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A fundamental problem in the field of protein evolutionary biology is determining the degree and nature of evolutionary relatedness among homologous proteins that have diverged to a point where they share less than 30% amino acid identity yet retain similar structures and/or functions. Such proteins are said to lie within the "Twilight Zone" of amino acid identity. Many researchers have leveraged experimentally determined structures in the quest to classify proteins in the Twilight Zone. Such endeavors can be highly time consuming and prohibitively expensive for large-scale analyses. Motivated by this problem, here we use molecular weight-hydrophobicity physicochemical dynamic time warping (MWHP DTW) to quantify similarity of simulated and real-world homologous protein domains. MWHP DTW is a physicochemical method requiring only the amino acid sequence to quantify similarity of related proteins and is particularly useful in determining similarity within the Twilight Zone due to its resilience to primary sequence substitution saturation. This is a step forward in determination of the relatedness among Twilight Zone proteins and most notably allows for the discrimination of random similarity and true homology in the 0%-20% identity range. This method was previously presented expeditiously just after the outbreak of COVID-19 because it was able to functionally cluster ACE2-binding betacoronavirus receptor binding domains (RBDs), a task that has been elusive using standard techniques. Here we show that one reason that MWHP DTW is an effective technique for comparisons within the Twilight Zone is because it can uncover hidden homology by exploiting physicochemical conservation, a problem that protein sequence alignment algorithms are inherently incapable of addressing within the Twilight Zone. Further, we present an extended definition of the Twilight Zone that incorporates the dynamic relationship between structural, physicochemical, and sequence-based metrics.

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Coastal areas conservation strategies often left deeper habitats, such as mesophotic ones, unprotected and exposed to anthropogenic activities. In this context, an approach for including the mesophotic zone inside protection plans is proposed, considering 27 Italian Marine Protected Areas (MPAs) as a model. MPAs were classified considering their bathymetries, exposure to marine heat waves (MHWs), mass mortality events (MMEs) and, using a local ecological knowledge (LEK) approach, the estimated resilience of certain sessile species after MMEs. Only 8 MPAs contained considerable mesophotic areas, with stronger MHWs mainly occurring in shallower MPAs, and MMEs mostly affecting coralligenous assemblages. Even with only a 10% response rate, the LEK approach provided useful information on the resilience of certain species, allowing us to suggest that the presence of nearby mesophotic areas can help shallower habitats facing climate change, thus making the "deep refugia" hypothesis, usually related to tropical habitats, applicable also for the Mediterranean Sea.

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BACKGROUND: The state of twilight consciousness is marked by a focused narrowing of awareness, maintaining vigilance and attention while simultaneously experiencing perceptual shifts in the surrounding environment. It is crucial to recognize that this twilight state represents not just a contraction but also an expansion of conscious experience. SUMMARY: Substances of abuse, particularly new psychoactive substances, play a significant role in inducing this twilight state. They achieve this by deconstructing essential components of consciousness, such as the perception of time and space. KEY MESSAGE: This paper aimed to explore the phenomenon of the twilight state of consciousness and shed light on how new psychoactive substances can alter the perception of time and space during this twilight phase, potentially triggering exogenous psychosis. This comprehensive inquiry employs a phenomenological approach to the study of consciousness, recognizing it as the primary tool for ascribing significance to this intricate yet often overlooked aspect of psychopathology.

