Neurotransmitters: Impressive regulators of tumor progression.

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

DYNLL1 accelerates cell cycle via ILF2/CDK4 axis to promote hepatocellular carcinoma development and palbociclib sensitivity.

BACKGROUND: Disorder of cell cycle represents as a major driver of hepatocarcinogenesis and constitutes an attractive therapeutic target. However, identifying key genes that respond to cell cycle-dependent treatments still facing critical challenges in hepatocellular carcinoma (HCC). Increasing evidence indicates that dynein light chain 1 (DYNLL1) is closely related to cell cycle progression and plays a critical role in tumorigenesis. In this study, we explored the role of DYNLL1 in the regulation of cell cycle progression in HCC. METHODS: We analysed clinical specimens to assess the expression and predictive value of DYNLL1 in HCC. The oncogenic role of DYNLL1 was determined by gain or loss-of-function experiments in vitro, and xenograft tumour, liver orthotopic, and DEN/CCl4-induced mouse models in vivo. Mass spectrometry analysis, RNA sequencing, co-immunoprecipitation assays, and forward and reverse experiments were performed to clarify the mechanism by which DYNLL1 activates the interleukin-2 enhancer-binding factor 2 (ILF2)/CDK4 signalling axis. Finally, the sensitivity of HCC cells to palbociclib and sorafenib was assessed by apoptosis, cell counting kit-8, and colony formation assays in vitro, and xenograft tumour models and liver orthotopic models in vivo. RESULTS: DYNLL1 was significantly higher in HCC tissues than that in normal liver tissues and closely related to the clinicopathological features and prognosis of patients with HCC. Importantly, DYNLL1 was identified as a novel hepatocarcinogenesis gene from both in vitro and in vivo evidence. Mechanistically, DYNLL1 could interact with ILF2 and facilitate the expression of ILF2, then ILF2 could interact with CDK4 mRNA and delay its degradation, which in turn activates downstream G1/S cell cycle target genes CDK4. Furthermore, palbociclib, a selective CDK4/6 inhibitor, represents as a promising therapeutic strategy for DYNLL1-overexpressed HCC, alone or particularly in combination with sorafenib. CONCLUSIONS: Our work uncovers a novel function of DYNLL1 in orchestrating cell cycle to promote HCC development and suggests a potential synergy of CDK4/6 inhibitor and sorafenib for the treatment of HCC patients, especially those with increased DYNLL1.

5†kW power-level 1050†nm narrow-linewidth fiber amplifier enabled by biconical-tapered active fiber.

Effective wavelength extension is vital in the applications of high-power narrow-linewidth fiber lasers. In this work, we demonstrate a 5-kW power-level narrow-linewidth fiber amplifier at 1050 nm utilizing a homemade biconical-tapered Yb-doped fiber (BT-YDF). Up to ∼4.96 kW fiber laser is achieved with a 3 dB linewidth of ∼0.54 nm and a beam quality factor of Mx 2 = 1.46, My 2 = 1.6. The experimental comparisons reveal that BT-YDF has the advantages of improving a stimulated Raman scattering threshold and balancing transverse mode instability suppression in the fiber amplifier. This work could provide a good reference for extending the operating wavelength of high-power fiber amplifiers.

Diagnostic efficiency of conventional ultrasound, shear wave elastography, and superb microvascular imaging in evaluating ulnar neuropathy at the elbow.

INTRODUCTION/AIMS: The current diagnosis of ulnar neuropathy at the elbow (UNE) relies mainly on the clinical presentation and nerve electrodiagnostic (EDX) testing, which can be uncomfortable and yield false negatives. The aim of this study was to investigate the diagnostic value of conventional ultrasound, shear wave elastography (SWE), and superb microvascular imaging (SMI) in diagnosing UNE. METHODS: We enrolled 40 patients (48 elbows) with UNE and 48 healthy volunteers (48 elbows). The patients were categorized as having mild, moderate or severe UNE based on the findings of EDX testing. The cross-sectional area (CSA) was measured using conventional ultrasound. Ulnar nerve (UN) shear wave velocity (SWV) and SMI were performed in a longitudinal plane. RESULTS: Based on the EDX findings, UNE severity was graded as mild in 4, moderate in 10, and severe in 34. The patient group showed increased ulnar nerve CSA and stiffness at the site of maximal enlargement (CSA mean at the site of max enlargement [CSAmax] and SWV mean at the site of max enlargement [SWVmax]), ulnar nerve CSA ratio, and stiffness ratio (elbow-to-upper arm), compared with the control group (p < .001). Furthermore, the severe UNE group showed higher ulnar nerve CSAmax and SWVmax compared with the mild and moderate UNE groups (p < .001). The cutoff values for diagnosis of UNE were 9.5 mm2 for CSAmax, 3.06 m/s for SWVmax, 2.00 for CSA ratio, 1.36 for stiffness ratio, and grade 1 for SMI. DISCUSSION: Our findings suggest that SWE and SMI are valuable diagnostic tools for the diagnosis and assessment of severity of UNE.

