Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

Immune checkpoint inhibitors (ICIs) have shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. In this study, we aim to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefit. We retrospective analyzed 69 GBC patients who had received ICI therapy between January 2016 and December 2020. Tumor samples were obtained for genomic sequencing and immunohistochemical analysis. The median progression-free survival (PFS) and overall survival (OS) was 4.4 months and 8.5 months, respectively. Multivariate analysis indicated that alcohol intake history, carcinoma embryonic antigen (CEA) level ≥100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for PFS. CEA level ≥100 U/mL and cutaneous irAEs were independent prognostic factors for OS. The objective response rate and disease control rate (DCR) were 15.9% and 37.7%, respectively. Patients with cutaneous irAEs, high CD8+ T cell infiltrated or immune inflamed GBCs had higher DCR. Patients with high CD8+ T cell infiltrated or immune inflamed GBCs also had a notably improved prognosis. These results suggest that ICIs were effective in patients with GBC. High CEA level, cutaneous irAEs, high CD8+ T cell infiltration, and immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC.

Senescent fibroblast facilitates re-epithelization and collagen deposition in radiation-induced skin injury through IL-33-mediated macrophage polarization.

BACKGROUND: The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. RESULTS: Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. CONCLUSIONS: In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner.

Factors influencing diffusion tensor imaging of knee cartilage in children ages 6-12 years: a prospective study.

BACKGROUND: Magnetic resonance diffusion tensor imaging (DTI) has recently been used to evaluate the developing cartilage of children, but the influencing factors have not been well studied. OBJECTIVE: The objective of this study was to investigate the influence of the diffusion gradient strength (b value), diffusion gradient direction, age and sex on knee cartilage DTI in healthy children aged 6-12 years. MATERIALS AND METHODS: A total of 30 healthy child volunteers, with an average age of 8.9 ± 1.6 (mean ± standard deviation) years, were enrolled in this study. They were categorized into three groups according to their age range: 6-8 years, 8-10 years and 10-12 years, ensuring equal sex distribution in each group (5 boys and 5 girls). These volunteers underwent routine left knee joint magnetic resonance imaging (MRI) and serial DTI scans. DTI parameters were altered as follows: when b value = 600 s/mm2, diffusion gradient direction was set to 6, 15, 25, 35 and 45; and when diffusion gradient direction = 25, b value was set to 300, 600, 900 and 1200 s/mm2. The values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were separately acquired using image post-processing techniques. The correlation between various b values, diffusion gradient directions, age and sex on the one hand and FA and ADC values on the other, was investigated. RESULTS: (1) When diffusion gradient direction was fixed and the b value was varied, both FA and ADC exhibited a decreasing trend as the b value increased (P < 0.001). (2) When the b value was fixed and diffusion gradient direction was varied, the FA of knee cartilage showed a decreasing trend with increasing diffusion gradient direction (P < 0.001). (3) The FA value increased with age (P < 0.05). CONCLUSION: The b value, diffusion gradient direction value and age exert a significant impact on both FA and ADC values in MR DTI of knee cartilage in children aged 6-12 years. In order to obtain a stable DTI, it is recommended to select a b value ≥ 600 s/mm2 and a diffusion gradient direction ≥ 25 during scanning.

Simultaneous Reconstruction of Gas Concentration and Temperature Using Acoustic Tomography.

Acoustic tomography utilizes sensor arrays to collect sound wave signals, enabling non-contact measurement of physical parameters within an area of interest. Compared to optical technologies, acoustic tomography offers the advantages of low cost, low maintenance, and easy installation. Current research in acoustic tomography mainly focuses on reconstruction algorithms for temperature fields, while monitoring the composition and concentration of gases is significant for ensuring safety and improving efficiency, such as in scenarios like boiler furnaces and aviation engine nozzles. In excitable gases, the speed of sound exhibits an S-shaped curve that changes with frequency, a characteristic that could be potentially useful for acoustic tomography. Therefore, this study primarily discusses the quantitative calculation of gas concentration and temperature based on the dispersion of the speed of sound. By employing graphic processing and pattern matching methods, a coupled relationship of the dispersion of the speed of sound with gas concentration and temperature is established. The projection intersection method is used to calculate the concentration and temperature of binary and ternary gas mixtures. Combined with the inversion method, a joint reconstruction method for gas concentration fields and temperature fields based on the dispersion of the speed of sound is developed. The feasibility of the proposed simultaneous reconstruction method for temperature and concentration fields is validated using numerical simulations. Additionally, an acoustic tomography experimental system was set up to conduct reconstruction experiments for binary gas concentration fields and temperature fields, confirming the effectiveness of the proposed method.

