Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Insights into the Unexpected Agonism of Tetracyclic Antidepressants at Serotonin Receptors 5-HT1eR and 5-HT1FR

Serotonin (5-hydroxytryptamine, 5-HT) acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT1eR have confirmed roles in native tissue and are validated drug targets. Despite 5-HT1eR’s therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT1eR’s pharmacology in relation to the highly homologous 5-HT1FR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT1e/1FR agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed anti-migraine properties. Using cryoEM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT1eR distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT1eR and 5-HT1FR contribute to the agonist activity of these antidepressants.
Impact of tropical cyclones on the intensity and phase propagation of fall Wyrtki jets

Observations and model simulations are used to study the impact of tropical cyclones (TC) on the fall Wyrtki jets (WJ). These strong narrow equatorial currents peak during November and play a vital role in the energy and mass transport in the tropical Indian Ocean (TIO). Maximum number of TCs is observed over TIO during November with longer than normal life span (8–15 days). These TCs enhance equatorial westerly winds (surface) and amplify monthly mean WJs (both at surface and subsurface) by 0.4 ms−1 (anomalies exceed 0.7 ms−1during TC), which is about half of the climatological amplitude. Intensified WJs increase the heat content of eastern TIO and modulate air‐sea interaction. It is also shown that movement of TCs is mainly responsible for the westward phase propagation of WJs, a previously unexplored mechanism. These features are evident in ECCO2 simulations as well.
The role of family and environment in determining the skin microbiome of captive aquatic frogs, Xenopus laevis

Background The amphibian skin microbiome has drawn interest due to the ecological threat posed by chytridiomycosis, which drives changes in symbiotic microbial communities and may be inhibited by certain bacterial taxa. However, skin microbes also play a role in amphibian tissue regeneration. Xenopus spp. are well-established model organisms used to study development, regeneration, genetics and disease. Husbandry protocols, including use of antibiotics and other sterilising agents, may affect experimental outcomes by altering microbiomes. It is therefore essential to improve our understanding of Xenopus microbiome characteristics and inheritance. We undertook bacterial 16S rRNA based sampling of a captive, closed Xenopus laevis colony. A total of 16 female frogs, their eggs, and tadpoles were sampled, covering multiple aquarium systems and tanks, along with testes from males used for in vitro fertilisation and a range of environmental samples. Results Tank environments supported the most complex microbial communities. Mother frogs harboured the most diverse microbial communities of the frog life stages, with tadpole skin microbiomes being relatively simple. Frog samples were dominated by Proteobacteria and Bacteroidota. Rhizobium and Chryseobacterium were dominant in tadpoles, whereas mothers supported high proportions of Vogesella and Acinetobacter as well as Chryseobacterium. While the mothers’ habitats contained low levels of these taxa, the tadpole’s environmental microbes were very similar to those on tadpole skin. A total of 34 genera were found to be differentially abundant between the mothers and tadpoles. Analysis of Bray-Curtis distances indicated that mother and tadpole microbiomes varied according to the mothers’ aquarium system, the tanks within them, and the individual mother. Source tracking analyses showed that egg jelly and tadpoles received a mean of approximately two thirds of their microbiomes via vertical transmission, although a sizeable proportion came from unknown sources at all life stages. Conclusions The skin of mother frogs appears to select for certain taxa that are otherwise present at low abundances in the environment. While tadpoles inherit a proportion of their microbiomes from their mothers via the egg, they support a distinct and less diverse microbial community than adult frogs. The microbiome varies between individual mothers, and is also affected by the aquarium system and individual tank within that the mother occupies.
Deep-sea in situ and laboratory proteomics provide insights into the sulfur metabolism of a novel deep-sea bacterium, Pseudodesulfovibrio serpens sp. nov.

