Clipless internal mammary artery harvesting for minimally invasive coronary artery bypass grafting using the shear-tip harmonic scalpel.

Background: The internal mammary artery (IMA) is the most commonly used graft in coronary artery bypass grafting (CABG) because of its superior long-term patency rate. However, its small diameter poses challenges in handling, and any vascular damage that may occur during harvesting can significantly affect surgical outcomes. The primary focus during IMA harvesting is to ensure safe and effective hemostasis without direct vascular injury, while ensuring secure and reliable ligation of the vascular branches. Various methods using multiple surgical instruments have been used for this purpose. Unlike traditional instruments, the shear-tip Harmonic scalpel offers more precise vessel branching control, while minimizing damage to surrounding tissues. In this study, we assessed the utility of the shear-tip Harmonic scalpel in patients undergoing minimally invasive coronary artery bypass grafting (MICABG). Methods: From April 2019 to May 2023, a total of 40 patients underwent MICABG. The IMA was harvested using the shear-tip Harmonic scalpel with a clipless skeletonized technique. In this cohort, 5 patients underwent complete endoscopic harvesting, while 34 patients underwent direct visualization harvesting through minimal thoracotomy. Graft patency was assessed by measuring a Doppler flowmeter in the bypass conduit. Results: Successful graft patency was achieved in all patients. The mean duration of IMA harvesting was 87 min. In total, 38 of the 40 patients underwent MICABG without the need for cardiopulmonary bypass, ensuring a stable procedure. There were no graft-related events or complications observed in any of the patients, and all were discharged without any issues. During a median follow-up period of 15.2 months, only one patient experienced graft occlusion necessitating intervention. Conclusions: The utilization of shear-tip Harmonic scalpel for IMA harvesting in MICABG is feasible and yields stable early results.

Tumor phagocytosis-driven STING activation invigorates antitumor immunity and reprograms the tumor micro-environment.

Immunogenic cell death (ICD) holds the potential for in situ tumor vaccination while concurrently eradicating tumors and stimulating adaptive immunity. Most ICD inducers, however, elicit insufficient immune responses due to negative feedback against ICD biomarkers, limited infiltration of antitumoral immune cells, and the immunosuppressive tumor micro-environment (TME). Recent findings highlight the pivotal roles of stimulators of interferon gene (STING) activation, particularly in stimulating antigen-presenting cells (APCs) and TME reprogramming, addressing ICD limitations. Herein, we introduced 'tumor phagocytosis-driven STING activation', which involves the activation of STING in APCs during the recognition of ICD-induced cancer cells. We developed a polypeptide-based nanocarrier encapsulating both doxorubicin (DOX) and diABZI STING agonist 3 (dSA3) to facilitate this hypothesis in vitro and in vivo. After systemic administration, nanoparticles predominantly accumulated in tumor tissue and significantly enhanced anticancer efficacy by activating tumor phagocytosis-driven STING activation in MC38 and TC1 tumor models. Immunological activation of APCs occurred within 12 h, subsequently leading to the activation of T cells within 7 days, observed in both the TME and spleen. Furthermore, surface modification of nanoparticles with cyclic RGD (cRGD) moieties, which actively target integrin αvß3, enhances tumor accumulation and eradication, thereby verifying the establishment of systemic immune memory. Collectively, this study proposes the concept of tumor phagocytosis-driven STING activation and its effectiveness in generating short-term and long-term immune responses.

Helical Topological Superconducting Pairing at Finite Excitation Energies.

We propose helical topological superconductivity away from the Fermi surface in three-dimensional time-reversal-symmetric odd-parity multiband superconductors. In these systems, pairing between electrons originating from different bands is responsible for the corresponding topological phase transition. Consequently, a pair of helical topological Dirac surface states emerges at finite excitation energies. These helical Dirac surface states are tunable in energy by chemical potential and strength of band splitting. They are protected by time-reversal symmetry combined with crystalline twofold rotation symmetry. We suggest concrete materials in which this phenomenon could be observed.

Gut microbiota-based machine-learning signature for the diagnosis of alcohol-associated and metabolic dysfunction-associated steatotic liver disease.

