Cre and somatic mutant lines, particularly for genes involved in hepatic commitment during development. Our findings suggest that SOX9 elimination may hold promise as a therapeutic approach for cHCC-CCA and underscore the need for further investigation to translate these preclinical insights into clinical applications.

Acute myocardial infarction prognosis prediction with reliable and interpretable artificial intelligence system.

OBJECTIVE: Predicting mortality after acute myocardial infarction (AMI) is crucial for timely prescription and treatment of AMI patients, but there are no appropriate AI systems for clinicians. Our primary goal is to develop a reliable and interpretable AI system and provide some valuable insights regarding short, and long-term mortality. MATERIALS AND METHODS: We propose the RIAS framework, an end-to-end framework that is designed with reliability and interpretability at its core and automatically optimizes the given model. Using RIAS, clinicians get accurate and reliable predictions which can be used as likelihood, with global and local explanations, and "what if" scenarios to achieve desired outcomes as well. RESULTS: We apply RIAS to AMI prognosis prediction data which comes from the Korean Acute Myocardial Infarction Registry. We compared FT-Transformer with XGBoost and MLP and found that FT-Transformer has superiority in sensitivity and comparable performance in AUROC and F1 score to XGBoost. Furthermore, RIAS reveals the significance of statin-based medications, beta-blockers, and age on mortality regardless of time period. Lastly, we showcase reliable and interpretable results of RIAS with local explanations and counterfactual examples for several realistic scenarios. DISCUSSION: RIAS addresses the "black-box" issue in AI by providing both global and local explanations based on SHAP values and reliable predictions, interpretable as actual likelihoods. The system's "what if" counterfactual explanations enable clinicians to simulate patient-specific scenarios under various conditions, enhancing its practical utility. CONCLUSION: The proposed framework provides reliable and interpretable predictions along with counterfactual examples.

PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.

Despite the robust regenerative capacity of the liver, prolonged and severe liver damage impairs liver regeneration, leading to liver failure. Since the liver co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to restore functional hepatocytes, augmenting LPC-mediated liver regeneration may be beneficial to patients with chronic liver diseases. However, the molecular mechanisms underlying LPC-to-hepatocyte differentiation have remained largely unknown. Using the zebrafish model of LPC-mediated liver regeneration, Tg(fabp10a:pt-ß-catenin), we present that peroxisome proliferator-activated receptor-alpha (PPARα) activation augments LPC-to-hepatocyte differentiation. We found that treating Tg(fabp10a:pt-ß-catenin) larvae with GW7647, a potent PPARα agonist, enhanced the expression of hepatocyte markers and simultaneously reduced the expression of biliary epithelial cell (BEC)/LPC markers in the regenerating livers, indicating enhanced LPC-to-hepatocyte differentiation. Mechanistically, PPARα activation augments the differentiation by suppressing YAP signaling. The differentiation phenotypes resulting from GW7647 treatment were rescued by expressing a constitutively active form of Yap1. Moreover, we found that suppression of YAP signaling was sufficient to promote LPC-to-hepatocyte differentiation. Treating Tg(fabp10a:pt-ß-catenin) larvae with the TEAD inhibitor K-975, which suppresses YAP signaling, phenocopied the effect of GW7647 on LPC differentiation. Altogether, our findings provide insights into augmenting LPC-mediated liver regeneration as a regenerative therapy for chronic liver diseases.

Clinical Practice Guidelines for Oropharyngeal Dysphagia.

OBJECTIVE: Dysphagia is a common clinical condition characterized by difficulty in swallowing. It is sub-classified into oropharyngeal dysphagia, which refers to problems in the mouth and pharynx, and esophageal dysphagia, which refers to problems in the esophageal body and esophagogastric junction. Dysphagia can have a significant negative impact one's physical health and quality of life as its severity increases. Therefore, proper assessment and management of dysphagia are critical for improving swallowing function and preventing complications. Thus a guideline was developed to provide evidence-based recommendations for assessment and management in patients with dysphagia. METHODS: Nineteen key questions on dysphagia were developed. These questions dealt with various aspects of problems related to dysphagia, including assessment, management, and complications. A literature search for relevant articles was conducted using Pubmed, Embase, the Cochrane Library, and one domestic database of KoreaMed, until April 2021. The level of evidence and recommendation grade were established according to the Grading of Recommendation Assessment, Development and Evaluation methodology. RESULTS: Early screening and assessment of videofluoroscopic swallowing were recommended for assessing the presence of dysphagia. Therapeutic methods, such as tongue and pharyngeal muscle strengthening exercises and neuromuscular electrical stimulation with swallowing therapy, were effective in improving swallowing function and quality of life in patients with dysphagia. Nutritional intervention and an oral care program were also recommended. CONCLUSION: This guideline presents recommendations for the assessment and management of patients with oropharyngeal dysphagia, including rehabilitative strategies.