Sulfate-reducing bacteria (SRB) are ubiquitously distributed across various biospheres and play key roles in global sulfur cycles. However, few deep-sea SRB have been cultivated and studied in situ, limiting our understanding of the true metabolism of SRB in the deep biosphere. Here, we firstly clarified the high abundance of SRB in deep-sea cold seep sediments and successfully isolated a sulfate-reducing bacterium (strain zrk46). Our genomic, physiological and phylogenetic analyses indicate that strain zrk46 is a novel species, which we propose as Pseudodesulfovibrio serpens. Based on the combined results from growth assays and proteomic analyses, we found that supplementation with sulfate (SO42-), thiosulfate (S2O32-), or sulfite (SO32-) promoted the growth of strain zrk46 by facilitating energy production through the dissimilatory sulfate reduction with the auxiliary functions of heterodisulfide reductases, ferredoxins, and nitrate reduction associated proteins, which were coupled with the oxidation of environmental organic matter in both laboratory and deep-sea in situ conditions. Moreover, metatranscriptomic results confirmed the dissimilatory sulfate reduction of deep-sea SRB in deep-sea environment, which might be coupled to the methane oxidation of anaerobic methanotrophic archaea (ANME-2) through direct interspecies electron transfer via cytochromes. IMPORTANCE The deep-sea cold seep sediments were ideal habitats for uncovering diverse metabolisms of SRB. Unfortunately, the paucity of SRB isolates has limited further insights into their physiological and metabolic features as well as ecological roles. In the present study, we demonstrated the high abundance of SRB in the deep-sea cold seep sediments and isolated a sulfate-reducing bacterium. Our results demonstrate that the existence of dissimilatory sulfate reduction of strain zrk46 in both laboratory and deep-sea in situ environments, accompanied by the auxiliary effect of heterodisulfide reductases, ferredoxins, and nitrate reduction associated proteins. Our findings also unravel that the sulfate reduction of deep-sea SRB in in situ environment might be coupled to the methane oxidation of ANME-2. Overall, these findings expand our understanding of deep-sea SRB, while highlighting their importance for deep-sea elemental cycles.
RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation

The Ras-MAPK pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While typically the impact of Ras on the proliferation of various cancer cell lines is assessed, it is poorly established how Ras affects cellular differentiation. Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that a minor pool of Pax7+ progenitors replenishes a major pool of transit amplifying cells that are ready to differentiate. Our data indicate that Ras isoforms have distinct roles in the differentiating culture, where K-Ras is more important than N-Ras to maintain the progenitor pool and H-Ras is significant for terminal differentiation. This assay could therefore provide significant new insights into Ras biology and Ras-driven diseases. In line with this, we found that all oncogenic Ras mutants block terminal differentiation of transit amplifying cells. Notably, while RASopathy K-Ras variants that are also NF1-GAP resistant also block differentiation, albeit less than their oncogenic counterparts. Profiling of targeted Ras-pathway drugs on oncogenic Ras mutants revealed their distinct abilities to restore normal differentiation as compared to triggering cell death. In particular, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTOR-inhibitor rapamycin broadly suppressed differentiation. We expect that this quantitative assessment of the impact of Ras-pathway mutants and drugs on cellular differentiation has great potential to complement cancer cell proliferation data.
The maize striate leaves2 (sr2) gene encodes a conserved DUF3732 domain and is homologous to the rice yss1 gene

Maize striate leaves2 (sr2) is a mutant that causes white stripes on leaves that has been used in mapping studies for decades, though the underlying gene has not been identified. The sr2 locus has been previously mapped to small regions of the normal chromosome 10 (N10) and a rearranged variant called Abnormal Chromosome 10 (Ab10). A comparison of assembled genomes carrying N10 and Ab10 revealed only five candidate sr2 genes. Analysis of a stock carrying the sr2 reference allele (sr2-ref) showed that one of the five genes has a transposon insertion that disrupts its protein sequence and has a severe reduction in mRNA. An independent Mutator transposon insertion in the gene (sr2-Mu) failed to complement the sr2-ref mutation, and plants homozygous for sr2-Mu showed white striped leaf margins. The sr2 gene encodes a DUF3732 protein with strong homology to a rice gene with a similar mutant phenotype called young seedling stripe1 (yss1). These and other published data suggest that sr2 may have a function in plastid gene expression.
Combined seismic inversion and gravity modeling of a shallow anomaly in the southern Barents Sea

A combination of prestack elastic inversion with gravity modeling has been applied to a shallow seismic anomaly in the southern Barents Sea. The anomaly is crosscutting dipping layers of late Paleocene age. Earlier seismic interpretations indicate a possible origin in gas‐hydrated sediments trapping underlying free gas. Our interpretation includes seismic inversion of a seismic model which consists of a stack of isotropic, homogeneous, and anelastic layers. The unknown parameters are the P‐ and S‐wave velocities, density, and thickness for each layer. As densities are poorly determined by this method, we included gravity modeling, which improved the density estimates. The resulting parameters have been integrated by rock physics calculations and the knowledge of typical attributes of gas hydrate occurrences. The top of the seismic anomaly is interpreted as a reflection from the base of a gas‐hydrated sediment trapping underlying free gas. The base of the anomaly is the gas‐water contact, which deviates fr.
A model of marmoset monkey vocal turn-taking

Vocal turn-taking has been described in a diversity of species. Yet a model that captures the various processes underlying this social behavior across species has not been developed. To this end, here we recorded a large and diverse dataset of marmoset monkey vocal behavior in social contexts comprising one, two and three callers and developed a model to determine the keystone factors that affect the dynamics of these natural communicative interactions. While a coupled oscillator model failed to account for turn-taking in marmosets, our model alternatively revealed four key factors that encapsulate much of patterns evident in the behavior, ranging from internal processes, such as the state of the individual, to social context driven suppression of calling. In addition, we show that the same key factors apply to the meerkat, a carnivorous species, in a multicaller setting. These findings indicate that vocal turn-taking is affected by a broader suite of mechanisms than previously considered and that our model provides a predictive framework with which to further explicate this natural behavior in marmosets and for direct comparisons with the analogous behavior in other species.
Neutrophil-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

