Lateral Habenula Neurons Signal Cold Aversion and Participate in Cold Aversion.

The aversion to cold is a fundamental motivated behavior that contributes to the body temperature homeostasis. However, the involvement of the lateral habenula (LHb) as a regulatory hub for negative emotions in this physiological process remains uninvestigated. In this study, we demonstrate an elevation in the population activity of LHb neurons following exposure to cold stimuli. Additionally, we establish the necessity of Vglut2-expressing neurons within the LHb for the encoding of cold aversion behaviors. Furthermore, we have elucidated a neural circuit from excitatory neurons of the dorsomedial hypothalamus (DMH) to LHb that plays a crucial role in this progress. Manipulation of the DMH-LHb circuit has a significant impact on cold aversion behavior in mice. It is worth noting that this circuit does not exhibit any noticeable effects on autonomic thermoregulation or depression-like behavior. The identification of these neural mechanisms involved in behavioral thermoregulation provides a promising avenue for future research.

Selectivity of PEG/Salt Aqueous Two-Phase System Enhanced by Surfactant@MWCNT Composites.

Aqueous two-phase systems (ATPS) are considered a new type of green separation system, but their low selectivity to target molecules limits their practical application. In this study, we used surfactant@MWCNT as an adjuvant to improve the selectivity of PEG/(NH4)2SO4 ATPS. The surfactants used include Triton X-100 (TX-100), Tween 80, sodium dodecyl sulfate (SDS), sodium dodecyl benzenesulfonate (SDBS), and bis(2-ethylhexyl)sulfosuccinate sodium salt (AOT). Nine aromatic compounds, including syringic acid, vanillin, tryptophan, phenylalanine, tyrosine, mandelic acid, theophylline, theobromine, and cephalexin, were selected as model extracts. The results showed that the use of the surfactant@MWCNT composite as an adjuvant significantly improved the selectivity of the ATPS toward syringic acid among the nine extracts. Moreover, the selectivity of the ATPS for syringic acid with the TX-100/MWCNT composite as the adjuvant is better than that with the Tween 80/MWCNT composite as the adjuvant, followed by that with the anionic surfactant/MWCNT composite as the adjuvant. The enhanced selectivity of ATPS by the surfactant/MWCNT composite is ascribed to the spatial effect and the electrostatic and hydrophobic interactions between the extract and the surfactant adsorbed on the MWCNT.

Genistein alleviates doxorubicin-induced cardiomyocyte autophagy and apoptosis via ERK/STAT3/c-Myc signaling pathway in rat model.

Doxorubicin (Dox) is a highly effective anti-neoplastic agent. Still, its utility in the clinic has been hindered by toxicities, including vomiting, hematopoietic suppression and nausea, with cardiotoxicity being the most serious side effect. Genistein (Gen) is a natural product with extensive biological effects, including anti-oxidation, anti-tumor, and cardiovascular protection. This study evaluated whether Gen protected the heart from Dox-induced cardiotoxicity and explored the underlying mechanisms. Male Sprague-Dawley (SD) rats were categorized into control (Ctrl), genistein (Gen), doxorubicin (Dox), genistein 20 mg/kg/day + doxorubicin (Gen20 + Dox) and genistein 40 mg/kg/day + doxorubicin (Gen40 + Dox) groups. Six weeks after injection, immunohistochemistry (IHC), transmission electron microscopy (TEM), and clinical cardiac function analyses were performed to evaluate the effects of Dox on cardiac function and structural alterations. Furthermore, each heart histopathological lesions were given a score of 0-3 in compliance with the articles for statistical analysis. In addition, molecular and cellular response of H9c2 cells toward Dox were evaluated through western blotting, Cell Counting Kit-8 (CCK8), AO staining and calcein AM/PI assay. Dox (5 µM in vitro and 18 mg/kg in vivo) was used in this study. In vivo, low-dose Gen pretreatment protected the rat against Dox-induced cardiac dysfunction and pathological remodeling. Gen inhibited extracellular signal-regulated kinase1/2 (ERK1/2)'s phosphorylation, increased the protein levels of STAT3 and c-Myc, and decreased the autophagy and apoptosis of cardiomyocytes. U0126, a MEK1/2 inhibitor, can mimic the effect of Gen in protecting against Dox-induced cytotoxicity both in vivo and in vitro. Molecular docking analysis showed that Gen forms a stable complex with ERK1/2. Gen protected the heart against Dox-induced cardiomyocyte autophagy and apoptosis through the ERK/STAT3/c-Myc signaling pathway.