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PURPOSE: Despite the many progresses with alignment algorithms, aligning divergent protein sequences with less than 20-35% pairwise identity (so called "twilight zone") remains a difficult problem. Many alignment algorithms have been using substitution matrices since their creation in the 1970's to generate alignments, however, these matrices do not work well to score alignments within the twilight zone. We developed Protein Embedding based Alignments, or PEbA, to better align sequences with low pairwise identity. Similar to the traditional Smith-Waterman algorithm, PEbA uses a dynamic programming algorithm but the matching score of amino acids is based on the similarity of their embeddings from a protein language model. METHODS: We tested PEbA on over twelve thousand benchmark pairwise alignments from BAliBASE, each one extracted from one of their multiple sequence alignments. Five different BAliBASE references were used, each with different sequence identities, motifs, and lengths, allowing PEbA to showcase how well it aligns under different circumstances. RESULTS: PEbA greatly outperformed BLOSUM substitution matrix-based pairwise alignments, achieving different levels of improvements of the alignment quality for pairs of sequences with different levels of similarity (over four times as well for pairs of sequences with <10% identity). We also compared PEbA with embeddings generated by different protein language models (ProtT5 and ESM-2) and found that ProtT5-XL-U50 produced the most useful embeddings for aligning protein sequences. PEbA also outperformed DEDAL and vcMSA, two recently developed protein language model embedding-based alignment methods. CONCLUSION: Our results suggested that general purpose protein language models provide useful contextual information for generating more accurate protein alignments than typically used methods.

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Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types: preeclampsia Type I and Type II. Type I preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like tyrosine kinase-1 levels, reduced placental growth factor levels, high peripheral vascular resistance, and low cardiac output. Type I is more often accompanied by fetal growth restriction, and low placental growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like tyrosine kinase-1-placental growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with fetal macrosomia, multiple pregnancies, or prolonged pregnancy. Support for the notion of 2 types of preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like tyrosine kinase-1 (FLT1) and placental growth factor, particularly marked in the syncytium of early preeclampsia cases. Classification of preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.

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Light exposure during twilight plays a critical role in the entrainment of the human circadian system. People are most often at home during dusk and dawn, and light exposure at home - either natural or from electric light - may therefore contribute substantially to sleep and well-being. However, very little research has focused on the effects of home lighting on sleep and well-being, and even less research has investigated the effects of light exposure during twilight. Therefore, a literature study was performed to collect studies on light exposure at home during dusk and dawn. Studies looking at light exposure during dusk and dawn have focused on either electric light intervention (i.e., dusk and dawn simulation) at home or in the laboratory or daylight exposure in the bedroom (i.e., the presence and type of curtains in the bedroom). Most research has focused on dawn simulation during the darker months of the year, often using sunrise alarms. In general, study results pointed to the importance of twilight light exposure at home for sleep and well-being. These results may depend on the characteristics of the user, such as age or chronotype.

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Studies on the timing of anopheline host-seeking are important for understanding mosquito ecology, behaviors, and possible role in disease transmission. To study the evening crepuscular host-seeking activity of anophelines and the effects of moonlight, anopheline mosquitoes were collected with light traps settled in a livestock area in the Brazilian Cerrado region. Traps (Silva traps) were placed next to animal enclosures at 1.5 m asl. The research was divided in 2 experiments: the first experiment (12 nights) comprised 2 trapping periods, one from 6 PM to 7 PM and one from 7 PM to 6 AM, and the second experiment (16 evenings) divided in three 20-min intervals based on the 3 twilight phases (civil: 6-6:20 PM; nautical: 6:20-6:40 PM; and astronomical: 6:40-7 PM). A total of 2,815 anopheline mosquitoes and 9 species were found. The main species were Anopheles triannulatus s.l., An. argyritarsis, An. goeldii, and An. evanse. Host-seeking mosquitoes were more frequently active during the first hour after sunset, with a significant peak in the second 20-min interval. After that, a decrease in the number of individuals was observed from the astronomical twilight onwards. Moonlight did not affect the evening flight activity of anophelines. By using LED-based passive light traps, the evening arrival time of anophelines at blood-feeding sites was demonstrated, and it may be a key time window for malaria vector control interventions.

