Topographical metal burden correlates with brain atrophy and clinical severity in Wilson's disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) is a post-processing technique that creates brain susceptibility maps reflecting metal burden through tissue magnetic susceptibility. We assessed topographic differences in magnetic susceptibility between participants with and without Wilson's disease (WD), correlating these findings with clinical severity, brain volume, and biofluid copper and iron indices. METHODS: A total of 43 patients with WD and 20 unaffected controls, were recruited. QSM images were derived from a 3T MRI scanner. Clinical severity was defined using the minimal Unified Wilson's Disease Rating Scale (M-UWDRS) and Montreal Cognitive Assessment scoring. Differences in magnetic susceptibilities between groups were evaluated using general linear regression models, adjusting for age and sex. Correlations between the susceptibilities and clinical scores were analyzed using Spearman's method. RESULTS: In age- and sex-adjusted analyses, magnetic susceptibility values were increased in WD patients compared with controls, including caudate nucleus, putamen, globus pallidus, and substantia nigra (all p < 0.01). Putaminal susceptibility was greater with an initial neuropsychiatric presentation (n = 25) than with initial hepatic dysfunction (n = 18; p = 0.04). Susceptibility changes correlated negatively with regional brain volume in almost all topographic regions. Serum ferritin, but not serum copper or ceruloplasmin, correlated positively with magnetic susceptibility level in the caudate nucleus (p = 0.04), putamen (p = 0.04) and the hippocampus (p = 0.03). The dominance of magnetic susceptibility in cortical over subcortical regions correlated with M-UWDRS scores (p < 0.01). CONCLUSION: The magnetic susceptibility changes could serve as a surrogate marker for patients with WD.

Predictors of functional cure of chronic hepatitis B virus infection - A long-term follow-up study.

BACKGROUND & AIMS: Functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg)-seroconversion. METHODS: We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients, who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg-seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks. RESULTS: After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per perperson-year, and increased to 0.96% per person-year after HBeAg-seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg-seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazard analysis of the cohort revealed that HBeAg-seroconversion at < 18 years of age, high genetic barrier nucleos(t)ide analogue(s) therapy before HBeAg-seroconversion, and a serum HBsAg titer < 1,000 IU/mL at 18 months after HBeAg-seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively). CONCLUSIONS: In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg-seroconversion in childhood, high genetic barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg-seroconversion were significant predictors of functional cure.

Defect Engineered Bi2Te3 Nanosheets with Enhanced Haloperoxidase Activity for Marine Antibiofouling.

Defective bismuth telluride (Bi2Te3) nanosheets, an artificial nanozyme mimicking haloperoxidase activity (hPOD), show promise as eco-friendly, bactericidal, and antimicrofouling materials by enhancing cytotoxic hypohalous acid production from halides and H2O2. Microscopic and spectroscopic characterization reveals that controlled NaOH (upto X = 250 µL) etching of the nearly inactive non-transition metal chalcogenide Bi2Te3 nanosheets creates controlled defects (d), such as Bi3+species, in d-Bi2Te3-X that induces enhanced hPOD activity. d-Bi2Te3-250 exhibits approximately eight-fold improved hPOD than the as-grown Bi2Te3 nanosheets. The antibacterial activity of d-Bi2Te3-250 nanozymes, studied by bacterial viability, show 1, and 45% viability for Staphylococcus aureus and Pseudomonas aeruginosa, respectively, prevalent in marine environments. The hPOD mechanism is confirmed using scavengers, implicating HOBr and singlet oxygen for the effect. The antimicrofouling property of the d-Bi2Te3-250 nanozyme has been studied on Pseudomonas aeruginosa biofilm in a lab setting by multiple assays, and also on titanium (Ti) plates coated with the nanozyme mixed commercial paint, exposed to seawater in a real setting. All studies, including direct microscopic evidence, exhibit inhibition of microfouling, up to ≈73%, in the presence of nanozymes. This approach showcases that defect engineering can induce antibacterial, and antimicrofouling activity in non-transition metal chalcogenides, offering an inexpensive alternative to noble metals.

Multicolour and lineage-specific interphase chromosome Flow-FISH: method development and clinical validation.