Alcoholic-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) show a high prevalence rate worldwide. As gut microbiota represents current state of ALD and MASLD via gut-liver axis, typical characteristics of gut microbiota can be used as a potential diagnostic marker in ALD and MASLD. Machine learning (ML) algorithms improve diagnostic performance in various diseases. Using gut microbiota-based ML algorithms, we evaluated the diagnostic index for ALD and MASLD. Fecal 16S rRNA sequencing data of 263 ALD (control, elevated liver enzyme [ELE], cirrhosis, and hepatocellular carcinoma [HCC]) and 201 MASLD (control and ELE) subjects were collected. For external validation, 126 ALD and 84 MASLD subjects were recruited. Four supervised ML algorithms (support vector machine, random forest, multilevel perceptron, and convolutional neural network) were used for classification with 20, 40, 60, and 80 features, in which three nonsupervised ML algorithms (independent component analysis, principal component analysis, linear discriminant analysis, and random projection) were used for feature reduction. A total of 52 combinations of ML algorithms for each pair of subgroups were performed with 60 hyperparameter variations and Stratified ShuffleSplit tenfold cross validation. The ML models of the convolutional neural network combined with principal component analysis achieved areas under the receiver operating characteristic curve (AUCs) > 0.90. In ALD, the diagnostic AUC values of the ML strategy (vs. control) were 0.94, 0.97, and 0.96 for ELE, cirrhosis, and liver cancer, respectively. The AUC value (vs. control) for MASLD (ELE) was 0.93. In the external validation, the AUC values of ALD and MASLD (vs control) were > 0.90 and 0.88, respectively. The gut microbiota-based ML strategy can be used for the diagnosis of ALD and MASLD.ClinicalTrials.gov NCT04339725.

Phase Transitions and Thermoelectric Properties of Charge-Compensated ZnxCu12-xSb4Se13.

In this study, we investigated the phase transitions and thermoelectric properties of charge-compensated hakite (ZnxCu12-xSb4Se13) as a function of Zn content. Based on X-ray diffraction and a differential scanning calorimetric phase analysis, secondary phases (permingeatite and bytizite) transformed into hakite depending on the Zn content, while Zn2Cu10Sb4Se13 existed solely as hakite. Nondegenerate semiconductor behavior was observed, exhibiting increasing electrical conductivity with a rising temperature. With an increase in Zn content, the presence of mixed phases of hakite and permingeatite led to enhanced electrical conductivity. However, Zn2Cu10Sb4Se13 with a single hakite phase exhibited the lowest electrical conductivity. The Seebeck coefficient exhibited positive values, indicating that even after charge compensation (electron supply) by Zn, p-type semiconductor characteristics were maintained. With the occurrence of an intrinsic transition within the measured temperature range, the Seebeck coefficient decreased as the temperature increased; at a certain temperature, Zn2Cu10Sb4Se13 exhibited the highest value. Thermal conductivity showed a low temperature dependence, obtaining low values below 0.65 Wm-1K-1. A power factor of 0.22 mWm-1K-2 and dimensionless figure of merit of 0.31 were achieved at 623 K for ZnCu11Sb4Se13.

Trends and Barriers in Diabetic Retinopathy Screening: Korea National Health and Nutritional Examination Survey 2016-2021.

BACKGROUND: The prevalence of diabetes is increasing globally, highlighting the importance of preventive healthcare. This study aimed to identify the diabetic retinopathy (DR) screening rates and risk factors linked to DR screening nonadherence in the Korean population through a nationally representative sample survey. METHODS: Among the Korea National Health and Nutrition Examination Survey database from 2016 to 2021, participants aged ≥ 40 years with diabetes were included. The weighted estimate for nonadherence to DR screening within a year was calculated. Risk factor analyses were conducted using univariate and multivariate logistic regression. RESULTS: Among the 3,717 participants, 1,109 (29.5%) underwent DR screening within the past year, and this national estimate exhibited no statistically significant difference from 2016 to 2021 (P = 0.809). Nonadherence to annual DR screening was associated with residing in rural areas, age ≥ 80 years, low educational level, self-reported good health, absence of ocular disease, current smoking, lack of exercise and dietary diabetes treatment, and no activity limitation (all P < 0.05). CONCLUSION: The recent DR screening rate in Korea was relatively low. Factors associated with apathy and complacency towards personal health were associated with the nonadherence to DR screening. Educational interventions have the potential to enhance the annual screening rate for diabetic patients.

