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.

TRPA1 nanovesicle-conjugated receptonics for rapid biocide screening.

Although biocides are important materials in modern society and help protect human health and the environment, increasing exposure to combined biocides can cause severe side effects in the human body, such as lung fibrosis. In this study, we developed a receptonics system to screen for biocides in combined household chemical products based on biocides. The system contains transient receptor potential ankyrin 1 (TRPA1) nanovesicles (NVs) to sense biocides based on pain receptors and a side-gated field-effect transistor (SGFET) using a single-layer graphene (SLG) micropattern channel. The binding affinities between the TRPA1 receptor and the various biocides were estimated by performing biosimulation and using a calcium ion (Ca2+) assay, and the sensitivity of the system was compared with that of TRPA1 NV receptonics systems. Based on the results of the TRPA1 NV receptonics system, the antagonistic and potentiation effects of combined biocides and household chemical products depended on the concentration. Finally, the TRPA1 NV receptonics system was applied to screen for biocides in real products, and its performance was successful. Based on these results, the TRPA1 NV receptonics system can be utilized to perform risk evaluations and identify biocides in a simple and rapid manner.

Ultrathin Boron Growth onto Nanodiamond Surfaces via Electrophilic Boron Precursors.

Diamond as a templating substrate is largely unexplored, and the unique properties of diamond, including its large bandgap, thermal conductance, and lack of cytotoxicity, makes it versatile in emergent technologies in medicine and quantum sensing. Surface termination of an inert diamond substrate and its chemical reactivity are key in generating new bonds for nucleation and growth of an overlayer material. Oxidized high-pressure high temperature (HPHT) nanodiamonds (NDs) are largely terminated by alcohols that act as nucleophiles to initiate covalent bond formation when an electrophilic reactant is available. In this work, we demonstrate a templated synthesis of ultrathin boron on ND surfaces using trigonal boron compounds. Boron trichloride (BCl3), boron tribromide (BBr3), and borane (BH3) were found to react with ND substrates at room temperature in inert conditions. BBr3 and BCl3 were highly reactive with the diamond surface, and sheet-like structures were produced and verified with electron microscopy. Surface-sensitive spectroscopies were used to probe the molecular and atomic structure of the ND constructs' surface, and quantification showed the boron shell was less than 1 nm thick after 1-24 h reactions. Observation of the reaction supports a self-terminating mechanism, similar to atomic layer deposition growth, and is likely due to the quenching of alcohols on the diamond surface. X-ray absorption spectroscopy revealed that boron-termination generated midgap electronic states that were originally predicted by density functional theory (DFT) several years ago. DFT also predicted a negative electron surface, which has yet to be confirmed experimentally here. The boron-diamond nanostructures were found to aggregate in dichloromethane and were dispersed in various solvents and characterized with dynamic light scattering for future cell imaging or cancer therapy applications using boron neutron capture therapy (BNCT). The unique templating mechanism based on nucleophilic alcohols and electrophilic trigonal precursors allows for covalent bond formation and will be of interest to researchers using diamond for quantum sensing, additive manufacturing, BNCT, and potentially as an electron emitter.

Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella.

Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity.

The unfolded features on the synchronized fashion of gut microbiota and Drynaria rhizome against obesity via integrated pharmacology.

Drynaria rhizome (DR) is used as a natural remedy to ameliorate obesity (OB) in East Asia; in parallel, the gut microbiota (GM) might exert a positive impact on OB through their metabolites. This study elucidates the orchestrated effects of DR and GM on OB. DR-GM, - a key signaling pathway-target-metabolite (DGSTM) networks were used to unveil the relationship between DR and GM, and Molecular Docking Test (MDT) and Density Functional Theory (DFT) were adopted to underpin the uppermost molecules. The NR1H3 (target) - 3-Epicycloeucalenol (ligand), and PPARG (target) - Clionasterol (ligand) conjugates from DR, FABP3 (target) - Ursodeoxycholic acid, FABP4 (target) - Lithocholic acid (ligand) or Deoxycholic acid (ligand), PPARA (target) - Equol (ligand), and PPARD (target) - 2,3-Bis(3,4-dihydroxybenzyl)butyrolactone (ligand) conjugates from GM formed the most stable conformers via MDT and DFT. Overall, these findings suggest that DR-GM might be a promising ameliorator on PPAR signaling pathway against OB.

Association between Pentosan Polysulfate and Subsequent Maculopathy: Insights from a Nationwide Population-Based Study in Korea.

