julilili42/papers huggingface dataset:
REWORKED MESOZOIC RADIOLARIANS IN MIOCENE-PLIOCENE FORELAND SEDIMENTS IN THE ZAGROS BELT, IRAN
2024-02-19

Micropaleontology can give important insights into the provenance and paleoenvironmental conditions in terrestrial sedimentary archives. For the current study, 84 samples representing a 2.6 km thick sedimentary profile from the SimplyFolded Zagros Mountain Belt were investigated. They span ca. 10.2 my from the late Middle Miocene (Serravallian) to the earliest Pleistocene (Gelasian), and comprised floodplain sediments and saline mudstones with an aeolian contribution. The mudstones revealed a unique Cretaceous radiolarian assemblage comprising largely of cryptothoracic Nassellarians and spherical spumellarians. This record highlights the reworking of sediments derived from Cretaceous Qulqula- Kermanshah radiolarian claystones and radiolarites in the Imbricated Zagros belt into the distal Neogene Zagros foreland sediments in Lurestan (Lurestan Arc). The high abundance of Holocryptocanium barbui (Dumitrica) and other cryptothoracic taxa compared to the Qulqula- Kermanshah radiolarian claystones and radiolarites potentially indicates a preferred erosion of softer units such as the Red Radiolarian Claystone Unit (RRCU) compared to harder radiolarian cherts. The observation of a reworked largely cryptothoracic assemblage might also point to additional sorting effects during fluvial and aeolian transport as well as during redeposition, depending on the morphology and hydrodynamic properties of individual radiolarian taxa.
Ancillary Ligand-Free Mixed Chlorido/Isobutylaluminato Lanthanide Complexes in Isoprene Polymerization
2024-02-19

Ternary catalyst mixtures are employed for industrial-scale rare-earth-metal-promoted diene polymerization. Thereby, the role of organoaluminum compounds in activating the rare-earth-metal component is still poorly understood. Mixed chlorido/amido complexes [Ln{N(SiMe3)2}2(μ-Cl)(THF)]2 are selected as well-defined precursors according to the chlorination/alkylation activation sequence. The heteroleptic lanthanide tetraisobutylaluminate complexes [Ln{N(SiMe3)2}(AliBu4)(μ-Cl)]2 (Ln = La, Nd) form when [Ln{N(SiMe3)2}2(μ-Cl)(THF)]2 is treated with triisobutylaluminum. By contrast, the [La{N(SiMe3)2}2(μ-Cl)(THF)]2/AlMe3 reaction afforded the isolable heteroaluminate complex [La{N(SiMe3)2}{(μ-CH3)(μ-N(SiMe3)2)AlMe2}(μ-Cl)]2, highlighting the distinct reactivity of aluminum alkyls. Complex [Nd{N(SiMe3)2}(AliBu4)(μ-Cl)]2 features catalytic activity in isoprene polymerization for the fabrication of high cis-selective polyisoprene and displays single-component polymerization activity. Compounds [Ln{N(SiMe3)2}2(μ-Cl)(THF)]2 are best accessed from La[N(SiMe3)2]3/LaCl3(THF) mixtures since starting out from LaCl3(THF)/K[N(SiMe3)2] leads to alkali-metal contaminations as revealed by the isolation of the mixed hydrido/isobutylaluminato complex [K(iBu3Al-μ–H-AliBu3)]n, formed upon reaction with triisobutylaluminum.
Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS -mutant cancers
2024-02-20

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRAS G12C and pan-RAS inhibitors in KRAS -mutant lung and colon cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of receptor tyrosine kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRAS G12C , and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRAS G12C -mutant lung and colon cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors
2024-02-20

Abstract Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.
Sleep shapes the associative structure underlying pattern completion in multielement event memory
2024-02-20