Single-cell analysis reveals cellular and molecular factors counteracting HPV-positive oropharyngeal cancer immunotherapy outcomes.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear. METHODS: To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets. RESULTS: We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4+ follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8+ resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161+ Trm and changes in tumor size. CONCLUSIONS: We found that CD161+ Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers. TRIAL REGISTRATION NUMBER: NCT03737968.

Efficient CRISPR-Cas12f1-Mediated Multiplex Bacterial Genome Editing via Low-Temperature Recovery.

CRISPR-Cas system is being used as a powerful genome editing tool with developments focused on enhancing its efficiency and accuracy. Recently, the miniature CRISPR-Cas12f1 system, which is small enough to be easily loaded onto various vectors for cellular delivery, has gained attention. In this study, we explored the influence of temperature conditions on multiplex genome editing using CRISPR-Cas12f1 in an Escherichia coli model. It was revealed that when two distinct targets in the genome are edited simultaneously, the editing efficiency can be enhanced by allowing cells to recover at a reduced temperature during the editing process. Additionally, employing 3'-end truncated sgRNAs facilitated the simultaneous single-nucleotide level editing of three targets. Our results underscore the potential of optimizing recovery temperature and sgRNA design protocols in developing more effective and precise strategies for multiplex genome editing across various organisms.

Triggered saccadic oscillations: case series and review of the literature.

Saccadic oscillations (SOs) mostly occur spontaneously, but can be occasionally triggered by various stimuli. To determine clinical characteristics and underlying mechanisms of triggered SOs, we analyzed the clinical features and quantitative eye-movement recordings of six new patients and 10 patients in the literature who exhibited with triggered SOs. Eleven of the 16 patients (69%) had a lesion involving cerebellum and/or brainstem such as cerebellar degeneration, cerebellitis, or cerebellar infarction. The other causes were vestibular migraine (n = 2), multiple sclerosis (n = 1), Krabbe disease (n = 1), and idiopathic (n = 1). Vestibular stimulation was the most common trigger (n = 11, 69%), followed by removal of visual fixation (n = 4, 25%), hyperventilation (n = 1), light (n = 1), and blink (n = 1). The types of triggered SOs were varied which included ocular flutter (n = 13), opsoclonus (n = 3), vertical SOs (n = 2), and macrosaccadic oscillations (n = 1). Three patients exhibited downbeat nystagmus either before (n = 1) or after (n = 2) the onset of SOs. The frequency of triggered SOs ranged from 4 to 15 Hz, and oscillations with smaller amplitudes had higher frequencies and smaller peak velocities. SOs can be triggered by the modulation of unstable saccadic neural networks through vestibular and visual inputs in lesions of the brainstem and cerebellum.

The synchronized feature of Saururus chinensis and gut microbiota against T2DM, NAFLD, obesity and hypertension via integrated pharmacology.

Type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), obesity (OB) and hypertension (HT) are categorized as metabolic disorders (MDs), which develop independently without distinct borders. Herein, we examined the gut microbiota (GM) and Saururus chinensis (SC) to confirm their therapeutic effects via integrated pharmacology. The overlapping targets from the four diseases were determined to be key protein coding genes. The protein-protein interaction (PPI) networks, and the SC, GM, signalling pathway, target and metabolite (SGSTM) networks were analysed via RPackage. Additionally, molecular docking tests (MDTs) and density functional theory (DFT) analysis were conducted to determine the affinity and stability of the conformer(s). TNF was the main target in the PPI analysis, and equol derived from Lactobacillus paracasei JS1 was the most effective agent for the formation of the TNF complex. The SC agonism (PPAR signalling pathway), and antagonism (neurotrophin signalling pathway) by SC were identified as agonistic bioactives (aromadendrane, stigmasta-5,22-dien-3-ol, 3,6,6-trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine, 4α-5α-epoxycholestane and kinic acid), and antagonistic bioactives (STK734327 and piclamilast), respectively, via MDT. Finally, STK734327-MAPK1 was the most favourable conformer according to DFT. Overall, the seven bioactives from SC and equol that can be produced by Lactobacillus paracasei JS1 can exert synergistic effects on these four diseases.

