Predicting potential small molecule-miRNA associations utilizing truncated schatten p-norm.

MicroRNAs (miRNAs) have significant implications in diverse human diseases and have proven to be effectively targeted by small molecules (SMs) for therapeutic interventions. However, current SM-miRNA association prediction models do not adequately capture SM/miRNA similarity. Matrix completion is an effective method for association prediction, but existing models use nuclear norm instead of rank function, which has some drawbacks. Therefore, we proposed a new approach for predicting SM-miRNA associations by utilizing the truncated schatten p-norm (TSPN). First, the SM/miRNA similarity was preprocessed by incorporating the Gaussian interaction profile kernel similarity method. This identified more SM/miRNA similarities and significantly improved the SM-miRNA prediction accuracy. Next, we constructed a heterogeneous SM-miRNA network by combining biological information from three matrices and represented the network with its adjacency matrix. Finally, we constructed the prediction model by minimizing the truncated schatten p-norm of this adjacency matrix and we developed an efficient iterative algorithmic framework to solve the model. In this framework, we also used a weighted singular value shrinkage algorithm to avoid the problem of excessive singular value shrinkage. The truncated schatten p-norm approximates the rank function more closely than the nuclear norm, so the predictions are more accurate. We performed four different cross-validation experiments on two separate datasets, and TSPN outperformed various most advanced methods. In addition, public literature confirms a large number of predictive associations of TSPN in four case studies. Therefore, TSPN is a reliable model for SM-miRNA association prediction.

Multirelational Hypergraph Representation Learning for Predicting circRNA-miRNA Associations.

One of the principal functions of circular RNA (circRNA) is to participate in gene regulation by sponging microRNAs (miRNAs). Using accumulated circRNA-miRNA associations (CMAs) to construct computational models for predicting potential associations provides a crucial tool for accelerating the validation of reliable associations through traditional experiments. Nevertheless, the current prediction models are constrained in their capacity to represent the higher-order relationships of CMAs and thus require further enhancement in terms of their predictive efficacy. In order to address this issue, we propose a new model based on multirelational hypergraph representation learning (MRHRL). This model employs hypergraphs to capture various higher-order relationships among RNAs and aggregates complementary information through a view attention mechanism. Furthermore, MRHRL introduces a hyperedge-level reconstruction task, jointly optimizing the prediction and reconstruction tasks within a unified framework to uncover potential information, thereby enhancing the model's predictive and generalization capabilities. Experiments conducted on three real-world data sets demonstrate that MRHRL achieves satisfactory results in CMAs prediction, significantly outperforming existing prediction models.

5-Hydroxytryptamine Enhances the Pacemaker Activity of Interstitial Cells of Cajal in Mouse Colon.

We examined the localization of the 5-hydroxytryptamine (5-HT) receptor and its effects on mouse colonic interstitial cells of Cajal (ICCs) using electrophysiological techniques. Treatment with 5-HT increased the pacemaker activity in colonic ICCs with depolarization of membrane potentials in a dose-dependent manner. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers blocked pacemaker activity and 5-HT-induced effects. Moreover, an adenylate cyclase inhibitor inhibited 5-HT-induced effects, and cell-permeable 8-bromo-cAMP increased the pacemaker activity. Various agonists of the 5-HT receptor subtype were working in colonic ICCs, including the 5-HT4 receptor. In small intestinal ICCs, 5-HT depolarized the membrane potentials transiently. Adenylate cyclase inhibitors or HCN blockers did not show any influence on 5-HT-induced effects. Anoctamin-1 (ANO1) or T-type Ca2+ channel blockers inhibited the pacemaker activity of colonic ICCs and blocked 5-HT-induced effects. A tyrosine protein kinase inhibitor inhibited pacemaker activity in colonic ICCs under controlled conditions but did not show any influence on 5-HT-induced effects. Among mitogen-activated protein kinase (MAPK) inhibitors, a p38 MAPK inhibitor inhibited 5-HT-induced effects on colonic ICCs. Thus, 5-HT's effect on pacemaker activity in small intestinal and colonic ICCs has excitatory but variable patterns. ANO1, T-type Ca2+, and HCN channels are involved in 5-HT-induced effects, and MAPKs are involved in 5-HT effects in colonic ICCs.

Targeted Delivery of Arctigenin Using Sialic Acid Conjugate-Modified Liposomes for the Treatment of Breast Cancer.