Sleep supports the consolidation of episodic memory. It is, however, a matter of ongoing debate how this effect is established, because, so far, it has been demonstrated almost exclusively for simple associations, which lack the complex associative structure of real-life events, typically comprising multiple elements with different association strengths. Because of this associative structure interlinking the individual elements, a partial cue (e.g., a single element) can recover an entire multielement event. This process, referred to as pattern completion, is a fundamental property of episodic memory. Yet, it is currently unknown how sleep affects the associative structure within multielement events and subsequent processes of pattern completion. Here, we investigated the effects of post-encoding sleep, compared with a period of nocturnal wakefulness (followed by a recovery night), on multielement associative structures in healthy humans using a verbal associative learning task including strongly, weakly, and not directly encoded associations. We demonstrate that sleep selectively benefits memory for weakly associated elements as well as for associations that were not directly encoded but not for strongly associated elements within a multielement event structure. Crucially, these effects were accompanied by a beneficial effect of sleep on the ability to recall multiple elements of an event based on a single common cue. In addition, retrieval performance was predicted by sleep spindle activity during post-encoding sleep. Together, these results indicate that sleep plays a fundamental role in shaping associative structures, thereby supporting pattern completion in complex multielement events.
Activation of gp130 signaling in T cells drives T H 17-mediated multi-organ autoimmunity
2024-02-20

The IL-6–gp130–STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3 GOF ) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130 , specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3 GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (T H 17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4 + and CD8 + T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3 GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to T H 17-driven autoimmunity that phenotypically resembles human STAT3 GOF disease.
Systematic optimization of siRNA productive uptake into resting and activated T cells ex vivo
2024-02-20

RNA-based medicines are ideally suited for precise modulation of T cell phenotypes in anti-cancer immunity, in autoimmune diseases and for ex vivo modulation of T-cell-based therapies. Therefore, understanding productive siRNA uptake to T cells is of particular importance. Most studies used unmodified siRNAs or commercially available siRNAs with undisclosed chemical modification patterns to show functionality in T cells. Despite being an active field of research, robust siRNA delivery to T cells still represents a formidable challenge. Therefore, a systematic approach is needed to further optimize and understand productive siRNA uptake pathways to T cells. Here, we compared conjugate-mediated and nanoparticle-mediated delivery of siRNAs to T cells in the context of fully chemically modified RNA constructs. We showed that lipid-conjugate-mediated delivery outperforms lipid-nanoparticle-mediated and extracellular-vesicle-mediated delivery in activated T cells ex vivo. Yet, ex vivo manipulation of T cells without the need of activation is of great therapeutic interest for CAR-T, engineered TCR-T and allogeneic donor lymphocyte applications. We are first to report productive siRNA uptake into resting T cells using lipid-conjugate-mediated delivery. Interestingly, we observed strong dependence of silencing activity on lipid-conjugate-identity in resting T cells but not in activated T cells. This phenomenon is consistent with our early uptake kinetics data. Lipid-conjugates also enabled delivery of siRNA to all mononuclear immune cell types, including both lymphoid and myeloid lineages. These findings are expected to be broadly applicable for ex vivo modulation of immune cell therapies.
The importance of context in teacher educators’ professional digital competence
2024-02-20

Digital technologies permeate modern life, and schools are accordingly expected to help students develop related knowledge and skills. As a result, educators' professional digital competence (PDC) has received substantial attention from school leaders, policymakers, teacher educators, and researchers. Theory and prior research suggest that educators' PDC does not solely determine their technology use, with contextual factors, such as competing curricular demands and access to technology, influencing technology implementation and ongoing PDC development. While some prior research has addressed how PK-12 teachers' contexts shape their digital technology use, few studies have explored similar matters with respect to teacher educators. Drawing on an established set of teacher educator technology competencies, we report results from an international survey of 336 teacher educators regarding their self-reported PDC and its development and enactment. Using qualitative coding, exploratory and confirmatory factor analysis, and quantitative analysis, we find that teacher educators develop and enact their competencies in various ways including through informal endeavours as well as formal, institutionally supported, and/or led activities. Three types of assets and barriers (access, leadership, personal characteristics) present differently for participants in different contexts. These findings have implications for how institutions support teacher educators' PDC development and technology integration in various settings.
Antibacterial Marinopyrroles and Pseudilins Act as Protonophores
2024-02-20