The protective correlates of Mycobacterium tuberculosis (Mtb) infection-elicited host immune responses are incompletely understood. Here we report pro-pathogenic crosstalk between IL-17, COX2, and Neutrophils. We show that most intracellular bacilli in the wild-type (WT) mice’s lungs are neutrophil-resident. In BCG-vaccinated WT mice, Mtb continues to persist inside neutrophils, which is sensitive to COX2 inhibition. Using a genetically susceptible IFNγ -/- mice model, we report that excessive neutrophil infiltration and corresponding bacteremia are dependent on neutrophil-derived IL-17. COX2 inhibition and IL-17 neutralization reverse neutrophil infiltration, associated pathology and death in IFNγ -/- mice. The IL-17-Neutrophils interplay also operates in WT mice, and RORγt inhibition enhances BCG’s protective efficacy. In a prospective clinical cohort of pulmonary TB, high neutrophil count and IL-17 precipitate adverse treatment outcomes. We propose targeting the pro-pathogenic IL-17- Neutrophils axis to enhance TB prevention and therapy in normal and vulnerable subjects.
Decoding the physics of observed actions in the human brain

Recognizing goal-directed actions is a computationally challenging task, requiring not only the visual analysis of body movements, but also analysis of how these movements causally impact, and thereby induce a change in, those objects targeted by an action. We tested the hypothesis that the analysis of body movements and the effects they induce relies on distinct neural representations in superior and anterior inferior parietal lobe (SPL and aIPL). In four fMRI sessions, participants observed videos of actions (e.g. breaking stick, squashing plastic bottle) along with corresponding point-light-display stick figures, pantomimes, and abstract animations of agent-object interactions (e.g. dividing or compressing a circle). Cross-decoding between actions and animations revealed that aIPL encodes abstract representations of action effect structures independent of motion and object identity. By contrast, cross-decoding between actions and point-light-displays revealed that SPL is disproportionally tuned to body movements independent of visible Interactions with objects. Lateral occipitotemporal cortex (LOTC) was sensitive to both action effects and body movements. Moreover, cross-decoding between pantomimes and animations revealed that right aIPL and LOTC represent action effects even in response to implied object interactions. These results demonstrate that parietal cortex and LOTC are tuned to physical action features, such as how body parts move in space relative to each other and how body parts interact with objects to induce a change (e.g. in position or shape/configuration). The high level of abstraction revealed by cross-decoding suggests a general neural code supporting mechanical reasoning about how entities interact with, and have effects on, each other. Significance statement Understanding the actions of others requires the analysis of how the body interacts with objects in the world and thereby induces a change (e.g. in location or configuration). Using fMRI in combination with multivariate pattern decoding, we show that the analysis of body movements and the effects they induce relies on distinct neural computations in superior and inferior parietal cortex. Importantly, representations of action effects were independent of movements and types of entities involved in the interaction. These findings elucidate key stages in the action recognition hierarchy and suggest that a critical role of parietal cortex in action recognition is the visuospatial analysis of how entities move and impact each other and thereby change their states.
Technical challenges, viability, and potential environmental impacts of oil production in the Dreki and Jan Mayen Ridge region

On the 4th of January 2013, the National Energy Authority in Iceland issued two licenses for the exploration and production of hydrocarbons in the Dreki Area, there is also a third license being considered at the moment. There are plenty of hazards and risks of a possible oil spill related to the exploration and production of hydrocarbons, this paper looks to address the oceanographic conditions at the Dreki and Jan Mayen Ridge region. It also looks into the use of comparisons, historic events, effects on the ecosystem and then mainly at what area is most likely to be affected should an oil spill occur and what can be done in the event of a spill. This paper found that conditions at the same latitude, but different longitudes (i.e. East Greenland vs. West Norway) are very different. The complexity of the dynamics between Atlantic and Arctic waters in the Nordic Seas cause these differences and a characteristic of these seas are anti-clockwise eddies. These will factor heavily in the distribution of a potential oil spill and will most likely prevent a spill from flowing to shore in Iceland, Norway or Greenland. Exploration and production has been conducted at sites that endure similar or more extreme conditions and the use of a floating platform will be integral for any large operations. Health and safety management will have to be held to high standards and frequently reviewed. The main factor that will be problematic for the planned exploration and potential production in the area is its remoteness. Facilities for production and for a disaster response team, equipment and vessels will either have to be established in Iceland or co-ordinated with and on Norway.
Sensitivity of a general circulation inverse model to sub-grid scale parametrization coefficients

