The Lyapunov exponent of a quantum system has been predicted to be bounded by
λ
L
≤
2
π
T
/
ħ
, where
T
is its temperature, as established by Maldacena, Shenker, and Stanford (MSS). This bound plays ...an important role in studying very diverse topics of physics, ranging from the dynamics of interacting many-body systems to the black hole information problem, and it is saturated when the system under consideration is the exact holographic dual of a black hole. Based on the fact that an inverted harmonic oscillator (IHO) may exhibit the behavior of thermal energy emission, in close analogy to the Hawking radiation emitted by black holes, we propose using a trapped ion as an implementation of the IHO to verify, in a concrete analogue-gravity system, whether the MSS bound can be identically saturated. To this end, we provide prescriptions for experimentally observing the scattering process at the IHO potential, which yields an analogue of Hawking radiation, as well as for how to measure the corresponding out-of-time-ordered correlation function (OTOC), diagnosing quantum chaos, in this thermally excited semiclassical system. We theoretically show, for an experimentally realizable analogue-gravity setup, that the effective Hawking temperature of the trapped-ion-IHO indeed matches the upper MSS bound for the speed of scrambling.
In order to identify anaplastic lymphoma kinase‐driven non‐small cell lung cancer (ALK+ NSCLC) patients with a worse outcome, who might require alternative therapeutic approaches, we retrospectively ...analyzed all stage IV cases treated at our institutions with one of the main echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK fusion variants V1, V2 and V3 as detected by next‐generation sequencing or reverse transcription‐polymerase chain reaction (n = 67). Progression under tyrosine kinase inhibitor (TKI) treatment was evaluated both according to Response Evaluation Criteria in Solid Tumors (RECIST) and by the need to change systemic therapy. EML4‐ALK fusion variants V1, V2 and V3 were found in 39%, 10% and 51% of cases, respectively. Patients with V3‐driven tumors had more metastatic sites at diagnosis than cases with the V1 and V2 variants (mean 3.3 vs. 1.9 and 1.6, p = 0.005), which suggests increased disease aggressiveness. Furthermore, V3‐positive status was associated with earlier failure after treatment with first and second‐generation ALK TKI (median progression‐free survival PFS by RECIST in the first line 7.3 vs. 39.3 months, p = 0.01), platinum‐based combination chemotherapy (median PFS 5.4 vs. 15.2 months for the first line, p = 0.008) and cerebral radiotherapy (median brain PFS 6.1 months vs. not reached for cerebral radiotherapy during first‐line treatment, p = 0.028), and with inferior overall survival (39.8 vs. 59.6 months in median, p = 0.017). Thus, EML4‐ALK fusion variant V3 is a high‐risk feature for ALK+ NSCLC. Determination of V3 status should be considered as part of the initial workup for this entity in order to select patients for more aggressive surveillance and treatment strategies.
What's new?
EML4‐ALK fusions are driving 5% of non‐small cell lung cancers (NSCLC). The present study shows for the first time that a specific fusion variant, namely V3 (E6;A20), is associated with more aggressive disease and worse overall survival due to earlier failure of several therapeutic modalities. This will necessitate inclusion of molecular assays beyond FISH in future diagnostic guidelines for ALK+ NSCLC and prompt development of more efficient strategies for the management of higher‐risk, V3‐positive cases.
Summary Background Necitumumab is a second-generation recombinant human immunoglobulin G1 EGFR monoclonal antibody that competitively inhibits ligand binding. We aimed to compare necitumumab plus ...pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC). Methods We did this randomised, open-label, controlled phase 3 study at 103 sites in 20 countries. Patients aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomisation scheme (block size of four) via a telephone-based interactive voice-response system or interactive web-response system. Patients received either cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 of a 3-week cycle for a maximum of six cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects. Randomisation was stratified by smoking history, ECOG performance status, disease histology, and geographical region. Patients and study investigators were not masked to group assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00982111. Findings Between Nov 11, 2009, and Feb 2, 2011, we randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n=315) or pemetrexed and cisplatin alone (n=318). Enrolment was stopped on Feb 2, 2011, after a recommendation from the independent data monitoring committee. There was no significant difference in overall survival between treatment groups, with a median overall survival of 11·3 months (95% CI 9·5–13·4) in the necitumumab plus pemetrexed and cisplatin group versus 11·5 months (10·1–13·1) in the pemetrexed and cisplatin group (hazard ratio 1·01 95% CI 0·84–1·21; p=0·96). The incidence of grade 3 or worse adverse events, including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5%) of 304 patients in the necitumumab group versus nine (3%) of 312 patients in the pemetrexed and cisplatin group. Serious adverse events were likewise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 51% of 304 vs 127 41% of 312 patients). Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3–4 rash (45 15% of 304 vs one <1% of 312 patients in the pemetrexed and cisplatin alone group), hypomagnesaemia (23 8% vs seven 2% patients), and grade 3 or higher venous thromboembolic events (23 8% vs 11 4% patients) than did those in the pemetrexed and cisplatin alone group. Interpretation Our findings show no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increases survival of previously untreated patients with stage IV non-squamous NSCLC. Unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin. Funding Eli Lilly and Company.