Flow cytometry can be applied in the detection of fluorescence in situ hybridisation (FISH) signals to efficiently analyse chromosomal aberrations. However, such interphase chromosome (IC) Flow-FISH protocols are currently limited to detecting a single colour. Furthermore, combining IC Flow-FISH with conventional multicolour flow cytometry is difficult because the DNA-denaturation step in FISH assay also disrupts cellular integrity and protein structures, precluding subsequent antigen-antibody binding and hindering concurrent labeling of surface antigens and FISH signals. We developed a working protocol for concurrent multicolour flow cytometry detection of nuclear IC FISH signals and cell surface markers. The protocol was validated by assaying sex chromosome content of blood cells, which was indicative of chimerism status in patients who had received sex-mismatched allogeneic haematopoietic stem cell transplants (allo-HSCT). The method was also adapted to detect trisomy 12 in chronic lymphocytic leukaemia (CLL) subjects. We first demonstrated the feasibility of this protocol in detecting multiple colours and concurrent nuclear and surface signals with high agreement. In clinical validation experiments, chimerism status was identified in clinical samples (n=56) using the optimised IC Flow-FISH method; the results tightly corresponded to those of conventional slide-based FISH (R2=0.9649 for XX cells and 0.9786 for XY cells). In samples from patients who received sex-mismatched allo-HSCT, individual chimeric statuses in different lineages could be clearly distinguished with high flexibility in gating strategies. Furthermore, in CLL samples with trisomy 12, this method could demonstrate that enriched trisomy 12 FISH signal was present in B cells rather than in T cells. Finally, by performing combined labelling of chromosome 12, X chromosome, and surface markers, we could detect rare residual recipient CLL cells with trisomy 12 after allo-HSCT. This adaptable protocol for multicolour and lineage-specific IC Flow-FISH advances the technique to allow for its potential application in various clinical contexts where conventional FISH assays are currently being utilised.

Performance of Baveno VII criteria for the screening of varices needing treatment in patients with biliary atresia.

OBJECTIVE: Biliary atresia (BA) is the leading cause of liver cirrhosis and chronic liver insufficiency in children in the world. Gastroesophageal varices bleeding is an ominous complication of cirrhosis in BA patients and is associated with high morbidity and mortality. In this study, we aimed to investigate the utility of noninvasive Baveno VI and Baveno VII criteria for the screening of varices need treatment (VNT) and the need for liver transplantation in BA patients. METHODS: This study enrolled 48 BA patients (23 females and 25 males) who underwent an esophagogastroduodenoscopy (EGD) and transient elastography at a mean age of 11.18 ± 1.48 years; the clinical data were surveyed in a retrospective design. RESULTS: The sensitivity and negative predictive value of Baveno VI and Baveno VII criteria for the prediction of VNT in BA patients are both 100% and 100%, respectively. The VNT missing rate of Baveno VI and Baveno VII criteria are both 0% in our cohort. The Baveno VI, expanded Baveno VI, and Baveno VII criteria are also predictive of the need for liver transplantation in our cohort (OR = 10.33, 4.24, and 21.33; p = 0.009, 0.03, and 0.007, respectively). CONCLUSION: The Baveno VI and Baveno VII criteria are useful for the screening of VNT and minimize non-necessary invasive EGD in BA patients with low VNT missing rates. The Baveno VI, expanded Baveno VI, and Baveno VII criteria are associated with the need for liver transplantation.

Microglia-mediated drug substance transfer promotes chemoresistance in brain tumors: insights from an in vitro co-culture model using GCV/Tk prodrug system.

BACKGROUND: It is well known that tumor-associated macrophages (TAMs) play essential roles in brain tumor resistance to chemotherapy. However, the detailed mechanisms of how TAMs are involved in brain tumor resistance are still unclear and lack a suitable analysis model. METHODS: A BV2 microglial cells with ALTS1C1 astrocytoma cells in vitro co-culture system was used to mimic the microglia dominating tumor stroma in the tumor invasion microenvironment and explore the interaction between microglia and brain tumor cells. RESULTS: Our result suggested that microglia could form colonies with glioma cells under high-density culturing conditions and protect glioma cells from apoptosis induced by chemotherapeutic drugs. Moreover, this study demonstrates that microglia could hijack drug substances from the glioma cells and reduce the drug intensity of ALTS1C1 via direct contact. Inhibition of gap junction protein prevented microglial-glioma colony formation and microglia-mediated chemoresistance. CONCLUSIONS: This study provides novel insights into how glioma cells acquire chemoresistance via microglia-mediated drug substance transferring, providing a new option for treating chemo-resistant brain tumors.

