julilili42/papers huggingface dataset:
GlnA3Mtis able to glutamylate spermine but it is not essential for the detoxification of spermine inMycobacterium tuberculosis
2023-12-15

ABSTRACT Mycobacterium tuberculosis is well adapted to survive and persist in the infected host, escaping the host immune response. Since polyamines, which are synthesized by infected macrophages are able to inhibit the growth of M. tuberculosis , the pathogen needs strategies to cope with toxic spermine. The actinomycete Streptomyces coelicolor , closely related to M. tuberculosis makes use of a gamma-glutamylation pathway to functionally neutralize spermine. We therefore considered whether a similar pathway would be functional in M. tuberculosis . In the current study we demonstrated that M. tuberculosis growth was inhibited by the polyamine spermine. Using a glutamine synthetase-based in vitro enzymatic activity assay we determined that GlnA3 Mt (Rv1878) is a gamma-glutamylspermine synthetase. In an in vitro phosphate release assay we showed that purified His-Strep-GlnA3 Mt as well as native GlnA3 Mt prefer spermine as a substrate to putrescine, cadaverine, spermidine or other monoamines and amino acids, suggesting that GlnA3 Mt may play a specific role in the detoxification of the polyamine spermine. However, the deletion of the glnA3 gene in M. tuberculosis did not result in growth inhibition or enhanced sensitivity of M. tuberculosis in the presence of high spermine concentrations. Subsequent RNAsequencing of M. tuberculosis bacteria revealed that the gene cluster consisting of the efflux pump-encoding rv3065-rv3066-rv3067 genes is upregulated upon spermine treatment, suggesting its involvement in bacterial survival under elevated spermine concentrations. IMPORTANCE Antibiotics for the treatment of Mycobacterium tuberculosis infections attack classical bacterial targets, such as the cell envelope or the ribosome. Upon M. tuberculosis infection macrophages synthesize the polyamine spermine which - at elevated concentrations - is toxic for M. tuberculosis . Based on our investigations of spermine resistance in the closely related actinomycete Streptomyces coelicolor , we hypothesized that the glutamyl-sperminesynthetase GlnA3 may be responsible for resistance against toxic spermine. Here we show that the mycobacterial glutamyl-sperminesynthetase indeed can inactivate spermine by glutamylation. However, GlnA3 is probably not the only resistance mechanism since a glnA3 mutant of M. tuberculosis can survive under spermine stress. Gene expression studies suggest that an efflux pump may participate in resistance. The functional role of GlnA3 Mt as well as of the spermine transporter in the pathogenicity of M. tuberculosis is of special interest for their validation as new targets of novel anti-tubercular drugs.
Contributions of tactile information to the sense of agency and its metacognitive representations
2023-12-15

Abstract We compared the contribution of tactile information to other sources of information in our representations of agency. Participants (N = 40) reached with their right hand toward a ridged plate with a specific orientation and saw online feedback that could match or differ from their action in one of three ways: the physical plate’s orientation, the action’s timing, or the hand’s position in space. Absolute subjective ratings revealed that an increased mismatch in tactile information led to a diminished sense of agency, similar to what has been reported for spatial and temporal mismatches. Further, estimations of metacognitive efficiency revealed similar M-ratios in the identification of tactile violation predictions as compared to temporal violations (but lower than spatial). These findings emphasize the importance of tactile information in shaping our experience of acting voluntarily, and show how this important component can be experimentally probed. Statement of Relevance The sense of agency is the feeling that we are the authors of our actions. It is essential not only for the control we assert over our bodies but also for how we interact with interfaces like a computer or a mobile phone. Despite the central role of touch in our daily activities, the role of tactile information in forming our sense of agency is often overlooked. In this project, we used a novel experimental design that allowed us to compare the role of tactile information relative to two other sources of information that have been previously reported to affect our agency, namely temporal and spatial information of the action. We provide evidence for the first time that tactile information is crucial for our subjective experience of agency and a tool to study this role further.
The epistemological orientation of Ottoman argumentation theory and its relation to kalām
2023-12-15

Abstract Islamic (Ottoman) argumentation theories provide strong evidence that the argumentation theory advocated by Ottoman theorists was epistemologically oriented, and has strong parallels with the argumentation theory of kalām (dialectical theology); indeed Ottoman argumentation theory and kalām interacted intensively and influenced each other. This article traces some snapshots of this discourse. In doing so, key concepts of Islamic (Ottoman) argumentation theories are introduced.
“What God Has Joined Together, Let No Man Pull Asunder”?
2023-12-15

