Browse Articles

High-impedance microwave resonators with two-photon nonlinear effects

AbstractNonlinear effects play a central role in photonics as they form the foundation for most of the device functionalities such as amplification and quantum state preparation and detection. Typically the nonlinear effects are weak and emerge only at high photon numbers with strong drive. Here we present an experimental study of a Josephson junction -based high-impedance resonator. We show that by taking the resonator to the limit of consisting effectively only of one junction, results in strong nonlinear effects already for the second photon while maintaining a high impedance of the resonance mode. Our experiment yields thus resonators with strong interactions both between individual resonator photons and from the resonator photons to other electric quantum systems. We also present an energy diagram technique which enables to measure, identify and analyse different multi-photon optics processes along their energy conservation lines.

Retrospective study of incidence/prevalence of pigmentary maculopathy and retinopathy in patients receiving pentosan polysulfate sodium

Purpose To evaluate prevalence and incidence rates of pigmentary maculopathy and retinopathy (PM/PR), and visual acuity (VA) changes in patients exposed to pentosan polysulfate sodium (PPS) and in patients with interstitial cystitis (IC) not exposed to PPS. Methods This is a retrospective cohort study (January 2015–March 2021) which included adult de-identified patients from the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight) and Komodo Health database. Three patient cohorts were identified: two PPS-exposed patient cohorts, and Non-PPS-exposed IC patient cohort. Key study outcomes included PM/PR/Any (defined based on prior literature regardless of PPS exposure) and PM/PR/PPS (further defined by an algorithm that was based on clinical notes and other protocol-prespecified criteria in PPS-exposed patients), and VA changes in each respective cohort. Results Prevalence of PM/PR/Any was relatively common in patients prior to PPS exposure (4.16%–8.43%). Incidence rate of PM/PR/PPS was uncommon in both PPS-exposed cohorts (0.13–0.15 per 100 person-years). Crude incidence rates of PM/PR/Any (based on ITT analysis) varied slightly across 3 study cohorts (2.13–2.81 and 2.38 per 100-person-years for PPS-exposed cohorts and Non-PPS-exposed IC cohort, respectively). Across all 3 study cohorts, patients with PM/PR/Any appeared to have approximately 2-fold higher proportion of 3 lines of VA worsening than those without PM/PR/Any. Conclusion Prevalence of PM/PR was common in patients prior to PPS exposure. Incidence of PM/PR/PPS that may be associated with PPS exposure was relatively uncommon. Crude incidence rates of PM/PR appeared similar across all patient cohorts regardless of PPS exposure.

Outcomes in patients with <i>ETV6</i>::<i>RUNX1</i> or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies

Abstract Children with ETV6::RUNX1 or high-hyperdiploid B-cell acute lymphoblastic leukemia (B-ALL) have favorable outcomes. The St. Jude (SJ) classification considers these patients low risk, regardless of their National Cancer Institute (NCI) risk classification, except when there is slow minimal residual disease (MRD) response or central nervous system/testicular involvement. We analyzed outcomes in children (aged 1-18.99 years) with these genotypes in the SJ Total XV/XVI studies (2000-2017). Patients with ETV6::RUNX1 (n = 222) or high-hyperdiploid (n = 296) B-ALL had 5-year event-free survival (EFS) of 97.7% ± 1.1% and 94.7% ± 1.4%, respectively. For ETV6::RUNX1, EFS was comparable between NCI standard-risk and high-risk patients and between SJ low-risk and standard-risk patients. Of the 40 NCI high-risk patients, 37 who received SJ low-risk therapy had excellent EFS (97.3% ± 2.8%). For high-hyperdiploid B-ALL, NCI high-risk patients had worse EFS than standard-risk patients (87.6% ± 4.5% vs 96.4% ± 1.3%; P = .016). EFS was similar for NCI standard-risk and high-risk patients classified as SJ low risk (96.0% ± 1.5% and 96.9% ± 3.2%; P = .719). However, EFS was worse for NCI high-risk patients than for NCI standard-risk patients receiving SJ standard/high-risk therapy (77.4% ± 8.2% vs 98.0% ± 2.2%; P = .004). NCI high-risk patients with ETV6::RUNX1 or high-hyperdiploid B-ALL who received SJ low-risk therapy had lower incidences of thrombosis (P = .013) and pancreatitis (P = .011) than those who received SJ standard/high-risk therapy. MRD-directed therapy yielded excellent outcomes, except for NCI high-risk high-hyperdiploid B-ALL patients with slow MRD response, who require new treatment approaches. Among NCI high-risk patients, 93% with ETV6::RUNX1 and 54% with high-hyperdiploid B-ALL experienced excellent outcomes with a low-intensity regimen. These trials were registered at www.clinicaltrials.gov as #NCT00137111 and #NCT00549848.