Acknowledgements I would like to thank Dr. Lisan Yu for helping me understand the code and its intricacies, allowing me to use the datasets she prepared for it, and getting me started in UNICOS and NCAR's IRJE; Dr. W. Brechner Owens for helping me to correlate the code's topographic file with a real atlas; Prof. Jochem Marotzke for his helpful comments and criticisms, and particularly for a long conversation one afternoon late April which was particularly illuminating; and especially Prof. Paola Rizzoli who inspired, guided, and supported me along the way. I also thank Bud Brown for his assistance with Figure 3.12. Finally, I thank most of all my wife, Aida, who truly bore me through the entire process.
An Efficient Key Management and Authentication Protocol for IoT Networks

The increasing integration of IoT technology into our daily lives through applications, it is critical to assure these systems security and privacy problems. Furthermore, time-critical IoT applications in healthcare necessary access to real-time private information from third parties (users) via wireless communication devices As a consequence; user identity concerns have to be handled in IoT wireless sensor system networks. (WSNs). In this paper, a secure and compact three-factor identification technique for future IoT WSN applications that relies on user biometric feature extraction. The method that was proposed depends on hash and XOR functions, and it includes (i) three-factor authentication; (ii) a shared session key; (iii) mutual authentication; and (iv) key freshness. The simulation tool here using is AVISPA for Rapid Verification of Internet Security Protocols and an informal security research that confirms its other qualities. Furthermore, our calculations show suggested method outperforms existing similar authentication methods with respect to of safety and usefulness, as well as communications and computing costs. Furthermore, the proposed protocol is suitable for usage in the vast majority of IoT and WSN applications Stresczenie. Rosn ą ca integracja
Pulmonary hypertension in Behçet’s disease: echocardiographic screening and multidisciplinary approach

Background/aim Little is known about the prevalence and causes of pulmonary hypertension (PH) in Behçet’s disease (BD). This study was conducted to determine the prevalence and causes of PH in BD. Materials and methods In this descriptive study, we screened 154 patients with BD for PH using transthoracic echocardiography between February 2017 and October 2017. An estimated systolic pulmonary arterial pressure (sPAP ≥ 40 mmHg) was used as the cut-off value to define PH. Patients with BD were categorized into 5 groups according to organ involvement including mucocutaneous/articular, ocular, vascular, gastrointestinal, and neurologic involvement. Additional laboratory and imaging results were obtained from hospital file records to determine the causes of PH. Results PH was detected in 17 (11%) patients. Nine (52.9%) of these patients had group II PH (due to left heart disease), 4 (23.5%) had IV PH (due to pulmonary arterial involvement), and 1 had III PH (due to chronic obstructive lung disease). The frequency of PH was higher in BD patients with vascular involvement than those without (52.9% vs 28.5%; p = 0.04). Among 10 patients with pulmonary artery involvement (PAI) 4 (40%) had PH. Although the vascular BD group had the highest rate of PH, we observed no statistically significant difference in the frequency of PH between the predefined BD subgroups. Conclusions PH is not rare in patients with BD. The majority of BD patients with PH are in group II or IV PH. Patients with vascular involvement carry a higher risk for the development of PH. Monitoring BD patients with PAI should be considered for the development of group IV PH.
Riffle: Reactive Relational State for Local-First Applications

The reactive paradigm for developing user interfaces promises both simplicity and scalability, but existing frameworks usually compromise one for the other. We present Riffle, a reactive state management system that achieves both simplicity and scalability by managing the entire state of a web application in a client-side persistent relational database. Data transformations over the application state are defined in a graph of reactive relational queries, providing developers with a simple spreadsheet-like reactivity model. Domain state and UI state are unified within the same system, and efficient incremental query maintenance ensures the UI remains responsive. We present a formative case study of using Riffle to build a music management application with complex data and stringent performance requirements.
Analisis Besi dalam Ekosistem Lamun dan Hubungannya dengan Sifat Fisikokimia Perairan Pantai Kabupaten Donggala

The objectives of the study are to describe the iron content of seagrass area ecosystem and its relation with nature of physico-chemical territorial water. The sampling of seagrass was conducted in purposive sampling technique for every status of the field and performed in three spots of the seagrass ecosystem region with reference to the depth of water and the current direction. Based on statistical tests of factorial and variance analysis indicate that the quality of physico-chemical territorial water in the coastal region of Donggala regency still very good, relatively. The result also showed, The Demand Oxygen and the turbidity gave a positive effect to Fe- seagrass improvement in its various association. Besides, the limiting factor for the low of Fe-seagrass is the height of salinity and water temperature. If the results were combined with another micro and macro mineral analysis will to become the basic for estimating the status of seagrass fertility.