Abstract In Mark 10:1–12, Jesus and the Pharisees discuss whether divorce is permissible. The Pharisees’ question and Jesus’s answer seem artificial against the background of ancient discourses on divorce. Particularly Jesus’s answer in Mark 10:9, which forbids divorce without exception, still gives rise to discussion today. It appears uncompromising and unyielding compared to other NT texts dealing with divorce (Matt 19:1–12; 1 Cor 7:10–16). I show that the prohibition of divorce in Mark 10:9 is the result of a conflict of authority between Jesus and the Pharisees that develops in the Streitgespräche in Mark’s Gospel up to Mark 10:1–12.
Reply on RC2
2023-12-15

<strong class="journal-contentHeaderColor">Abstract.</strong> An increasing number of climate model simulations is becoming available for the transition from the Last Glacial Maximum to the Holocene. Assessing the simulations&rsquo; reliability requires benchmarking against environmental proxy records. To date, no established method exists to compare these two data sources in space and time over a period with changing background conditions. Here, we develop a new algorithm to rank simulations according to their deviation from reconstructed magnitudes and temporal patterns of orbital- as well as millennial-scale temperature variations. The use of proxy forward modeling avoids the need to reconstruct gridded or regional mean temperatures from sparse and uncertain proxy data. First, we test the reliability and robustness of our algorithm in idealized experiments with prescribed deglacial temperature histories. We quantify the influence of limited temporal resolution, chronological uncertainties, and non-climatic processes by constructing noisy pseudo-proxies. While model-data comparison results become less reliable with increasing uncertainties, we find that the algorithm discriminates well between simulations under realistic non-climatic noise levels. To obtain reliable and robust rankings, we advise spatial averaging of the results for individual proxy records. Second, we demonstrate our method by quantifying the deviations between an ensemble of transient deglacial simulations and a global compilation of sea surface temperature reconstructions. The ranking of the simulations differs substantially between the considered regions and timescales. We attribute this diversity in the rankings to more regionally confined temperature variations in reconstructions than in simulations, which could be the result of uncertainties in boundary conditions, shortcomings in models, or regionally varying characteristics of reconstructions such as recording seasons and depths. Future work towards disentangling these potential reasons can leverage the flexible design of our algorithm and its demonstrated ability to identify varying levels of model-data agreement.
Reply on RC1
2023-12-15

<strong class="journal-contentHeaderColor">Abstract.</strong> An increasing number of climate model simulations is becoming available for the transition from the Last Glacial Maximum to the Holocene. Assessing the simulations&rsquo; reliability requires benchmarking against environmental proxy records. To date, no established method exists to compare these two data sources in space and time over a period with changing background conditions. Here, we develop a new algorithm to rank simulations according to their deviation from reconstructed magnitudes and temporal patterns of orbital- as well as millennial-scale temperature variations. The use of proxy forward modeling avoids the need to reconstruct gridded or regional mean temperatures from sparse and uncertain proxy data. First, we test the reliability and robustness of our algorithm in idealized experiments with prescribed deglacial temperature histories. We quantify the influence of limited temporal resolution, chronological uncertainties, and non-climatic processes by constructing noisy pseudo-proxies. While model-data comparison results become less reliable with increasing uncertainties, we find that the algorithm discriminates well between simulations under realistic non-climatic noise levels. To obtain reliable and robust rankings, we advise spatial averaging of the results for individual proxy records. Second, we demonstrate our method by quantifying the deviations between an ensemble of transient deglacial simulations and a global compilation of sea surface temperature reconstructions. The ranking of the simulations differs substantially between the considered regions and timescales. We attribute this diversity in the rankings to more regionally confined temperature variations in reconstructions than in simulations, which could be the result of uncertainties in boundary conditions, shortcomings in models, or regionally varying characteristics of reconstructions such as recording seasons and depths. Future work towards disentangling these potential reasons can leverage the flexible design of our algorithm and its demonstrated ability to identify varying levels of model-data agreement.
Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus
2023-12-15

ABSTRACT Mycobacterium abscessus ( Mab ) affects patients with immunosuppression, Cystic Fibrosis (CF), or underlying structural lung diseases. Additionally, Mab poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with a β-lactamase inhibitors [BLI; avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration MIC values for 54 clinical Mab isolates and ATCC19977 (MIC 50 and MIC 90 ≤ 0.25 μg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ∼1.5 Log 10 CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in additional reduction of CFUs (∼3 Log 10 for sulopenem-CXM and AVI and ∼4 Log 10 for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (LDTs; LDT Mab1 –LDT Mab4 ), Penicillin-Binding-Protein B (PBP-B), and D,D-Carboxypeptidase (DDC). Acyl complexes identified via mass spectrometry analysis, demonstrated the binding of sulopenem with Ldt Mab2 -Ldt Mab4 , DDC, and PBP B, and CXM with Ldt Mab2 and PBP-B. Molecular docking suggested formation of a covalent adduct between sulopenem and Ldt Mab2 after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring, and the establishment of a thioester bond linking the Ldt Mab2 with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLI. These findings potentially broaden selection of oral therapeutic agents to combat Mab .
Olfactory neuroblastoma in children and adolescents: The EXPeRT recommendations for diagnosis and management
2023-12-17