Impact of population screening for Lynch syndrome insights from the All of Us data

Relative validity and reproducibility of a short semi-quantitative food frequency questionnaire for Chinese athletes

A convenient but efficient tool for evaluating dietary intakes in Chinese professional athletes has yet to be established. The aim of this study was to assess the validity of a short semi-quantitative food frequency questionnaire (FFQ) through comparison with 3-day weighed food records (3DWFRs) and corresponding serum biomarkers from a cohort of 102 professional athletes, while also evaluating its reproducibility. The relative validity was assessed using Spearman correlation coefficients, cross-quintiles classification, weighted kappa, and Bland–Altman analysis, while reproducibility was evaluated using the Spearman correlation coefficients and intraclass correlation coefficient (ICC) between two FFQs. The results showed the median (range) crude correlation coefficients (CCs) between the first FFQ and 3DWFRs for energy and nutrients, and the food groups were 0.331 (0.219 to 0.568) and 0.292 (-0.035 to 0.455), respectively. Omega-3 polyunsaturated fatty acid (EPA, DHA, and EPA+DHA) intake estimated from the FFQ significantly correlated with corresponding serum biomarkers, with CCs ranging from 0.389 to 0.520. Weighted kappa statistics, indicating acceptable consistency (&gt; 0.2) for most items, varied from -0.076 to 0.581, except for vitamin C, vegetables, and oils. Misclassification of nutrients and food groups into extreme quartiles was rare, with a median misclassification rate of 2% (ranging from 1% to 12%) and 3% (ranging 0 to 10%), respectively. Bland–Altman analysis revealed good agreement between FFQ and 3DWFRs, with over 90% of data points falling within the limits of agreement (LOA) for all assessed nutrients and food groups. In the reproducibility analysis, the median (range) crude CC and ICC for energy and nutrients were 0.574 (0.423 to 0.643) and 0.668 (0.558 to 0.763), respectively, while for food groups, they were 0.681 (0.242 to 0.764) and 0.640 (0.371 to 0.787), respectively. In conclusion, the short FFQ demonstrated acceptable relative validity and reproducibility for most nutrients and food groups, suggesting its potential as a valuable tool for assessing dietary intake and nutrition status among young Chinese athletes.

The current landscape of frontline large B-cell lymphoma trials

Abstract At least 25% to 35% of patients with large B-cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (pola-R-CHP [polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone]) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary end point, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. Although this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years.

Author Correction: Pervasive fire danger continued under a negative emission scenario

CAMSAP2 is required for bridging fiber assembly to ensure mitotic spindle assembly and chromosome segregation in human epithelial Caco-2 cells

In mammalian epithelial cells, cytoplasmic microtubules are mainly non-centrosomal, through the functions of the minus-end binding proteins CAMSAP2 and CAMSAP3. When cells enter mitosis, cytoplasmic microtubules are reorganized into the spindle composed of both centrosomal and non-centrosomal microtubules. The function of the CAMSAP proteins upon spindle assembly remains unknown, as these do not exhibit evident localization to spindle microtubules. Here, we demonstrate that CAMSAP2, but not CAMSAP3, is required for spindle assembly upon mitotic entry. CAMSAP2 knockout (KO) Caco-2 cells showed a delay in mitotic progression, whereas CAMSAP3 KO cells did not. The spindle in CAMSAP2 KO cells was short and displayed a reduced microtubule density, particularly around chromosomes. This indicated a loss of bridging fibers, which are known to assist alignment of sister kinetochores through interaction with kinetochore fibers. Consistent with this, live-cell imaging of CAMSAP2 KO cells captured slow elongation of the anaphase spindle and errors in chromosome segregation. Therefore, we propose that CAMSAP2 ensures efficient reorganization of cytoplasmic microtubules into the mitotic spindle through constructing bridging fibers that assist faithful segregation of sister chromatids.