Determining the Number of Graphene Nanoribbons in Dual-Gate Field-Effect Transistors.

Bottom-up synthesized graphene nanoribbons (GNRs) are increasingly attracting interest due to their atomically controlled structure and customizable physical properties. In recent years, a range of GNR-based field-effect transistors (FETs) has been fabricated, with several demonstrating quantum-dot (QD) behavior at cryogenic temperatures. However, understanding the relationship between the cryogenic charge-transport characteristics and the number of the GNRs in the device is challenging, as the length and location of the GNRs in the junction are not precisely controlled. Here, we present a methodology based on a dual-gate FET that allows us to identify different scenarios, such as single GNRs, double or multiple GNRs in parallel, and a single GNR interacting with charge traps. Our dual-gate FET architecture therefore offers a quantitative approach for comprehending charge transport in atomically precise GNRs.

Binding dynamics of cavity solitons in a Kerr resonator with high order dispersion.

Cavity solitons are persistent light pulses arising from the externally driven Kerr resonators. Thanks to the passive parametric gain, cavity soliton has been endowed with the natural advantage of the chip-scaled integration since it was first experimentally generated in the fiber-based platform. Deterministic single soliton with smooth spectrum is a preferred state for numerous applications. However, multiple solitons are more common in the resonators with anomalous dispersion. In this condition, adjacent solitons are easily perturbed to attract and collide with each other. Some experimental observations deviated from the aforementioned description have recorded the stable soliton intervals that can last for a long time scale. This phenomenon is known as soliton binding and is attributed to the presence of narrow resonant sidebands in the spectrum. While the stationary configuration of two binding solitons has been investigated, the dynamical evolution remains an area for further exploration. In this paper, we discuss the binding dynamics of the cavity solitons in the presence of high-order dispersion. The proposed theoretical predictions match well with the numerical results, encompassing both the stationary stable intervals and dynamic trajectories. Our research will provide a comprehensive insight into the soliton motion induced by the internal perturbations.

Hematological characteristics of COVID-19 patients with fever infected by the Omicron variant in Shanghai: A retrospective cohort study in China.

BACKGROUND: A wave of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread in Shanghai, China. Hematological abnormalities have been reported in coronavirus disease 2019 (COVID-19) patients; however, the difference in hematological parameters between COVID-19 patients with fever and patients who are febrile from other causes remains unexplored. METHODS: This retrospective cohort study enrolled 663 SARS-CoV-2 positive patients identified by RT-PCR. Clinical parameters, including age, sex, and threshold cycle values of all COVID-19 patients, and hematological parameters of COVID-19 patients in the fever clinic were abstracted for analysis. RESULTS: Overall, 60.8% of COVID-19 patients were male, and the median age was 45 years. Most of COVID-19 patients were asymptomatic, while 25.8% of patients showed fever and 10.9% of patients had other emergencies. COVID-19 patients with fever had significantly lower white blood cells (WBCs), neutrophils, lymphocytes, platelets and C-reactive protein (CRP), and significantly higher monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and mean platelet volume-to-platelet ratio (MPR) levels, compared with those in SARS-CoV-2 negative patients with fever from other causes (p < 0.05). Neutrophil-to-lymphocyte ratio (NLR), PLR, and systemic inflammatory index (SII) levels were significantly higher in COVID-19 patients with emergencies (p < 0.05). WBCs showed the best performance with an area under the curve (0.756), followed by neutrophils (0.730) and lymphocytes (0.694) in the diagnosis of COVID-19 in the fever clinic. CONCLUSION: WBCs, neutrophils, lymphocytes, platelets, CRP and MLR, PLR, and MPR may be useful in early diagnosis of COVID-19 in the fever clinic.