Olfactory neuroblastoma (ON) is a rare tumor commonly presenting between 50 and 60 years of age. In pediatric age this tumor is even rarer, with an estimated incidence of 0.1 per 100,000 children up to 15 years. It arises from the olfactory neurorepithelium of the nasal cavity, and it can be locally aggressive, spreading to the orbital cavity, skull base, intracranial cavity. In rarer cases it can also give distant metastasis, more frequently to regional lymph nodes and less commonly to distant sites like liver, lungs and bones. Prognosis varies depending on the stage at presentation (including dural invasion, regional nodal involvement, and distant metastasis), the histological grade, and aspects related to the treatment, such as the possibility to achieve clear margins with surgery and the multimodal approach. Chemotherapy, surgery and radiotherapy have been used to treat these patients and the different approaches have been reported in the literature. Given the rarity of the disease no shared guidelines exist for the management of this entity in children, but some suggestions can be given to optimize the ON management.&#13;\\nThis study presents the internationally recognized recommendations for the diagnosis and treatment of ON in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).
Proverb comprehension in schizophrenia: A comprehensive review and meta-analysis
2023-12-17

While lower abstraction and higher bizarreness seems a characteristic of iSCZ, the diagnostic specificity of a concrete response was astonishingly low. The lack of a unified definition for concretism and limited consideration of cultural diversity contributed to these complex findings. Future research should focus on exploring the qualitative aspects of proverb comprehension and the association between symptomatology types and misinterpretations to improve diagnostic accuracy.
Fosfomycin Uptake in Escherichia coli Is Mediated by the Outer-Membrane Porins OmpF, OmpC, and LamB
2023-12-17

The antibiotic fosfomycin (FOS) is widely recognized for the treatment of lower urinary tract infections with <i>Escherichia coli</i> and has lately gained importance as a therapeutic option to combat multidrug-resistant bacteria. However, resistance to FOS frequently develops through mutations reducing its uptake. Although the inner-membrane transport of FOS has been extensively studied in <i>E. coli</i>, its outer-membrane (OM) transport remains insufficiently understood. While evaluating minimal inhibitory concentrations in OM porin-deficient mutants, we observed that the <i>E. coli</i> Δ<i>ompF</i>Δ<i>ompC</i> strain is four times more resistant to FOS than the wild type and the respective single mutants. Continuous monitoring of FOS-induced lysis of porin-deficient strains additionally highlighted the importance of LamB. The relevance of OmpF, OmpC, and LamB to FOS uptake was confirmed by electrophysiological and transcriptional analysis. Our study gives for the first time in-depth insight into the transport of FOS through the OM in <i>E. coli</i>.
The “Okusuri Charm” movement in Japan: Prescription drug accessories emerging on X (Twitter)
2023-12-17

Abstract Background In this digital age, social networks may offer an avenue for individuals to obtain drugs illicitly beyond the prescribed amount. Users on X (Twitter)® have ingeniously fabricated fashionable accessories that employ prescription drug sheets, termed “Okusuri Charm”. Methods This cross‐sectional study scrutinized the emerging “Okusuri Charm” trend, by searching the term in Japanese on X (Twitter)® and analyzing related posts. Results Alongside illegal prescription drug trading, individuals crafted accessories from drug sheets, particularly prescribed psychiatric drugs, and dealt with other users, leading to a growing trend this year. Conclusions A positive outlook toward this trend is the emergence of a new artistic movement, but a pessimistic viewpoint is the creators' misuse of prescription drugs, potentially fostering illegal drug dealings.
Socio-emotional Skills and the Socioeconomic Achievement Gap
2023-12-18

Empirical evidence suggests children’s socio-emotional skills—an important determinant of school achievement—vary according to socioeconomic family background. This study assesses the degree to which differences in socio-emotional skills contribute to the achievement gap between socioeconomically advantaged and disadvantaged children. We used data on 74 countries from the 2018 Programme for International Student Assessment, which contains an extensive set of psychological measures, including growth mindset, self-efficacy, and work mastery. We developed three conceptual scenarios to analyze the role of socio-emotional skills in learning inequality: simple accumulation, multiplicative accumulation, and compensatory accumulation. Our findings are in line with the simple accumulation scenario: Socioeconomically advantaged children have somewhat higher levels of socio-emotional skills than their disadvantaged peers, but the effect of these skills on academic performance is largely similar in both groups. Using a counterfactual decomposition method, we show that the measured socio-emotional skills explain no more than 8.8 percent of the socioeconomic achievement gap. Based on these findings, we argue that initiatives to promote social and emotional learning are unlikely to substantially reduce educational inequality.
First X-Ray Polarization Measurement Confirms the Low Black Hole Spin in LMC X-3
2023-12-18