Hydrothermal and anion exchange synthesis of Mn(V)-doped Ba5(PO4)3Cl nano-apatite toward NIR-II temperature sensing.

The second near-infrared window (NIR-II) in the range of 1000-1400 nm is ideal for in vivo imaging and sensing through reduced scattering, absorption, and autofluorescence. However, there are only a few nanophosphor systems with emission in the NIR-II region. Here, we report on Mn5+-doped Ba5(PO4)3Cl nanoparticles (BPCl:Mn5+ NPs, d < 50 nm) toward NIR-II temperature sensing. BPCl:Mn5+ NPs are made by a two-step (hydrothermal and anion exchange) method. XRD, SEM, and TEM results showed that the as-prepared BPCl:Mn5+ NPs show high crystallinity, uniform size, and sphere-like morphology. The nanoparticles exhibit a broad excitation band of 500-850 nm and a temperature-sensitive peak emission at 1175 nm in the NIR-II range. NIR-II temperature sensing by 1E emission intensity is demonstrated with good linear fitting (R2 = 0.9895), high sensitivity (2.30% at 373 K), and good repeatability (99.0%). Thus, our study provides a path to develop a new NIR-II thermometer based on tetrahedral Mn(V) coordination.

Extraction of genomic DNA for sequencing from snail Helix lucorum.

In the past, there were no easily distinct and recognizable features as a guide for precise clinical and genetic diagnosis of cases with chromosome microdeletions involving 15q26 including CHD2,. The present study analysed the clinical data and collected venous blood samples from a pediatric patient and his healthy family members for DNA testing. The whole-exome sequencing was performed by the next-generation sequencing (NGS). Chromosomal copy-number variations were tested based on NGS. We present a review of all cases with chromosome microdeletions affecting CHD2. A novel de novo 5.82-Mb deletion at 15q25.3-15q26.1 including CHD2 was identified in our patient who is an 11.6-year-old boy. We first found surprising efficacy of lamotrigine in controlling intractable drop seizures in the individual. These cases have development delay, behavioural problems, epilepsy, variable multiple anomalies, etc. Phenotypes of individuals with deletions involving 15q26 including CHD2 are highly variable with regard to facial features and multiple developmental anomalies. We first found the special clinical entity of development delay, behavioural problems, epilepsy, variable skeletal and muscular anomalies, abnormalities of variable multiple systems and characteristic craniofacial phenotypes in patients with chromosome microdeletions involving CHD2. The larger deletions involving 15q26 including CHD2 tend to cause the classical phenotype. A distinctive craniofacial appearance of the classical phenotype is midface hypoplasia and perifacial protrusion.

To Investigate the Mechanism of Qinpi Tongfeng Formula in Treating Acute Gouty Arthritis by UHPLC-Q-Orbitrap-MS, Network Pharmacology and Experimental Validation.