Dulong People's Traditional Knowledge of Caryota obtusa (Arecaceae): a Potential Starch Plant with Emphasis on Its Starch Properties and Distribution Prediction.

The greatest global challenge is to ensure that all people have access to adequate and nutritious food. Wild edible plants, particularly those that provide substitutes for staple foods, can play a key role in enhancing food security and maintaining a balanced diet in rural communities. We used ethnobotanical methods to investigate traditional knowledge on Caryota obtusa, a substitute staple food plant of the Dulong people in Northwest Yunnan, China. The chemical composition, morphological properties, functional, and pasting properties of C. obtusa starch were evaluated. We used MaxEnt modeling to predict the potential geographical distribution of C. obtusa in Asia. Results revealed that C. obtusa is a vital starch species with cultural significance in the Dulong community. There are large areas suitable for C. obtusa in southern China, northern Myanmar, southwestern India, eastern Vietnam, and other places. As a potential starch crop, C. obtusa could substantially contribute to local food security and bring economic benefit. In the future, it is necessary to study the breeding and cultivation of C. obtusa, as well as the processing and development of starch, to solve long-term and hidden hunger in rural areas.

Bacterial Cytochrome P450 Catalyzed Post-translational Macrocyclization of Ribosomal Peptides.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a fascinating group of natural products that exhibit diverse structural features and bioactivities. P450-catalyzed RiPPs stand out as a unique but underexplored family. Herein, we introduce a rule-based genome mining strategy that harnesses the intrinsic biosynthetic principles of RiPPs, including the co-occurrence and co-conservation of precursors and P450s and interactions between them, successfully facilitating the identification of diverse P450-catalyzed RiPPs. Intensive BGC characterization revealed four new P450s, KstB, ScnB, MciB, and SgrB, that can catalyze the formation of Trp-Trp-Tyr (one C-C and two C-N bonds), Tyr-Trp (C-C bond), Trp-Trp (C-N bond), and His-His (ether bond) crosslinks, respectively, within three or four residues. KstB, ScnB, and MciB could accept non-native precursors, suggesting they could be promising starting templates for bioengineering to construct macrocycles. Our study highlights the potential of P450s to expand the chemical diversity of strained macrocyclic peptides and the range of biocatalytic tools available for peptide macrocyclization.

Growth Optimization and Device Integration of Narrow-Bandgap Graphene Nanoribbons.

The electronic, optical, and magnetic properties of graphene nanoribbons (GNRs) can be engineered by controlling their edge structure and width with atomic precision through bottom-up fabrication based on molecular precursors. This approach offers a unique platform for all-carbon electronic devices but requires careful optimization of the growth conditions to match structural requirements for successful device integration, with GNR length being the most critical parameter. In this work, the growth, characterization, and device integration of 5-atom wide armchair GNRs (5-AGNRs) are studied, which are expected to have an optimal bandgap as active material in switching devices. 5-AGNRs are obtained via on-surface synthesis under ultrahigh vacuum conditions from Br- and I-substituted precursors. It is shown that the use of I-substituted precursors and the optimization of the initial precursor coverage quintupled the average 5-AGNR length. This significant length increase allowed the integration of 5-AGNRs into devices and the realization of the first field-effect transistor based on narrow bandgap AGNRs that shows switching behavior at room temperature. The study highlights that the optimized growth protocols can successfully bridge between the sub-nanometer scale, where atomic precision is needed to control the electronic properties, and the scale of tens of nanometers relevant for successful device integration of GNRs.

Chamaejasmenin E from Stellera chamaejasme induces apoptosis of hepatocellular carcinoma cells by targeting c-Met in vitro and in vivo.

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome. There is an urgent need to find novel therapeutic approaches to treat HCC. At present, natural products have served as a valuable source for drug discovery. Here, we obtained five known biflavones from the root of Stellera chamaejasme and evaluated their activities against HCC Hep3B cells in vitro. Chamaejasmenin E (CE) exhibited the strongest inhibitory effect among these biflavones. Furthermore, we found that CE could suppress the cell proliferation and colony formation, as well as the migration ability of HCC cells, but there was no significant toxicity on normal liver cells. Additionally, CE induced mitochondrial dysfunction and oxidative stress, eventually leading to cellular apoptosis. Mechanistically, the potential target of CE was predicted by database screening, showing that the compound might exert an inhibitory effect by targeting at c-Met. Next, this result was confirmed by molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis. Meanwhile, CE also reduced the downstream proteins of c-Met in HCC cells. In concordance with above results, CE is efficacious and non-toxic in tumor xenograft model. Taken together, our findings revealed an underlying tumor-suppressive mechanism of CE, which provided a foundation for identifying the target of biflavones.

microRNAs: Key Players in Plant Response to Metal Toxicity.