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The analysis of the relationship between sequence and structure similarities during the evolution of a protein family has revealed a limit of sequence divergence for which structural conservation can be confidently assumed and homology modeling is reliable. Below this limit, the twilight zone corresponds to sequence divergence for which homology modeling becomes increasingly difficult and requires specific methods. Either with conventional threading methods or with recent deep learning methods, such as AlphaFold, the challenge relies on the identification of a template that shares not only a common ancestor (homology) but also a conserved structure with the query. As both homology and structural conservation are transitive properties, mining of sequence databases followed by multidimensional scaling (MDS) of the query sequence space can reveal intermediary sequences to infer homology and structural conservation between the query and the template. Here, as a case study, we studied the plethodontid receptivity factor isoform 1 (PRF1) from Plethodon jordani, a member of a pheromone protein family present only in lungless salamanders and weakly related to cytokines of the IL6 family. A variety of conventional threading methods led to the cytokine CNTF as a template. Sequence mining, followed by phylogenetic and MDS analysis, provided missing links between PRF1 and CNTF and allowed reliable homology modeling. In addition, we compared automated models obtained from web servers to a customized model to show how modeling can be improved by expert information.

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The twilight zone is an important depth of the ocean where particulate organic matter (POM) remineralization takes place, and prokaryotes contribute to more than 70% of the estimated remineralization. However, little is known about the microbial community and metabolic activity associated with different particles in the twilight zone. The composition and distribution of particle-attached prokaryotes in the twilight zone of the South China Sea (SCS) were investigated using high-throughput sequencing and quantitative PCR, together with the Biolog Ecoplate™ microplates culture to analyze the microbial metabolic activity. We found that α- and γ-Proteobacteria dominating at the lower and upper boundary of the twilight zone, respectively; Methanosarcinales and Halobacteriales of the Euyarchaeota occupied in the larger particles at the upper boundary. Similar microbial community existed between euphotic layer and the upper boundary. Higher amount of shared Operational Taxonomic Units (OTUs) in the larger particles along the water depths, might be due to the fast sinking and major contribution of carbon flux of the larger particles from the euphotic layer. In addition to polymers as the major carbon source, carbohydrates and amino acids were preferentially used by microbial community at the upper and lower boundary, respectively. This could potentially be attributed to the metabolic capabilities of attached microbial groups in different particles, and reflected the initial preference of the carbon source by the natural microbes in the twilight zone as well. The microbial structure and carbon metabolic profiles could be complemented with metatranscriptomic analysis in future studies to augment the understanding of the complex carbon cycling pathways in the twilight zone.

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A 17-year-old female patient presented to our hospital with repeated transient loss of consciousness lasting less than 10 min. After regaining consciousness, she experienced no disorientation, confusion, tongue-biting, or incontinence. Physical findings, blood tests, electrocardiogram, and echocardiogram showed no obvious abnormalities. On being asked whether she had experienced sudden rapid body movements, she answered "yes." Therefore, we suspected juvenile myoclonic epilepsy (JME) and obtained an electroencephalogram, which showed diffuse bilateral bursts of spike-and-wave complexes, confirming the diagnosis. In adolescent patients with transient loss of consciousness, myoclonic jerks should be actively confirmed for the diagnosis of JME.

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BACKGROUND: Current protein family modeling methods like profile Hidden Markov Model (pHMM), k-mer based methods, and deep learning-based methods do not provide very accurate protein function prediction for proteins in the twilight zone, due to low sequence similarity to reference proteins with known functions. RESULTS: We present a novel method EnsembleFam, aiming at better function prediction for proteins in the twilight zone. EnsembleFam extracts the core characteristics of a protein family using similarity and dissimilarity features calculated from sequence homology relations. EnsembleFam trains three separate Support Vector Machine (SVM) classifiers for each family using these features, and an ensemble prediction is made to classify novel proteins into these families. Extensive experiments are conducted using the Clusters of Orthologous Groups (COG) dataset and G Protein-Coupled Receptor (GPCR) dataset. EnsembleFam not only outperforms state-of-the-art methods on the overall dataset but also provides a much more accurate prediction for twilight zone proteins. CONCLUSIONS: EnsembleFam, a machine learning method to model protein families, can be used to better identify members with very low sequence homology. Using EnsembleFam protein functions can be predicted  using just sequence information with better accuracy than state-of-the-art methods.