Background: Acute gouty arthritis (AGA) is characterized by the accumulation of monosodium urate crystals within the joints, leading to inflammation and severe pain. Western medicine treatments have limitations in addressing this condition. Previous studies have shown the efficacy of Qinpi Tongfeng formula (QPTFF) in treating AGA, but further investigation is needed to understand its mechanism of action. Methods: We used ultra-high-performance liquid chromatography tandem Q-Exactive Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS) to identify compounds in QPTFF. Target proteins regulated by these compounds were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Chemistry Database, and Swiss Target Prediction Database. AGA-related targets were searched and screened from various databases, including Genecards, PharmGKB, Drugbank, etc. Intersection targets of QPTFF and AGA were analyzed for protein-protein interaction networks, GO function enrichment, and KEGG pathway enrichment. We then verified QPTFF's mechanism of action using an AGA rat model, assessing pathological changes via H&E staining and target expression via ELISA, RT-qPCR, and Western blot. Results: UHPLC-Q-Orbitrap-MS identified 207 compounds in QPTFF, with 55 selected through network pharmacology. Of 589 compound-regulated targets and 1204 AGA-related targets, 183 potential targets were implicated in QPTFF's treatment of AGA. Main target proteins included IL-1ß, NFKBIA, IL-6, TNF, CXCL8, and MMP9, with the IL-17 signaling pathway primarily regulated by QPTFF. Experimental results showed that medium and high doses of QPTFF significantly reduced serum inflammatory factors and MMP-9 expression, and inhibited IL-17A, IL-6, IKK-ß, and NF-κB p65 mRNA and protein expression in AGA rats compared to the model group. Conclusion: Key targets of QPTFF include IL-1ß, NFKBIA, IL-6, TNF-α, CXCL8, and MMP9. QPTFF effectively alleviates joint inflammation in AGA rats, with high doses demonstrating no liver or kidney toxicity. Its anti-inflammatory mechanism in treating AGA involves the IL-17A/NF-κB p65 signaling pathway.

Neuroprotective effects and mechanisms of action of artemisinin in retinal ganglion cells in a mouse model of traumatic optic neuropathy.

Introduction: Traumatic optic neuropathy is known to be a critical condition that can cause blindness; however, the specific mechanism underlying optic nerve injury is unclear. Recent studies have reported that artemisinin, considered vital in malaria treatment, can also be used to treat neurodegenerative diseases; however, its precise role and mechanism of action remain unknown. Therefore, in this study, we aimed to investigate the impact and probable mechanism of action of artemisinin in retinal ganglion cells (RGCs) in a mouse model of traumatic optic neuropathy induced by optic nerve crush (ONC). Methods: ONC was induced in the left eye of mice by short-term clamping of the optic nerve; oral artemisinin was administered daily. The neuroprotective effect of the drug was assessed using Tuj-1 staining in RGCs. In addition, the inflammatory response and the expression levels of phosphorylated tau protein and tau oligomers were observed using RT-qPCR, TUNEL assay, and fluorescence staining to investigate the underlying mechanisms. Results: Artemisinin increased the survival rate of RGCs 14 days after ONC. Artemisinin significantly reduced the levels of inflammatory factors such as CXCL10, CXCR3, and IL-1ß in the retina and decreased the apoptosis of RGCs. Moreover, downregulation of the phosphorylation of tau proteins and the expression of tau oligomers were observed after artemisinin treatment. Conclusion: Our results suggest that artemisinin can increase the survival rate of RGCs after ONC and reduce their apoptosis. This effect may be achieved by inhibiting the inflammatory response it triggers and downregulating tau protein phosphorylation and tau oligomer expression. These findings suggest the potential application of artemisinin as a therapeutic agent for neuropathy.

XAI Driven Intelligent IoMT Secure Data Management Framework.

The Internet of Medical Things (IoMT) has transformed traditional healthcare systems by enabling real-time monitoring, remote diagnostics, and data-driven treatment. However, security and privacy remain significant concerns for IoMT adoption due to the sensitive nature of medical data. Therefore, we propose an integrated framework leveraging blockchain and explainable artificial intelligence (XAI) to enable secure, intelligent, and transparent management of IoMT data. First, the traceability and tamper-proof of blockchain are used to realize the secure transaction of IoMT data, transforming the secure transaction of IoMT data into a two-stage Stackelberg game. The dual-chain architecture is used to ensure the security and privacy protection of the transaction. The main-chain manages regular IoMT data transactions, while the side-chain deals with data trading activities aimed at resale. Simultaneously, the perceptual hash technology is used to realize data rights confirmation, which maximally protects the rights and interests of each participant in the transaction. Subsequently, medical time-series data is modeled using bidirectional simple recurrent units to detect anomalies and cyberthreats accurately while overcoming vanishing gradients. Lastly, an adversarial sample generation method based on local interpretable model-agnostic explanations is provided to evaluate, secure, and improve the anomaly detection model, as well as to make it more explainable and resilient to possible adversarial attacks. Simulation results are provided to illustrate the high performance of the integrated secure data management framework leveraging blockchain and XAI, compared with the benchmarks.