Building the future management of follicular lymphoma with T-cell–redirecting strategies

Abstract Follicular lymphoma (FL) usually requires multiple lines of therapy, and disease control remains largely insufficient with conventional chemoimmunotherapy. Several T-cell–redirecting strategies recently approved in the relapsed/refractory setting have the potential to improve outcomes and change the treatment algorithm in FL. This review focuses on the role of chimeric antigen receptor T cells and bispecific antibodies in FL, paying special attention to sequencing approaches and future directions.

Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation

AbstractMutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.

Linguistically informed ChatGPT prompts to enhance Japanese-Chinese machine translation: A case study on attributive clauses

In the field of Japanese-Chinese translation linguistics, the issue of correctly translating attributive clauses has persistently proven to be challenging. Present-day machine translation tools often fail to accurately translate attributive clauses from Japanese to Chinese. In light of this, this paper investigates the linguistic problem underlying such difficulties, namely how does the semantic role of the modified noun affect the selection of translation patterns for attributive clauses, from a linguistic perspective. Through the analysis of numerous examples, the study develops a novel three-step prompt chaining strategy, which was tested using ChatGPT. The experimental results demonstrate that this approach significantly improves translation quality, with an average score increase of over 43%. These findings highlight the effectiveness and potential of linguistically informed prompt design in enhancing the translation accuracy of complex sentence structures. This study not only offers a new perspective on the integration of linguistics theory and machine translation technologies, but also provides valuable insights for optimizing large language models prompt and improving language education tools.

CD123 to the rescue

Coverage bias in small molecule machine learning

Abstract Small molecule machine learning aims to predict chemical, biochemical, or biological properties from molecular structures, with applications such as toxicity prediction, ligand binding, and pharmacokinetics. A recent trend is developing end-to-end models that avoid explicit domain knowledge. These models assume no coverage bias in training and evaluation data, meaning the data are representative of the true distribution. However, the domain of applicability is rarely considered in such models. Here, we investigate how well large-scale datasets cover the space of known biomolecular structures. For doing so, we propose a distance measure based on solving the Maximum Common Edge Subgraph (MCES) problem, which aligns well with chemical similarity. Although this method is computationally hard, we introduce an efficient approach combining Integer Linear Programming and heuristic bounds. Our findings reveal that many widely-used datasets lack uniform coverage of biomolecular structures, limiting the predictive power of models trained on them. We propose two additional methods to assess whether training datasets diverge from known molecular distributions, potentially guiding future dataset creation to improve model performance.

Determinants of agricultural employment during the COVID-19 pandemic: A spatial analysis of Brazilian municipalities

The impact of COVID-19 has extended beyond the health toll it has taken on populations. The global economy has experienced significant downturns, with unemployment rates reaching unprecedented highs for this century. Nonetheless, the agricultural sector has been uniquely affected by the pandemic, particularly given its crucial role in food supply. This study sought to examine the effects of the COVID-19 pandemic on agricultural employment in Brazilian municipalities. To achieve this, we employed a dataset spanning the period before and during the pandemic (2018–2021). Spatial econometrics was utilized to identify potential spatial factors linked to this occurrence. Notably, the findings reveal that the transfer policies implemented by the Brazilian Federal Government have had a positive impact on agricultural employment in Brazilian municipalities, challenging the common assumption that such measures might discourage job-seeking efforts. Moreover, the results suggest that the agricultural sector has managed to absorb individuals displaced from other sectors of the economy, demonstrating remarkable resilience in the face of economic challenges.

In APL, 2 targets are better than 1!

Vertex model with internal dissipation enables sustained flows

AbstractComplex tissue flows in epithelia are driven by intra- and inter-cellular processes that generate, maintain, and coordinate mechanical forces. There has been growing evidence that cell shape anisotropy, manifested as nematic order, plays an important role in this process. Here we extend an active nematic vertex model by replacing substrate friction with internal viscous dissipation, dominant in epithelia not supported by a substrate or the extracellular matrix, which are found in many early-stage embryos. When coupled to cell shape anisotropy, the internal viscous dissipation allows for long-range velocity correlations and thus enables the spontaneous emergence of flows with a large degree of spatiotemporal organisation. We demonstrate sustained flow in epithelial sheets confined to a channel, providing a link between the cell-level vertex model of tissue dynamics and continuum active nematics, whose behaviour in a channel is theoretically understood and experimentally realisable. Our findings also show a simple mechanism that could account for collective cell migration correlated over distances large compared to the cell size, as observed during morphogenesis.