Arctigenin (ATG) is a broad-spectrum antitumor drug with an excellent inhibitory effect on malignant tumors such as breast cancer, glioblastoma, liver cancer, and colon cancer. However, the clinical application of ATG is limited by its poor water solubility and quick hydrolysis in the liver, intestine, and plasma, which might hinder its application. Sialic acid (SA) recognizes selectin receptors overexpressed on the surface of tumor-associated macrophages. In this study, SA was conjugated with octadecylamine (ODA) to prepare SA-ODA, which was employed to prepare SA functionalized nanoliposomes (SA-Lip) to achieve breast cancer targeting. The formulations were finely optimized using the Box-Behnken design to achieve higher ATG loading. The size, ζ potential, entrapment efficiency, drug loading, and release behavior of ATG@SA-Lip were fully investigated in comparison with conventional ATG@Lip. The ATG@SA-Lip displayed more potent cytotoxicity and higher cellular internalization compared to ATG@Sol and ATG@Lip in both MCF7 and 4T1 cells. Notably, ATG@SA-Lip showed the lowest impact on the immune system. Our study demonstrates that SA-Lip has strong potential as a delivery system for the targeted delivery of ATG.

Sub-high amylose maize starch: an ideal substrate to generate starch with lower digestibility by fermentation of Qu.

BACKGROUND: The fermentation of Qu (FQ) is a novel method to modify the properties of starch to expand its application and especially to increase the resistant starch (RS) content. Using waxy maize starch (WMS) as a fermentation substrate can increase the RS content significantly but it may be time consuming and not cost effective due to the almost negligible RS content of WMS. To solve this problem, we hypothesized that sub-high amylose starch (s-HAMS), with an amylose content close to 50% could be an ideal substrate for FQ. RESULTS: The results showed that FQ did not change the shape and the particle size of starch granules, the gelatinization peak (Tp), or the conclusion temperature (Tc), but the slowly digested starch content declined. Rapidly digested starch content fluctuated during FQ and the amylose content decreased within 36 h and then increased. Within 24h, FQ significanlty increased these values: the RS content, relative crystallinity (RC), the ratio of FTIR absorbances at 1047/1022cm-1, the diffraction peak at 19.8° in X-ray diffraction (XRD), and the gelatinization onset temperature (To) increased significantly, within 24 h of FQ. However, after 24 h of fermentation, the RS content, RC, the ratio of FTIR absorbances at 1047/1022 cm-1, and gelatinization enthalpy (ΔH) decreased significantly. CONCLUSION: Sub-high amylose starch is more suitable for FQ to produce low digestibility starch, and the increase in RS may be due to the formation of 'amylose-lipid' complexes (RS5). © 2024 Society of Chemical Industry.

Sulfur, sterol and trehalose metabolism in the deep-sea hydrocarbon seep tubeworm Lamellibrachia luymesi.

BACKGROUND: Lamellibrachia luymesi dominates cold sulfide-hydrocarbon seeps and is known for its ability to consume bacteria for energy. The symbiotic relationship between tubeworms and bacteria with particular adaptations to chemosynthetic environments has received attention. However, metabolic studies have primarily focused on the mechanisms and pathways of the bacterial symbionts, while studies on the animal hosts are limited. RESULTS: Here, we sequenced the transcriptome of L. luymesi and generated a transcriptomic database containing 79,464 transcript sequences. Based on GO and KEGG annotations, we identified transcripts related to sulfur metabolism, sterol biosynthesis, trehalose synthesis, and hydrolysis. Our in-depth analysis identified sulfation pathways in L. luymesi, and sulfate activation might be an important detoxification pathway for promoting sulfur cycling, reducing byproducts of sulfide metabolism, and converting sulfur compounds to sulfur-containing organics, which are essential for symbiotic survival. Moreover, sulfide can serve directly as a sulfur source for cysteine synthesis in L. luymesi. The existence of two pathways for cysteine synthesis might ensure its participation in the formation of proteins, heavy metal detoxification, and the sulfide-binding function of haemoglobin. Furthermore, our data suggested that cold-seep tubeworm is capable of de novo sterol biosynthesis, as well as incorporation and transformation of cycloartenol and lanosterol into unconventional sterols, and the critical enzyme involved in this process might have properties similar to those in the enzymes from plants or fungi. Finally, trehalose synthesis in L. luymesi occurs via the trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP) pathways. The TPP gene has not been identified, whereas the TPS gene encodes a protein harbouring conserved TPS/OtsA and TPP/OtsB domains. The presence of multiple trehalases that catalyse trehalose hydrolysis could indicate the different roles of trehalase in cold-seep tubeworms. CONCLUSIONS: We elucidated several molecular pathways of sulfate activation, cysteine and cholesterol synthesis, and trehalose metabolism. Contrary to the previous analysis, two pathways for cysteine synthesis and the cycloartenol-C-24-methyltransferase gene were identified in animals for the first time. The present study provides new insights into particular adaptations to chemosynthetic environments in L. luymesi and can serve as the basis for future molecular studies on host-symbiont interactions and biological evolution.

