Unveiling Nonsecular Collisional Dissipation of Molecular Alignment.

We conducted a joint theoretical and experimental study to investigate the collisional dissipation of molecular alignment. By comparing experimental measurements to the quantum simulations, the nonsecular effect in the collision dissipation of molecular alignment was unveiled from the gas-density-dependent decay rates of the molecular alignment revival signals. Different from the conventional perspective that the nonsecular collisional effect rapidly fades within the initial few picoseconds following laser excitation, our simulations of the time-dependent decoherence process demonstrated that this effect can last for tens of picoseconds in the low-pressure regime. This extended timescale allows for the distinct identification of the nonsecular effect from molecular alignment signals. Our findings present the pioneering evidence that nonsecular molecular collisional dissipation can endure over an extended temporal span, challenging established concepts and strengthening our understanding of molecular dynamics within dissipative environments.

Textbook anastomotic success in patients with low rectal cancer treated by intersphincteric resection: reappraising surgical, oncological, and functional outcomes.

Previous studies on successful anastomosis after intersphincteric resection (ISR) for low rectal cancer (LRC) primarily focused on anastomotic complications rather than functional outcomes. Here, we improved the anastomotic success criteria by considering surgical, oncological, and functional outcomes and proposed a new composite outcome, "textbook anastomotic success" (TASS). This retrospective single-center study included patients with LRC treated with ISR from January 2014 to April 2020. TASS was defined as (1) no anastomotic complications occurring after ISR; (2) ileostomy was closed and there was no severe intestinal dysfunction 2 years after ISR; and (3) no local recurrence within 2 years of surgery. TASS was achieved upon meeting all indicators. We analyzed 259 patients with LRC, with 125 (48.3%) achieving TASS. Multivariate analysis showed that male sex (OR 0.47; 95% CI 0.27-0.81; p = 0.007), hypertension (OR 0.48; 95% CI 0.24-0.97; p = 0.041), ASA score ≥ 3 (OR 0.28; 95% CI 0.10-0.81; p = 0.018), pre-treatment major low anterior resection syndrome (OR 0.37; 95% CI 0.15-0.94; p = 0.037), and preoperative neoadjuvant chemoradiotherapy (OR 0.41; 95% CI 0.22-0.77; p = 0.006) were independent risk factors for not achieving TASS. Conversely, transverse coloplasty pouch (OR 2.13; 95% CI 1.07-4.25; p = 0.032) and higher anastomosis level (OR 1.56; 95% CI 1.05-2.30; p = 0.026) were independent protective factors for achieving TASS. The nomogram constructed to evaluate the probability of achieving TASS demonstrated good accuracy in the dataset (area under curve, 0.737). TASS provides a comprehensive quality assessment for ISR in patients with LRC. The nomogram predicting TASS may assist surgeons in decision-making for managing LRC.

In situ self-assembled near-infrared phototherapeutic agent: unleashing hydrogen free radicals and coupling with NADPH oxidation.

Investigation of electron transfer (ET) between photosensitizers (PSs) and adjacent substrates in hypoxic tumors is integral to highly efficient tumor therapy. Herein, the oxygen-independent ET pathway to generate hydrogen free radicals (H˙) was established by the in situ self-assembled phototherapeutic agent d-ST under near-infrared (NIR)-light irradiation, coupled with the oxidation of reduced coenzyme NADPH, which induced ferroptosis and effectively elevated the therapeutic performance in hypoxic tumors. The higher surface energy and longer exciton lifetimes of the fine crystalline d-ST nanofibers were conducive to improving ET efficiency. In hypoxic conditions, the excited d-ST can effectively transfer electrons to water to yield H˙, during which the overexpressed NADPH with rich electrons can power the electron flow to facilitate the generation of H˙, accompanied by NADP+ formation, disrupting cellular homeostasis and triggering ferroptosis. Tumor-bearing mouse models further showed that d-ST accomplished excellent phototherapy efficacy. This work sheds light onto the versatile electron pathways between PSs and biological substrates.

