Diagnostic Utility of a 90-Gene Expression Assay (Canhelp-Origin) for Patients with Metastatic Cancer with an Unclear or Unknown Diagnosis.

BACKGROUND: Metastatic cancers with unclear or unknown origins pose significant challenges in diagnosis and management, frequently leading to suboptimal outcomes. Studies have demonstrated that a 90-gene expression assay is effective in predicting the primary origin and guiding the site-specific therapy to improve prognosis. This study aimed to evaluate the clinical effectiveness of a 90-gene expression assay in patients with unclear or unknown diagnoses. METHODS: The study encompassed patients for whom a 90-gene expression assay was requested as part of standard care. Data on patient demographics, tumor characteristics, and clinical history were collected. The assay's performance was evaluated by comparing its predicted tumor type with the final histopathological diagnosis. RESULTS: Among 303 cases analyzed, a 90-gene expression assay successfully identified a molecular-based tumor type for 295 (97.4%) patients. Comparison with histopathological diagnosis revealed an overall agreement of 88.5% (170/192). In patients with a single suspected primary site (n = 140), the assay confirmed the suspected diagnosis in 90.7% of cases. For those with a differential diagnosis (n = 52), the assay narrowed down the possibilities in 82.7% of cases. Moreover, in cases where the histopathology report indicated cancer of unknown primary (n = 103), the assay offered a molecular tumor type prediction with potential clinical significance. CONCLUSIONS: This study demonstrates the significant impact of a 90-gene expression assay on diagnosis and potential treatment selection for difficult-to-diagnose patients, highlighting its clinical value as a standardized molecular approach to streamline further diagnostic testing for patients with metastatic cancer of unclear or unknown origin. Further prospective study is required to assess whether employing molecular diagnostic classifiers enhances clinical outcomes in these patients.

Altitude characteristics in the response of rain-on-snow flood risk to future climate change in a high-latitude water tower.

Global warming is profoundly impacting snowmelt runoff processes in seasonal freeze-thaw zones, thereby altering the risk of rain-on-snow (ROS) floods. These changes not only affect the frequency of floods but also alter the allocation of water resources, which has implications for agriculture and other key economic sectors. While these risks present a significant threat to our lives and economies, the risk of ROS floods triggered by climate change has not received the attention it deserves. Therefore, we chose Changbai Mountain, a water tower in a high-latitude cold zone, as a typical study area. The semi-distributed hydrological model SWAT is coupled with CMIP6 meteorological data, and four shared socioeconomic pathways (SSP126, SSP245, SSP370, and SSP585) are selected after bias correction, thus quantifying the impacts of climate change on hydrological processes in the Changbai Mountain region as well as future evolution of the ROS flood risk. The results indicate that: (1) Under future climate change scenarios, snowmelt in most areas of the Changbai Mountains decreases. The annual average snowmelt under SSP126, SSP245, SSP370, and SSP585 is projected to be 148.65 mm, 135.63 mm, 123.44 mm, and 116.5 mm, respectively. The onset of snowmelt is projected to advance in the future. Specifically, in the Songhua River (SR) and Yalu River (YR) regions, the start of snowmelt is expected to advance by 1-11 days. Spatially, significant reductions in snowmelt were observed in both the central part of the watershed and the lower reaches of the river under SSP585 scenario. (2) In 2021-2060, the frequency of ROS floods decreases sequentially for different scenarios, with SSP 126 > SSP 245 > SSP 370 > SSP 585. The frequency increments of ROS floods in the source area for the four scenarios were 0.12 days/year, 0.1 d/yr, 0.13 days/year, and 0.15 days/year, respectively. The frequency of high-elevation ROS events increases in the YR in the low emission scenario. Conversely, in high emission scenarios, YR high-elevation ROS events will only increase in 2061-2100. This phenomenon is more pronounced in the Tumen River (TR), where floods become more frequent with increasing elevation.

Diversity and Composition of Fungicolous Fungi Residing in Macrofungi from the Qinling Mountains.

