A Dual-Gene Reporter-Amplifier Architecture for Enhancing the Sensitivity of Molecular MRI by Water Exchange.

The development of genetic reporters for magnetic resonance imaging (MRI) is essential for investigating biological functions in vivo. However, current MRI reporters have low sensitivity, making it challenging to create significant contrast against the tissue background, especially when only a small fraction of cells express the reporter. To overcome this limitation, we developed an approach for amplifying the sensitivity of molecular MRI by combining a chemogenetic contrast mechanism with a biophysical approach to increase water diffusion through the co-expression of a dual-gene construct comprising an organic anion transporting polypeptide, Oatp1b3, and a water channel, Aqp1. We first show that the expression of Aqp1 amplifies MRI contrast in cultured cells engineered to express Oatp1b3. We demonstrate that the contrast amplification is caused by Aqp1-driven increase in water exchange, which provides the gadolinium ions internalized by Oatp1b3-expressing cells with access to a larger water pool compared with exchange-limited conditions. We further show that our methodology allows cells to be detected using approximately 10-fold lower concentrations of gadolinium than that in the Aqp1-free scenario. Finally, we show that our approach enables the imaging of mixed-cell cultures containing a low fraction of Oatp1b3-labeled cells that are undetectable on the basis of Oatp1b3 expression alone.

Impact of treatment interval between neoadjuvant immunochemotherapy and surgery in lung squamous cell carcinoma.

OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.

CBS/CSE mediated H2S production induced AMPs expression through Toll pathway in crabs with black gill syndrome.

The occurrence of black gill syndrome (BGS) is a serious threat to the healthy culture of Eriocheir sinensis. Studying the innate immune ability of E. sinensis with BGS can help develop new strategies for disease prevention and treatment. Antimicrobial peptides (AMPs) have crucial roles in crustacean humoral immunity. In this study, we found that the expression levels of two antilipopolysaccharide factor (EsALF7 and EsALF-L), one Toll receptor 3 (EsToll3), and one Pelle kinase (EsPelle) were upregulated in E. sinensis with BGS. Moreover, ALFs expressions in E. sinensis with BGS were positively regulated by EsToll3 and EsPelle. The content of hydrogen sulfide (H2S) in the gills of E. sinensis with BGS was increased. Further studies showed that the expressions of cystathionine ß-synthase (EsCBS) and cystathionine γ-lyase (EsCSE) in the gills of E. sinensis with BGS were upregulated, which positively regulate the production of H2S. Whether there was a correlation between the upregulation of ALFs expression and changes in H2S content? Further studies showed that 1) the expressions of EsToll3, EsPelle, EsALF7, and EsALF-L in the gills of E. sinensis were upregulated under H2S exposure and 2) the knockdown of EsCBS and EsCSE in E. sinensis reduced the transcriptions of EsToll3, EsPelle, EsALF7, and EsALF-L. To sum up, these findings suggest that upregulation of H2S content induced by CBS/CSE promotes the expression of ALFs through the Toll pathway in E. sinensis suffering from BGS.

Identification of a FOXO gene and its roles in anti-WSSV infection through regulation of Dicers and Argos in Macrobrachium nipponense.

Forkhead box O (FOXO) proteins are a subgroup of the forkhead family of transcription factors that play important roles in the immune response. In this study, we cloned and identified a FOXO gene named MnFOXO from Macrobrachium nipponense. The full-length cDNA of MnFOXO is 2086 bp and contains a 1302 bp open reading frame, which encodes 433 amino acids. MnFOXO consists of five low-complexity regions and a conserved DNA-binding domain (forkhead domain). Evolutionary analyses indicate that MnFOXO proteins cluster with FOXO proteins from crustaceans. Tissue distribution analysis showed that MnFOXO was expressed in all detected tissues, with relatively higher expression levels in the intestine, eyestalks, stomach, and hemocytes than in the hepatopancreas, gills, and heart. The expression levels of MnFOXO in the hepatopancreas and intestine were significantly up-regulated in M. nipponense infected with white spot syndrome virus (WSSV) at 24 and 48 h. Furthermore, knockdown of MnFOXO increased the expression of WSSV envelope protein VP28 during WSSV infection. Further studies showed that knockdown of the MnFOXO gene in M. nipponense inhibited the synthesis of Dicers (MnDicer1, MnDicer2) and Argonautes (MnArgo1, MnArgo2) during WSSV invasion. These findings suggest that MnFOXO positively regulates the expression of Dicers and Argos, and inhibits the expression of VP28. This study provides new evidence for understanding the role of FOXO in antiviral innate immunity in crustaceans.