Nanoenzyme Hydrogel Film-Based Portable Point-of-Care Testing Platform for Double-Signal Visual Detection of PSA.

The development of the Point-of-Care Testing (POCT) platform that combines convenience and cost-effectiveness is crucial for enabling the visual detection of disease biomarkers. In this work, a POCT platform for the sensitive in situ detection of prostate specific antigen (PSA) with dual-signal output was constructed by functionalizing the Eppendorf (EP) tube. This was achieved through the modification of aptamer hairpin probes (AHPs) on the lid of the EP tube and the assembly of a nanoenzyme hydrogel film on its inner wall. The target could trigger the release of Ag+ by AHP and subsequently activate Ag+-dependent DNAzyme (Ag-DNAzyme). This would initiate the cleavage of the DNA-Au/Pt NP hydrogel network, leading to the release of Au/Pt NPs. The released Au/Pt NPs exhibit both peroxidase (POD)-like and catalase (CAT)-like activity to produce a colorimetric response and induce liquid flow under pressure. Therefore, the target can be measured visually and quantitatively through colorimetric analysis and the measurement of total dissolved solids (TDS) using a pressure-triggered liquid flow device integrated into the platform. The designed platform is distinguished by its simplicity, specificity, cost-effectiveness, and remarkable sensitivity. It allows for the visual detection of PSA within concentration ranges of 0.5-100 ng/L (colorimetric) and 3-100 ng/L (TDS reading), boasting detection limits as low as 0.15 ng/L (colorimetric) and 0.57 ng/L (TDS reading). The strategy of target-triggered nanoenzyme release significantly enhances sensitivity and provides a guiding approach for visual biomarker detection.

Serum albumin-embedding copper nanoclusters inhibit Alzheimer's ß-amyloid fibrillogenesis and neuroinflammation.

Increasing evidence suggests that the accumulations of reactive oxygen species (ROS), ß-amyloid (Aß), and neuroinflammation are crucial pathological hallmarks for the onset of Alzheimer's disease (AD), yet there are few effective treatment strategies. Therefore, design of nanomaterials capable of simultaneously elimination of ROS and inhibition of Aß aggregation and neuroinflammation is urgently needed for AD treatment. Herein, we designed human serum albumin (HSA)-embedded ultrasmall copper nanoclusters (CuNCs@HSA) via an HSA-mediated fabrication strategy. The as-prepared CuNCs@HSA exhibited outstanding multiple enzyme-like properties, including superoxide dismutase (>5000 U/mg), catalase, and glutathione peroxidase activities as well as hydroxyl radicals scavenging ability. Besides, CuNCs@HSA prominently inhibited Aß fibrillization, and its inhibitory potency was 2.5-fold higher than native HSA. Moreover, CuNCs@HSA could significantly increase the viability of Aß-treated cells from 60 % to over 96 % at 40 µg/mL and mitigate Aß-induced oxidative stresses. The secretion of neuroinflammatory cytokines by lipopolysaccharide-induced BV-2 cells, including tumor necrosis factor-α and interleukin-6, was alleviated by CuNCs@HSA. In vivo studies manifested that CuNCs@HSA effectively suppressed the formation of plaques in transgenic C. elegans, reduced ROS levels, and extended C. elegans lifespan by 5 d. This work, using HSA as a template to mediate the fabrication of copper nanoclusters with robust ROS scavenging capability, exhibited promising potentials in inhibiting Aß aggregation and neuroinflammation for AD treatment.

Self-protecting CoFeAl-layered double hydroxides enable stable and efficient brine oxidation at 2 A cm-2.

Low-energy consumption seawater electrolysis at high current density is an effective way for hydrogen production, however the continuous feeding of seawater may result in the accumulation of Cl-, leading to severe anode poisoning and corrosion, thereby compromising the activity and stability. Herein, CoFeAl layered double hydroxide anodes with excellent oxygen evolution reaction activity are synthesized and delivered stable catalytic performance for 350 hours at 2 A cm-2 in the presence of 6-fold concentrated seawater. Comprehensive analysis reveals that the Al3+ ions in electrode are etched off by OH- during oxygen evolution reaction process, resulting in M3+ vacancies that boost oxygen evolution reaction activity. Additionally, the self-originated Al(OH)n- is found to adsorb on the anode surface to improve stability. An electrode assembly based on a micropore membrane and CoFeAl layered double hydroxide electrodes operates continuously for 500 hours at 1 A cm-2, demonstrating their feasibility in brine electrolysis.