Sporocarps of macrofungi support other diverse fungal species that are termed fungicolous fungi. However, the external environmental factors that affect the diversity and composition of fungicolous fungal communities remains largely unknown. In this study, the diversities, composition, and trophic modes of fungicolous fungal communities residing in host macrofungi from diverse habitats in the Qinling Mountains were analyzed. Additionally, the number of carbohydrate-active enzymes (CAZymes) encoded by saprophytic, pathogenic, and symbiotic fungi was also quantified and compared. The results revealed that the diversity and composition of fungicolous fungal communities varied with months of collection and the habitats of host fungi, and saprophytic fungi were more abundant on wood than on the ground. Meanwhile, it was also found that saprophytic fungi possessed higher abundances of cell-wall-degrading enzymes than pathogenic or symbiotic fungi. Based on the above findings, it was hypothesized that the greater abundance of saprophytic fungi on wood compared to the ground may be due to their possession of a more diverse array of enzymes capable of degrading wood cell walls, thereby allowing for more efficient nutrient acquisition from decaying wood.

Chronic polystyrene microplastics exposure-induced changes in thick-shell mussel (Mytilus coruscus) metaorganism: A holistic perspective.

Microplastics have emerged as a significant global concern, particularly in marine ecosystems. While extensive research has focused on the toxicological effects of microplastics on marine animals and/or their associated microorganisms as two separate entities, the holistic perspective of the adaptability and fitness of a marine animal metaorganism-comprising the animal host and its microbiome-remains largely unexplored. In this study, mussel metaorganisms subjected chronic PS-MPs exposure experienced acute mortality but rapidly adapted. We investigated the response of innate immunity, digestive enzymes and their associated microbiomes to chronic PS-MPs exposure. We found that PS-MPs directly and indirectly interacted with the host and microbe within the exposure system. The adaptation was a joint effort between the physiological adjustments of mussel host and genetic adaptation of its microbiome. The mussel hosts exhibited increased antioxidant activity, denser gill filaments and increased immune cells, enhancing their innate immunity. Concurrently, the gill microbiome and the digestive gland microbiome respective selectively enriched for plastic-degrading bacteria and particulate organic matter-utilizing bacteria, facilitating the microbiome's adaptation. The microbial adaptation to chronic PS-MPs exposure altered the ecological roles of mussel microbiome, as evidenced by alterations in microbial interactions and nutrient cycling functions. These findings provided new insights into the ecotoxicological impact of microplastics on marine organisms from a metaorganism perspective.

Mechanisms for carbon stock driving and scenario modeling in typical mountainous watersheds of northeastern China.

Watershed ecosystems play a pivotal role in maintaining the global carbon cycle and reducing global warming by serving as vital carbon reservoirs for sustainable ecosystem management. In this study, we based on the "quantity-mechanism-scenario" frameworks, integrate the MCE-CA-Markov and InVEST models to evaluate the spatiotemporal variations of carbon stocks in mid- to high-latitude alpine watersheds in China under historical and future climate scenarios. Additionally, the study employs the Geographic Detector model to explore the driving mechanisms influencing the carbon storage capacity of watershed ecosystems. The results showed that the carbon stock of the watershed increased by about 15.9 Tg from 1980 to 2020. Fractional Vegetation Cover (FVC), Digital Elevation Model (DEM), and Mean Annual Temperature (MAT) had the strongest explanatory power for carbon stocks. Under different climate scenarios, it was found that the SSP2-4.5 scenario had a significant rise in carbon stock from 2020 to 2050, roughly 24.1 Tg. This increase was primarily observed in the southeastern region of the watersheds, with forest and grassland effectively protected. Conversely, according to the SSP5-8.5 scenario, the carbon stock would decrease by about 50.53 Tg with the expansion of cultivated and construction land in the watershed's southwest part. Therefore, given the vulnerability of mid- to high-latitude mountain watersheds, global warming trends continue to pose a greater threat to carbon sequestration in watersheds. Our findings carry important implications for tackling potential ecological threats in mid- to high-latitude watersheds in the Northern Hemisphere and assisting policymakers in creating carbon sequestration plans, as well as for reducing climate change.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Recent advances in living cell nucleic acid probes based on nanomaterials for early cancer diagnosis.