Photocatalytic synthesis of azaheterocycle-fused piperidines and pyrrolidines via tandem difunctionalization of unactivated alkenes.

A variety of azaheterocycle-fused piperidines and pyrrolidines bearing CF3 and CHF2 functionalities were obtained using CF3SO2Na and CHF2SO2Na by visible light photocatalysis. This protocol involves a radical cascade cyclization via tandem tri- and difluoromethylation-arylation of pendent unactivated alkenes. Benzimidazole, imidazole, theophylline, purine, and indole serve as applicable anchors, thereby enriching the structural diversity of piperidine and pyrrolidine derivatives. This method features mild, additive-free and transition metal-free conditions.

Improved BDS-2/3 Satellite Ultra-Fast Clock Bias Prediction Based with the SSA-ELM Model.

Ultra-fast satellite clock bias (SCB) products play an important role in real-time precise point positioning. Considering the low accuracy of ultra-fast SCB, which is unable to meet the requirements of precise point position, in this paper, we propose a sparrow search algorithm to optimize the extreme learning machine (SSA-ELM) algorithm in order to improve the performance of SCB prediction in the Beidou satellite navigation system (BDS). By using the sparrow search algorithm's strong global search and fast convergence ability, we further improve the prediction accuracy of SCB of the extreme learning machine. This study uses ultra-fast SCB data from the international GNSS monitoring assessment system (iGMAS) to perform experiments. First, the second difference method is used to evaluate the accuracy and stability of the used data, demonstrating that the accuracy between observed data (ISUO) and predicted data (ISUP) of the ultra-fast clock (ISU) products is optimal. Moreover, the accuracy and stability of the new rubidium (Rb-II) clock and hydrogen (PHM) clock onboard BDS-3 are superior to those of BDS-2, and the choice of different reference clocks affects the accuracy of SCB. Then, SSA-ELM, quadratic polynomial (QP), and a grey model (GM) are used for SCB prediction, and the results are compared with ISUP data. The results show that when predicting 3 and 6 h based on 12 h of SCB data, the SSA-ELM model improves the prediction model by ~60.42%, 5.46%, and 57.59% and 72.27%, 44.65%, and 62.96% as compared with the ISUP, QP, and GM models, respectively. When predicting 6 h based on 12 h of SCB data, the SSA-ELM model improves the prediction model by ~53.16% and 52.09% and by 40.66% and 46.38% compared to the QP and GM models, respectively. Finally, multiday data are used for 6 h SCB prediction. The results show that the SSA-ELM model improves the prediction model by more than 25% compared to the ISUP, QP, and GM models. In addition, the prediction accuracy of the BDS-3 satellite is better than that of the BDS-2 satellite.

PRM-D* Method for Mobile Robot Path Planning.

Various navigation tasks involving dynamic scenarios require mobile robots to meet the requirements of a high planning success rate, fast planning, dynamic obstacle avoidance, and shortest path. PRM (probabilistic roadmap method), as one of the classical path planning methods, is characterized by simple principles, probabilistic completeness, fast planning speed, and the formation of asymptotically optimal paths, but has poor performance in dynamic obstacle avoidance. In this study, we use the idea of hierarchical planning to improve the dynamic obstacle avoidance performance of PRM by introducing D* into the network construction and planning process of PRM. To demonstrate the feasibility of the proposed method, we conducted simulation experiments using the proposed PRM-D* (probabilistic roadmap method and D*) method for maps of different complexity and compared the results with those obtained by classical methods such as SPARS2 (improving sparse roadmap spanners). The experiments demonstrate that our method is non-optimal in terms of path length but second only to graph search methods; it outperforms other methods in static planning, with an average planning time of less than 1 s, and in terms of the dynamic planning speed, our method is two orders of magnitude faster than the SPARS2 method, with a single dynamic planning time of less than 0.02 s. Finally, we deployed the proposed PRM-D* algorithm on a real vehicle for experimental validation. The experimental results show that the proposed method was able to perform the navigation task in a real-world scenario.

Novel Bimetallic Activated Center Alloying Mechanism Positive Electrodes for Aluminum Storage.

