High Ductility and Excellent Thermoelectric Performance in Te-Stabilized Cubic Ag2TexS1-x Solid Solutions.

The stabilization at low temperatures of the Ag2S cubic phase could afford the design of high-performance thermoelectric materials with excellent mechanical behavior, enabling them to withstand prolonged vibrations and thermal stress. In this work, we show that the Ag2TexS1-x solid solutions, with Te content within the optimal range 0.20 ≤ x ≤ 0.30, maintain a stable cubic phase across a wide temperature range from 300 to 773 K, thus avoiding the detrimental phase transition from monoclinic to cubic phase observed in Ag2S. Notably, the Ag2TexS1-x (0.20 ≤ x ≤ 0.30) samples showed no fractures during bending tests and displayed superior ductility at room temperature compared to Ag2S, which fractured at a strain of 6.6%. Specifically, the Ag2Te0.20S0.80 sample demonstrated a bending average yield strength of 46.52 MPa at 673 K, significantly higher than that of Ag2S, whose bending average yield strength dropped from 80.15 MPa at 300 K to 12.66 MPa at 673 K. Furthermore, the thermoelectric performance of the Ag2TexS1-x (0.20 ≤ x ≤ 0.30) samples surpassed that of both InSe and pure Ag2S, with the Ag2Te0.30S0.70 sample achieving the highest ZT value of 0.59 at 723 K. These results indicate substantial potential for practical applications due to enhanced durability and thermoelectric performance.

JA/ethylene and NaWRKY6/3 regulated Alternaria resistance depends on ethylene response factor 1B-like in wild tobacco.

Biosynthesis of the phytoalexins scopoletin and scopolin in Nicotiana species is regulated by upstream signals including jasmonate (JA), ethylene (ET) and NaWRKY3 in response to the necrotrophic fungus Alternaria alternata, which causes brown spot disease. However, how these signals are coordinated to regulate these phytoalexins remains unknown. By analyzing RNA sequencing data and RNA interference, we identified NaERF1B-like (NaERF1B-L) as a key player in Nicotiana attenuata during A. alternata infection by regulating the transcripts of Feruloyl-CoA 6'-hydroxylase 1 (NaF6'H1), encoding a key enzyme for scopoletin biosynthesis, and NaVS1-like (NaVS1-L), a putative biosynthetic gene of the phytoalexin solavetivone. We further demonstrated that the synergistic induction of these two genes by JA and ET signaling is mediated by NaERF1B-L. Additionally, we found that the two closely related proteins NaWRKY6 and NaWRKY3 physically interact to enhance NaERF1B-L expression by directly binding and activating the NaERF1B-L promoter. Collectively, our current results demonstrate that NaERF1B-L plays a positive role in resistance to A. alternata by modulating phytoalexins biosynthesis through the integration of JA/ET and NaWRKY6/3 signaling. Our findings reveal a fine-tuned transcriptional regulatory hierarchy mediated by NaERF1B-L for brown spot disease resistance in wild tobacco.

Rational Design of Cu Vacancies and Antisite Defects for Boosting the Thermoelectric Properties of CuGaTe2-Based Compounds.

CuGaTe2-based compounds show great promise in the application for high-temperature thermoelectric power generation; however, its wide bandgap feature poses a great challenge for enhancing thermoelectric performance via structural defects modulation and doping the system. Herein, it is discovered that the presence of GaCu antisite defects in the CuGaTe2 compound promotes the formation of Cu vacancies, and vice versa, which tends to form the charge-neutral structure defects combination with one GaCu antisite defect and two Cu vacancies. The accumulation of Cu vacancies in the structure of the (Cu2Te)x(Ga2Te3)1-x compounds evolves into twins and stacking faults. This in conjunction with GaCu antisite defects intensify the point defects phonon scattering, yielding a dramatic reduction on lattice thermal conductivity from 6.95 W m-1 K-1 for the pristine CuGaTe2 sample to 2.98 W m-1 K-1 for the (Cu2Te)0.45(Ga2Te3)0.55 sample at room temperature. Furthermore, the high concentration of charge-neutral defects combination narrows the band gap and increases the carrier concentration, leading to an improved power factor of 1.58 mW/mK2 at 600 K for the (Cu2Te)0.49(Ga2Te3)0.51 sample, which is 41% higher than for the pristine CuGaTe2 sample. Consequently, the highest ZT value of 0.82 is achieved at 915 K for Cu0.015(Cu2Te)0.48(Ga2Te3)0.52, which represents an enhancement of about 22% over that of the pristine CuGaTe2 compound.