The early diagnosis of cancer is vital for effective treatment and improved prognosis. Tumor biomarkers, which can be used for the early diagnosis, treatment, and prognostic evaluation of cancer, have emerged as a topic of intense research interest in recent years. Nucleic acid, as a type of tumor biomarker, contains vital genetic information, which is of great significance for the occurrence and development of cancer. Currently, living cell nucleic acid probes, which enable the in situ imaging and dynamic monitoring of nucleic acids, have become a rapidly developing field. This review focuses on living cell nucleic acid probes that can be used for the early diagnosis of tumors. We describe the fundamental design of the probe in terms of three units and focus on the roles of different nanomaterials in probe delivery.

Comprehensive comparison of water quality risk and microbial ecology between new and old cast iron pipe distribution systems.

The effects of cast iron pipe corrosion on water quality risk and microbial ecology in drinking water distribution systems (DWDSs) were investigated. It was found that trihalomethane (THMs) concentration and antibiotic resistance genes (ARGs) increased sharply in the old DWDSs. Under the same residual chlorine concentration conditions, the adenosine triphosphate concentration in the effluent of old DWDSs (Eff-old) was significantly higher than that in the effluent of new DWDSs. Moreover, stronger bioflocculation ability and weaker hydrophobicity coexisted in the extracellular polymeric substances of Eff-old, meanwhile, iron particles could be well inserted into the structure of the biofilms to enhance the mechanical strength and stability of the biofilms, hence enhancing the formation of THMs. Old DWDSs significantly influenced the microbial community of bulk water and triggered stronger microbial antioxidant systems response, resulting in higher ARGs abundance. Corroded cast iron pipes induced a unique interaction system of biofilms, chlorine, and corrosion products. Therefore, as the age of cast iron pipes increases, the fluctuation of water quality and microbial ecology should be paid more attention to maintain the safety of tap water.

Assessing the potential spray drift of a six-rotor unmanned aerial vehicle sprayer using a test bench and airborne drift collectors under low wind velocities: impact of atomization characteristics and application parameters.

BACKGROUND: The unmanned aerial spraying systems (UASS) have gained widespread use for plant protection in recent years. However, spray drift from UASS is a major concern when controlling weeds over large areas and warrants a thorough investigation. This study examined the atomization characteristics of the herbicide florpyrauxifen-benzyl under downwash airflow using a UASS spray test platform. Potential spray drift was assessed using a test bench (TB) and airborne drift collectors (ADCs) in the field under low wind speeds (<1 m s-1). RESULTS: Atomization characteristics were significantly affected by the spray liquid, adjuvant, nozzle type and spray pressure. The addition of an adjuvant reduced the liquid sheet length, improved physicochemical properties and increased droplet size under the downwash airflow field. Drift evaluation in the field using the TB revealed that sediment spray drift predominantly occurred from the middle to the entire length of the device when fine-to-medium droplets were produced after the sprayer passed. ADC assessment found that higher flight altitudes and finer droplets resulted in higher drift values, whereas the addition of an adjuvant and the use of an air-induction nozzle reduced drift <3 m aboveground. CONCLUSION: The combination of using TB in the target area and ADCs in the off-target area as an alternative method to determine residual droplets in the current airflow provided valuable insights into airborne drift assessment for UASS. © 2024 Society of Chemical Industry.

KEMoS: A knowledge-enhanced multi-modal summarizing framework for Chinese online meetings.

The demand for "online meetings" and "collaborative office work" keeps surging recently, producing an abundant amount of relevant data. How to provide participants with accurate and fast summarizing service has attracted extensive attention. Existing meeting summarizing models overlook the utilization of multi-modal information and the information offsetting during summarizing. In this paper, we develop a knowledge-enhanced multi-modal summarizing framework. Firstly, we construct a three-layer multi-modal meeting knowledge graph, including basic, knowledge, and multi-modal layer, to integrate meeting information thoroughly. Then, we raise a topic-based hierarchical clustering approach, which considers information entropy and difference simultaneously, to capture the semantic evolution of meetings. Next, we devise a multi-modal enhanced encoding strategy, including a sentence-level cross-modal encoder, a joint loss function, and a knowledge graph embedding module, to learn the meeting and topic-level presentations. Finally, when generating summaries, we design a topic-enhanced decoding strategy for the Transformer decoder which mitigates semantic offsetting with the aid of topic information. Extensive experiments show that our proposed work consistently outperforms state-of-the-art solutions on the Chinese meeting dataset, where the ROUGE-1, ROUGE-2, and ROUGE-L are 49.98%, 21.03%, and 32.03% respectively.