A Comparative Study of Endoscopic versus Percutaneous Epidural Neuroplasty in Lower Back Pain: Outcomes at Six-Month Follow Up.

Background and Objectives: Endoscopic epidural neuroplasty (EEN) facilitates adhesiolysis through direct epiduroscopic visualization, offering more precise neural decompression than that exhibited by percutaneous epidural neuroplasty (PEN). We aimed to compare the effects of EEN and PEN for 6 months after treatment with lower back and radicular pain in patients. Methods: This retrospective study compared the visual analog scale (VAS) and Oswestry disability index (ODI) scores in patients with low back and radicular pain who underwent EEN or PEN with a steering catheter. The medical records of 107 patients were analyzed, with 73 and 34 undergoing EEN and PEN, respectively. Results: The VAS and ODI scores decreased at all time points after EEN and PEN. VAS and ODI scores decreased more in the EEN group than those in the PEN group at 1 day and 1- and 6-months post-procedure, indicating superior pain relief for both lower back and radicular pain through EEN. Conclusions: EEN is a superior treatment of pain control than PEN in lower back and radicular pain patients.

Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.

Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.

Steroid receptor coactivators in Treg and Th17 cell biology and function.

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in governing numerous aspects of CD4+ T cell biology. Here we review findings that establish the SRCs as essential regulators of regulatory T cells (Tregs) and T helper 17 (Th17) cells, with a focus on their crucial roles in Treg immunity in cancer and Treg-Th17 cell phenotypic plasticity.

N-Myc and STAT Interactor is an endometriosis suppressor.

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3, and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including ß-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure.

Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

PURPOSE: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. RESULTS: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. CONCLUSION: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

Multiplex CRISPR-Cas Genome Editing: Next-Generation Microbial Strain Engineering.

Genome editing is a crucial technology for obtaining desired phenotypes in a variety of species, ranging from microbes to plants, animals, and humans. With the advent of CRISPR-Cas technology, it has become possible to edit the intended sequence by modifying the target recognition sequence in guide RNA (gRNA). By expressing multiple gRNAs simultaneously, it is possible to edit multiple targets at the same time, allowing for the simultaneous introduction of various functions into the cell. This can significantly reduce the time and cost of obtaining engineered microbial strains for specific traits. In this review, we investigate the resolution of multiplex genome editing and its application in engineering microorganisms, including bacteria and yeast. Furthermore, we examine how recent advancements in artificial intelligence technology could assist in microbial genome editing and engineering. Based on these insights, we present our perspectives on the future evolution and potential impact of multiplex genome editing technologies in the agriculture and food industry.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

A novel vector field analysis for quantitative structure changes after macular epiretinal membrane surgery.

The aim of this study was to introduce novel vector field analysis for the quantitative measurement of retinal displacement after epiretinal membrane (ERM) removal. We developed a novel framework to measure retinal displacement from retinal fundus images as follows: (1) rigid registration of preoperative retinal fundus images in reference to postoperative retinal fundus images, (2) extraction of retinal vessel segmentation masks from these retinal fundus images, (3) non-rigid registration of preoperative vessel masks in reference to postoperative vessel masks, and (4) calculation of the transformation matrix required for non-rigid registration for each pixel. These pixel-wise vector field results were summarized according to predefined 24 sectors after standardization. We applied this framework to 20 patients who underwent ERM removal to obtain their retinal displacement vector fields between retinal fundus images taken preoperatively and at postoperative 1, 4, 10, and 22 months. The mean direction of displacement vectors was in the nasal direction. The mean standardized magnitudes of retinal displacement between preoperative and postoperative 1 month, postoperative 1 and 4, 4 and 10, and 10 and 22 months were 38.6, 14.9, 7.6, and 5.4, respectively. In conclusion, the proposed method provides a computerized, reproducible, and scalable way to analyze structural changes in the retina with a powerful visualization tool. Retinal structural changes were mostly concentrated in the early postoperative period and tended to move nasally.