Fluoride impairs vascular smooth muscle A7R5 cell lines via disrupting amino acids metabolism.

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.

Anterior Shoulder Stabilization Using Single Needle-Assisted Outside-In Remplissage Technique and Bankart Repair.

Arthroscopic repair of Bankart injury is the first choice for the treatment of anterior shoulder instability. How to avoid recurring shoulder joint dislocation is a challenge, especially when combined with Hill-Sachs lesions. The arthroscopy technology allows for broader vision and less surgical trauma but is limited by a smaller operating space. At present, extensive descriptions about the surgical procedure of arthroscopic Bankart repair have been published. In this Technical Note, we describe the use of remplissage filling with Hill-Sachs lesion combined with Bankart repair to further improve the surgical accuracy and clinical efficacy. In particular, the application of single needle-assisted outside-in remplissage technique and Bankart repair is introduced in detail.

Overexpressing Bcl-2 enhances murine chimeric antigen receptor T cell therapy against solid tumor.

Chimeric antigen receptor T (CART) cell therapy has demonstrated promising potential in the treatment of hematologic malignancies. However, its application to solid tumors is limited due to the restrictive nature of the tumor microenvironment, resulting in functional failure and poor persistence of CART cells. Overexpression of Bcl-2 in human CART cells (hCART) has been found to significantly enhance their anti-apoptotic effects both in vitro and in vivo. Nevertheless, the evaluation of hCART cells in preclinical studies has predominantly relied on immunodeficient mice xenograft tumor models, making it challenging to assess the impact of hCART cells on normal tissues and the immune system. We established a murine CART (mCART) that overexpresses Bcl-2 and targets the epidermal growth factor receptor variant III (EGFRvIII), named EGFRvIII·mCART-Bcl2. It demonstrated superior proliferation, cytotoxicity, and anti-apoptotic capabilities in vitro. In an immunocompetent mouse model of abdominal metastasis of colorectal cancer, EGFRvIII·mCART-Bcl2 exhibited improved survival of CART in the abdomen, increased tumor clearance, and significantly prolonged overall mouse survival. In summary, our study provides evidence that the introduction of Bcl-2 into mCART cells can enhance their therapeutic efficacy against solid tumors while ensuring safety.

Analysis of Ileal Atresia from Prenatal Ultrasound to Postoperative Follow-up: Two Case Reports.

BACKGROUND: Congenital ileal atresia is a rare neonatal disease, the most common type of intestinal malformation in newborns, and one of the most common causes of congenital intestinal obstruction. It can cause various digestive system symptoms, including abdominal distension, vomiting, abnormal bowel movements, etc. In severe cases, it can be life-threatening. A prenatal ultrasound examination can assist clinical diagnosis of congenital ileal atresia, and those with a clear prenatal diagnosis should undergo surgical treatment after birth. CASE PRESENTATION: We have, herein, reported two cases of congenital ileal atresia, both of which showed fetal intestinal dilation (>7mm) and excessive amniotic fluid on prenatal ultrasound. Both newborns underwent surgical treatment after delivery and were confirmed to have congenital ileal atresia during surgery. Due to the different prenatal ultrasound manifestations of the two patients, they were divided into two different subtypes based on intraoperative manifestations. We observed significant differences in the prognosis of the two patients after surgery. CONCLUSION: Accurately locating and classifying ileal atresia using prenatal ultrasound is challenging; however, it plays an effective role in disease progression, gestational assessment, and prognosis. Accurately identifying intestinal diseases and/or the location of lesion sites through direct and indirect ultrasound findings in the fetal abdominal cavity is an important research direction for prenatal ultrasound.

Longitudinal change of serum exosomal miR-186-5p estimates major adverse cardiac events in acute myocardial infarction patients receiving percutaneous coronary intervention.