Pseudomonas aeruginosa High-Risk Sequence Type 463 Co-Producing KPC-2 and AFM-1 Carbapenemases, China, 2020-2022.

We report the clonal spread and evolution of high-risk Pseudomonas aeruginosa sequence type 463 co-producing KPC-2 and AFM-1 carbapenemases isolated from hospital patients in China during 2020-2022. Those strains pose a substantial public health threat and surveillance and stricter infection-control measures are essential to prevent further infections.

Ultrashort echo time magnetization transfer imaging of knee cartilage and meniscus after long-distance running.

OBJECTIVE: To assess the detection of changes in knee cartilage and meniscus of amateur marathon runners before and after long-distance running using a 3D ultrashort echo time MRI sequence with magnetization transfer preparation (UTE-MT). METHODS: We recruited 23 amateur marathon runners (46 knees) in this prospective cohort study. MRI scans using UTE-MT and UTE-T2* sequences were performed pre-race, 2 days post-race, and 4 weeks post-race. UTE-MT ratio (UTE-MTR) and UTE-T2* were measured for knee cartilage (eight subregions) and meniscus (four subregions). The sequence reproducibility and inter-rater reliability were also investigated. RESULTS: Both the UTE-MTR and UTE-T2* measurements showed good reproducibility and inter-rater reliability. For most subregions of cartilage and meniscus, the UTE-MTR values decreased 2 days post-race and increased after 4 weeks of rest. Conversely, the UTE-T2* values increased 2 days post-race and decreased after 4 weeks. The UTE-MTR values in lateral tibial plateau, central medial femoral condyle, and medial tibial plateau showed a significant decrease at 2 days post-race compared to the other two time points (p < 0.05). By comparison, no significant UTE-T2* changes were found for any cartilage subregions. For meniscus, the UTE-MTR values in medial posterior horn and lateral posterior horn regions at 2 days post-race were significantly lower than those at pre-race and 4 weeks post-race (p < 0.05). By comparison, only the UTE-T2* values in medial posterior horn showed a significant difference. CONCLUSIONS: UTE-MTR is a promising method for the detection of dynamic changes in knee cartilage and meniscus after long-distance running. KEY POINTS: • Long-distance running causes changes in the knee cartilage and meniscus. • UTE-MT monitors dynamic changes of knee cartilage and meniscal non-invasively. • UTE-MT is superior to UTE-T2* in monitoring dynamic changes in knee cartilage and meniscus.

Eligibility for elective surgery in patients recovering from mild COVID-19: A propensity-matched analysis.

OBJECTIVE: To study the timing of surgery after a recent Omicron variant infection, to provide a reference for policymakers, clinicians, and patients. METHODS: This single-center propensity-matched analysis was designed and reported according to the EQUATOR-STROBE guidelines. Patients recovering from COVID-19 infection were divided into three groups based on the period from disappearance of respiratory symptoms to surgery: ≤7 days, 8-14 days, and >14 days groups. Outcome measures included postoperative respiratory complications, vascular thrombosis, myocardial infarction, ischemic stroke, and mortality. RESULTS: Between August 1 and December 31, 2022, 9023 surgical procedures were performed, of which 7490 surgeries met the inclusion criteria. Propensity matching resulted in a final cohort of 227 patients recovered from COVID-19 and 2043 SARS-CoV-2 negative patients. Compared with the SARS-CoV-2 negative group, the incidence of postoperative respiratory complications was significantly higher (15.91% vs. 6.71%, p = 0.028) only in the ≤7 days group. There were no statistically significant differences in the other 30-day outcomes between the SARS-CoV-2 negative and the three COVID-19 recovery groups. CONCLUSIONS: Patients who have recovered from mild COVID-19 may be eligible for elective surgery at least 7 days after recovery, since they do not have an increased risk of postoperative complications or mortality within 30 days.