Efficacy, safety, and tolerability of adjunctive Lacosamide therapy for focal seizures in young children aged ≥1 month to ≤4 years: A real-world study.

AIMS: To evaluate the efficacy, safety, and tolerability of adjunctive lacosamide therapy against focal seizures in young children (1 month - 4 years). METHODS: This non-randomized, open-label, and self-controlled real-world study included 105 children (1 month-4 years) with focal seizures treated with adjunctive lacosamide therapy at Children's Hospital of Chongqing Medical University. RESULTS: (1) The 50% response rates at 3, 6, 9, and 12 months of follow-up were 58.1%, 61.0%, 57.1%, and 56.2%, while the seizure-free rates were 27.6%, 34.3%, 32.4%, and 37.1%, respectively. The 50% response rate of the first addition of lacosamide for focal seizures was much higher than the second and later added treatment at 3 months (p = 0.038). After 1 year of follow-up, these children showed an improvement in neurodevelopmental levels (p < 0.05). (2) Lacosamide retention rate was 72.7% (64/88) after 1 year of follow-up. Lack of efficacy and serious adverse events were independent risk factors for the lacosamide retention rate. (3) During adjunctive lacosamide therapy, 13 (12.4%) patients reported adverse events and five (4.7%) patients withdrew due to adverse events, including vomiting drowsiness, ataxia (0.94%), neck itching with eczema (0.94%), irritability (1.88%), and gastrointestinal discomfort (0.94%). CONCLUSION: Adjunctive lacosamide therapy was effective, safe, and well-tolerated in young Chinese children with focal seizures in this study.

[Screening and fermentation of high-yield glycolic acid strains].

Glycolic acid is an important chemical product widely used in various fields, including cosmetics, detergents, textiles, and more. Currently, microbial production of glycolic acid has disadvantages such as poor genetic stability, low yield, and high cost. Additionally, whole-cell catalytic production of glycolic acid typically requires the addition of relatively expensive sorbitol as a carbon source, which limits its industrial production. To develop an industrially applicable method for glycolic acid production, this study used ethylene glycol as a substrate to screen the glycolic acid-producing strains through whole-cell catalysis, obtaining a Rhodotorula sp. capable of producing glycolic acid. The strain was then subjected to UV mutagenesis and high throughput screening, and the positive mutant strain RMGly-20 was obtained. After optimization in shake flasks, the glycolic acid titer of RMGly-20 reached 17.8 g/L, a 10.1-fold increase compared to the original strain. Using glucose as the carbon source and employing a fed-batch culture in a 5 L fermenter, strain RMGly-20 produced 61.1 g/L of the glycolic acid. This achievement marks the preliminary breeding of a genetically stable glycolic acid-producing strain using a cheap carbon source, providing a new host for the biosynthesis of glycolic acid and promoting further progress toward industrial production.

Identification and Characterization of an R-M System in P. denitrificans DYTN-1 to Improve the Plasmid Conjugation Transfer Efficiency.

Paracoccus denitrificans has been identified as a representative strain with heterotrophic nitrificationaerobic denitrification capabilities (HN-AD), and demonstrates strong denitrification proficiency. Previously, we isolated the DYTN-1 strain from activated sludge, and it has showcased remarkable nitrogen removal abilities and genetic editability, which positions P. denitrificans DYTN-1 as a promising chassis cell for synthetic biology engineering, with versatile pollutant degradation capabilities. However, the strain's low stability in plasmid conjugation transfer efficiency (PCTE) hampers gene editing efficacy, and is attributed to its restriction modification system (R-M system). To overcome this limitation, we characterized the R-M system in P. denitrificans DYTN-1 and identified a DNA endonuclease and 13 DNA methylases, with the DNA endonuclease identified as HNH endonuclease. Subsequently, we developed a plasmid artificial modification approach to enhance conjugation transfer efficiency, which resulted in a remarkable 44-fold improvement in single colony production. This was accompanied by an increase in the frequency of positive colonies from 33.3% to 100%. Simultaneously, we cloned, expressed, and characterized the speculative HNH endonuclease capable of degrading unmethylated DNA at 30°C without specific cutting site preference. Notably, the impact of DNA methylase M9 modification on the plasmid was discovered, significantly impeding the cutting efficiency of the HNH endonuclease. This revelation unveils a novel R-M system in P. denitrificans and sheds light on protective mechanisms employed against exogenous DNA invasion. These findings pave the way for future engineering endeavors aimed at enhancing the DNA editability of P. denitrificans.