A fundamental requirement for the development of advanced electronic device architectures based on graphene nanoribbon (GNR) technology is the ability to modulate the band structure and charge ...carrier concentration by substituting specific carbon atoms in the hexagonal graphene lattice with p- or n-type dopant heteroatoms. Here we report the atomically precise introduction of group III dopant atoms into bottom-up fabricated semiconducting armchair GNRs (AGNRs). Trigonal-planar B atoms along the backbone of the GNR share an empty p-orbital with the extended π-band for dopant functionality. Scanning tunneling microscopy (STM) topography reveals a characteristic modulation of the local density of states along the backbone of the GNR that is superimposable with the expected position and concentration of dopant B atoms. First-principles calculations support the experimental findings and provide additional insight into the band structure of B-doped 7-AGNRs.
Advancements in artificial intelligence are rapidly increasing. The new‐generation large language models, such as ChatGPT and GPT‐4, bear the potential to transform educational approaches, such as ...peer‐feedback. To investigate peer‐feedback at the intersection of natural language processing (NLP) and educational research, this paper suggests a cross‐disciplinary framework that aims to facilitate the development of NLP‐based adaptive measures for supporting peer‐feedback processes in digital learning environments. To conceptualize this process, we introduce a peer‐feedback process model, which describes learners' activities and textual products. Further, we introduce a terminological and procedural scheme that facilitates systematically deriving measures to foster the peer‐feedback process and how NLP may enhance the adaptivity of such learning support. Building on prior research on education and NLP, we apply this scheme to all learner activities of the peer‐feedback process model to exemplify a range of NLP‐based adaptive support measures. We also discuss the current challenges and suggest directions for future cross‐disciplinary research on the effectiveness and other dimensions of NLP‐based adaptive support for peer‐feedback. Building on our suggested framework, future research and collaborations at the intersection of education and NLP can innovate peer‐feedback in digital learning environments.
Practitioner notes
What is already known about this topic
There is considerable research in educational science on peer‐feedback processes.
Natural language processing facilitates the analysis of students' textual data.
There is a lack of systematic orientation regarding which NLP techniques can be applied to which data to effectively support the peer‐feedback process.
What this paper adds
A comprehensive overview model that describes the relevant activities and products in the peer‐feedback process.
A terminological and procedural scheme for designing NLP‐based adaptive support measures.
An application of this scheme to the peer‐feedback process results in exemplifying the use cases of how NLP may be employed to support each learner activity during peer‐feedback.
Implications for practice and/or policy
To boost the effectiveness of their peer‐feedback scenarios, instructors and instructional designers should identify relevant leverage points, corresponding support measures, adaptation targets and automation goals based on theory and empirical findings.
Management and IT departments of higher education institutions should strive to provide digital tools based on modern NLP models and integrate them into the respective learning management systems; those tools should help in translating the automation goals requested by their instructors into prediction targets, take relevant data as input and allow for evaluating the predictions.
Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions ...(NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK(-/-)cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK-Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration.
Low-enthalpy geothermal wells are considered a sustainable energy source, particularly for district heating in the Netherlands. The cement sheath in these wells experiences thermal cycles. The ...stability of cement recipes under such conditions is not well understood. In this work, thermal cycling experiments for intermediate- and low-temperature geothermal well cements have been conducted. The samples were cured either under ambient conditions or under realistic pressure and temperature for 7 days. The samples did not show any signs of failure after performing 10 cycles of thermal treatment between 100 °C and 18 °C. We also tested cement formulations under drying conditions. Drying shrinkage is caused by a reduction in the water content of cement, which leads to capillary forces that can damage cement. Such circumstances lead to tensile stresses causing radial cracks. Most samples exhibited cracks under low humidity conditions (drying). Fiber reinforcement, especially using short PP fibers, improved the cement's resilience to temperature and humidity changes. Such additives can improve the longevity of cement sheaths in geothermal wells.
Thiamine deficiency has been typically associated with alcoholism or as a prevalent problem in low‐ and middle‐income countries (LMICs) whose populations rely on staple foods with a low content of ...thiamine. We conducted a literature review of published and unpublished data to identify relevant adult cases with confirmed thiamine deficiency of nonalcoholic cause in developed countries. We selected 17 reports with 81 adult cases of confirmed thiamine deficiency affecting adult patients with a wide range of ages and underlying conditions (e.g., cancer, gastrointestinal diseases, heart failure, and obesity). Thiamine deficiency may have been caused by disease‐related malnutrition, bariatric surgery, chronic use of diuretics, repeated vomiting, lack of thiamine in parenteral nutrition formulas, food insecurity, and reliance on monotonous or restrictive diets. Treatment with intravenous thiamine resulted in partial or complete recovery from the symptoms (cardiac, neurologic, and metabolic disorders) for most patients. The number and variety of symptomatic thiamine‐deficient adults identified in this review demonstrates that thiamine deficiency is not exclusive to LMICs and, in high‐income settings, is not exclusive to alcoholic patients. In developed countries, this serious but treatable condition can be expected in patients suffering from various medical conditions or following certain dietary patterns.
Cytotoxic T lymphocytes (CTLs) kill infected and cancerous cells. We detected transfer of cytotoxic multiprotein complexes, called supramolecular attack particles (SMAPs), from CTLs to target cells. ...SMAPs were rapidly released from CTLs and were autonomously cytotoxic. Mass spectrometry, immunochemical analysis, and CRISPR editing identified a carboxyl-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing. Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nanometer diameter. Cryo-soft x-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules. We propose that SMAPs are autonomous extracellular killing entities that deliver cytotoxic cargo targeted by the specificity of shell components.
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