A bio-based durable reactive flame retardant for cotton fabric based on lentinan.

Cotton fabric has extensive application due to its comfort and breathability. However, the inherent flammability limits its wide application. Durable polysaccharide-based flame retardants with a low impact on the softness of fabrics are rarely reported. In this work, a novel flame retardant ammonium phosphate of lentinan (APLNT) was synthesized and grafted on the surface of cotton fabric. The treated cotton fabric had a high limiting oxygen index (LOI) value of 43.3 % and passed the vertical burning test (VBT) with a 21.1 % weight gain of APLNT. Compared with control cotton, the peak heat release rate and total heat release values of Cotton-APLNT2 decreased by 92.8 % and 50.9 %, respectively. In addition, the cotton fabric still passed the VBT and kept an LOI value of 27.0 % even after 50 laundering cycles, indicating that the fabric can be used for daily needs. More importantly, the treated fabric remains soft. This research provided a new strategy for preparing bio-based durable flame retardant cotton fabrics.

Continuous quality improvement project to reduce the downtime of medical linear accelerators: A case study at Zhejiang Cancer Hospital.

Objective: To analyse and continually improve existing issues in the quality improvement process of medical linear accelerators (LINACs) and enhance the quality control management of LINACs. Methods: Data were collected from eight LINACs (sourced from three manufacturers) at Zhejiang Cancer Hospital using Excel diaries between January 2019 and December 2020. The data description and analysis were performed using the analytic hierarchy process, SPSSAU and Excel software, and mean-time-to-repair (MTTR)/mean-time-between-failure (MTBF) metrics. Continuous quality improvement was executed using the quality control circle (QCC) quality management method. Results: After quality improvement, the risk frequency of 'LINAC down' events decreased by 43.63% and downtime was reduced by 40.45%. The weight of downtime risk improved by 73.69%. The MTTR recovery value increased by 31.90%, and MTBF reliability increased by 2.97 h. The simulation results demonstrated that the proposed quality improvement measures could effectively decrease the frequency and duration of downtimes, consequently extending the normal operational time of LINACs. Conclusion: Transitioning from instant repair to preventative maintenance can enhance the operational efficiency of equipment and yield economic benefits for hospitals. The QCC method and the event risk evaluation model are effective in reducing the downtime of LINACs and improving their quality control management.

CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation.

Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.

Machine learning models reveal the critical role of nighttime systolic blood pressure in predicting functional outcome for acute ischemic stroke after endovascular thrombectomy.

Background: Blood pressure (BP) is a key factor for the clinical outcomes of acute ischemic stroke (AIS) receiving endovascular thrombectomy (EVT). However, the effect of the circadian pattern of BP on functional outcome is unclear. Methods: This multicenter, retrospective, observational study was conducted from 2016 to 2023 at three hospitals in China (ChiCTR2300077202). A total of 407 patients who underwent endovascular thrombectomy (EVT) and continuous 24-h BP monitoring were included. Two hundred forty-one cases from Beijing Hospital were allocated to the development group, while 166 cases from Peking University Shenzhen Hospital and Hainan General Hospital were used for external validation. Postoperative systolic BP (SBP) included daytime SBP, nighttime SBP, and 24-h average SBP. Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), Boruta were used to screen for potential features associated with functional dependence defined as 3-month modified Rankin scale (mRS) score ≥ 3. Nine algorithms were applied for model construction and evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. Results: Three hundred twenty-eight of 407 (80.6%) patients achieved successful recanalization and 182 patients (44.7%) were functional independent. NIHSS at onset, modified cerebral infarction thrombolysis grade, atrial fibrillation, coronary atherosclerotic heart disease, hypertension were identified as prognostic factors by the intersection of three algorithms to construct the baseline model. Compared to daytime SBP and 24-h SBP models, the AUC of baseline + nighttime SBP showed the highest AUC in all algorithms. The XGboost model performed the best among all the algorithms. ROC results showed an AUC of 0.841 in the development set and an AUC of 0.752 in the validation set for the baseline plus nighttime SBP model, with a brier score of 0.198. Conclusion: This study firstly explored the association between circadian BP patterns with functional outcome for AIS. Nighttime SBP may provide more clinical information regarding the prognosis of patients with AIS after EVT.