BAP1-mediated MAFF deubiquitylation regulates tumor growth and is associated with adverse outcomes in colorectal cancer.

BACKGROUND: Despite improvements in colorectal cancer (CRC) treatment, the prognosis for advanced CRC patients remains poor. Disruption of protein stability is one of the important factors in cancer development and progression. In this study, we aim to identify and analyze novel dysregulated proteins in CRC, assessing their significance and the mechanisms. METHODS: Using quantitative proteomics, expression pattern analysis, and gain-of-function/loss-of-function experiments, we identify novel functional protein dysregulated by ubiquitin-proteasome axis in CRC. Prognostic significance was evaluated in a training cohort of 546 patients and externally validated in 794 patients. Mechanistic insights are gained through molecular biology experiments, deubiquitinating enzymes (DUBs) expression library screening, and RNA sequencing. RESULTS: MAFF protein emerged as the top novel candidate substrate regulated by ubiquitin-proteasome in CRC. MAFF protein was preferentially downregulated in CRC compared to adjacent normal tissues. More importantly, multicenter cohort study identified reduced MAFF protein expression as an independent predictor of overall and disease-free survival in CRC patients. The in vitro and vivo assays showed that MAFF overexpression inhibited CRC growth, while its knockdown had the opposite effect. Intriguingly, we found the abnormal expression of MAFF protein was predominantly regulated via ubiquitination of MAFF, with K48-ubiquitin being dominant. BAP1 as a nuclear deubiquitinating enzyme (DUB), bound to and deubiquitinated MAFF, thereby stabilizing it. Such stabilization upregulated DUSP5 expression, resulting in the inhibition of ERK phosphorylation. CONCLUSIONS: This study describes a novel BAP1-MAFF signaling axis which is crucial for CRC growth, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.

Intraglandular dissemination: a special pathological feature.

Intraglandular dissemination is an important pathological feature of thyroid cancer, yet the biological characteristics of this phenomenon remain relatively underexplored. This paper aims to provide a comprehensive overview of its biological behaviors, protein expressions, and identification methods. Several retrospective studies have found that thyroid cancers with intraglandular dissemination have higher rates of lymph node metastasis, capsule invasion, and vascular invasion, exhibiting more aggressive biological behavior. Immunohistochemistry results show abnormal expression of proteins such as FKBP5, CENPF, CX26, KIF11, PTK7, which are associated with poor prognosis in thyroid cancers with intraglandular dissemination, offering potential guidance for specific targeted therapy in the future. Moreover, adjunctive techniques including ultrasound, fine-needle aspiration, and genetic testing offer valuable support in accurately identifying these cases, facilitating moreproactive treatment and closer follow-up.

Decrypting the viral community in aerobic activated sludge reactors treating antibiotic production wastewater.

Viruses are the most abundant yet understudied members that may influence microbial metabolism in activated sludge treating antibiotic production wastewater. This study comprehensively investigated virome community characteristics under the selection pressure of nine types and different concentrations of antibiotics using a metagenomics approach. Of the 15,514 total viral operational taxonomic units (tOTUs) recovered, only 37.5 % were annotated. Antibiotics altered the original viral community structure in activated sludge. The proportion of some pathogenic viral families, including Herpesviridae_like, increased significantly in reactors treating erythromycin production wastewater. In total, 16.5 % of the tOTUs were associated with two or more hosts. tOTUs rarely carried antibiotic resistance genes (ARGs), and the ARG types in the tOTUs did not match the ARGs carried by the bacterial hosts. This suggests that transduction contributes little to the horizontal ARG transfer. Auxiliary metabolic genes (AMGs) were prevalent in tOTUs, and those involved in folate biosynthesis were particularly abundant, indicating their potential to mitigate antibiotic-induced host damage. This study provides comprehensive insights into the virome community in activated sludge treating antibiotic production wastewater and sheds light on the potential role of viral AMGs in mitigating antibiotic-induced stress.