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Febrile status epilepticus evolves from a febrile seizure (FS) in 5% of cases. Its prompt recognition is challenging, especially when motor manifestations are absent or subtle. We describe the ictal electroclinical features of non-convulsive febrile status epilepticus (NCFSE) following an apparently concluded FS, initially misinterpreted as postictal obtundation and in some way mimicking the described "non-epileptic twilight state". We present an electroclinical study of 18 children, collected in our unit, who presented with NCFSE after an apparently resolved FS, longitudinally followed for one year to seven years and nine months (mean: four years and three months). The age at first NCFSE ranged between one year and two months and five years and eight months (mean: two years and six months). Patients were examined after spontaneous or rectal diazepam-induced resolution of a FS, while showing persisting impairment of awareness. A lack of responsiveness to painful stimulation, abnormal posturing and aphasia were present in all cases, variably associated with perioral cyanosis, hypersalivation, automatisms, gaze deviation and other lateralizing signs; eyes were open. The EEG recording started 20 to 140 minutes after the apparent resolution of the FS and was invariably characterized by delta or theta-delta pseudorhythmic activity, mainly involving the fronto-temporal regions, with hemispheric predominance in two thirds of the cases. The electroclinical condition, lasting 25 to 210 minutes, quickly recovered after intravenous diazepam. Follow-up revealed normal neurodevelopment and EEG in almost all patients (learning disability emerged in three). In five subjects, NCSE relapsed (twice in two). None presented afebrile seizures. Our series highlights the electroclinical features of focal NCFSE. Distinctive elements are a lack of reactivity, cyanosis, lateralizing clinical and EEG signs, and resolution clearly tied to intravenous benzodiazepine administration.

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Many large marine predators make excursions from surface waters to the deep ocean below 200 m. Moreover, the ability to access meso- and bathypelagic habitats has evolved independently across marine mammals, reptiles, birds, teleost fishes, and elasmobranchs. Theoretical and empirical evidence suggests a number of plausible functional hypotheses for deep-diving behavior. Developing ways to test among these hypotheses will, however, require new ways to quantify animal behavior and biophysical oceanographic processes at coherent spatiotemporal scales. Current knowledge gaps include quantifying ecological links between surface waters and mesopelagic habitats and the value of ecosystem services provided by biomass in the ocean twilight zone. Growing pressure for ocean twilight zone fisheries creates an urgent need to understand the importance of the deep pelagic ocean to large marine predators.

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Dual antiplatelet therapy (DAPT) is mandatory in patients undergoing percutaneous coronary interventions (PCIs), but carries an increased bleeding risk which must be weighed over the expected antithrombotic benefit. In recent years, DAPT optimization strategy has been enriched by the concept of early withdrawal of aspirin ('aspirin-free' strategy). This strategy is supported by the modern advancements in pharmacological and procedural fields (i.e. the availability of P2Y12 receptor inhibitors with a concomitant 'aspirin-like' effect), the advocated use of pharmacological non-antiplatelet secondary prevention strategies (i.e. angiotensin-converting enzyme inhibitor, statins, beta-blockers), the use of modern stents and the increasingly widespread use of intra-coronary imaging techniques. In the last few years, five clinical trials (GLOBAL LEADERS, TWILIGHT, STOP-DAPT2, SMART CHOICE, TICO) and their own meta-analysis have been followed, aiming to evaluate the efficacy and safety of different 'aspirin-free' strategies. They showed that aspirin withdrawal (1-3 months after PCI), determines a consistent reduction of bleeding risk, without compromising efficacy endpoints. It resulted in a class IIa indication in the 2020 European Society of Cardiology Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation, which suggested the early withdrawal of aspirin in patients undergoing PCI and considered to be at low ischaemic and low bleeding risk, or at high bleeding risk.

