bluuebunny/crossref_metadata_2025 huggingface dataset:
Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia
Authors: Watts Justin M. , Shaw Simon J. , Jonas Brian A.
Published: October 2024

Opinion Statement

Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.
Assessment of a Medical Student–Run Multidisciplinary Oncology Shadowing Program
Authors: Santos Teles Marco , Shah Shrey B. , Mattes Malcolm D.
Published: October 2024

Clinical exposures during the first two years of medical school (MS1-2) provide students an opportunity for early networking, mentorship and career exploration. The feasibility and perceived value of an extracurricular, student-run multidisciplinary oncology shadowing program was evaluated in this study. At a single institution, an oncology interest group collaborated with oncologists to create a shadowing program for MS1-2 students. Three radiation oncology (RO), two medical oncology (MO), and four surgical oncology (SO) faculty participated. A quarterly sign-up form was emailed to all MS1-2 students with available shadowing sessions. Electronic surveys were sent to students (after shadowing) and faculty (after 18 months of program operation) with multiple choice and 5-point Likert-type (1 = low, 5 = high) questions about their experiences. A total of 57 of the 97 participating students, and all 9 of the 9 participating faculty, responded to surveys (response rates 59% and 100%, respectively). Thirty students (53%) shadowed in RO, 23 (40%) in SO, and 4 (7%) in MO. Most students were very satisfied with their interactions with faculty (mean Likert-type rating of 4.14 ± standard deviation 0.85) and their overall experience compared to prior shadowing experiences (3.84 ± 0.85). Fifty-four students (96%) would recommend the experience to a classmate. Four faculty (44%) reported much more shadowing than before. Seven faculty (78%) felt the experience was best when residents or fellows were also present. All physicians planned to continue participating. This study demonstrated that a student-run, oncology shadowing program was feasible to implement, and viewed favorably by faculty and student participants.
Cardinal inequalities involving the weak Rothberger and cellularity games
Authors: Bella Angelo , Chiozini Lucas , Spadaro Santi
Published: October 2024

We prove several results in the theory of topological cardinal invariants involving the game-theoretic versions of the weak Lindelöf degree and of cellularity. One of them is related to Bell, Ginsburg and Woods’s 1978 question of whether every weakly Lindelöf regular first-countable space has cardinality at most continuum and another one is connected with Arhangel’skii’s 1970 question on the weak Lindelöf degree of the

$$G_\delta $$

G
δ

topology on a compact space. We provide a few application of our results, including some bounds on the cardinality of sequential and radial spaces. We finish with a series of counterexamples, which show the sharpness of our results and disprove a few natural conjectures about the impact of infinite games on topological cardinal invariants.
The Longitudinal Impact of Family, Religious, and School Support on the Mental Health of Filipino and Korean American Youth Across Adolescence
Authors: Park Michael , Park In Young , Choi Yoonsun , Henly Julia R.
Published: October 2024

Asian Americans, currently the most rapidly expanding racial group in the USA, are experiencing persistent mental health inequities. These inequities are particularly pronounced during adolescence, highlighting the critical need for dedicated focus on this demographic. Social support is a key shield against mental distress among these adolescents, yet little research has examined the collective impact of multiple sources of support over time, across developmental stages, and for different ethnic subgroups. Drawing on the integrated conceptual framework, this longitudinal study is the first to our knowledge to examine how support from families, religious organizations, and schools together predicts mental health over time across adolescents’ developmental stages. We further examined how these relationships may be moderated by age groups, distinguishing between the early adolescence cohort and the middle adolescence cohort. Data were from the Midwest Longitudinal Study of Asian American Families (MLSAAF) project that survey-interviewed 378 Filipino American and 408 Korean American adolescents (Mage = 15 years). Findings reveal that family support consistently buffers against mental distress throughout adolescence for both groups. Religious support distinctly aids Filipino American early adolescents, while school support notably benefits early adolescents regardless of ethnicity. These findings emphasize the universal protective effects of social support, while also highlighting the nuanced ways that developmental stage and ethnicity may influence how different sources of support impact mental health. This underscores the need for developmentally and culturally sensitive mental health strategies for Asian American adolescents.
Obesity-related drug transporter expression alterations in human liver and kidneys
Authors: Kosicka-Noworzyń Katarzyna , Romaniuk-Drapała Aleksandra , Sheng Yi-Hua , Yohn Christine , Brunetti Luigi , Kagan Leonid
Published: October 2024

Background

Pathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug’s PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters.