Controlling the Subcellular Localization of Signaling Proteins Using Chemically Induced Dimerization and Optogenetics.

A given protein can perform numerous roles in a cell with its participation in protein complexes and distinct localization within the cell playing a critical role in its diverse functions. Thus, the ability to artificially dimerize proteins and recruit proteins to specific locations in a cell has become a powerful tool for the investigation of protein function and the understanding of cell biology. Here, we discuss two systems that have been used to activate signal transduction pathways, a chemically inducible dimerization (CID) and a light-inducible (LI) system to control signaling and cytoskeletal regulation in a spatial and temporal manner.

A position-enhanced sequential feature encoding model for lung infections and lymphoma classification on CT images.

PURPOSE: Differentiating pulmonary lymphoma from lung infections using CT images is challenging. Existing deep neural network-based lung CT classification models rely on 2D slices, lacking comprehensive information and requiring manual selection. 3D models that involve chunking compromise image information and struggle with parameter reduction, limiting performance. These limitations must be addressed to improve accuracy and practicality. METHODS: We propose a transformer sequential feature encoding structure to integrate multi-level information from complete CT images, inspired by the clinical practice of using a sequence of cross-sectional slices for diagnosis. We incorporate position encoding and cross-level long-range information fusion modules into the feature extraction CNN network for cross-sectional slices, ensuring high-precision feature extraction. RESULTS: We conducted comprehensive experiments on a dataset of 124 patients, with respective sizes of 64, 20 and 40 for training, validation and testing. The results of ablation experiments and comparative experiments demonstrated the effectiveness of our approach. Our method outperforms existing state-of-the-art methods in the 3D CT image classification problem of distinguishing between lung infections and pulmonary lymphoma, achieving an accuracy of 0.875, AUC of 0.953 and F1 score of 0.889. CONCLUSION: The experiments verified that our proposed position-enhanced transformer-based sequential feature encoding model is capable of effectively performing high-precision feature extraction and contextual feature fusion in the lungs. It enhances the ability of a standalone CNN network or transformer to extract features, thereby improving the classification performance. The source code is accessible at https://github.com/imchuyu/PTSFE .

Finite element analysis of the treatment of a minimally invasive approach combined with a novel anatomical locking plate for scapular body fractures.

BACKGROUND: The minimally invasive approach for the treatment of displaced scapular neck or body fractures has the advantages of less trauma and minimal muscle dissection. In clinical practice, the minimally invasive approach combined with an anatomical locking plate has been used to treat scapular body fractures. In addition, we have made minor modifications to the minimally invasive approach. However, the biomechanical study about the approach combined with an anatomical locking plate in treating scapular body fractures was limited. METHODS: Finite element analysis (FEA) was used to conduct the biomechanical comparison between the anatomical locking plate (AP model) and reconstructive plate (RP model) in the treatment of scapular body fractures through the modified minimally invasive approach. A healthy male volunteer with no history of scapula or systemic diseases was recruited. High-resolution computed tomography images of his right scapula were obtained. Two scapula models were constructed and analyzed by the software of Mimics 21.0, Geomagic Wrap 2021, SolidWorks 2021, and ANSYS Workbench 2022, respectively. RESULTS: Through static structural analysis, in terms of equivalent von Mises stress, equivalent elastic strain, and total deformation, the AP model exhibited superior safety characteristics, enhanced flexibility, and anticipated stability compared with the RP model. This was evidenced by lower maximum stress, lower maximum strain and displacement. CONCLUSION: The minimally invasive approach combined with an anatomical locking plate for scapular body fractures had better biomechanical stability. The study provided a biomechanical basis to guide the clinical treatment of scapular body fractures.