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Fear of predation can have wide-ranging ecological effects.1-4 This is especially true in the ocean's pelagic zone, the Earth's largest habitat, where vertical gradients in light and primary productivity force numerous taxa to migrate vertically each night to feed at the surface while minimizing risk from visual predators.5-7 Despite its importance and the fact that it is driven by spatial differences in perceived risk,8 diel vertical migration (DVM) is rarely considered within the "landscape of fear"3,8,9 framework.10 It is also far from the only such process in the pelagic zone. We used continuous, year-long records from an upward-looking echosounder and broadband hydrophone at a cabled observatory off Central California, USA, to observe avoidance reactions by several groups of pelagic animals to the presence of their predators. As expected, vertical migration was ubiquitous, but we also observed behaviors at shorter and longer timescales that were best explained by fear of predation. The presence of foraging odontocetes induced immediate diving behavior in mesopelagic sound-scattering layers, and schools of epipelagic fishes induced similar reaction in layers of zooplankton and mesopelagic micronekton. At longer timescales, the presence of fish schools significantly deepened vertical migration, rearranging life throughout the water column. We argue that behavioral reactions to predation risk are common in the pelagic zone at a range of spatiotemporal scales and that our understanding of food webs and biogeochemical cycling in this immense biome will be incomplete unless we account for fear.

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Cultivation of hemp (Cannabis sativa L.) in tropical and subtropical regions can be challenging if the flowering behavior of a given cultivar is unknown, poorly understood, or not accurately selected for the photoperiod. Identifying cultivars adapted to local environmental conditions is key to optimizing hemp vegetative and flowering performance. We investigated the effects of varying light cycles in regulating extension growth and flowering response of 15 essential oil and 12 fiber/grain hemp cultivars both indoors and outdoors. Plants were subjected to 11 photoperiods in the controlled rooms ranging from 12 to 18 h, and natural day length in the field. The critical photoperiod threshold was identified for seven essential oil cultivars and two fiber/grain cultivars. "Cherry Wine-CC," "PUMA-3," and "PUMA-4" had the shortest critical day length between 13 h 45 min and 14 h. The flowering of essential oil cultivars was generally delayed by 1-2 days when the photoperiod exceeded 13 h compared with 12 h, and flowering was further delayed by 7-8 days when the photoperiod exceeded 14 h. In fiber/grain cultivars, flowering was generally delayed by 1-3 days when the day length exceeded 14 h. Flowering for most essential oil cultivars was delayed by 5-13 days under a 14-h photoperiod compared with 13 h 45 min, suggesting a photoperiod difference as little as 15 min can significantly influence the floral initiation of some essential oil cultivars. Cultivars represented by the same name but acquired from different sources can perform differently under the same environmental conditions, suggesting genetic variation among cultivars with the same name. Average days to flower of fiber/grain cultivars was correlated with reported cultivar origin, with faster flowering occurring among northern cultivars when compared with southern cultivars. Plant height generally increased as the day length increased in essential oil cultivars but was not affected in fiber/grain cultivars. In addition, civil twilight of ~2 µmol·m-2·s-1 was discovered to be biologically effective in regulating hemp flowering. Collectively, we conclude that most of the essential oil cultivars and some southern fiber/grain cultivars tested express suitable photoperiods for tropical and sub-tropical region cultivation.