Demonstration of a roll-to-roll-configurable, all-solution-based progressive assembly of flexible transducer devices consisting of functional nanowires on micropatterned electrodes.

We demonstrate continuous fabrication of flexible transducer devices consisting of interdigitated (IDT) Ag microelectrodes interconnected by ZnO nanowires (ZNWs), created via serially connected solution-processable micro- and nanofabrication processes. On an Ag layer obtainable from the mild thermal reduction of an ionic Ag ink coating, the roll-to-roll-driven photolithography process [termed photo roll lithography (PRL)] followed by wet-etching can be applied to continuously define the IDT microelectrode structure. Conformal ZNWs can then be grown selectively on the Ag electrodes to interconnect them via an Ag-mediated hydrothermal ZNW growth that does not require high-temperature seed sintering. Given that all of these constitutive processes are vacuum-free and solution-processable at a low temperature, and are compatible with continuous processing onto flexible substrates, they can be eventually configured into the roll-to-roll-processable progressive assembly. Through parametric optimizations of processes consisting of the roll-to-roll-configurable, solution-based progressive assembly of nanostructures (ROLSPAN), a flexible transducer consisting of ZNW-interconnected, PRL-ed IDT Ag electrodes can be developed. This flexible architecture faithfully performs UV sensing as well as optoelectronic transduction. The ROLSPAN concept along with its specific applicability to flexible devices may inspire many diverse functional systems requiring high-throughput low-temperature fabrication over large-area flexible substrates.

Update on Hepatobiliary Plasticity.

The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.

DNA methylation in cell plasticity and malignant transformation in liver diseases.

The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.

Influence of Genetically Modified Soybean Expressing Epidermal Growth Factor on Arthropod Biodiversity.

The field study was undertaken to examine the potential for adverse effects of transgenic soybean expressing bioactive human epidermal growth factor (with tolerance to the herbicide glufosinate, PPT) on the abundance and diversity of plant-dwelling arthropods by comparing with those of a non-GM parental cultivar, Gwangan soybean. Field surveys of soybean fields were carried out over two consecutive years, 2016 and 2017 at Ochang and Jeonju, Korea. The number of captured individuals associated with either of EGF and Gwangan soybean plants increased in 2017 compared with 2016 in both Ochang and Jeonju. During the survey period, the diversity and richness of the occurred insects and arachnids increased, dominance decreased, and the evenness of the insects remained static. The insects of Hymenoptera Order occurred most often comprised 25.4% of total captured insect pests. On the contrary, natural enemy from Hymenoptera Order and other insects from Diptera Order occurred more frequently (29.9% and 19.0%, respectively) in both the survey regions during the study periods. The score from PROXSCAL multidimensional scaling using combined data showed that the occurrence of insects and arachnids were separated due to their cultivation regions and years, irrespective of soybean cultivars. Consequently, the results indicated that there happened no notable change in the composition of arthropod communities in soybean agroecosystem due to GM event in soybean expressing EGF.

NaCl-Assisted Temperature-Dependent Controllable Growth of Large-Area MoS2 Crystals Using Confined-Space CVD.

Due to its semiconducting nature, controlled growth of large-area chemical vapor deposition (CVD)-grown two-dimensional (2D) molybdenum disulfide (MoS2) has a lot of potential applications in photodetectors, sensors, and optoelectronics. Yet the controllable, large-area, and cost-effective growth of highly crystalline MoS2 remains a challenge. Confined-space CVD is a very promising method for the growth of highly crystalline MoS2 in a controlled manner. Herein, we report the large-scale growth of MoS2 with different morphologies using NaCl as a seeding promoter for confined-space CVD. Changes in the morphologies of MoS2 are reported by variation in the amount of seeding promoter, precursor ratio, and the growth temperature. Furthermore, the properties of the grown MoS2 are analyzed using optical microscopy, scanning electron microscopy (SEM), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), and atomic force microscopy (AFM). The electrical properties of the CVD-grown MoS2 show promising performance from fabricated field-effect transistors. This work provides new insight into the growth of large-area MoS2 and opens the way for its various optoelectronic and electronic applications.