Elucidating the mechanism of action (MoA) of antibacterial natural products is crucial to evaluating their potential as novel antibiotics. Marinopyrroles, pentachloropseudilin, and pentabromopseudilin are densely halogenated, hybrid pyrrole-phenol natural products with potent activity against Gram-positive bacterial pathogens like <i>Staphylococcus aureus</i>. However, the exact way they exert this antibacterial activity has not been established. In this study, we explore their structure-activity relationship, determine their spatial location in bacterial cells, and investigate their MoA. We show that the natural products share a common MoA based on membrane depolarization and dissipation of the proton motive force (PMF) that is essential for cell viability. The compounds show potent protonophore activity but do not appear to destroy the integrity of the cytoplasmic membrane via the formation of larger pores or interfere with the stability of the peptidoglycan sacculus. Thus, our current model for the antibacterial MoA of marinopyrrole, pentachloropseudilin, and pentabromopseudilin stipulates that the acidic compounds insert into the membrane and transport protons inside the cell. This MoA may explain many of the deleterious biological effects in mammalian cells, plants, phytoplankton, viruses, and protozoans that have been reported for these compounds.
Lithium Cepheid V708 Car with an unusual chemical composition
2024-02-20

Aims . The purpose of this work is to spectroscopically analyse the classical Cepheid V708 Car. A preliminary check of the spectrum of V708 Car showed that this is a lithium-rich supergiant. We also found that V708 Car has an unusual chemical composition in that the abundances of various elements correlate with their condensation temperatures. We tried to find an explanation of this feature, which is unusual for classical Cepheids. Methods . For the spectroscopic analysis, we used methods based on the assumption of local and non-local thermodynamic equilibrium. Results . We determined the fundamental parameters of our program star V708 Car. This long-period Cepheid has a mass of about 12 M ⊙ . We derived the abundances of 27 chemical elements in this star. They are clearly correlated with their condensation temperature: the higher the condensation temperature, the lower the abundance (there are exceptions for sodium and barium, however). We explain this peculiar chemical composition of the V708 Car atmosphere by the gas–dust separation in the envelope of this star. A similar mechanism leads to the observed peculiarities of the chemical composition of λ Boo, W Vir, and asymptotic giant branch stars.
User Friendliness and Perioperative Guidance Benefits of a Cataract Surgery Education App: Randomized Controlled Trial
2024-02-20

Background Cataract surgeries are among the most performed surgeries worldwide. A thorough patient education is essential to inform patients about the perioperative process and postoperative target results concerning the intraocular lens and objectives for visual outcomes. However, addressing all relevant aspects and questions is time-consuming. Mobile apps can facilitate this process for both patients and physicians and thus be beneficial. However, the success of such an app depends on its user friendliness and acceptance by patients. Objective This study aimed to evaluate the user friendliness and acceptance of a cataract surgery education app on mobile devices among patients undergoing cataract surgery, the characteristics of patients who benefit the most from app use, and the influence of the app on patient satisfaction with treatment. Methods All patients who underwent cataract surgery at an ophthalmological practice from August 2020 to July 2021 were invited to participate in this randomized controlled trial. Out of 493 invited patients, 297 (60.2%) were enrolled in this study. Patients were randomized into 3 different groups. Half of the patients were offered to participate in Group 1 with use of the “Patient Journey” app. However, if they decided not to use the app, they were included in Group 2 (app denial). The other half of the patients were included in Group 3 (control) with no use of the app and with information provided conventionally. The app provided general information on the ophthalmological center, surgeons, cataract, and treatment options. Different questionnaires were used in all 3 groups to evaluate satisfaction with the perioperative process. Group 1 evaluated the app. Demographic characteristics, such as age, gender, and educational degree, were assessed. Results Group 1 included 77 patients (median age 69 years). Group 2 included 61 patients, and their median age was higher (median age 79 years). Group 3 included 159 patients (median age 74 years). There was no difference in satisfaction with the perioperative process and clinic between the 3 groups. Almost all app users appreciated the digital details provided for the organization and the information on the surgery. Age did not play a major role in appreciation of the app. Female patients tended to appreciate the information provided more than male patients. Patients who did not have a higher university degree experienced more benefits from the informational content of the app and were the most satisfied with the information. However, male patients and academics were in general more aware of technology and handled the app more easily. Conclusions The app showed high user friendliness and acceptance, and could particularly benefit specific patient groups. App users demonstrated a noninferior high satisfaction with the treatment in the ophthalmological center in comparison with patients who were informed about the surgery only conventionally.
Nasal commensals reduceStaphylococcus aureusproliferation by restricting siderophore availability
2024-02-20