Unimodal and bimodal curves of ground reaction force-time profiles identify the drop jump performance.

This study aimed to investigate the kinematics and kinetics differences in ground reaction force (GRF)-time profiles with uni- and bimodal curves (UNC and BIC) during the concentric phase of the drop jump (DJ). Twenty two male Physical Education college student who met UNC (N = 11) or BIC (N = 11) of the GRF-time profile of were recruited. Two force plates and eight infrared optical cameras were synchronised to collect the GRF and motion data during DJ from a 30-cm height. The Shapiro-Wilk test was used to assess the normality of data. The Wilcoxon test was used when data were not normally distributed. Otherwise, Independent t-tests were used to compare differences between the UNC and BIC groups for each dependent variable. The UNC group demonstrated shorter ground contact time, lower jump height, greater leg stiffness, greater peak power during the eccentric phase, less work during the eccentric and concentric phases, and greater hip and knee joint flexion and extension angle displacements (p < 0.05). No significant intergroup differences were found in reactive strength index (p > 0.05). The UNC and BIC of the GRF-time profiles can indicate whether athletes can practice DJ appropriately. UNC can be representative of a better DJ performance with an efficient stretch-shortening cycle function.

Effect of peroral endoscopic myotomy on growth and esophageal motility for pediatric esophageal achalasia.

BACKGROUND/PURPOSE: Peroral endoscopic myotomy (POEM), a novel minimally invasive treatment for esophageal achalasia, has been shown to be effective and safe for both adult and pediatric patients. However, studies on its application in children in Taiwan and its impact on growth and esophageal motility are lacking. METHODS: We conducted a retrospective study on consecutive pediatric patients who were diagnosed with esophageal achalasia at National Taiwan University Hospital and underwent POEM during 2015-2022. Disease characteristics and treatment outcomes were analyzed. RESULTS: Ten patients (age 16.9 ± 3.1 years), nine newly diagnosed and one previously treated with pneumatic dilatation, underwent POEM for achalasia (type I/II/III: 3/7/0). Average symptom duration before diagnosis was 19.4 ± 19.9 months, mean POEM procedure time was 83.6 ± 30.7 min, and clinical success (Eckardt score ≤3) was achieved in all patients. Eight patients experienced mild adverse events during POEM, but none required further endoscopic or surgical intervention. Over a mean follow-up period of 3.7 ± 1.6 years, mean Eckardt score decreased significantly from 5.7 ± 2.4 to 1.1 ± 0.7 (p = 0.0001). The BMI z-score also increased significantly after POEM (p = 0.023). Five patients received follow-up high-resolution impedance manometry (HRIM), and all had improved lower esophageal sphincter resting pressures (p = 0.011), body contractility, and bolus transit (p = 0.019). CONCLUSION: POEM is an effective and safe treatment for pediatric achalasia in Taiwan. Early diagnosis and treatment with POEM may help to restore esophageal function and nutrition status in children.

Follow-up care and assessment of comorbidities and complications in patients with primary aldosteronism: The clinical practice guideline of the Taiwan Society of aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension, characterized by excess aldosterone production that leads to an increased risk of cardiovascular events and target organ damage. Both adrenalectomy and medical treatment have shown efficacy in improving clinical outcomes and comorbidities associated with PA, including a specific subtype of PA with autonomous cortisol secretion (ACS). Understanding the comorbidities of PA and establishing appropriate follow-up protocols after treatment are crucial for physicians to enhance morbidity and mortality outcomes in patients with PA. Additionally, the screening for hypercortisolism prior to surgery is essential, as the prognosis of patients with coexisting PA and ACS differs from those with PA alone. In this review, we comprehensively summarize the comorbidities of PA, encompassing cardiovascular, renal, and metabolic complications. We also discuss various post-treatment outcomes and provide insights into the strategy for glucocorticoid replacement in patients with overt or subclinical hypercortisolism. This clinical practice guideline aims to equip medical professionals with up-to-date information on managing concurrent hypercortisolism, assessing treatment outcomes, and addressing comorbidities in patients with PA, thereby improving follow-up care.