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Pseudanthiashangapiko sp. nov. (Teleostei, Serranidae, Anthiadinae) is herein described from three specimens collected from a depth of 83 m in a mesophotic coral ecosystem off Hanga Piko, Rapa Nui (Easter Island), Chile. Pseudanthiashangapiko sp. nov. can be distinguished from its congeners in live coloration and by the following combination of characters: dorsal-fin rays X, 17; anal-fin rays III, 8; pectoral-fin rays 16 (left side of one specimen 17); vertebrae 10+16; scales relatively large, two scales above lateral-line to base of fifth dorsal spine, and 16-17 circumpeduncular scales; gill rakers 11+23; and a slender body, with greatest body depth 3.6 (3.4-3.8) in SL. The most similar DNA barcodes (mitochondrial COI gene) are from Pseudanthiasventralis Randall, 1979 and Pseudanthiashawaiiensis Randall, 1979, with 16.8% and 17.0% uncorrected divergence, respectively. This fish is one of four new species that were documented from a pair of technical dives at a single location in Rapa Nui, emphasizing the high number of undescribed species likely still unknown in mesophotic coral ecosystems, especially in geographically remote locations. Pseudanthiashangapiko sp. nov. adds to the Rapa Nui ichthyofauna, which hosts the second-highest level of endemism in both shallow and deep-water fishes.

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The twilight zone (from the base of the euphotic zone to the depth of 1,000 m) is the major area of particulate organic carbon (POC) remineralization in the ocean, and heterotrophic microbes contribute to more than 70% of the estimated remineralization. However, little is known about the microbial community and metabolic activity directly associated with POC remineralization in this chronically understudied realm. Here, we characterized the microbial community proteomes of POC samples collected from the twilight zone of three contrasting sites in the Northwest Pacific Ocean using a metaproteomic approach. The particle-attached bacteria from Alteromonadales, Rhodobacterales, and Enterobacterales were the primary POC remineralizers. Hydrolytic enzymes, including proteases and hydrolases, that degrade proteinaceous components and polysaccharides, the main constituents of POC, were abundant and taxonomically associated with these bacterial groups. Furthermore, identification of diverse species-specific transporters and metabolic enzymes implied niche specialization for nutrient acquisition among these bacterial groups. Temperature was the main environmental factor driving the active bacterial groups and metabolic processes, and Enterobacterales replaced Alteromonadales as the predominant group under low temperature. This study provides insight into the key bacteria and metabolic processes involved in POC remineralization, and niche complementarity and species substitution among bacterial groups are critical for efficient POC remineralization in the twilight zone. IMPORTANCE The ocean's twilight zone is a critical zone where more than 70% of the sinking particulate organic carbon (POC) is remineralized. Therefore, the twilight zone determines the size of biological carbon storage in the ocean and regulates the global climate. Prokaryotes are major players that govern remineralization of POC in this region. However, knowledge of microbial community structure and metabolic activity is still lacking. This study unveiled microbial communities and metabolic activities of POC samples collected from the twilight zone of three contrasting environments in the Northwest Pacific Ocean using a metaproteomic approach. Alteromonadales, Rhodobacterales, and Enterobacterales were the major remineralizers of POC. They excreted diverse species-specific hydrolytic enzymes to split POC into solubilized POC or dissolved organic carbon. Temperature played a crucial role in regulating the community composition and metabolism. Furthermore, niche complementarity or species substitution among bacterial groups guaranteed the efficient remineralization of POC in the twilight zone.

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Two new polyketide natural products, globosuxanthone F (1), and 2'-hydroxy bisdechlorogeodin (2), were isolated from the fungus Pleosporales sp. NBUF144, which was derived from a 62 m deep Chalinidae family sponge together with four known metabolites, 3,4-dihydroglobosuxanthone A (3), 8-hydroxy-3-methylxanthone-1-carboxylate (4), crosphaeropsone C (5), and 4-megastigmen-3,9-dione (6). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR and high-resolution electrospray ionization mass spectra (HRESIMS) data. The absolute configuration of 1 was further established by single-crystal X-ray diffraction studies. Compounds 1-5 were evaluated for cytotoxicity towards CCRF-CEM human acute lymphatic leukemia cells, and it was found that 1 had an IC50 value of 0.46 µM.

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