Environmental metal pollution is a common problem threatening sustainable and safe crop production. Heavy metals (HMs) cause toxicity by targeting key molecules and life processes in plant cells. Plants counteract excess metals in the environment by enhancing defense responses, such as metal chelation, isolation to vacuoles, regulating metal intake through transporters, and strengthening antioxidant mechanisms. In recent years, microRNAs (miRNAs), as a small non-coding RNA, have become the central regulator of a variety of abiotic stresses, including HMs. With the introduction of the latest technologies such as next-generation sequencing (NGS), more and more miRNAs have been widely recognized in several plants due to their diverse roles. Metal-regulated miRNAs and their target genes are part of a complex regulatory network. Known miRNAs coordinate plant responses to metal stress through antioxidant functions, root growth, hormone signals, transcription factors (TF), and metal transporters. This article reviews the research progress of miRNAs in the stress response of plants to the accumulation of HMs, such as Cu, Cd, Hg, Cr, and Al, and the toxicity of heavy metal ions.

Expanded Sequence Space of Radical S-Adenosylmethionine-Dependent Enzymes Involved in Post-translational Macrocyclization.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) represent one of the largest but primarily underexplored natural product families in bacteria. The genetically encoded nature of RiPPs simplifies the prediction and prioritization of their biosynthetic gene clusters (BGCs). We report a small peptide and enzyme co-occurrence analysis workflow (SPECO), which allowed us to identify 32 220 prospective rSAM-catalyzed RiPP BGCs from 161 954 bacterial genomes and prioritize 25 families with new biosynthetic architectures or precursor patterns. We characterized three new enzymes that respectively catalyze cysteine-glycine (BlaB), histidine-aliphatic side chain (ScaB), and tyrosine/histidine-arginine (VguB) cross-links. The cyclophane-forming enzyme ScaB exhibits broad substrate selectivity, allowing it to catalyze diverse triceptide formation. These results demonstrate the strength of the SPECO workflow in discovering new enzymes for peptide macrocyclization.

BN-Anthracene for High-Mobility Organic Optoelectronic Materials through Periphery Engineering.

Despite the remarkable synthetic accomplishments in creating diverse polycyclic aromatic hydrocarbons with B-N bonds (BN-PAHs), their optoelectronic applications have been less exploited. Herein, we report the achievement of high-mobility organic semiconductors based on existing BN-PAHs through a "periphery engineering" strategy. Tetraphenyl- and diphenyl-substituted BN-anthracenes (TPBNA and DPBNA, respectively) are designed and synthesized. DPBNA exhibits the highest hole mobility of 1.3 cm2  V-1 s-1 in organic field-effect transistors, significantly outperforming TPBNA and all the reported BN-PAHs. Remarkably, this is the first BN-PAH with mobility over 1 cm2  V-1 s-1 , which is a benchmark value for practical applications as compared with amorphous silicon. Furthermore, high-performance phototransistors based on DPBNA are also demonstrated, implying the high potential of BN-PAHs for optoelectronic applications when the "periphery engineering" strategy is implemented.

Development of an Automatic Column Chromatography Separation Device for Metal Isotope Analysis Based on Droplet Counting.