Differential expression of sNPF in male and female eyestalk leading to sex dimorphism of AMP expression in Procambarus clarkii intestine.

Antimicrobial peptide (AMP) is an important component of crustaceans' innate immune system. In this study, a short neuropeptide F (sNPF) gene (Pc-sNPF) and a Forkhead box O (FOXO) gene (PcFOXO) from Procambarus clarkii were identified. Analysis findings showed that the expression level of AMP genes differed between male and female P. clarkii. Furthermore, Pc-sNPF and PcFOXO were related to the sex dimorphism of AMP. Knockdown of Pc-sNPF in the eyestalk significantly upregulated the expression of PcFOXO and two anti-lipopolysaccharide factors (PcALF4 and PcALFL) in the intestine of P. clarkii. The expression of PcFOXO in the intestine of female P. clarkii was higher than in that of males. Results from RNA interference revealed that PcFOXO positively regulated the expression of PcALF4 and PcALFL in the intestine of male and female P. clarkii. In summary, our study showed that differences in Pc-sNPF expression in eyestalk of male and female P. clarkii leading to sex dimorphism of AMP expression in the intestine are mediated by the sNPF-FOXO-AMP signal pathway called the eyestalk-intestine axis.

Spatial pattern and compositional distribution of organochlorine pesticides in the black soil region of Shenyang.

Organochlorine pesticides (OCPs) are persistent organic pollutants (POPs) prevalent in soils with carcinogenic, teratogenic and mutagenic hazards that are commonly found in soils and remain in the environment even though they have been banned. In order to fill the gap of fewer studies after the ban, soil samples were collected from 308 agricultural fields of cash crops and grain crops in the black soil area of Shenyang City (Liaozhong District, Faku County, Xinmin City and Kangping County) in this study. The aim was to determine, the use and distribution characteristics of OCPs in agricultural soils in the black soil region of Shenyang City. Compositional analysis showed that the detection rate of banned OCPs in agricultural soils was 71.75%, including contaminants such as technical dichloro-diphenyl-trichloroethane (DDT), chlordane and hexachlorobenzene (HCB), which were widely distributed in Liaozhong District, Faku County, Xinmin City and Kangping County, with 45.25% of the fields having compounded contamination of OCPs, and several areas were involved in the fresh inputs of contaminants such as technical DDT. Among them, Kangping County and Faku County are more seriously polluted, with 66.29% and 60.71% of OCPs exceeding the standard. Soil OCPs is more serious in cabbage and rice farmland among cash and food crop farmland. Based on Chinese policy on control, prevention and other pesticide management measures, it was concluded that the framework should be strengthened to prevent further illegal use of banned OCPs.

Team-Based Approach to Reduce Malignancies in People with Diabetes and Obesity.

PURPOSE OF REVIEW: Numerous observations have indicated an increased risk of developing various types of cancers, as well as cancer-related mortality, among patients with diabetes and obesity. The purpose of this review is to outline multiple-cancer screening among these patients through a team-based approach and to present the findings of a pioneering integrated care program designed for patients with obesity with a specific emphasis on cancer prevention. RECENT FINDINGS: A community-based multi-cancer prevention program, which provides all services in one location and utilizes team-based approaches, is reported to be feasible and has the potential to enhance the uptake rate of multiple cancers screening among patients with diabetes and obesity. The team-based approach is a commonly utilized method for managing patients with diabetes, obesity, and cancer, and has been shown to be efficacious. Nevertheless, research on team-based cancer screening programs for patients with diabetes and obesity remains limited. Providing a comprehensive screening for colorectal, prostate, and breast cancer, as well as metabolic syndrome, during a single clinic visit has been proven effective and well-received by participants.

Meta-analysis of microbial source tracking for the identification of fecal contamination in aquatic environments based on data-mining.