MedChatZH: A tuning LLM for traditional Chinese medicine consultations.

Generative Large Language Models (LLMs) have achieved significant success in various natural language processing tasks, including Question-Answering (QA) and dialogue systems. However, most models are trained on English data and lack strong generalization in providing answers in Chinese. This limitation is especially evident in specialized domains like traditional Chinese medical QA, where performance suffers due to the absence of fine-tuning and high-quality datasets. To address this, we introduce MedChatZH, a dialogue model optimized for Chinese medical QA based on transformer decoder with LLaMA architecture. Continued pre-training on a curated corpus of Chinese medical books is followed by fine-tuning with a carefully selected medical instruction dataset, resulting in MedChatZH outperforming several Chinese dialogue baselines on a real-world medical dialogue dataset. Our model, code, and dataset are publicly available on GitHub (https://github.com/tyang816/MedChatZH) to encourage further research in traditional Chinese medicine and LLMs.

Recent advances in cotton fabric-based photocatalytic composites for the degradation of organic contaminants.

Cotton is one of the oldest and most widely used natural fibers in the world. It enables a wide range of applications due to its excellent moisture absorption, thermal insulation, heat resistance, and durability. Benefiting from current developments in textile technology and materials science, people are constantly seeking more comfortable, more beautiful and more versatile cotton fabrics. As the second skin of body, clothing not only provides the basic needs of wear but also increases the protection of body against different environmental stimuli. In this article, a comprehensive review is proposed regarding research activities of systematically summarise the development and research of cotton fabric-based photocatalytic composites for the degradation of organic contaminants in the area of self-cleaning, degradation of gaseous contaminants, pathogenic bacteria or viruses, and chemical warfare agents. Specifically, we begin with a brief exposition of the background and significance of cotton fabric-based photocatalytic composites. Next, a systematical review on cotton fabric-based photocatalytic composites is provided according to their mechanisms and advanced applications. Finally, a simple summary and analysis concludes the current limitations and future directions in these composites for the degradation of organic contaminants.

Transperitoneal vs retroperitoneal laparoscopic radical nephrectomy: a double-arm, parallel-group randomized clinical trial.

OBJECTIVE: To compare the outcomes of patients undergoing Retroperitoneal laparoscopic Radical nephrectomy (RLRN) and Transperitoneal laparoscopic Radical nephrectomy (TLRN). METHODS: A total of 120 patients with localized renal cell carcinoma were randomized into either RLRN or TLRN group. Mainly by comparing the patient perioperative related data, surgical specimen integrity, pathological results and tumor results. RESULTS: Each group comprised 60 patients. The two group were equivalent in terms of perioperative and pathological outcomes. The mean integrity score was significantly lower in the RLRN group than TLRN group. With a median follow-up of 36.4 months after the operation, Kaplan-Meier survival analysis showed no significant difference between RLRN and TLRN in overall survival (89.8% vs. 88.5%; P = 0.898), recurrence-free survival (77.9% vs. 87.7%; P = 0.180), and cancer-specific survival (91.4% vs. 98.3%; P = 0.153). In clinical T2 subgroup, the recurrence rate and recurrence-free survival in the RLRN group was significantly worse than that in the TLRN group (43.2% vs. 76.7%, P = 0.046). Univariate and multivariate COX regression analysis showed that RLRN (HR: 3.35; 95%CI: 1.12-10.03; P = 0.030), male (HR: 4.01; 95%CI: 1.07-14.99; P = 0.039) and tumor size (HR: 1.23; 95%CI: 1.01-1.51; P = 0.042) were independent risk factor for recurrence-free survival. CONCLUSIONS: Our study showed that although RLRN versus TLRN had roughly similar efficacy, TLRN outperformed RLRN in terms of surgical specimen integrity. TLRN was also significantly better than RLRN in controlling tumor recurrence for clinical T2 and above cases. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=24400 ), identifier: ChiCTR1800014431, date: 13/01/2018.

A role for the cerebellum in motor-triggered alleviation of anxiety.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.