Real-world efficacy and safety of low-dose pembrolizumab in patients with advanced and refractory gynecologic cancers.

OBJECTIVE: The approved standard dose of pembrolizumab (200 mg administrated every 3 weeks) for cancer treatment imposes a significant financial burden on patients. However, no study has analyzed the clinical outcomes of low-dose pembrolizumab among individuals diagnosed with gynecologic cancer. The primary objective of this study was to assess the effectiveness and safety of a low-dose pembrolizumab regimen in real-world clinical practice. METHODS: We retrospectively assessed the efficacy and safety data of patients with gynecologic malignancies who received pembrolizumab between 2017 and 2022 at Kaohsiung Chang Gung Memorial Hospital. Furthermore, we conducted a comparative analysis of the objective response rate (ORR) and progression-free survival (PFS) between patients with deficient mismatch repair (dMMR) and proficient MMR (pMMR). RESULTS: A total of thirty-nine patients were included and received pembrolizumab at fixed dosages of 50 mg (5.1%), 100 mg (84.6%) and 200 mg (10.3%) per cycle. Compared to the pMMR group, the dMMR group exhibited a tendency toward improved ORR (45.5% vs. 13.0%, p = 0.074), and notably, the median duration of response remained unreached. There was no significant difference in PFS between the dMMR and pMMR groups; however, the patients with dMMR in tumor tissue had a trend of better survival (p = 0.079). Incidence of immune-related adverse events (irAEs) of any grade was observed in 13 patients (33.3%), with 3 individuals (7.7%) experiencing grade 3 or 4 events. CONCLUSION: Low-dose pembrolizumab may be a cost-effective and safe treatment option without compromising clinical outcomes in patients with refractory gynecologic cancers.

Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

Primary aldosteronism is associated with various types of cardiovascular and cerebrovascular damage independently of hypertension. Although chronic hypertension and related cerebral arteriosclerosis are the main risk factors for intracerebral hemorrhage, the effects of aldosteronism remain poorly understood. We enrolled 90 survivors of hypertensive intracerebral hemorrhage, 21 of them with aldosteronism and 69 with essential hypertension as controls in this study. Clinical parameters and neuroimaging markers of cerebral small vessel disease were recorded, and its correlations with aldosteronism were investigated. Our results showed that the aldosteronism group (55.2 ± 9.7 years, male 47.6%) had similar hypertension severity but exhibited a higher cerebral microbleed count (interquartile range) (8.5 [2.0‒25.8] vs 3 [1.0‒6.0], P = 0.005) and higher severity of dilated perivascular space in the basal ganglia (severe perivascular space [number >20], 52.4% vs. 24.6%, P = 0.029; large perivascular space [>3 mm], 52.4% vs. 20.3%, P = 0.010), compared to those with essential hypertension (53.8 ± 11.7 years, male 73.9%). In multivariate models, aldosteronism remained an independent predictor of a higher (>10) microbleed count (odds ratio = 8.60, P = 0.004), severe perivascular space (odds ratio = 4.00, P = 0.038); the aldosterone-to-renin ratio was associated with dilated perivascular space (P = 0.043) and large perivascular space (P = 0.008). In conclusions, survivors of intracerebral hemorrhage with aldosteronism showed a tendency towards more severe hypertensive arteriopathy than the essential hypertension counterparts independently of blood pressure; aldosteronism may contribute to dilated perivascular space around the deep perforating arteries. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

Reversal of arterial stiffness in medically and surgically treated unilateral primary aldosteronism.