PURPOSE: To determine the association between pentosan polysulfate (PPS) use and the subsequent development of maculopathy in Asian population. DESIGN: A nationwide population-based retrospective cohort study using the Health Insurance Review and Assessment Service database. PARTICIPANTS: 103,553 individuals in the PPS user group and 205,792 individuals in the PPS non-user group, all newly diagnosed with cystitis between 2009 and 2020. METHODS: The association between PPS use and maculopathy was evaluated using a time dependent Cox proportional hazard model. Additionally, two sensitivity analyses were conducted by defining PPS users as individuals with an observation period over 6 months from the initial prescription or those with cumulative dose exceeding 9 g, employing the same analysis. MAIN OUTCOME MEASURES: The outcome measures included the hazard ratios (HR) representing the association between PPS use and maculopathy. RESULTS: PPS use was associated with an increased risk of subsequent maculopathy in univariate (HR, 1.7; 95% confidence intervals [CI], 1.66-1.75) and multivariate analysis (HR, 1.34; 95% CI, 1.31-1.38). These results were also confirmed in two sensitivity analyses. The mean cumulative dose of PPS for the cohort was 37.2 ± 76.7 g. CONCLUSIONS: In this nationwide cohort study involving an Asian population, individuals with cystitis using PPS exhibit an increased risk of developing subsequent maculopathy.

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.

Shock index and shock index, pediatric age-adjusted as predictors of mortality in pediatric patients with trauma: A systematic review and meta-analysis.

This study aimed to assess the predictive ability of the shock index (SI) and the shock index, pediatric age-adjusted (SIPA) for mortality among pediatric patients with trauma (aged ≤ 18 years). A systematic search used PubMed, Embase, and Cochrane Library databases to identify pertinent articles published from their inception to 13 February 2023. For each SI and SIPA, the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) with the corresponding 95% confidence intervals were calculated. We planned a priori meta-regression analyses to explore heterogeneity using the following covariates: country, clinical setting, type of center, data source, and cutoff value. Twelve studies were included based on the inclusion criteria. Among them, nine studies with 195,469 patients were included for the SIPA at the hospital, four studies with 4,970 patients were included for the pre-hospital SIPA, and seven studies with 606,445 patients were included to assess the ability of the SI in predicting mortality. The pooled sensitivity and specificity with 95% confidence interval for predicting mortality were as follows: 0.58 (0.44-0.70) and 0.72 (0.60-0.82), respectively, for the SIPA at the hospital; 0.61 (0.47-0.74) and 0.67 (0.61-0.73), respectively, for the pre-hospital SIPA; and 0.71 (0.59-0.81) and 0.45 (0.31-0.59), respectively for the SI. The DOR were 3.80, 3.28, and 2.06 for the SIPA at the hospital, pre-hospital SIPA, and SI, respectively. The AUC were 0.693, 0.689, and 0.618 for the SIPA at the hospital, pre-hospital SIPA, and SI, respectively. The SI and SIPA are simple predictive tools with sufficient accuracy that can be readily applied to pediatric patients with trauma, but SIPA and SI should be utilized cautiously due to their limited sensitivity and specificity, respectively.

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.

Label-free optical detection of calcium ion influx in cell-derived nanovesicles using a conical Au/PDMS biosensor.

Ion channels, which are key to physiological regulation and drug discovery, control ion flux across membranes, and their dysregulation leads to various diseases. Ca2+ monitoring is crucial for cellular signaling when performing Ca-based assays in ion channel research; these assays are widely utilized in both academic and pharmaceutical contexts for drug screening and pharmacological profiling. However, existing detection methods are limited by slow detection speeds, low throughput, complex processes, and low analyte viability. In this study, we developed a label-free optical biosensing method using a conical Au/polydimethylsiloxane platform tailored to detect Ca2+ influx in A549-originated nanovesicles facilitated by the transient receptor potential ankyrin 1 (TRPA1) channel. Nanovesicles expressing cellular signaling components mimic TRPA1 signal transduction in cell membranes and improve analyte viability. The conical Au/polydimethylsiloxane sensor converted Ca2+ influx events induced by specific agonist exposure into noticeable changes in relative transmittance under visible light. The optical transmittance change accompanying Ca2+ influx resulted in an enhanced sensing response, high accuracy and reliability, and rapid detection (∼5 s) without immobilization or ligand treatments. In the underlying sensing mechanism, morphological variations in nanovesicles, which depend on Ca2+ influx, induce a considerable light scattering change at an interface between the nanovesicle and Au, revealed by optical simulation. This study provides a foundation for developing biosensors based on light-matter interactions. These sensors are simple and cost-effective with superior performance and diverse functionality.

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.

Gut microbiome and metabolome signatures in liver cirrhosis-related complications.

Background/Aims: Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis. Methods: Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight-mass spectrometry. Correlation analyses were performed targeting the gut- microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased). Results: Veillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella_uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC > 0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites. Conclusion: Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

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.

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.

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.

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.

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.