Aluminum is the most abundant metal element in the Earth's crust, thus developing the rechargeable aluminum-ion batteries (AIBs) provides an ideal opportunity to realize cells with pleasing energy-to-price ratios. However, the further development of AIBs is plagued by the scarcity of suitable positive electrode materials. Here, for the first time, a tin-based alloy positive electrode material for AIBs, Co3 Sn2 wrapped with graphene oxide (Co3 Sn2 @GO composite) is well-designed and investigated to understand the aluminum storage behavior. A series of experimental measurements and theoretical calculations results reveal that a novel "bimetallic activated center alloying reaction" aluminum storage mechanism is occurred on the prepared Co3 Sn2 positive electrode. The reversible alloying/de-alloying process in AlCl3 /[EMIm]Cl ionic liquid, where both Co and Sn in Co3 Sn2 alloys react electrochemically with Al3+ to form Alx Sn and Aly Co is first put forward. This study delineates new insights on the aluminum storage mechanism, which may guide to ultimately exploit the energy benefits of "bimetallic activated center alloying redox".

Concise Synthesis of 1-Thioalkyl Glycoside Donors by Reaction of Per-O-acetylated Sugars with Sodium Alkanethiolates under Solvent-Free Conditions.

A relatively green method for synthesizing 1-thioalkyl glycosides has been developed, where sodium alkanethiolates were used to react with per-O-acetylated sugars instead of odorous alkyl mercaptans in the presence of BF3·Et2O without the use of solvents under mild conditions. Furthermore, we found that 1,2-trans-ß-thioglycosides can be converted into corresponding 1,2-cis-α-thioglycosides in the presence of trifluoromethanesulfonic acid in nonpolar solvents under mild conditions. This provides a simple and efficient new approach for synthesizing challenging 1,2-cis-α-thioglycosides.

The key sulfometuron-methyl degrading bacteria isolation based on soil bacterial phylogenetic molecular ecological networks and application for bioremediation of contaminated soil by immobilization.

The analysis of soil bacterial community has guiding significance for fully utilization of soil microbial resources. The results of high-throughput sequencing (HTS) showed that the bacteria in the three sulfometuron-methyl contaminated soil samples were mainly composed of 677 genera, including Phenylobacterium, Bacillus, belonging to 28 phyla, including Proteobacteria, Firmicutes. The diversity and richness of bacterial community decreased with the increase in sulfometuron-methyl concentration. In addition, sulfometuron-methyl could also affect the soil bacterial function based on PICRUSt functional predictive analysis. Combined with the results of HTS and phylogenetic molecular ecological networks (pMENs), 12 genera, including Ralstonia (Pi=0.64), were identified as the key soil microflora (intra-module connectivity Zi ≥ 2.5 or inter-module connectivity Pi ≥ 0.62), and the abundance of Ralstonia significantly increased with the concentration of sulfometuron-methyl, indicating that the strains of this genus might be the potential degrading bacteria and could form a stable relationship with indigenous microorganisms. Among the isolated bacteria of genus Ralstonia, one strain, named Ralstonia sp. JM-1, was verified to possess higher sulfometuron-methyl degradation efficiency, which completely degraded 20 mg L-1 of sulfometuron-methyl within 96 h. Furthermore, the immobilized strains generated by the mixture of 2.0 g bamboo charcoal and 3.0 mL bacterial suspension for 24 h had the highest sulfometuron-methyl degradation rate than that under other conditions, and the dynamic process degrading 10-30 mg L-1 of sulfometuron-methyl conforms to the zero-order kinetic equation. The bioremediation of contaminated soil showed the immobilized strains could completely degrade sulfometuron-methyl (1.39 mg kg-1) in contaminated soil within 9 d, which is higher than that application of strains in the free state (74.8%). This study could provide ideas for the isolation of functional strains and a theoretical basis for the bioremediation of STM and other contaminated soils.

Study on endocrine disruption effect of paclobutrazol and uniconazole on the thyroid of male and female rats based on lipidomics.

The present study investigated the effects of paclobutrazol and uniconazole on thyroid endocrine system in rats. Lipidomic analysis was performed to obtain the biomarkers of thyroid endocrine disruption induced by paclobutrazol and uniconazole. Network pharmacology was further used to discover potential targets of biomarkers related to drugs and diseases. After paclobutrazol and uniconazole administration, seven and four common biomarkers related to thyroid endocrine disruption for female and male rats were obtained, respectively. Paclobutrazol and uniconazole significantly increased the biomarker levels of PG (12:0/15:0), PS (14:0/16:0), PA (20:1/15:0) and PG (13:0/17:0) in both sexes of rats. Exposure to paclobutrazol additionally caused a significant decrease of PG (22:6/20:2), PE (24:1/18:1) and PE (24:0/18:0) in female rats, while an increase in male rats. Changes of the common biomarkers for paclobutrazol and uniconazole revealed similar endocrine disruption effect, which was higher in the females. Network pharmacology and KEGG pathway analysis indicated that the thyroid endocrine disrupting effects of paclobutrazol and uniconazole may be related to V-akt murine thymoma viral oncogene homolog (Akts), mitogen-activated protein kinase (MAPKs), epidermal growth factor receptor (EGFR), Insulin-like growth factor (IGF-1), IGF-IR and V-Raf murine sarcoma viral oncogene homolog B1 (BRAF). The results demonstrated that paclobutrazol and uniconazole could cause thyroid endocrine disorders in male and female rats, which were sex-specific, thus highlighting the importance of safe and effective application of these plant growth regulators.