Effect of adenosine-1 receptor activation on pacemaker activity of interstitial cells of Cajal from mouse colon.

Adenosine plays an important role on gastrointestinal (GI) motility through adenosine receptors. Interstitial cells of Cajal (ICC) are pacemaker cells that regulate GI smooth muscle activity. The functional role and its signal mechanism of adenosine on the pacemaker activity were investigated using whole-cell patch clamp, RT-PCR, and intracellular Ca2+-imaging with ICC from mouse colon. Adenosine depolarized the membrane potentials and increased the pacemaker potential frequency, which was blocked by a selective A1-receptor antagonist, but not A2a-, A2b, or A3-receptor antagonist. A selective A1 receptor agonist represented similar effects as those of adenosine and mRNA transcript of A1-receptor was expressed in ICC. The adenosine-induced effects were blocked by phospholipase C (PLC) and a Ca2+-ATPase inhibitor. Adenosine increased spontaneous intracellular Ca2+ oscillations, as seen fluo4/AM. Both hyperpolarization-activated cyclic nucleotide (HCN) channel inhibitors and adenylate cyclase inhibitors blocked the adenosine-induced effects. And adenosine increased the basal cellular adenylate cyclase activity in colonic ICC. However, adenosine and adenylate cyclase inhibitors did not show any influence on pacemaker activity in small intestinal ICC for a comparison with that of the small intestine. These results suggest adenosine modulates the pacemaker potentials by acting HCN channels- and intracellular Ca2+- dependent mechanisms through A1-receptor. Therefore, adenosine may be a therapeutic target in colonic motility disorders.

Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds.

The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.

Fluorine assembly nanocluster breaks the shackles of immunosuppression to turn the cold tumor hot.

Clinical investigations have shown that a nonimmunogenic "cold" tumor is usually accompanied by few immunopositive cells and more immunosuppressive cells in the tumor microenvironment (TME), which is still the bottleneck of immune activation. Here, a fluorine assembly nanocluster was explored to break the shackles of immunosuppression, reawaken the immune system, and turn the cold tumor "hot." Once under laser irradiation, FS@PMPt produces sufficient reactive oxygen species (ROS) to fracture the ROS-sensitive linker, thus releasing the cisplatin conjugated PMPt to penetrate into the tumors and kill the regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Meanwhile, ROS will induce potent immunogenic cell death (ICD) and further promote the accumulation of dendritic cells (DCs) and T cells, therefore not only increasing the infiltration of immunopositive cells from the outside but also reducing the immunosuppressive cells from the inside to break through the bottleneck of immune activation. The FS@PMPt nanocluster regulates the immune process in TME from negative to positive, from shallow to deep, to turn the cold tumor into a hot tumor and provoke a robust antitumor immune response.

Blind Detection of Broadband Signal Based on Weighted Bi-Directional Feature Pyramid Network.

With the development of wireless technology, signals propagating in space are easy to mix, so blind detection of communication signals has become a very practical and challenging problem. In this paper, we propose a blind detection method for broadband signals based on a weighted bi-directional feature pyramid network (BiFPN). The method can quickly perform detection and automatic modulation identification (AMC) on time-domain aliased signals in broadband data. Firstly, the method performs a time-frequency analysis on the received signals and extracts the normalized time-frequency images and the corresponding labels by short-time Fourier transform (STFT). Secondly, we build a target detection model based on YOLOv5 for time-domain mixed signals in broadband data and learn the features of the time-frequency distribution image dataset of broadband signals, which achieves the purpose of training the model. The main improvements of the algorithm are as follows: (1) a weighted bi-directional feature pyramid network is used to achieve a simple and fast multi-scale feature fusion approach to improve the detection probability; (2) the Efficient-Intersection over Union (EIOU) loss function is introduced to achieve high accuracy signal detection in a low Signal-Noise Ratio (SNR) environment. Finally, the time-frequency images are detected by an improved deep network model to complete the blind detection of time-domain mixed signals. The simulation results show that the method can effectively detect the continuous and burst signals in the broadband communication signal data and identify their modulation types.

Surface Subsidence Monitoring of Mining Areas in Hunan Province Based on Sentinel-1A and DS-InSAR.