Microbial source tracking (MST) technology represents an innovative approach employed to trace fecal contamination in environmental water systems. The performance of primers may be affected by amplification techniques, target primer categories, and regional differences. To investigate the influence of these factors on primer recognition performance, a meta-analysis was conducted on the application of MST in water environments using three databases: Web of Science, Scopus, and PubMed (n = 2291). After data screening, 46 studies were included in the final analysis. The investigation encompassed Polymerase Chain Reaction (PCR)/quantitative PCR (qPCR) methodologies, dye-based (SYBR)/probe-based (TaqMan) techniques, and geographical differences of a human host-specific (HF183) primer and other 21 additional primers. The results indicated that the primers analyzed were capable of differentiating host specificity to a certain degree. Nonetheless, by comparing sensitivity and specificity outcomes, it was observed that virus-based primers exhibited superior specificity and recognition capacity, as well as a stronger correlation with human pathogenicity in water environments compared to bacteria-based primers. This finding highlights an important direction for future advancements. Moreover, within the same category, qPCR did not demonstrate significant benefits over conventional PCR amplification methods. In comparing dye-based and probe-based techniques, it was revealed that the probe-based method's advantage lay primarily in specificity, which may be associated with the increased propensity of dye-based methods to produce false positives. Furthermore, the heterogeneity of the HF183 primer was not detected in China, Canada, and Singapore respectively, indicating a low likelihood of regional differences. The variation among the 21 other primers may be attributable to regional differences, sample sources, detection techniques, or alternative factors. Finally, we identified that economic factors, climatic conditions, and geographical distribution significantly influence primer performance.

First principles study on modulating electronic and optical properties with h-BN intercalation in AlN/MoS2heterostructure.

The van der Waals (vdW) heterostructures formed by stacking layered two-dimensional materials can improve the performance of materials and provide more applications. In our paper, six configurations of AlN/MoS2vdW heterostructures were constructed, the most stable structure was obtained by calculating the binding energy. On this basis, the effect of external vertical strain on AlN/MoS2heterostructure was analyzed, the calculated results show that the optimal interlayer distance was 3.593 Å and the band structure was modulated. Then the h-BN intercalation was inserted into the AlN/MoS2heterostructure, by fixing the distance between h-BN and AlN or MoS2, two kinds of models were obtained. Furthermore, the electronic properties of AlN/MoS2heterostructure can be regulated by adding h-BN intercalation layer and adjusting its position. Finally, the optical properties show that the absorption coefficient of AlN/MoS2heterostructure exhibits enhancement characteristic compared with that of the individual monolayers. Meantime, compared with AlN/MoS2, the AlN/h-BN/MoS2shows a redshift effect and the light absorption peak intensity increased, which indicated that h-BN intercalation layer can be used to regulate the electronic and optical properties of AlN/MoS2heterostructure.

A General Protocol for C-H Difluoromethylation of Carbon Acids with TMSCF2 Br.

An efficient method for the selective C-difluoromethylation of carbon acids with the reagent TMSCF2 Br has been developed. A variety of structurally diverse sp3 - and sp-hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, ß-ketoesters, malonates, and other activated C-H nucleophiles, could be efficiently and selectively transformed into the corresponding C-difluoromethylated products under mild conditions. This protocol is also effective for the late-stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF2 Br.

From C1 to C2 : TMSCF3 as a Precursor for Pentafluoroethylation.

A highly efficient copper-mediated aromatic pentafluoroethylation method using TMSCF3 as the sole fluoroalkyl source is described. The reaction proceeds by a key C1 to C2 process, that is, the generation of CuCF3 from TMSCF3 , followed by a subsequent spontaneous transformation into CuC2 F5 . Various aryl iodides were pentafluoroethylated with the TMSCF3 -derived CuC2 F5 . This method represents the first practical and efficient method for pentafluoroethylation of aryl iodides using commercially available TMSCF3 as a pentafluoroethyl precursor.

A dual-gene reporter-amplifier architecture for enhancing the sensitivity of molecular MRI by water exchange.

The development of genetic reporters for magnetic resonance imaging (MRI) is essential for investigating biological functions in intact animals. However, current MRI reporters have low sensitivity, making it challenging to create significant contrast against the tissue background, especially when only a small percentage of cells express the reporter. To overcome this limitation, we developed an approach that amplifies signals by co-expressing an MRI reporter gene, Oatp1b3, with a water channel, aquaporin-1 (Aqp1). We first show that the expression of Aqp1 amplifies the paramagnetic relaxation effect of Oatp1b3 by facilitating transmembrane water exchange. This mechanism provides Oatp1b3-expressing cells with access to a larger water pool compared with typical exchange-limited conditions. We further demonstrated that our methodology allows dual-labeled cells to be detected using approximately 10-fold lower concentrations of contrast agent than that in the Aqp1-free scenario. Finally, we show that our approach enables the imaging of mixed-cell populations containing a low fraction of Oatp1b3-labeled cells that are otherwise undetectable based on Oatp1b3 expression alone.

LLM-Enhanced multimodal detection of fake news.