Efficient Synthesis of 2-OH Thioglycosides from Glycals Based on the Reduction of Aryl Disulfides by NaBH4.

An improved method to efficiently synthesize 2-OH thioaryl glycosides starting from corresponding per-protected glycals was developed, where 1,2-anhydro sugars were prepared by the oxidation of glycals with oxone, followed by reaction of crude crystalline 1,2-anhydro sugars with NaBH4 and aryl disulfides. This method has been further used in a one-pot reaction to synthesize glycosyl donors having both "armed" and "NGP (neighboring group participation)" effects.

Single core-offset Mach-Zehnder interferometer coated with PVA for simultaneous measurement of relative humidity and temperature.

A single core-offset Mach-Zehnder interferometer (MZI) coated with polyvinyl alcohol (PVA) for simultaneous measurement of relative humidity (RH) and temperature is proposed in this paper. The sensing structure is fabricated by splicing dispersion compensating fiber (DCF) and no-core fiber (NCF) and splicing two single-mode fibers (SMF) at both ends, where the core-offset is located at the splicing of SMF and DCF. A part of the cladding of DCF is etched to excite the high-order cladding mode (LP10), and PVA is coated on the etched area. The refractive index of PVA varies due to the adsorption of water molecules. Therefore, when the ambient relative humidity and temperature change, the change of MZI phase difference causes the wavelength of the resonant dip to shift. The experimental results indicate that the proposed sensor has a sensitivity of 0.256 nm/RH% for RH range of 30%-95%, and a sensitivity of 0.153 nm/℃ for temperature range of 20℃-80℃, respectively. The simultaneous measurement of RH and temperature can be achieved by demodulating the sensitivity coefficient matrix. The proposed sensor has the characteristics of good repeatability, high sensitivity, and good stability, which make it potentially applications for the detection of RH and temperature measurement.

Insights into non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction: Development and perspective.

The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.

Voltage-Gated Sodium Channel ß1 Gene: An Overview.

BACKGROUND: Voltage-gated sodium channels are protein complexes composed of 2 subunits, namely, pore-forming α- and regulatory ß-subunits. A ß-subunit consists of 5 proteins encoded by 4 genes (i.e., SCN1B-SCN4B). SUMMARY: ß1-Subunits regulate sodium ion channel functions, including gating properties, subcellular localization, and kinetics. Key Message: Sodium channel ß1- and its variant ß1B-subunits are encoded by SCN1B. These variants are associated with many human diseases, such as epilepsy, Brugada syndrome, Dravet syndrome, and cancers. On the basis of previous research, we aimed to provide an overview of the structure, expression, and involvement of SCN1B in physiological processes and focused on its role in diseases.

Fabrication and Evaluation of Alginate/Bacterial Cellulose Nanocrystals-Chitosan-Gelatin Composite Scaffolds.

It is common knowledge that pure alginate hydrogel is more likely to have weak mechanical strength, a lack of cell recognition sites, extensive swelling and uncontrolled degradation, and thus be unable to satisfy the demands of the ideal scaffold. To address these problems, we attempted to fabricate alginate/bacterial cellulose nanocrystals-chitosan-gelatin (Alg/BCNs-CS-GT) composite scaffolds using the combined method involving the incorporation of BCNs in the alginate matrix, internal gelation through the hydroxyapatite-d-glucono-δ-lactone (HAP-GDL) complex, and layer-by-layer (LBL) electrostatic assembly of polyelectrolytes. Meanwhile, the effect of various contents of BCNs on the scaffold morphology, porosity, mechanical properties, and swelling and degradation behavior was investigated. The experimental results showed that the fabricated Alg/BCNs-CS-GT composite scaffolds exhibited regular 3D morphologies and well-developed pore structures. With the increase in BCNs content, the pore size of Alg/BCNs-CS-GT composite scaffolds was gradually reduced from 200 µm to 70 µm. Furthermore, BCNs were fully embedded in the alginate matrix through the intermolecular hydrogen bond with alginate. Moreover, the addition of BCNs could effectively control the swelling and biodegradation of the Alg/BCNs-CS-GT composite scaffolds. Furthermore, the in vitro cytotoxicity studies indicated that the porous fiber network of BCNs could fully mimic the extracellular matrix structure, which promoted the adhesion and spreading of MG63 cells and MC3T3-E1 cells on the Alg/BCNs-CS-GT composite scaffolds. In addition, these cells could grow in the 3D-porous structure of composite scaffolds, which exhibited good proliferative viability. Based on the effect of BCNs on the cytocompatibility of composite scaffolds, the optimum BCNs content for the Alg/BCNs-CS-GT composite scaffolds was 0.2% (w/v). On the basis of good merits, such as regular 3D morphology, well-developed pore structure, controlled swelling and biodegradation behavior, and good cytocompatibility, the Alg/BCNs-CS-GT composite scaffolds may exhibit great potential as the ideal scaffold in the bone tissue engineering field.