A clinically-recommended MR whole lung imaging protocol using free-breathing 3D isotropic zero echo time sequence.

Rationale and objectives: This study aimed to assess the feasibility and image quality of free-breathing 3D isotropic zero echo time (ZTE) whole-lung imaging and explore a clinically appropriate protocol for MR lung imaging. Materials and methods: The study was approved by the local ethics committee. A total of thirty healthy volunteers were enrolled in this study from October 2022 to May 2023. Free-breathing pulmonary 3D isotropic ZTE scans were implemented with various acquisition planes and the number of excitations (NEX). ZTE images were evaluated by two radiologists for the overall Image quality and visibility of intrapulmonary structures as well as the signal-to-noise ratio (SNR) of the lung parenchyma. ZTE images with different acquisition parameters were compared. For preliminary clinical visual assessment, three patients with interstitial lung disease underwent both ZTE imaging and computed tomography (CT). Results: The overall image quality of the lung in healthy subjects was good to excellent. The visibilities of pulmonary arteries and bronchus were up to the 7th and 5th generation, respectively. The display of lung fissures was poor. The overall image quality, the visibility of the pulmonary artery, and lung fissures in the axial acquisition were better than in the coronal acquisition (P = 0.011, 0.008, 0.010, respectively) but not statistically different from those in the sagittal acquisition (all P > 0.05). Conclusion: The free-breathing pulmonary ZTE is feasible and may serve as an alternative method in chest imaging. Either axial or sagittal ZTE image acquisition would be preferred in clinical practice.

Predictive Value of Pretreatment Neutrophil to Albumin Ratio in Response to Neoadjuvant Chemotherapy of Breast Cancer.

Background: The immune system appears to play a crucial role in how breast cancer responds to chemotherapy. In this study, we investigated a peripheral marker of immune and inflammation named the neutrophil to albumin ratio (NAR) to explore its potential relationship with pathological complete response (pCR) in locally advanced breast cancer patients who underwent neoadjuvant chemotherapy (NAC). Methods: We conducted a retrospective analysis of 212 consecutive breast cancer patients who received NAC. The NAR was calculated by examining the complete blood cell count and albumin level in peripheral blood before starting NAC. Through ROC curve analysis, we determined the optimal cutoff value for NAR as 0.0877. We used Pearson's chi-square test or Fisher's exact test to evaluate the relationship between NAR and pCR, as well as other clinical and pathological characteristics. Logistic regression models were employed for univariate and multivariate analyses. Results: The results of both univariate and multivariate logistic regression analyses showed that NAR was associated with tumor pathological regression. The NAR high group had a higher pCR rate compared to the NAR low group (OR 3.127 [95% CI 1.545-6.328]; p = 0.002). Conclusion: According to this study, it was observed that patients with breast cancer who had high levels of NAR were more likely to achieve pCR when undergoing NAC.

Ultrafast Picometer-Resolved Molecular Structure Imaging by Laser-Induced High-Order Harmonics.

Real-time visualization of molecular transformations is a captivating yet challenging frontier of ultrafast optical science and physical chemistry. While ultrafast x-ray and electron diffraction methods can achieve the needed subangstrom spatial resolution, their temporal resolution is still limited to hundreds of femtoseconds, much longer than the few femtoseconds required to probe real-time molecular dynamics. Here, we show that high-order harmonics generated by intense femtosecond lasers can be used to image molecules with few-ten-attosecond temporal resolution and few-picometer spatial resolution. This is achieved by exploiting the sensitive dependence of molecular recombination dipole moment to the geometry of the molecule at the time of harmonic emission. In a proof-of-principle experiment, we have applied this high-harmonic structure imaging (HHSI) method to monitor the structural rearrangement in NH_{3}, ND_{3}, and N_{2} from one to a few femtoseconds after the molecule is ionized by an intense laser. Our findings establish HHSI as an effective approach to resolve molecular dynamics with unprecedented spatiotemporal resolution, which can be extended to trace photochemical reactions in the future.