YAP1 activation and Hippo pathway signaling in the pathogenesis and treatment of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, is a highly lethal epithelial cell malignancy exhibiting features of cholangiocyte differentiation. iCCAs can potentially develop from multiple cell types of origin within liver, including immature or mature cholangiocytes, hepatic stem cells/progenitor cells, and from transdifferentiation of hepatocytes. Understanding the molecular mechanisms and genetic drivers that diversely drive specific cell lineage pathways leading to iCCA has important biological and clinical implications. In this context, activation of the YAP1-TEAD dependent transcription, driven by Hippo-dependent or -independent diverse mechanisms that lead to the stabilization of YAP1 is crucially important to biliary fate commitment in hepatobiliary cancer. In preclinical models, YAP1 activation in hepatocytes or cholangiocytes is sufficient to drive their malignant transformation into iCCA. Moreover, nuclear YAP1/TAZ is highly prevalent in human iCCA irrespective of the varied etiology, and significantly correlates with poor prognosis in iCCA patients. Based on the ubiquitous expression and diverse physiologic roles for YAP1/TAZ in the liver, recent studies have further revealed distinct functions of active YAP1/TAZ in regulating tumor metabolism, as well as the tumor immune microenvironment. In the current review, we discuss our current understanding of the various roles of the Hippo-YAP1 signaling in iCCA pathogenesis, with a specific focus on the roles played by the Hippo-YAP1 pathway in modulating biliary commitment and oncogenicity, iCCA metabolism, and immune microenvironment. We also discuss the therapeutic potential of targeting the YAP1/TAZ-TEAD transcriptional machinery in iCCA, its current limitations, and what future studies are needed to facilitate clinical translation.

Are Outcomes Comparable for Repair of AO/OTA Type 13C1 and Type 13C2 Distal Humeral Fractures Using the Paratricipital Approach?

Background: Studies have reported favorable outcomes using the paratricipital approach for fixation of distal humeral intra-articular fractures. However, literature evaluating the clinical results of the approach remains limited. The objective of this study was to compare clinical outcomes between type 13C2 and type 13C1 distal humeral fractures after open reduction and internal fixation performed using the same approach and same type of plate. Methods: A total of 52 adults with type 13C1 or 13C2 distal humeral fractures were treated surgically at our institution during 2006 to 2018. We retrospectively analyzed data from 29 of these patients (19 with type 13C1 fractures and 10 with 13C2 fractures) who met the inclusion criteria. All subjects were followed for a minimum of 2 years postoperatively. Clinical and radiologic results were analyzed to determine differences in outcomes between the two types of fractures. Clinical results were evaluated using elbow range of motion (ROM), Mayo Elbow Performance Score (MEPS), and Quick Disabilities of the Arm, Shoulder and Hand (Q-DASH) score. Alignment, fracture union, and presence of posttraumatic arthritis were evaluated radiologically. Results: The patients' mean age was 51 years, and the mean duration of follow-up was 29 months. Mean ROM was 129.5° ± 21.5° in the type 13C1 group and 123.0° ± 20.6° in the 13C2 group (p = 0.20). Mean Q-DASH score was 12.6 ± 11.7 in the 13C1 group and 16.2 ± 19.8 in the 13C2 group (p = 0.60). Mean MEPS was 92.9 ± 8.5 in the 13C1 group and 85.0 ± 14.1 in the 13C2 group (p = 0.09). Carrying angle did not differ significantly between the 13C1 and 13C2 groups. No patient in either group exhibited nonunion or posttraumatic arthritis. Conclusions: Although the paratricipital approach has the disadvantage of limited visualization of articular surfaces, there were no differences in surgical outcomes between type 13C1 and type 13C2 distal humeral fractures after fixation using this approach. Thus, surgeons may need to consider using the paratricipital approach for open reduction and internal fixation of 13C2 distal humeral fractures.

Synovial joint cavitation initiates with microcavities in interzone and is coupled to skeletal flexion and elongation in developing mouse embryo limbs.