Fake news detection is growing in importance as a key topic in the information age. However, most current methods rely on pre-trained small language models (SLMs), which face significant limitations in processing news content that requires specialized knowledge, thereby constraining the efficiency of fake news detection. To address these limitations, we propose the FND-LLM Framework, which effectively combines SLMs and LLMs to enhance their complementary strengths and explore the capabilities of LLMs in multimodal fake news detection. The FND-LLM framework integrates the textual feature branch, the visual semantic branch, the visual tampering branch, the co-attention network, the cross-modal feature branch and the large language model branch. The textual feature branch and visual semantic branch are responsible for extracting the textual and visual information of the news content, respectively, while the co-attention network is used to refine the interrelationship between the textual and visual information. The visual tampering branch is responsible for extracting news image tampering features. The cross-modal feature branch enhances inter-modal complementarity through the CLIP model, while the large language model branch utilizes the inference capability of LLMs to provide auxiliary explanation for the detection process. Our experimental results indicate that the FND-LLM framework outperforms existing models, achieving improvements of 0.7%, 6.8% and 1.3% improvements in overall accuracy on Weibo, Gossipcop, and Politifact, respectively.

Mono- and Difluoromethylation of 3(2H)-Pyridazinones.

A method for direct N-monofluoromethylation of pyridazinones with S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium triflate is disclosed. A method for the N- and O-difluoromethylated pyridazinones with TMSCF2Br as the only promising difluorocarbene precursor is also reported. Substrates with various relevant functional groups, including analogues of Lynparza, are tolerated under both methods.

Baicalin suppresses macrophage JNK-mediated adipose tissue inflammation to mitigate insulin resistance in obesity.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix scutellariae (the root of Scutellaria baicalensis Georgi) is a traditional Chinese medicine (TCM) used to treat a wide range of inflammation-related diseases, such as obesity, diabetes, diabetic kidney disease, and COVID-19-associated inflammatory states in the lung and kidney. Baicalin is the major anti-inflammatory component of Radix scutellariae and has shown the potential to inhibit inflammation in metabolic disorders. In this study, we explored the ability and underlying mechanisms of baicalin to modulate the macrophage to mitigate insulin resistance in obesity. MATERIALS AND METHODS: Obese mice were administered baicalin (50 mg/kg/day) intraperitoneally for 3 weeks. RAW264.7 and BMDM cells were stimulated with LPS and treated with baicalin for 24 h, while 3T3-L1 and primary white adipocytes were treated with the supernatants from baicalin-treated RAW264.7 cells for 24 h. RESULTS: The results showed that baicalin significantly improved glucose and insulin tolerance as well as decreased fat and adipose tissue macrophage levels in obese mice. Besides, baicalin significantly reduced serum and adipose tissue IL-1ß, TNF-α and IL-6 levels in obese mice, as well as suppressed LPS-induced IL-1ß, TNF-α and IL-6 expression and release in macrophages. Furthermore, treatment with the supernatant from baicalin-treated RAW264.7 cells increased the levels of PGC-1α, SIRT1, p-IRS-1 and p-AKT in adipocytes. Moreover, baicalin treatment dramatically downregulated macrophage p-p38, p-JNK, and Ac-p65Lys310 levels while increasing SIRT1 both in vivo and in vitro. Importantly, JNK inhibitor SP600125 blocked most of the effects of baicalin on SIRT1, Ac-p65Lys310 and pro-inflammatory factors in macrophages. CONCLUSION: Therefore, these results demonstrated for the first time that baicalin exerts its anti-inflammatory effects in obese adipose tissue macrophages mainly through suppressing JNK/SIRT1/p65 signaling. These findings amplified the mechanisms of baicalin and its potential to attenuate insulin resistance.

Lectin diversity and their positive roles in WSSV replication through regulation of calreticulin expression and inhibiting ALFs expression.

In biological evolution, gene duplication (GD) generates new genes to facilitate new functions. C-type lectins (CTLs) in crayfish have been extended by GD to expand their family members. In this study, four CTL genes generated by GD were identified from Procambarus clarkii (PcLec1-4). Among these four genes, PcLec1 can also generate new isoforms with different numbers of tandem repeats through DNA slip mispairing. PcLec1-4 was widely expressed in multiple tissues. The expression levels of PcLec1-4 were upregulated in the intestine of P. clarkii upon white spot syndrome virus (WSSV) challenge at multiple time points. Further analysis indicated that GATA transcription factor regulated PcLec1-4 expression. RNA interference and recombinant PcLec1-4 protein injection experiments suggested that PcLec1-4 promoted the expression of calreticulin (PcCRT) and negatively regulated the expression of antimicrobial peptides, thereby promoting WSSV replication. This study contributes to the understanding of the function of CTLs produced by GD during WSSV invasion in crustaceans.