Background The human microbiome is critically associated with human health and disease. One aspect of this is that antibiotic-resistant opportunistic bacterial pathogens such as methicillin-resistant Staphylococcus aureus can reside within the nasal microbiota which increases the risk of infections. Epidemiological studies of the nasal microbiome have revealed positive and negative correlations between non-pathogenic species and S. aureus , but the underlying molecular mechanisms remain poorly understood. The nasal cavity is iron-limited and bacteria are known to produce iron-scavenging siderophores to proliferate in such environments. Siderophores are public goods that can be consumed by all members of a bacterial community. Accordingly, siderophores are known to mediate bacterial competition and collaboration but their role in the nasal microbiome is unknown. Results Here we show that siderophore acquisition is crucial for S. aureus nasal colonization in vivo . We screened 94 nasal bacterial strains from seven genera for their capacity to produce siderophores as well as to consume the siderophores produced by S. aureus. We found that 80% of the strains engaged in siderophoremediated interactions with S. aureus. Non-pathogenic corynebacterial species were found to be prominent consumers of S. aureus siderophores. In co-culture experiments, consumption of siderophores by competitors reduced S. aureus growth in an iron-dependent fashion. Conclusions Our data show a wide network of siderophore mediated interactions between the species of the human nasal microbiome and provide mechanistic evidence for inter-species competition and collaboration impacting pathogen proliferation. This opens avenues for designing nasal probiotics to displace S. aureus from the nasal cavity of humans.
SpacerPlacer: Ancestral reconstruction of CRISPR arrays reveals the evolutionary dynamics of spacer deletions
2024-02-20

Bacteria employ CRISPR-Cas systems for defense by integrating invader-derived sequences, termed spacers, into the CRISPR array, which constitutes an immunity memory. While spacer deletions occur randomly across the array, newly acquired spacers are predominantly integrated at the leader end. Consequently, spacer arrays can be used to derive the chronology of spacer insertions. Reconstruction of ancestral spacer acquisitions and deletions could help unravel the coevolution of phages and bacteria, the evolutionary dynamics in microbiomes, or track pathogens. However, standard reconstruction methods produce misleading results by overlooking insertion order and joint deletions of spacers. Here, we present SpacerPlacer, a maximum likelihood-based ancestral reconstruction approach for CRISPR array evolution. We used SpacerPlacer to reconstruct and investigate ancestral deletion events of 4565 CRISPR arrays, revealing that spacer deletions occur 374 times more frequently than mutations and are regularly deleted jointly, with an average of 2.7 spacers. Surprisingly, we observed a decrease in the spacer deletion frequency towards both ends of the reconstructed arrays. While the resulting trailer-end conservation is commonly observed, a reduced deletion frequency is now also detectable towards the variable leader end. Finally, our results point to the hypothesis that frequent loss of recently acquired spacers may provide a selective advantage.
Comment on egusphere-2023-3071
2024-02-20

<strong class="journal-contentHeaderColor">Abstract.</strong> For many ice core related scientific questions, like the analysis of fast changing climate signals, the depth resolution of conventional methods of analysis is not sufficient. In this study we present a setup of Laser Ablation Inductively Coupled Plasma &ndash; Mass Spectrometry (LA-ICP-MS) for high resolution glacier ice impurity analysis to the sub-millimetre scale. This setup enables chemical impurity ice core analysis to a depth resolution of ~ 80 &mu;m while consuming only minimal amounts of ice. The system was used for simultaneous analysis of sodium, magnesium and aluminium incorporated in the ice structure. In a first case study within the framework of the WACSWAIN (WArm Climate Stability of the West Antarctic ice sheet in the last INterglacial) project, the method was applied to a selection of samples from Skytrain ice core (West Antarctica), on a total length of 6.7 m consisting of about 130 single samples. The main goal of this study was to use the new LA-ICP-MS method to extract meaningful climate signals on a depth resolution level beyond the limits of Continuous Flow Analysis (CFA). A comparison between low resolution CFA data and the high resolution LA-ICP-MS data reveals generally good agreement on the decimetre scale. Stacking of parallel laser measurements together with frequency analysis is used to analyse the high resolution LA-ICP-MS data on the millimetre scale. Spectral analysis revealed that despite effects of impurity accumulation in ice crystal grain boundaries, periodic concentration changes in the Skytrain ice core on the millimetre scale can be identified in ice from 26 ka BP (kilo years before present; 1950 CE) and also from the Last Interglacial (LIG). These findings can open new possibilities for climate data interpretation with respect to fast changes in the last glacial and beyond.