The synovial cavity and its fluid are essential for joint function and lubrication, but their developmental biology remains largely obscure. Here, we analyzed E12.5 to E18.5 mouse embryo hindlimbs and discovered that cavitation initiates around E15.0 with emergence of multiple, discrete, µm-wide tissue discontinuities we term microcavities in interzone, evolving into a single joint-wide cavity within 12 h in knees and within 72-84 h in interphalangeal joints. The microcavities were circumscribed by cells as revealed by mTmG imaging and exhibited a carbohydrate and protein content based on infrared spectral imaging at micro and nanoscale. Accounting for differing cavitation kinetics, we found that the growing femur and tibia anlagen progressively flexed at the knee over time, with peak angulation around E15.5 exactly when the full knee cavity consolidated; however, interphalangeal joint geometry changed minimally over time. Indeed, cavitating knee interzone cells were elongated along the flexion angle axis and displayed oblong nuclei, but these traits were marginal in interphalangeal cells. Conditional Gdf5Cre-driven ablation of Has2 - responsible for production of the joint fluid component hyaluronic acid (HA) - delayed the cavitation process. Our data reveal that cavitation is a stepwise process, brought about by sequential action of microcavities, skeletal flexion and elongation, and HA accumulation. This article has an associated First Person interview with the first author of the paper.

Correlation of Body Composition via Bioelectrical Impedance Analysis and Motor Function and Recovery of Upper Extremity in Patients Undergoing Stroke Rehabilitation.

Bioelectrical impedance analysis (BIA) has been used to investigate the body compositions and predict functional outcomes in patients with stroke, while the role of BIA to predict motor function or recovery in stroke has not been clarified. This study aimed to investigate relationship between body composition measured by BIA and upper limb motor function and recovery. Body compositions (soft tissue lean mass, phase angle, body fat mass and body water) of fifty patients who are admitted to the stroke rehabilitation unit were segmentally analyzed via BIA. The motor recovery of upper extremity (UE) was evaluated via Fugl-Meyer Assessment (UE-FMA) at the time of transfer and discharge. Correlations between body composition and UE-FMA at discharge were analyzed using Spearman correlation coefficient. Multiple regression analysis was used to determine the regression between body composition and motor function and recovery. The Δ Phase angle, the difference of both sides was significantly linearly inversely correlated with UE-FMA at discharge. However, in multiple regression analysis, body compositions including phase angle did not significantly predict motor function at discharge or motor recovery. The Δ Phase angle is related to the severity of upper limb motor function at discharge in subacute stroke patients, and further studies are needed to determine its value as a predictor for motor recovery.

Concurrence of Congenital Muscular Torticollis and Congenital Torticollis Due to Other Anomalies: Two Case Reports.

Introduction: Congenital muscular torticollis (CMT) is the most common cause of torticollis in infants; other causes, including osseous, ocular, and central nervous system torticollis can easily be overlooked. We report two rare cases of CMT with concurrent osseous or ocular torticollis. Case 1: A 1-month-old female infant with a right neck mass and right-tilting head posture was referred. Neck ultrasonography showed diffuse hypertrophy and hyperechoic findings on the right sternocleidomastoid (SCM) muscle, which was consistent with right CMT. A clavicle X-ray imaging was conducted to identify an associated fracture due to birth trauma on the same day and a suspected congenital vertebral anomaly was coincidentally found. Subsequent three-dimensional computed tomography of the cervical spine showed a T1 hemivertebra causing the right-tilting head. The patient was diagnosed with the concurrent manifestation of CMT and congenital osseous torticollis. Case 2: A 3-month-old male infant with a 20° head tilt to the right with a limited cervical range of motion was referred. Neck ultrasonography showed a fibromatosis colli in the right SCM, suggesting CMT. He proceeded to physical therapy for seven months; however, there was little clinical improvement in his head and neck posture. The patient underwent an additional ophthalmologic examination and orbital magnetic resonance imaging (MRI) at 10 months of age. The result showed congenital agenesis of the left fourth cranial nerve with hypoplasia of the superior oblique muscle causing the right-tilting of the head. Ultimately, the boy was diagnosed with a concurrent manifestation of CMT and congenital ocular torticollis. Conclusion: Unless careful examinations are conducted, congenital vertebral anomalies and congenital agenesis of the fourth cranial nerve can go unnoticed in the present two cases. If a patient with CMT displays unusual features or does not respond to physical therapy, clinicians should consider not only a differential diagnosis but also concurrence with other causes of congenital torticollis.