Two-Dimensional-Like Phonons in Three-Dimensional-Structured Rhombohedral GeSe-Based Compounds with Excellent Thermoelectric Performance.

The coupling of charge and phonon transport in solids is a long-standing issue for thermoelectric performance enhancement. Herein, two new narrow-gap semiconductors with the same chemical formula of GeSe0.65Te0.35 (GST) are rationally designed and synthesized: one with a layered hexagonal structure (H-GST) and the other with a non-layered rhombohedral structure (R-GST). Thanks to the three-dimensional (3D) network structure, R-GST possesses a significantly larger weighted mobility than H-GST. Surprisingly, 3D-structured R-GST displays an extremely low lattice thermal conductivity of ∼0.5 W m-1 K-1 at 523 K, which is comparable to that of layered H-GST. The two-dimensional (2D)-like phonon transport in R-GST stems from the unique off-centering Ge atoms that induce ferroelectric instability, yielding soft polar phonons, as demonstrated by the Boson peak detected by the low-temperature specific heat and calculated phonon spectra. Furthermore, 1 mol % doping of Sb is utilized to successfully suppress the undesired phase transition of R-GST toward H-GST at elevated temperatures. Consequently, a peak ZT of 1.1 at 623 K is attained in the rhombohedral Ge0.99Sb0.01Se0.65Te0.35 sample, which is 1 order of magnitude larger than that of GeSe. This work demonstrates the feasibility of exploring high-performance thermoelectric materials with decoupled charge and phonon transport in off-centering compounds.

Targeting the Ophthalmic Diseases Using Extracellular Vesicles 'Exosomes': Current Insights on Their Clinical Approval and Present Trials.

Ophthalmic diseases encompass a diverse range of conditions, each necessitating tailored treatment strategies. In the realm of ophthalmic research and therapeutic interventions, various subtypes of exosomes are being explored for their regenerative, neuroprotective, and anti-inflammatory properties. Exosomes have garnered increasing attention as promising therapeutic vehicles due to their natural role in cell-to-cell communication and targeted delivery capabilities. Derived from cells, these small vesicles facilitate the transportation of numerous molecules between cells, offering advantages such as low immunogenicity, stability, and precise cell targeting. These inherent qualities make exosomes an enticing avenue for advancing treatment options for ophthalmic diseases. While ongoing research and clinical applications continue to evolve, several exosome subtypes have demonstrated potential for addressing various ophthalmic conditions, including glaucoma, age-related macular degeneration, retinal degenerative disorders, and ocular inflammatory conditions.

Alleviation of lipid metabolic dysfunction through regulation of intestinal bacteriophages and bacteria by green tea polyphenols in Ob/Ob mice.

Green tea polyphenols (GTP) have been shown to ameliorate lipid metabolic disorders by regulating intestinal bacteria. Given the significant role of intestinal bacteriophages in shaping the gut microbiota, this study investigates GTP's influence on gut bacteriophage-bacteria interactions and lipid metabolism using metagenomics and metabonomics. The research results indicated that GTP significantly reduced body weight, serum triglycerides, leptin, insulin resistance, interleukin-6, and TNF-α levels while increasing adiponectin in ob/ob mice fed high-fat diet, aiding intestinal repair. GTP improved gut health by decreasing Enterobacter, Siphoviridae and Enterobacteria_phage_sfv, increasing Bifidobacterium and intestinal metabolites SCFA and hippuric acid. Correlation analysis showed negative correlations between Enterobacter sp. 50,588,862 and Enterobacteria_phages, Shigella_phages with 4-hydroxyphenylpyruvate and hippuric acid. Bifidobacterium choerinum and Bifidobacterium sp. AGR2158 were positively correlated with fatty acids and bile acids. In conclusion, GTP reduced fat accumulation and inflammation, enhanced gut barrier function in obese mice, closely associated with changes in the gut bacteriophage community.

FZ-AD005, A Novel DLL3-Targeted Antibody-drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models.

Delta-like ligand 3 (DLL3) is overexpressed in small-cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine (Rova-T) was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with Rova-T. In this study, we developed a novel DLL-3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody FZ-A038 and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of SCLC patients.

Research on Phenolic Content and Its Antioxidant Activities in Fermented Rosa rugosa 'Dianhong' Petals with Brown Sugar.