Monitoring the surface subsidence in mining areas is conducive to the prevention and control of geological disasters, and the prediction and early warning of accidents. Hunan Province is located in South China. The mineral resource reserves are abundant; however, large and medium-sized mines account for a low proportion of the total, and the concentration of mineral resource distribution is low, meaning that traditional mining monitoring struggles to meet the needs of large-scale monitoring of mining areas in the province. The advantages of Interferometric Synthetic Aperture Radar (InSAR) technology in large-scale deformation monitoring were applied to identify and monitor the surface subsidence of coal mining fields in Hunan Province based on a Sentinel-1A dataset of 86 images taken from 2018 to 2020, and the process of developing surface subsidence was inverted by selecting typical mining areas. The results show that there are 14 places of surface subsidence in the study area, and accidents have occurred in 2 mining areas. In addition, the railway passing through the mining area of Zhouyuan Mountain is affected by the surface subsidence, presenting a potential safety hazard.

Comparing the Efficacy of Multiple Drugs Injection for the Treatment of Hypertrophic Scars and Keloid: A Network Meta-Analysis.

BACKGROUND: There is no consensus regarding the choice of injected drugs for pathological scars. Although the clinical efficacy of different drug treatments was shown in many randomized controlled trials, the efficacies of many drugs are inconsistent. Therefore, this study aimed to determine how different effective drugs are for treating pathological scars. It is anticipated that the study findings may serve as guidelines for plastic surgeons. METHODS: Relevant literature was extracted from the following databases Cochrane Library, Embase, PubMed, Web of Science, CNKI, Weipu, and Wanfang until June 2022, such as randomized clinical trials (RCTs) evaluating different injected drugs for the treatment of pathological scars, including BTA, TAC, 5-Fu, VER, and BLE. RESULTS: This network meta-analysis of 1539 patients from 23 articles revealed that the most effective treatment for a pathological scar was TAC + BTA. The effective rate of TAC + BTA combination therapy was significantly different from that of the BTA, TAC, 5-Fu, VER, and BLM monotherapies. TAC+5-FU was more effective than TAC, 5-FU, VER, or BLM alone, and BTA was more effective than both TAC and 5-Fu. The effectiveness of VER and BLM was the same, but both were better than TAC and 5-Fu. No big differences were found between any of the other local injection therapies. CONCLUSIONS: According to this network meta-analysis, a combination of keloid and hypertrophic scar injection treatment is recommended, especially BTA+TAC. However, this network meta-analysis has some limitations and must be further verified by larger samples and higher quality RCTs. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

A new insight into the biosynthesis, structure, and functionality of waxy maize starch under drought stress.

BACKGROUND: Drought stress (DS) is the main abiotic stress that maize suffers during its whole growth period, and maize is also sensitive to DS. It had been demonstrated that DS could improve the quality of normal maize starch. However, waxy maize, which has special properties, has not been explored in depth, which limits the breeding and cultivation of waxy maize varieties and the application of waxy maize starch. Therefore, in this study, we investigated the effects of DS on the biosynthesis, structure, and functionality of waxy maize starch. RESULTS: The results showed that DS decreased the expression level of SSIIb, SSIIIa, GBSSIIa, SBEI, SBEIIb, ISAII, and PUL, but increased the expression level of SSI and SBEIIa. DS did not change the average chain length of amylopectin, while increased the relative content of fa chains (RCfa ) and decreased the RCfb1 and RCfb3 . Furthermore, DS decreased the amylose content, amorphous lamellar distance da , semi-crystalline repeat distance, and average particle size, whereas it increased the relative crystallinity, crystalline distance dc , the content of rapidly digested starch in the uncooked system and resistant starch content in both the uncooked and cooked system. CONCLUSIONS: For waxy maize, DS could raise the relative expression level of SSI and SBEIIa, thus increasing RCfa . The larger number of RCfa could create steric hindrance, which can lead to producing more resistant starch in waxy maize starch. © 2023 Society of Chemical Industry.

A Novel Aluminum-Based Metal-Organic Framework with Uniform Micropores for Trace BTEX Adsorption.