The effects of additional electrical stimulation combined with repetitive transcranial magnetic stimulation and motor imagery on upper extremity motor recovery in the subacute period after stroke: A preliminary study.

BACKGROUND: To evaluate the therapeutic effects of additional electrical stimulation (ES) combined with low frequency (LF)-repetitive transcranial magnetic stimulation (rTMS) and motor imagery (MI) training on upper extremity (UE) motor function following stroke. METHODS: The participants with subacute stroke in the experimental group (n = 8) received LF rTMS + MI + active ES interventions, and those in control group (n = 9) received LF rTMS + MI + sham ES interventions. Interventions were performed 5 days a week for 2 weeks, for a total of 10 sessions. All participants were given the same dosage of conventional rehabilitation during the study period. The primary outcome measure was the UE Fugl-Meyer Assessment (FMA). The secondary outcome measures were the shoulder abduction and finger extension scores, modified Barthel Index, Purdue Pegboard Test, and finger tapping test. All scores were measured before and just after the intervention. RESULTS: After the 2-week intervention period, the FMA and modified Barthel Index scores were improved in both groups compared to baseline assessment (P < .001 in the experimental group and P = .008 in the control group). Of note, the change in FMA scores was significantly higher in the experimental group compared with that of the control group (P = .04). CONCLUSION: These results suggest that the use of LF rTMS + MI combined with additional ES lead to greater improvement of UE motor function after stroke. As such, this intervention may be a promising adjuvant therapy in UE motor training.

Application of Titanium-Carbide MXene-Based Transparent Conducting Electrodes in Flexible Smart Windows.

Among various available materials used in transparent and flexible devices, MXenes are attracting attention as a brand-new candidate in this category. Ti3C2Tx MXene as a 2D material has exceptional properties, making it a potential material having numerous applications in different areas. Because of its high conductivity, it can be used in transparent conducting electrodes (TCEs). In this study, the MXenes etched by highly concentrated acid at 50 °C,were spin-coated on polyethylene terephthalate (PET) film and annealed at moderate temperatures up to 170 °C. The adhesion of MXene to PET was found to be remarkably improved by annealing. These TCEs exhibited a sheet resistance of ∼424 Ω/sq. and transmittance of ∼87%. The aging stability of MXene-coated PET films against oxidation under ambient conditions was studied up to 28 days and resistance change was found ∼30% during this period. The flexibility test showed low bending resistance change (∼1.5%) at 1000th cycle and cumulative resistance change of ∼20% at a bending radius of ∼3.9 mm after 1000 cycles. These transparent, flexible, and conducting electrodes were used to fabricate polymer dispersed liquid crystal (PDLC)-based flexible smart windows. The smart windows fabricated by curing PDLC mixture sandwiched between the MXene electrodes were also found flexible in ON/OFF states. The MXene-based flexible smart windows resulted in good opacity in the OFF state and high transparency in the ON state, exhibiting low threshold voltage <10 V and high transmittance ∼80% at 60 V. The flexible smart windows operated normally even at ∼4 mm bending radius.

Anatomic Repair of the Central Slip with Anchor Suture Augmentation for Treatment of Established Boutonniere Deformity.

BACKGROUD: The rupture of the central slip of an extensor tendon of a finger causes a boutonniere (or buttonhole) deformity, characterized by pathologic flexion at the proximal interphalangeal (PIP) joint and hyperextension at the distal interphalangeal (DIP) joint. Currently, there are no standard treatment guidelines for this deformity. This study aimed to report clinical results of surgery to correct chronic boutonniere deformity. METHODS: This retrospective case series was conducted between January 2010 and December 2018 and only 13 patients with trauma-induced chronic deformity were included. After excision of elongated scar tissue, a direct anatomic end-to-end repair using a loop suture technique with supplemental suture anchor augmentation was conducted. Total active motion was assessed before and after surgery and self-satisfaction scores were collected from phone surveys. RESULTS: All patients presented with Burton stage I deformities defined as supple and passively correctable joints. The initial mean extension lag of the PIP joint (43.5°) was improved by an average of 21.9° at the final follow-up (p < 0.001). The mean hyperextension of the DIP joint averaged 19.2° and improved by 0.8° flexion contracture (p < 0.001). The average total active motion was 220.4° (range, 160°-260°). Based on the Souter's criteria, 69.2% (9/13) of the patients had good results. Only 1 patient reported fair outcome and 23.1% (3/13) reported poor outcome. The average Strickland formula score was 70 (range, 28.6-97.1). In total, 10 patients (77%) had excellent or good results. Of 10 patients contacted by phone, self-reported satisfaction score was very satisfied in 2, satisfied in 3, average in 3, poor in 1, and very poor in 1. Three patients reported a relapse of the deformity during range of motion exercises, 1 of whom underwent revision surgery. One patient complained of PIP joint flexion limitation, and 2 complained of DIP joint flexion limitation at final follow-up. CONCLUSIONS: In chronic boutonniere deformity, central slip reconstruction with anchor suture augmentation can be an easily applicable surgical option, which offers fair to excellent outcome in 77% of the cases. The risk of residual extension lag and recurrence of deformity should be discussed prior to surgery.