Structural modifications of indolinones bearing a pyrrole moiety and discovery of a multi-kinase inhibitor with potent antitumor activity.

Structural modifications of compound 2, an angiokinase inhibitor reported by our group were performed, which led to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h). Compound 7h exhibited excellent inhibitory activity against angiokinases including VEGFR-1/2/3, PDGFRα/ß, and FGFR-1, as well as LYN and c-KIT kinases. At the cellular level, compound 7h significantly attenuated phosphorylation of AKT and ERK proteins, potently inhibited colony formation of HT-29, MKN74, and HepG2 cancer cells, and induced cell apoptosis. Upon incubation with human liver microsome, 7h exhibited comparable metabolic stability to nintedanib. Compound 7h has emerged as a promising lead compound for future drug design.

The Role of miR-210 in the Biological System: A Current Overview.

BACKGROUND: MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19-23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. SUMMARY: miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.

Telecentric 3D profilometry based on phase-shifting fringe projection.

Three dimensional shape measurement in the microscopic range becomes increasingly important with the development of micro manufacturing technology. Microscopic fringe projection techniques offer a fast, robust, and full-field measurement for field sizes from approximately 1 mm2 to several cm2. However, the depth of field is very small due to the imaging of non-telecentric microscope, which is often not sufficient to measure the complete depth of a 3D-object. And the calibration of phase-to-depth conversion is complicated which need a precision translation stage and a reference plane. In this paper, we propose a novel telecentric phase-shifting projected fringe profilometry for small and thick objects. Telecentric imaging extends the depth of field approximately to millimeter order, which is much larger than that of microscopy. To avoid the complicated phase-to-depth conversion in microscopic fringe projection, we develop a new system calibration method of camera and projector based on telecentric imaging model. Based on these, a 3D reconstruction of telecentric imaging is presented with stereovision aided by fringe phase maps. Experiments demonstrated the feasibility and high measurement accuracy of the proposed system for thick object.

The clinical, molecular, and therapeutic implications of time from primary diagnosis to brain metastasis in lung and breast cancer patients.

PURPOSE: Lung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM. METHODS: We retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan-Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively. RESULTS: The median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple-negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM. CONCLUSIONS: This single-institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.

Effect of ultrasonic degradation on the physicochemical characteristics, GLP-1 secretion, and antioxidant capacity of Polygonatum cyrtonema polysaccharide.

This study aimed to evaluate the influence of ultrasonic degradation on the physicochemical and biological characteristics of Polygonatum cyrtonema polysaccharide (PCP, 8.59 kDa). PCP was subjected to ultrasonic treatment for 8, 16, and 24 h and yielded the degraded fractions PCP-8, PCP-16, and PCP-24 (5.06, 4.13, and 3.69 kDa), respectively. Compared with the intact PCP, PCP-8, PCP-16 and PCP-24 had a reduced particle size (decrements of 28.03 %, 46.15 % and 62.54 %, respectively). Although ultrasonic degradation did not alter the primary structure of PCP, its triple helical and superficial structures were disrupted, with degraded fractions demonstrating reduced thermal stability and apparent viscosities compared with those of the intact PCP. Furthermore, the functional properties of the degraded fractions were different. PCP-16 most favourably affected GLP-1 secretion, while PCP-8 and PCP-24 exhibited the strongest antioxidant and enzyme inhibitory activities, respectively. Hence, controlled ultrasound irradiation is an appealing approach for partially degrading PCP and enhancing its bioactivity as a functional agent.