How traditional cultural load affects tourists’ purchasing intention of tourist souvenirs

Based on the previous studies on the impact of traditional culture on tourists’ purchasing intentions, this study aims to further explore the mechanism and boundary conditions regarding the traditional cultural load in tourist souvenir packaging. Through seven simulated experiments (N = 3203), the impact of different degrees of traditional cultural load on tourists’ purchasing intentions has been examined, with value perception, cultural identity, and purchase purpose, advancing the research in the field of traditional culture and tourism marketing. The findings provide insights for managers in the industry of tourism and souvenir marketing for their package design.

Acute promyelocytic leukemia: long-term outcomes from the HARMONY project

Abstract Treatment outcomes for acute promyelocytic leukemia (APL) have improved with the widespread use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Our study aimed to validate these data in a large patient cohort, and to redefine prognostic factors. Leveraging the HARMONY Platform, we analyzed 1438 newly diagnosed patients with APL, diagnosed between 1999 and 2022. Patient data derived from the 2 international multicenter Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA)-APL0406 and National Cancer Research Institute (NCRI)-AML17 trials and 4 European registries: the Haemato Oncology Foundation for Adults in the Netherlands, Belgium and Luxembourg (HOVON), AML Study Group (AMLSG), Swedish AML Registry, and Study Alliance Leukemia (SAL). The study cohort included 721 males and 717 females, with a median age of 50.5 years (range, 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO, and 747 idarubicin-based chemotherapy (AIDA-like CHT). Early death (ED) occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz risk score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.04-1.08; and OR, 4.65; 95% CI, 2.55-8.51, respectively). The median follow-up was 5.5 years (interquartile range, 3.2-7.5 years). ATRA-ATO regimen was associated with the best outcome, reaching 91% 7-year overall survival (vs 81% for AIDA-like CHT; hazard ratio [HR], 2.14; 95% CI, 1.51-3.05), 89% event-free survival (vs 71% for AIDA-like CHT; HR, 2.72; 95% CI, 2.01–3.69), and 3% relapse (vs 13% for AIDA-like CHT; HR, 4.19; 95% CI, 2.38-7.39; P &amp;lt; .001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients’ age, Sanz risk score, and treatment scenario. Our study confirms the superiority of ATRA-ATO over ATRA-chemotherapy in patients with APL. Reducing the risk of ED still represents an unmet medical need, in particular in older patients and in high-risk APL.

Inequitable distribution of risks associated with occupational heat exposure driven by trade

Clinical, histopathological and parasitological follow-up of dogs naturally infected by Leishmania infantum before and after miltefosine treatment and associated therapies

In Brazil, Visceral Leishmaniases is caused by Leishmania infantum, and domestic dogs are the main reservoirs in its urban transmission cycle. As an alternative to euthanizing dogs, miltefosine has been used to treat canine visceral leishmaniasis since 2016. In this study, we have assessed the efficacy of miltefosine for treating canine visceral leishmaniasis in a new endemic area through follow-up of naturally infected dogs was evaluated. The clinical, parasitological, and histopathological characteristics of 21 dogs naturally infected with L. infantum were assessed at three time points: on the day before initiating miltefosine treatment (T0), immediately after treatment completion (T1), and 6 months after treatment completion (T2). Three dogs were treated exclusively with miltefosine, while eighteen received combination therapy with miltefosine with other treatments such as allopurinol, domperidone and immunotherapy. Skin biopsies were obtained from the abdomen to assess inflammatory responses and to quantify parasite loads using qPCR. The parasites were isolated using aspirates acquired from popliteal lymph nodes. Molecular and parasitological analyses confirmed the presence of L. infantum in all dogs, validating the effectiveness of skin and lymph node samples for diagnosis. The clinical conditions of the infected animals were improved and the skin parasite load decreased after treatment, even when distinct combination therapies were performed. The histopathological assessment revealed a miltefosine-induced reduction in the inflammatory response and a decrease in amastigotes number. Furthermore, a positive correlation was established between the reduction in parasite load and the enhancement of clinical scoring, as well as a reduction in the skin inflammatory response. Our findings suggest that miltefosine-based combination therapies reduce skin parasite load and improve clinical outcomes, while the dogs treated with miltefosine alone showed increased parasitic load and worsened clinical staging at T2. Considering this data belonging to a recent transmission area, treatment strategy suggests effective in controlling canine visceral leishmaniasis.