Fermented Rosa rugosa 'Dianhong' petals with brown sugar, a biologically active food popularized in Dali Prefecture, Northwest Yunnan, China, are rich in bioactive compounds, especially polyphenols, exhibiting strong antioxidant activity. This study evaluated their antioxidant activities, total phenolic contents, and concentrations of polyphenols at different fermentation conditions using different assays: DPPH free-radical scavenging activity, Trolox equivalent antioxidant capacity (TEAC), ferric reducing antioxidant power (FRAP), Folin-Ciocalteu assays, and HPLC-MS/MS and HPLC-DAD methods. The results indicated that fermentation significantly increased (p < 0.05) the antioxidant activity and polyphenol concentration of R. rugosa 'Dianhong'. Furthermore, Saccharomyces rouxii TFR-1 fermentation achieved optimal bioactivity earlier than natural fermentation. Overall, we found that the use of Saccharomyces rouxii (TFR-1) is a more effective strategy for the production of polyphenol-rich fermented R. rugosa 'Dianhong' petals with brown sugar compared to natural fermentation.

A speech fluency brain network derived from gliomas.

The brain network of speech fluency has not yet been investigated via a study with a large and homogenous sample. This study analysed multimodal imaging data from 115 patients with low-grade glioma to explore the brain network of speech fluency. We applied voxel-based lesion-symptom mapping to identify domain-specific regions and white matter pathways associated with speech fluency. Direct cortical stimulation validated the domain-specific regions intra-operatively. We then performed connectivity-behaviour analysis with the aim of identifying connections that significantly correlated with speech fluency. Voxel-based lesion-symptom mapping analysis showed that damage to domain-specific regions (the middle frontal gyrus, the precentral gyrus, the orbital part of inferior frontal gyrus and the insula) and white matter pathways (corticospinal fasciculus, internal capsule, arcuate fasciculus, uncinate fasciculus, frontal aslant tract) are associated with reduced speech fluency. Furthermore, we identified connections emanating from these domain-specific regions that exhibited significant correlations with speech fluency. These findings illuminate the interaction between domain-specific regions and 17 domain-general regions-encompassing the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus and rolandic operculum, superior temporal gyrus, temporal pole, inferior temporal pole, middle cingulate gyrus, supramarginal gyrus, fusiform gyrus, inferior parietal lobe, as well as subcortical structures such as thalamus-implicating their collective role in supporting fluent speech. Our detailed mapping of the speech fluency network offers a strategic foundation for clinicians to safeguard language function during the surgical intervention for brain tumours.

General synthesis of ionic-electronic coupled two-dimensional materials.

Two-dimensional (2D) AMX2 compounds are a family of mixed ionic and electronic conductors (where A is a monovalent metal ion, M is a trivalent metal, and X is a chalcogen) that offer a fascinating platform to explore intrinsic coupled ionic-electronic properties. However, the synthesis of 2D AMX2 compounds remains challenging due to their multielement characteristics and various by-products. Here, we report a separated-precursor-supply chemical vapor deposition strategy to manipulate the chemical reactions and evaporation of precursors, facilitating the successful fabrication of 20 types of 2D AMX2 flakes. Notably, a 10.4 nm-thick AgCrS2 flake shows superionic behavior at room temperature, with an ionic conductivity of 192.8 mS/cm. Room temperature ferroelectricity and reconfigurable positive/negative photovoltaic currents have been observed in CuScS2 flakes. This study not only provides an effective approach for the synthesis of multielement 2D materials with unique properties, but also lays the foundation for the exploration of 2D AMX2 compounds in electronic, optoelectronic, and neuromorphic devices.

Bicontinuous RuO2 nanoreactors for acidic water oxidation.

Improving activity and stability of Ruthenium (Ru)-based catalysts in acidic environments is eager to replace more expensive Iridium (Ir)-based materials as practical anode catalyst for proton-exchange membrane water electrolyzers (PEMWEs). Here, a bicontinuous nanoreactor composed of multiscale defective RuO2 nanomonomers (MD-RuO2-BN) is conceived and confirmed by three-dimensional tomograph reconstruction technology. The unique bicontinuous nanoreactor structure provides abundant active sites and rapid mass transfer capability through a cavity confinement effect. Besides, existing vacancies and grain boundaries endow MD-RuO2-BN with generous low-coordination Ru atoms and weakened Ru-O interaction, inhibiting the oxidation of lattice oxygen and dissolution of high-valence Ru. Consequently, in acidic media, the electron- and micro-structure synchronously optimized MD-RuO2-BN achieves hyper water oxidation activity (196 mV @ 10 mA cm-2) and an ultralow degradation rate of 1.2 mV h-1. A homemade PEMWE using MD-RuO2-BN as anode also conveys high water splitting performance (1.64 V @ 1 A cm-2). Theoretical calculations and in-situ Raman spectra further unveil the electronic structure of MD-RuO2-BN and the mechanism of water oxidation processes, rationalizing the enhanced performance by the synergistic effect of multiscale defects and protected active Ru sites.