A novel, simple, cost-effective, reliable, and practical automatic column chromatography separation device capable of simultaneously purifying samples for radiogenic and non-traditional stable isotope analysis has been developed. The device avoids the use of any pump and features eluent driving by the siphon effect (gravity) and quantitative control by infrared droplet counting. Several factors affecting the control of droplets were investigated, including types and concentrations of eluents and the height of the liquid level. Results showed that accurate dripping of the eluent could be readily achieved by controlling the number of droplets under selected conditions. The separation performance of the device was first demonstrated by the elution of Sr and Cd in synthetic matrix solutions. The recoveries of Sr and Cd samples were better than 87.6 and 95.0%, respectively, and the whole procedure blank was about 0.3 ng for Sr and 0.1 ng for Cd. Finally, the reliability of the device was further validated by the purification of Sr and Cd from different geological reference materials (NIST 2711a, Nod-A-1, BCR-2, and BHVO-2). The determined Cd and Sr isotope values agree well with their reference values within the uncertainty range. All these results clearly demonstrate the reliability and practicability of the proposed device, which provides a promising method for the automated purification of isotope samples.

The role of E3 ubiquitin ligase HECTD3 in cancer and beyond.

Ubiquitin modification plays significant roles in protein fate determination, signaling transduction, and cellular processes. Over the past 2 decades, the number of studies on ubiquitination has demonstrated explosive growth. E3 ubiquitin ligases are the key enzymes that determine the substrate specificity and are involved in cancer. Several recent studies shed light on the functions and mechanisms of HECTD3 E3 ubiquitin ligase. This review describes the progress in the recent studies of HECTD3 in cancer and other diseases. We propose that HECTD3 is a potential biomarker and a therapeutic target, and discuss the future directions for HECTD3 investigations.

Design and analysis of a compact subwavelength-grating-assisted 1.55/2 µm wavelength demultiplexer.

The wavelength demultiplexer (deWMUX) is an indispensable component for the wavelength diversity system. In this paper, we propose a subwavelength-grating-assisted ${{1}} \times {{2}}$ deWMUX based on the principle of multimode interference, which aims to output 1.55 and 2 µm wavelengths from two different channels. The simulation results show that the contrast of the designed deWMUX at both wavelengths is greater than 24 dB, the insertion loss is less than 0.5 dB, and the 1 dB bandwidth is wider than 100 nm. In addition, the manufacturing tolerances of the device are also studied.

A UPLC-MS/MS method for determination of endogenous l-carnitine and acetyl-l-carnitine in serum of patients with depression.

A simple, rapid, and selective ultra-performance liquid chromatography-tandem mass spectrometry method for determination of l-carnitine (LC) and acetyl-l-carnitine (ALC) in human serum was developed. Acetyl-l-carnitine-d3 (ALC-d3 ) was selected as internal standard (IS). After protein precipitation with acetonitrile-water (1 mL, 2:1, v/v), the analytes and IS were separated on a 2.5-µm XSelect HSS T3 C18 column by gradient elution with methanol-water (containing 0.01% ammonia water) as the mobile phase at a flow rate of 0.2 mL/min. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization. Good linearity (R2 > 0.999) was observed in the concentration range for LC and ALC. The inter- and intra-day values of relative error were -10.4% to 10.0% with CVs less than 9.84%. The average recoveries of the two analytes were 91.29%-98.23%. Blood samples containing LC and ALC were stable under various storage conditions. Normal, haemolytic, and hyperlipidaemic serum had no significant effect on the quantification of LC and ALC. This method was successfully applied to study the concentrations of endogenous LC and ALC in the serum of patients with first-episode depression.

Isolation and structure elucidation of anti-tyrosinase compounds from the seeds of Crotalaria pallida.

Three new compounds, crotalariapallins A-C (1-3), were isolated from the 95% EtOH extract of the seeds of Crotalaria pallida. Their structures were established based on extensive spectroscopic methods, including HRESIMS, UV, 1D and 2D NMR. All compounds were evaluated for their inhibitory activities to tyrosinase. These compounds showed different degrees of inhibitory activities, among them, compound 3 exhibited the strongest inhibition activity (IC50 = 0.42 mM).

Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor.

Cobalamin (Vitamin B12) is an adenosyl- or methyl-donating cofactor for many enzymes, yet many proteins with unknown or nonenzymatic function also contain B12-binding domains. Recent studies show that light excitation energy can promote covalent linkage of B12 to transcription factors with this linkage, affecting gene expression. Thus, B12 now has a newly described regulatory function. Here, our bioinformatics analysis reveals other transcription factors, photoreceptors, kinases, and oxygen sensors that harbor a B12-binding domain that could also regulate activity in response to light absorption.