OBJECTIVE: Hyperaldosteronism has adverse effects on cardiovascular structure and function. Laparoscopic adrenalectomy is the gold standard for patients with unilateral primary aldosteronism. For unilateral primary aldosteronism patients unable or unwilling to undergo surgery, the effects of mineralocorticoid receptor antagonists (MRAs) on the reversibility of arterial stiffness and other clinical data remain unclear. We aimed to compare the reversibility of arterial stiffness using pulse wave velocity (PWV) and other clinical parameters between surgically and medically treated unilateral primary aldosteronism patients. METHODS: We prospectively enrolled 306 unilateral primary aldosteronism patients, of whom 247 received adrenalectomy and 59 received medical treatment with MRAs. Detailed medical history, basic biochemistry and PWV data were collected in both groups before treatment and 1 year after treatment. After propensity score matching (PSM) for age, sex, SBP and DBPs, 149 patients receiving adrenalectomy and 54 patients receiving MRAs were included for further analysis. RESULTS: After PSM, the patients receiving adrenalectomy had a greater reduction in blood pressure, increase in serum potassium, and change in PWV (ΔPWV, -53 ±â€Š113 vs. -10 ±â€Š140 cm/s, P  = 0.028) than those receiving MRAs 1 year after treatment. Multivariable regression analysis further identified that surgery (compared with MRA treatment), baseline PWV, baseline DBP, the change in DBP and the use of diuretics were independently correlated with ΔPWV. CONCLUSION: Adrenalectomy is superior to MRA treatment with regards to vascular remodeling when treating unilateral primary aldosteronism patients.

Treatment of primary aldosteronism: Clinical practice guidelines of the Taiwan Society of Aldosteronism.

Primary aldosteronism (PA) is the most common cause of secondary hypertension and one of the few medical diseases that can be cured by surgery. Excessive aldosterone secretion is highly associated with cardiovascular complications. Many studies have shown that patients with unilateral PA treated with surgery have better survival, cardiovascular, clinical, and biochemical outcomes than those who receive medical treatment. Consequently, laparoscopic adrenalectomy is the gold standard for treating unilateral PA. Surgical methods should be individualized according to the patient's tumor size, body shape, surgical history, wound considerations, and surgeon's experience. Surgery can be performed through a transperitoneal or retroperitoneal approach, and via a single-port or multi-port laparoscopic approach. However, total or partial adrenalectomy remains controversial in treating unilateral PA. Partial excision will not completely eradicate the disease and is prone to recurrence. Mineralocorticoid receptor antagonists should be considered for patients with bilateral PA or patients who cannot undergo surgery. There are also emerging alternative interventions, including radiofrequency ablation and transarterial adrenal ablation, for which data on long-term outcomes are currently lacking. The Task Force of Taiwan Society of Aldosteronism developed these clinical practice guidelines with the aim of providing medical professionals with more updated information on the treatment of PA and improving the quality of care.

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer: A Randomized Clinical Trial.

Importance: The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. Objective: To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). Design, Setting, and Participants: This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Interventions: Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. Main Outcomes and Measures: The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. Results: A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. Conclusions and Relevance: The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02185352.

The predictors of long-term outcomes after targeted therapy for primary Aldosteronism.

Unilateral primary aldosteronism is thought to be a surgically curable disease, and unilateral adrenalectomy is the mainstay treatment. The Primary Aldosteronism Surgical Outcome (PASO) consensus was developed to assess clinical and biochemical outcomes to standardize the classification of surgical outcomes. However, fewer than half of patients are cured of hypertension after adrenalectomy; therefore, preoperative patient counseling and evaluation might be necessary. Moreover, current studies show that genetic mutations and histopathology classification are associated with the treatment outcome. The Task Force of Taiwan PA recommends using a specific scoring system, including the PASO score and nomogram-based preoperative score, to predict the clinical outcome before adrenalectomy. Herein, we discuss the associations of current histopathological classification and specific somatic gene mutations with clinical outcomes after surgery.

Reproducible SERS substrates manipulated by interparticle spacing and particle diameter of gold nano-island array using in-situ thermal evaporation.

Gold (Au) nano-island arrays were deposited on the glass substrate to fabricate surface-enhanced Raman scattering (SERS) substrates by in-situ thermal evaporation (deposited and annealed samples at the same time). The optimal SERS intensity deposited by various thicknesses and in-situ annealing temperatures of Au nano-island arrays would be investigated. The biomolecules (adenine) were dropped on the well-designed SERS substrate for precise and quantitative SERS detection. The characterization of Au nano-island arrays SERS substrate would be evaluated by scanning electron microscope (SEM) and Raman spectroscopy. The results showed that the optimal deposition thickness and annealing temperature of Au nano-island arrays SERS substrate is about 14 nm and 200 °C respectively, which can construct the smallest interparticle spacing (W)/ particle diameter (D) ratio and the lowest reflection (%) and transmittance (%) to form the strongest SERS intensity. Moreover, finite-difference time-domain (FDTD) simulation of the electromagnetic field distributions on Au nano-island arrays displays the similar trend with the experimental results. The 14 nm deposition with 200 °C in-situ annealing temperature would display the highest density of hot-spots by FDTD simulation. The reproducible Au nano-island arrays SERS substrates with tunable surface roughness, W/D ratio, and lower reflection and transmittance show promising potential for SERS detection of biomolecules, bacteria, and viruses.