A subject-specific unsupervised deep learning method for quantitative susceptibility mapping using implicit neural representation.

Quantitative susceptibility mapping (QSM) is an MRI-based technique that estimates the underlying tissue magnetic susceptibility based on phase signal. Deep learning (DL)-based methods have shown promise in handling the challenging ill-posed inverse problem for QSM reconstruction. However, they require extensive paired training data that are typically unavailable and suffer from generalization problems. Recent model-incorporated DL approaches also overlook the non-local effect of the tissue phase in applying the source-to-field forward model due to patch-based training constraint, resulting in a discrepancy between the prediction and measurement and subsequently suboptimal QSM reconstruction. This study proposes an unsupervised and subject-specific DL method for QSM reconstruction based on implicit neural representation (INR), referred to as INR-QSM. INR has emerged as a powerful framework for learning a high-quality continuous representation of the signal (image) by exploiting its internal information without training labels. In INR-QSM, the desired susceptibility map is represented as a continuous function of the spatial coordinates, parameterized by a fully-connected neural network. The weights are learned by minimizing a loss function that includes a data fidelity term incorporated by the physical model and regularization terms. Additionally, a novel phase compensation strategy is proposed for the first time to account for the non-local effect of tissue phase in data consistency calculation to make the physical model more accurate. Our experiments show that INR-QSM outperforms traditional established QSM reconstruction methods and the compared unsupervised DL method both qualitatively and quantitatively, and is competitive against supervised DL methods under data perturbations.

A novel peptide-drug conjugate for glioma-targeted drug delivery.

The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.

Hematochezia due to rectal invasion by an internal iliac artery aneurysm: A case report.

BACKGROUND: This case report presents the rare occurrence of hematochezia due to an internal iliac artery aneurysm leading to an arterioenteric fistula, expanding the differential diagnosis for gastrointestinal bleeding. It emphasizes the importance of considering vascular origins in cases of atypical hematochezia, particularly in the absence of common gastrointestinal causes, and highlights the role of imaging and multidisciplinary management in diagnosing and treating such unusual presentations. CASE SUMMARY: A 75-year-old man with a history of hypertension presented with 12 d of hematochezia, experiencing bloody stools 7-8 times per day. Initial computed tomography (CT) scans revealed an aneurysmal rupture near the right internal iliac artery with suspected hematoma development. Hemoglobin levels progressively decreased to 7 g/dL. Emergency arterial angiography and iliac artery-covered stent placement were performed, followed by balloon angioplasty. Despite initial stabilization, minor rectal bleeding and abdominal pain persisted, leading to further diagnostic colonoscopy. This identified a neoplasm and potential perforation at the proximal rectum. An exploratory laparotomy confirmed the presence of a hematoma and an aneurysm invading the rectal wall, necessitating partial rectal resection, intestinal anastomosis, and ileostomy. Postoperative recovery was successful, with no further bleeding incidents and normal follow-up CT and colonoscopy results after six months. CONCLUSION: In cases of unusual gastrointestinal bleeding, it is necessary to consider vascular causes for effective diagnosis and intervention.

The Integration of Transcriptome and Metabolome Analyses Provides Insights into the Determinants of the Wood Properties in Toona ciliata.

Toona ciliata, also known as Chinese mahogany, is a high-quality and fast-growing wood species with a high economic value. The wood properties of T. ciliata of different provenances vary significantly. In this study, we conducted comprehensive transcriptome and metabolome analyses of red and non-red T. ciliata wood cores of different provenances to compare their wood properties and explore the differential metabolites and genes that govern the variation in their wood properties. Through combined analyses, three differential genes and two metabolites were identified that are possibly related to lignin synthesis. The lignin content in wood cores from T. ciliata of different provenances shows significant variation following systematic measurement and comparisons. The gene Tci09G002190, one of the three differential genes, was identified as a member of the CAD (Cinnamyl alcohol dehydrogenase) gene family of T. ciliata, which is associated with lignin synthesis. Our data provide insights into the determinants of the wood properties in T. ciliata, providing a solid foundation for research into the subsequent mechanisms of the formation of T. ciliata wood.

The Failure Mechanism of Micro Thermoelectric Devices under the Action of the Temperature Field.