Electroacupuncture Promotes Functional Recovery after Facial Nerve Injury in Rats by Regulating Autophagy via GDNF and PI3K/mTOR Signaling Pathway.

OBJECTIVE: To explore the mechanism of electroacupuncture (EA) in promoting recovery of the facial function with the involvement of autophagy, glial cell line-derived neurotrophic factor (GDNF), and phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway. METHODS: Seventy-two male Sprague-Dawley rats were randomly allocated into the control, sham-operated, facial nerve injury (FNI), EA, EA+3-methyladenine (3-MA), and EA+GDNF antagonist groups using a random number table, with 12 rats in each group. An FNI rat model was established with facial nerve crushing method. EA intervention was conducted at Dicang (ST 4), Jiache (ST 6), Yifeng (SJ 17), and Hegu (LI 4) acupoints for 2 weeks. The Simone's 10-Point Scale was utilized to monitor the recovery of facial function. The histopathological evaluation of facial nerves was performed using hematoxylin-eosin (HE) staining. The levels of Beclin-1, light chain 3 (LC3), and P62 were detected by immunohistochemistry (IHC), immunofluorescence, and reverse transcription-polymerase chain reaction, respectively. Additionally, IHC was also used to detect the levels of GDNF, Rai, PI3K, and mTOR. RESULTS: The facial functional scores were significantly increased in the EA group than the FNI group (P<0.05 or P<0.01). HE staining showed nerve axons and myelin sheaths, which were destroyed immediately after the injury, were recovered with EA treatment. The expressions of Beclin-1 and LC3 were significantly elevated and the expression of P62 was markedly reduced in FNI rats (P<0.01); however, EA treatment reversed these abnormal changes (P<0.01). Meanwhile, EA stimulation significantly increased the levels of GDNF, Rai, PI3K, and mTOR (P<0.01). After exogenous administration with autophagy inhibitor 3-MA or GDNF antagonist, the repair effect of EA on facial function was attenuated (P<0.05 or P<0.01). CONCLUSIONS: EA could promote the recovery of facial function and repair the facial nerve damages in a rat model of FNI. EA may exert this neuroreparative effect through mediating the release of GDNF, activating the PI3K/mTOR signaling pathway, and further regulating the autophagy of facial nerves.

High-Performance Wearable Organic Photodetectors by Molecular Design and Green Solvent Processing for Pulse Oximetry and Photoplethysmography.

White-light detection from the visible to the near-infrared region is central to many applications such as high-speed cameras, autonomous vehicles, and wearable electronics. While organic photodetectors (OPDs) are being developed for such applications, several challenges must be overcome to produce scalable high-detectivity OPDs. This includes issues associated with low responsivity, narrow absorption range, and environmentally friendly device fabrication. Here, an OPD system processed from 2-methyltetrahydrofuran (2-MeTHF) sets a record in light detectivity, which is also comparable with commercially available silicon-based photodiodes is reported. The newly designed OPD is employed in wearable devices to monitor heart rate and blood oxygen saturation using a flexible OPD-based finger pulse oximeter. In achieving this, a framework for a detailed understanding of the structure-processing-property relationship in these OPDs is also developed. The bulk heterojunction (BHJ) thin films processed from 2-MeTHF are characterized at different length scales with advanced techniques. The BHJ morphology exhibits optimal intermixing and phase separation of donor and acceptor moieties, which facilitates the charge generation and collection process. Benefitting from high charge carrier mobilities and a low shunt leakage current, the newly developed OPD exhibits a specific detectivity of above 1012  Jones over 400-900 nm, which is higher than those of reference devices processed from chlorobenzene and ortho-xylene.

Co-Salient Object Detection With Co-Representation Purification.

Co-salient object detection (Co-SOD) aims at discovering the common objects in a group of relevant images. Mining a co-representation is essential for locating co-salient objects. Unfortunately, the current Co-SOD method does not pay enough attention that the information not related to the co-salient object is included in the co-representation. Such irrelevant information in the co-representation interferes with its locating of co-salient objects. In this paper, we propose a Co-Representation Purification (CoRP) method aiming at searching noise-free co-representation. We search a few pixel-wise embeddings probably belonging to co-salient regions. These embeddings constitute our co-representation and guide our prediction. For obtaining purer co-representation, we use the prediction to iteratively reduce irrelevant embeddings in our co-representation. Experiments on three datasets demonstrate that our CoRP achieves state-of-the-art performances on the benchmark datasets. Our source code is available at https://github.com/ZZY816/CoRP.