Objective: Our recently published study discovers that exosomal microRNA (miR)-186-5p promotes vascular smooth muscle cell viability and invasion to facilitate atherosclerosis. This research aimed to explore the prognostic implication of serum exosomal miR-186-5p in acute myocardial infarction (AMI) patients receiving percutaneous coronary intervention (PCI). Methods: One hundred and fifty AMI patients receiving PCI and 50 healthy controls (HCs) were screened. Serum exosomal miR-186-5p was detected by reverse transcriptase-quantitative polymerase chain reaction assay in AMI patients at admission and after PCI, as well as in HCs after enrollment. Major adverse cardiac events (MACE) were recorded during follow-up in AMI patients receiving PCI. Results: Serum exosomal miR-186-5p was raised in AMI patients vs. HCs (P < 0.001). Besides, serum exosomal miR-186-5p was positively linked to body mass index (P = 0.048), serum creatinine (P = 0.021), total cholesterol (P = 0.029), and C-reactive protein (P = 0.018); while it was reversely linked with estimated glomerular filtration rate (P = 0.023) in AMI patients. Interestingly, serum exosomal miR-186-5p was correlated with the diagnosis of ST-segment elevation myocardial infarction (P = 0.034). Notably, serum exosomal miR-186-5p was decreased after PCI vs. at admission (P < 0.001). The 6-, 12-, 18-, and 24-month accumulating MACE rates were 4.5%, 8.9%, 14.8%, and 14.8% in AMI patients. Furthermore, serum exosomal miR-186-5p ≥3.39 (maximum value in HCs) after PCI (P = 0.021) and its decrement percentage

The role of aldehydes on sulfur based-new particle formation: a theoretical study.

Aldehydes play a crucial role in the formation of atmospheric particles, attracting significant attention due to their environmental impact. However, the microscopic mechanisms underlying the formation of aldehyde-involved particles remain uncertain. In this study, through quantum chemical calculations and molecular dynamics (MD) simulations, we investigate the microscopic formation mechanisms of binary and ternary systems composed of three representative aldehydes, two sulfur-based acids, water, and two bases. Our research findings reveal that the most stable structures of acid-aldehyde clusters involve the connection of acids and aldehyde compounds through hydrogen bonds without involving proton transfer reactions, indicating relatively poor cluster stability. However, with the introduction of a third component, the stability of 18 clusters significantly increase. Among these, in ten systems, acids act as catalysts, facilitating reactions between aldehyde compounds and water or alkaline substances to generate glycols and amino alcohols. However, according to MD simulations conducted at 300 K, these acids readily dissociate from the resulting products. In the remaining eight systems, the most stable structural feature involves ion pairs formed by proton transfer reactions between acids and aldehyde compounds. These clusters exhibit remarkable thermodynamic stability. Furthermore, the acidity of the acid, the nature of nucleophilic agents, and the type of aldehyde all play significant roles in cluster stability and reactivity, and they have synergistic effects on the nucleation process. This study offers microscopic insights into the processes of new particle formation involving aldehydes, contributing to a deeper understanding of atmospheric chemistry at the molecular level.

A novel approach for denoising electrocardiogram signals to detect cardiovascular diseases using an efficient hybrid scheme.

Background: Electrocardiogram (ECG) signals are inevitably contaminated with various kinds of noises during acquisition and transmission. The presence of noises may produce the inappropriate information on cardiac health, thereby preventing specialists from making correct analysis. Methods: In this paper, an efficient strategy is proposed to denoise ECG signals, which employs a time-frequency framework based on S-transform (ST) and combines bi-dimensional empirical mode decomposition (BEMD) and non-local means (NLM). In the method, the ST maps an ECG signal into a subspace in the time frequency domain, then the BEMD decomposes the ST-based time-frequency representation (TFR) into a series of sub-TFRs at different scales, finally the NLM removes noise and restores ECG signal characteristics based on structural self-similarity. Results: The proposed method is validated using numerous ECG signals from the MIT-BIH arrhythmia database, and several different types of noises with varying signal-to-noise (SNR) are taken into account. The experimental results show that the proposed technique is superior to the existing wavelet based approach and NLM filtering, with the higher SNR and structure similarity index measure (SSIM), the lower root mean squared error (RMSE) and percent root mean square difference (PRD). Conclusions: The proposed method not only significantly suppresses the noise presented in ECG signals, but also preserves the characteristics of ECG signals better, thus, it is more suitable for ECG signals processing.

ABBV-319: A CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).