Supercapacitors based on Ti3C2Tx MXene extracted from supernatant and current collectors passivated by CVD-graphene.

An ultrahigh capacity supercapacitor is fabricated using a nano-layered MXene as an active electrode material, and Ni-foil is used as a current collector. The high-quality Ti3C2Tx obtained from supernatant during etching and washing processes improves the specific capacitance significantly. As another strategy, the surface of Ni-foil is engineered by coating chemical vapor deposition-grown graphene. The graphene grown directly on the Ni-foil is used as a current collector, forming the electrode structure of Ti3C2Tx/graphene/Ni. The surface passivation of the current collectors has a high impact on charge-transfer, which in turn increases the capacitance of the supercapacitors. It is found that the capacitance of the graphene-based supercapacitors is more than 1.5 times of the capacitance without graphene. A high specific capacitance, ~ 542 F/g, is achieved at 5 mV/s scan rate based on cyclic voltammetry analysis. Also, the graphene-based supercapacitor exhibits a quasi-rectangular form in cyclic voltammetry curves and a symmetric behavior in charge/discharge curves. Furthermore, cyclic stability up to 5000 cycles is confirmed with high capacitance retention at high scan rate 1000 mV/s. A reduced series resistance with a high limit capacitance is revealed by equivalent circuit analysis with the Nyquist plot.

Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish.

BACKGROUND AND AIMS: Following mild liver injury, pre-existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC-driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end-stage liver diseases. Despite this attention, the molecular basis of BEC-driven liver regeneration remains poorly understood. APPROACH AND RESULTS: By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC-driven liver regeneration. Here we show that FXR activation blocks the process through the FXR-PTEN (phosphatase and tensin homolog)-PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC-driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K-AKT-mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC-driven liver regeneration, as did FXR activation. CONCLUSIONS: FXR activation impairs BEC-driven liver regeneration by enhancing PTEN activity; the PI3K-AKT-mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.

Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish.

BACKGROUND AND AIMS: The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver injury settings. In chronic liver diseases, the number of liver progenitor cells (LPCs) correlates proportionally to disease severity, implying that their inefficient differentiation into hepatocytes exacerbates the disease. Moreover, LPCs secrete proinflammatory cytokines; thus, their prolonged presence worsens inflammation and induces fibrosis. Promoting LPC-to-hepatocyte differentiation in patients with advanced liver disease, for whom liver transplantation is currently the only therapeutic option, may be a feasible clinical approach because such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. APPROACH AND RESULTS: Here, using zebrafish models of LPC-mediated liver regeneration, we present a proof of principle of such therapeutics by demonstrating a role for the epidermal growth factor receptor (EGFR) signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC-to-hepatocyte differentiation through the mitogen-activated ERK kinase (MEK)-extracellular signal-regulated kinase (ERK)-sex-determining region Y-box 9 (SOX9) cascade. Pharmacological inhibition of EGFR or MEK/ERK promoted LPC-to-hepatocyte differentiation as well as genetic suppression of the EGFR-ERK-SOX9 axis. Moreover, Sox9b overexpression in LPCs blocked their differentiation into hepatocytes. In the zebrafish liver injury model, both hepatocytes and biliary epithelial cells contributed to LPCs. EGFR inhibition promoted the differentiation of LPCs regardless of their origin. Notably, short-term treatment with EGFR inhibitors resulted in better liver recovery over the long term. CONCLUSIONS: The EGFR-ERK-SOX9 axis suppresses LPC-to-hepatocyte differentiation during LPC-mediated liver regeneration. We suggest EGFR inhibitors as a proregenerative therapeutic drug for patients with advanced liver disease.