Metal-organic frameworks (MOFs) are potential porous adsorbents for benzene, toluene, ethylbenzene and xylene (BTEX). A novel MOF, using low toxic aluminum (Al) as the metal, named as ZJU-620(Al), with uniform micropore size of 8.37±0.73 Šand specific surface area of 1347 m2 g-1 , was synthesized. It is constructed by one-dimensional rod-shaped AlO6 clusters, formate ligands and 4,4',4''-(2,4,6-trimethylbenzene-1,3,5-triyl) tribenzoic ligands. ZJU-620(Al) exhibits excellent chemical-thermal stability and adsorption for trace BTEX, e.g., benzene adsorption of 3.80 mmol g-1 at P/P0 =0.01 and 298 K, which is the largest one reported. Using Grand Canonical Monte Carlo simulations and Single-crystal X-ray diffraction analyses, it was observed that the excellent adsorption could be attributed to the high affinity of BTEX molecules in ZJU-620(Al) micropores because the kinetic diameters of BTEX are close up to the pore size of ZJU-620(Al).

Hyperpolarization-activated cyclic nucleotide-gated channels working as pacemaker channels in colonic interstitial cells of Cajal.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels function as pacemaker channels in spontaneously active cells. We studied the existence of HCN channels and their functional roles in the interstitial cells of Cajal (ICC) from the mouse colon using electrophysiological, immunohistochemical and molecular techniques. HCN1 and HCN3 channels were detected in anoctamin-1 (Ca2+ -activated Cl- channel; ANO1)-positive cells within the muscular and myenteric layers in colonic tissues. The mRNA transcripts of HCN1 and HCN3 channels were expressed in ANO1-positive ICC. In the deletion of HCN1 and HCN3 channels in colonic ICC, the pacemaking potential frequency was reduced. Basal cellular adenylate cyclase activity was decreased by adenylate cyclase inhibitor in colonic ICC, whereas cAMP-specific phosphodiesterase inhibitors increased it. 8-Bromo-cyclic AMP and rolipram increased spontaneous intracellular Ca2+ oscillations. In addition, Ca2+ -dependent adenylate cyclase 1 (AC1) mRNA was detected in colonic ICC. Sulprostone, a PGE2 -EP3 agonist, increased the pacemaking potential frequency, maximum rate of rise of resting membrane in pacemaker potentials and basal cellular adenylate cyclase activity in colonic ICC. These results indicate that HCN channels exist in colonic ICC and participate in generating pacemaking potentials. Thus, HCN channels may be therapeutic targets in disturbed colonic motility disorders.

Mechano-bioconjugation Strategy Empowering Fusion Protein Therapeutics with Aggregation Resistance, Prolonged Circulation, and Enhanced Antitumor Efficacy.

Bioconjugation is a powerful protein modification strategy to improve protein properties. Herein, we report mechano-bioconjugation as a novel approach to empower fusion protein therapeutics and demonstrate its utility by a protein heterocatenane (cat-IFN-ABD) containing interferon-α2b (IFN) mechanically interlocked with a consensus albumin-binding domain (ABD). The conjugate was selectively synthesized in cellulo following a cascade of post-translational events using a pair of heterodimerizing p53dim variants and two orthogonal split-intein reactions. The catenane topology was proven by combined techniques of LC-MS, SDS-PAGE, SEC, and controlled proteolytic digestion. Not only did cat-IFN-ABD retain activities comparable to those of the wild-type IFN and ABD, the conjugate also exhibited enhanced aggregation resistance and prolonged circulation time over the simple linear and cyclic fusions. Consequently, cat-IFN-ABD potently inhibited tumor growth in the mouse xenograft model. Therefore, mechano-bioconjugation by catenation accomplishes function integration with additional benefits, providing an alternative pathway for developing advanced protein therapeutics.

Constraining the Symmetron Model with the HUST-2020 Torsion Pendulum Experiment.

The search for dynamically screening the coupling between the scalar field and matter in high-density environment is achievable with the symmetron model. The high-accuracy and short-range gravity experiment is proposed to test the symmetron model. In this Letter, the data of the HUST-2020 torsion pendulum experiment testing the inverse-square law at submillimeter range is analyzed to constrain the symmetron model. The results show that the HUST-2020 experiment is uniquely sensitive to probe the symmetron model with a mass scale of µ=7.2×10^{-3} eV, and the self-coupling parameter λ≲105 is excluded at mass scale M=0.3 TeV. Especially, at the dark energy scale µ=2.4×10^{-3} eV, the constraint at M=1.3 TeV is improved by about 10 times the previous constraints on the torsion pendulum experiment.