Abstract X-ray polarization is a powerful tool to investigate the geometry of accreting material around black holes, allowing independent measurements of the black hole spin and orientation of the innermost parts of the accretion disk. We perform X-ray spectropolarimetric analysis of an X-ray binary system in the Large Magellanic Cloud, LMC X-3, that hosts a stellar-mass black hole, known to be persistently accreting since its discovery. We report the first detection of the X-ray polarization in LMC X-3 with the Imaging X-ray Polarimetry Explorer, and find the average polarization degree (PD) of 3.2% ± 0.6% and a constant polarization angle of −42° ± 6° over the 2–8 keV range. Using accompanying spectroscopic observations by NICER, NuSTAR, and the Neil Gehrels Swift observatories, we confirm previous measurements of the black hole spin via the X-ray continuum method, a ≈ 0.2. From polarization analysis only, we found consistent results with low black hole spin, with an upper limit of a &lt; 0.7 at a 90% confidence level. A slight increase in the PD with energy, similar to other black hole X-ray binaries in the soft state, is suggested from the data but with a low statistical significance.
Entangled time-crystal phase in an open quantum light-matter system
2023-12-18

Time crystals are nonequilibrium many-body phases in which the state of the system dynamically approaches a limit cycle. While these phases have recently been the focus of intensive research, it is still far from clear whether they can host quantum correlations. In fact, mostly classical correlations have been observed so far, and time crystals appear to be effectively classical high-entropy phases. Here, we consider the nonequilibrium behavior of an open quantum light-matter system, realizable in current experiments, which maps to a paradigmatic time-crystal model after an adiabatic elimination of the light field. The system displays a bistable regime with coexistent time-crystal and stationary phases, terminating at a tricritical point from which a second-order phase transition line departs. While light and matter are uncorrelated in the stationary phase, the time-crystal phase features bipartite correlations of both quantum and classical nature. Our work unveils that time-crystal phases in collective open quantum systems can sustain quantum correlations, including entanglement, and are thus more than effectively classical many-body phases.
The problem of antimalarial resistance and its implications for drug discovery
2023-12-18

While employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future. Incorporating resistance propensity assessment during this developmental process will increase the likelihood of effective and enduring malaria treatments.
The aesthetic valve: how aesthetic appreciation may switch emotional states from anxiety to curiosity
2023-12-18

Pursuing new knowledge in the entropic environment is pivotal for survival. However, dealing with uncertainty is a costly challenge for the agent surrounded by the stochastic sensory world, giving rise to different epistemic emotions, such as curiosity and anxiety. We recently proposed that aesthetic appreciation may have the role of associating pleasant feedback with the update of predictive representations. According to this idea, aesthetic appreciation and its associated rewarding feeling could drive people to seek new knowledge over anxiety. However, the relationship between aesthetic appreciation, curiosity, and anxiety has been still under-examined in the literature. Here, we explore the relationship between these epistemic emotions in a series of three experiments. In study 1, we examined whether music-induced aesthetic appreciation would influence curiosity in a gambling task. In studies 2a and 2b, we explore the relationship between music-induced aesthetic appreciation and anxiety state. Overall, aesthetic appreciation promoted curiosity-driven behaviour while it was negatively associated with anxiety. These results were consistent with the idea that aesthetic appreciation could act as a ‘valve’, prompting the individual to perceive curiosity (i.e. to consider novelty as a valuable opportunity to acquire new knowledge) rather than anxiety (i.e. to consider novelty as a risk to be avoided). This article is part of the theme issue ‘Art, aesthetics and predictive processing: theoretical and empirical perspectives’.
Two birds with one stone: human SIRPα nanobodies for functional modulation and in vivo imaging of myeloid cells
2023-12-18

Signal-regulatory protein α (SIRPα) expressed by myeloid cells is of particular interest for therapeutic strategies targeting the interaction between SIRPα and the “don’t eat me” ligand CD47 and as a marker to monitor macrophage infiltration into tumor lesions. To address both approaches, we developed a set of novel human SIRPα (hSIRPα)–specific nanobodies (Nbs). We identified high-affinity Nbs targeting the hSIRPα/hCD47 interface, thereby enhancing antibody-dependent cellular phagocytosis. For non-invasive in vivo imaging, we chose S36 Nb as a non-modulating binder. By quantitative positron emission tomography in novel hSIRPα/hCD47 knock-in mice, we demonstrated the applicability of 64 Cu-hSIRPα-S36 Nb to visualize tumor infiltration of myeloid cells. We envision that the hSIRPα-Nbs presented in this study have potential as versatile theranostic probes, including novel myeloid-specific checkpoint inhibitors for combinatorial treatment approaches and for in vivo stratification and monitoring of individual responses during cancer immunotherapies.