The micro thermoelectric device (m-TED) boasts features such as adjustable volume, straightforward structure, and precise, rapid temperature control, positioning it as the only current solution for managing the temperature of microelectronic systems. It is extensively utilized in 5G optical modules, laser lidars, and infrared detection. Nevertheless, as the size of the m-TED diminishes, the growing proportion of interface damages the device's operational reliability, constraining the advancement of the m-TED. In this study, we used commercially available bismuth telluride materials to construct the m-TED. The device's reliability was tested under various temperatures: -40, 85, 125, and 150 °C. By deconstructing and analyzing the devices that failed during the tests, we discovered that the primary cause of device failure was the degradation of the solder layer. Moreover, we demonstrated that encapsulating the device with polydimethylsiloxane (PDMS) could effectively delay the deterioration of its performance. This study sparks new insights into the service reliability of m-TEDs and paves the way for further optimizing device interface design and enhancing the device manufacturing process.

Electrically Triggered Domain Wall Movement in Cu2Se Semiconductor.

The ion-conductive α-Cu2Se is found to possess antipolar dipoles, and the movement of the domain boundary under the applied voltage causes change of resistance, showing promising application in memristors. However, due to the complex ordering of Cu ions in the α-Cu2Se, there are multiple types of domain wall structure. Here, we show that two typical domain walls in α-Cu2Se can be formed, by controlling the voltage during phase transition from high-temperature cubic ß-Cu2Se to α-Cu2Se. We also show by in situ transmission electron microscopy that the formed [01̅0]/[101̅] domain wall performs a reversible movement under the applied external voltage, while the [010]/[01̅0] domain wall does not move. We further demonstrate that pinning of the [010]/[01̅0] domain wall could be due to the formed dislocations in the interface. This study shows that applying preprocess conditions is important to obtain the designed microstructure and resistive properties of α-Cu2Se.

NaWRKY70 is a key regulator of Nicotiana attenuata resistance to Alternaria alternata through regulation of phytohormones and phytoalexins biosynthesis.

Jasmonate (JA) and abscisic acid (ABA) are two major phytohormones involved in pathogen resistance. However, how their biosynthesis is regulated is not well understood. We silenced NaWRKY70 in wild tobacco Nicotiana attenuata and determined its role in regulating genes involved in the production of JA, ABA and the phytoalexin capsidiol in response to the fungal pathogen Alternaria alternata using techniques including electrophoretic mobility shift, chromatin immunoprecipitation, transient overexpression and virus-induced gene silencing. Silencing NaWRKY70 dramatically reduced both basal and A. alternata-induced jasmonoyl-isoleucine (JA-Ile) and ABA. Further evidence showed that NaWRKY70 directly binds to the W-boxes of the promoters of NaAOS and NaJAR4 (JA biosynthesis), NaNCED1 and NaXD1-like (ABA biosynthesis), and NaMPK4 (ABA signaling) to activate their expression, while binding but repressing the expression of NaCYP707A4-like3 (ABA degradation). Additionally, NaWRKY70 regulates capsidiol production through its key enzyme genes NaEASs and NaEAHs, and interacts with its regulator NaERF2-like to enhance their expression, whereas ABA negatively regulates capsidiol biosynthesis. Our results highlight the key role of NaWRKY70 in controlling both JA-Ile and ABA production, as well as capsidiol production, thus providing new insight into the defense mechanism of plant resistance to A. alternata.

Intrinsic Defect-Driven Synergistic Synaptic Heterostructures for Gate-Free Neuromorphic Phototransistors.

The optoelectronic synaptic devices based on two-dimensional (2D) materials offer great advances for future neuromorphic visual systems with dramatically improved integration density and power efficiency. The effective charge capture and retention are considered as one vital prerequisite to realizing the synaptic memory function. However, the current 2D synaptic devices are predominantly relied on materials with artificially-engineered defects or intricate gate-controlled architectures to realize the charge trapping process. These approaches, unfortunately, suffer from the degradation of pristine materials, rapid device failure, and unnecessary complication of device structures. To address these challenges, an innovative gate-free heterostructure paradigm is introduced herein. The heterostructure presents a distinctive dome-like morphology wherein a defect-rich Fe7S8 core is enveloped snugly by a curved MoS2 dome shell (Fe7S8@MoS2), allowing the realization of effective photocarrier trapping through the intrinsic defects in the adjacent Fe7S8 core. The resultant neuromorphic devices exhibit remarkable light-tunable synaptic behaviors with memory time up to ≈800 s under single optical pulse, thus demonstrating great advances in simulating visual recognition system with significantly improved image recognition efficiency. The emergence of such heterostructures foreshadows a promising trajectory for underpinning future synaptic devices, catalyzing the realization of high-efficiency and intricate visual processing applications.