Neuromodulatory Compensation of Cortical Neural Activity on Electrodeposited Pt/Ir Modified Microelectrode Arrays for Temperature Transients.

Temperature has a profound influence on various neuromodulation processes and has emerged as a focal point. However, the effects of acute environmental temperature fluctuations on cultured cortical networks have been inadequately elucidated. To bridge this gap, we have developed a brain-on-a-chip platform integrating cortical networks and electrodeposited Pt/Ir modified microelectrode arrays (MEAs) with 3D-printed bear-shaped triple chambers, facilitating control of temperature transients. This innovative system administers thermal stimuli while concurrently monitoring neuronal activity, including spikes and local field potentials, from 60 microelectrodes (diameter: 30 µm; impedance: 9.34 ± 1.37 kΩ; and phase delay: -45.26 ± 2.85°). Temperature transitions of approximately ±10 °C/s were applied to cortical networks on MEAs via in situ perfusion within the triple chambers. Subsequently, we examined the spatiotemporal dynamics of the brain-on-a-chip under temperature regulation at both the group level (neuronal population) and their interactions (network dynamics) and the individual level (cellular activity). Specifically, we found that after the temperature reduction neurons enhanced the overall information transmission efficiency of the network through synchronous firing to compensate for the decreased efficiency of single-cell level information transmission, in contrast to temperature elevation. By leveraging the integration of high-performance MEAs with perfusion chambers, this investigation provides a comprehensive understanding of the impact of temperature on the spatiotemporal dynamics of neural networks, thereby facilitating future exploration of the intricate interplay between temperature and brain function.

Ras suppression potentiates rear actomyosin contractility-driven cell polarization and migration.

Ras has been extensively studied as a promoter of cell proliferation, whereas few studies have explored its role in migration. To investigate the direct and immediate effects of Ras activity on cell motility or polarity, we focused on RasGAPs, C2GAPB in Dictyostelium amoebae and RASAL3 in HL-60 neutrophils and macrophages. In both cellular systems, optically recruiting the respective RasGAP to the cell front extinguished pre-existing protrusions and changed migration direction. However, when these respective RasGAPs were recruited uniformly to the membrane, cells polarized and moved more rapidly, whereas targeting to the back exaggerated these effects. These unexpected outcomes of attenuating Ras activity naturally had strong, context-dependent consequences for chemotaxis. The RasGAP-mediated polarization depended critically on myosin II activity and commenced with contraction at the cell rear, followed by sustained mTORC2-dependent actin polymerization at the front. These experimental results were captured by computational simulations in which Ras levels control front- and back-promoting feedback loops. The discovery that inhibiting Ras activity can produce counterintuitive effects on cell migration has important implications for future drug-design strategies targeting oncogenic Ras.

Arsenic activated GLUT1-mTORC1/HIF-1α-PKM2 positive feedback networks promote proliferation and migration of bladder epithelial cells.

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

The physiological and pathological roles of RNA modifications in T cells.

RNA molecules undergo dynamic chemical modifications in response to various external or cellular stimuli. Some of those modifications have been demonstrated to post-transcriptionally modulate the RNA transcription, localization, stability, translation, and degradation, ultimately tuning the fate decisions and function of mammalian cells, particularly T cells. As a crucial part of adaptive immunity, T cells play fundamental roles in defending against infections and tumor cells. Recent findings have illuminated the importance of RNA modifications in modulating T cell survival, proliferation, differentiation, and functional activities. Therefore, understanding the epi-transcriptomic control of T cell biology enables a potential avenue for manipulating T cell immunity. This review aims to elucidate the physiological and pathological roles of internal RNA modifications in T cell development, differentiation, and functionality drawn from current literature, with the goal of inspiring new insights for future investigations and providing novel prospects for T cell-based immunotherapy.