X-ray polarization evidence for a 200-year-old flare of Sgr A.

The centre of the Milky Way Galaxy hosts a black hole with a solar mass of about 4 million (Sagittarius A* (Sgr A)) that is very quiescent at present with a luminosity many orders of magnitude below those of active galactic nuclei1. Reflection of X-rays from Sgr A* by dense gas in the Galactic Centre region offers a means to study its past flaring activity on timescales of hundreds and thousands of years2. The shape of the X-ray continuum and the strong fluorescent iron line observed from giant molecular clouds in the vicinity of Sgr A* are consistent with the reflection scenario3-5. If this interpretation is correct, the reflected continuum emission should be polarized6. Here we report observations of polarized X-ray emission in the direction of the molecular clouds in the Galactic Centre using the Imaging X-ray Polarimetry Explorer. We measure a polarization degree of 31% ± 11%, and a polarization angle of -48° ± 11°. The polarization angle is consistent with Sgr A* being the primary source of the emission, and the polarization degree implies that some 200 years ago, the X-ray luminosity of Sgr A* was briefly comparable to that of a Seyfert galaxy.

Fragment Linker Prediction Using the Deep Encoder-Decoder Network for PROTACs Drug Design.

A drug discovery and development pipeline is a prolonged and complex process that remains challenging for both computational methods and medicinal chemists and has not been able to be resolved using computational methods. Deep learning has been utilized in various fields and achieved tremendous success in designing novel molecules in the pharmaceutical industry. Herein, we use state-of-the-art techniques to propose a deep neural network, AIMLinker, to rapidly design and generate meaningful drug-like proteolysis targeting chimeras (PROTACs) analogs. The model extracts the structural information from the input fragments and generates linkers to incorporate them. We integrate filters in the model to exclude nondruggable structures guided via protein-protein complexes while retaining molecules with potent chemical properties. The novel PROTACs subsequently pass through molecular docking, taking root-mean-square deviation (RMSD), relative Gibbs free energy (ΔΔGbinding), molecular dynamics (MD) simulation, and free energy perturbation (FEP) calculations as the measurement criteria for testing the robustness and feasibility of the model. The generated novel PROTACs molecules possess similar structural information with superior binding affinity to the binding pockets compared to the existing CRBN-dBET6-BRD4 ternary complexes. We demonstrate the effectiveness of the methodology of leveraging AIMLinker to design novel compounds for PROTACs molecules exhibiting better chemical properties compared to the dBET6 crystal pose.

Room-Temperature Gate Voltage Modulation of Plasmonic Nanolasers.

Stable electrical modulation of plasmonic nanolasers is achieved on a hybrid graphene-insulator-metal (GIM) platform at room temperature. To support surface plasmon polariton (SPP) resonance, a zinc oxide (ZnO) nanowire is placed on the GIM platform to create a plasmonic cavity with a compact mode volume of 2.6 × 10-2 λ3, and the graphene layer is used as a transparent electrode for electrical modulation. When a gate voltage is applied, the surface electron density of Al varied, which results in the shifting of its plasma frequency and thus affects its SPP dispersion. In particular, this variation strongly changes the internal loss of the SPP mode; thus, the lasing thresholds of the ZnO nanowire plasmonic nanolasers on the GIM platform can be modulated by the gate voltage. This study demonstrates the gate voltage modulation of ZnO nanowire plasmonic nanolasers on a GIM platform at room temperature. These nanolasers can exhibit ultrahigh modulation speed on the order of terahertz. Accordingly, plasmonic nanolasers with gate voltage modulation have high potential for plasmonic circuit applications with high operation speed and versatility.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.