Methods

Human liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m2) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m2). Real-time quantitative PCR was performed for the analysis of 84 drug transporters.

Results

Our results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1.

Conclusions

The observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.
Die Jahre 1989/90 als Wagnis für ostdeutsche Allgemeinmediziner:innen
Authors: Kirschner Hariet , Henkel Rhea , Knoepffler Nikolaus , Bleidorn Jutta
Published: October 2024

Hintergrund

Ostdeutsche Allgemeinmediziner:innen (AM) waren im Transformationsprozesses um 1989/90 mit dem Anschluss an das BRD-Gesundheitssystem und der Niederlassung in eigener Praxis konfrontiert. Dies stellte einen herausfordernden Prozess dar.

Ziel der Arbeit

Nach über 30 Jahren werden Einsichten ostdeutscher AM zu repräsentierten Herausforderungen, Einflüssen und Bewertungen bez. des gesundheitspolitischen Systemwechsels um 1989/90 erfasst.

Material und Methoden

Anhand leitfadengestützter Interviews mit Thüringer AM wurden Transformationserfahrungen zum Systemwechsel um 1989/90 erhoben. Das Material wurde mit der inhaltlich-strukturierenden Inhaltsanalyse nach Kuckartz ausgewertet.

Ergebnisse

Es werden Einsichten in den Kategorien Herausforderungen, Bewältigung und Bewertung des Systemumbruchs im ambulanten Gesundheitssystem erfasst. Herausforderungen werden im Zuge der Einnahme einer Unternehmer:innenrolle und der Entwicklung der hausärztlichen Niederlassung erinnert. Zur Bewältigung wurden unterschiedliche Unterstützungserfahrungen, aber auch das Bewusstsein der beruflichen Kompetenz und Ausbildung in der DDR erwähnt. Die Bewertung des Umbruchprozesses wird auf unterschiedlichen Ebenen positiv wie negativ erfasst.

Diskussion

Die berufliche Umbruchserfahrung um 1989/90 wird von den ostdeutschen AM heterogen, jedoch als krisenbehaftete Phase erinnert. Diese Facette der gesellschaftspolitischen Transformation sollte als spezifisch ostdeutsche Erfahrung weitere Aufarbeitung auch hinsichtlich der Bewältigung kommender Aufgaben im Gesundheitssystem erfahren.
Recentring the Political in Education for Sustainable Development: Participatory Photovoice Research as Prefigurative Politics Towards Social-ecological Transformation
Authors: Pettig Fabian , Lippe Daniela
Published: October 2024

Based on the critique of education for sustainable development (ESD) as a socio-political control element of ecological modernisation, we discuss the prefigurative potential of participatory photovoice research in schools in light of social-ecological transformation. We argue that engaging students in prefigurative practices of change in which (sustainable) counter-futures are explored in the (unsustainable) present can help to re-politicise ESD, and we view photovoice as a way to guide this transformative process. Drawing on examples from a participatory research project on the transformation of local food systems in Graz, Austria, we critically explored photovoice as a method of transformative education that creates power-critical spaces of possible futures in which (un)sustainable hegemony and collectively internalised patterns of thought and action can be questioned to envision and negotiate liveable futures for all.
Baltic sea ice thickness estimation based on X-band SAR data and background information
Authors: Karvonen Juha Antero , Cheng Bin
Published: October 2024

In this study an operational sea ice thickness (SIT) estimation algorithm, based on HH-polarized X-band synthetic aperture radar (SAR) data, background information from the most recent, typically from the previous day, available daily Baltic Sea ice chart and the operational Finnish Meteorological Institute (FMI) thermodynamic ice model, was developed and evaluated. The algorithm was designed to complement the C-band SAR SIT algorithm developed earlier at FMI and applied daily as part of the operational Copernicus Marine Service (CMS). The X-band SIT algorithm was developed by utilizing the sea ice thickness measurements made onboard the Finnish and Swedish ice breakers during two winters seasons: 2021–2022 and 2022–2023. The former season measurements were used for defining the algorithm parameters and the later season for evaluation of the algorithm performance. According to the evaluation metrics the X-band algorithm performance is slightly better than that of the operational CMS C-band SAR SIT algorithm, indicating its suitability for operational use in CMS.
Whittaker coefficients of geometric Eisenstein series
Authors: Taylor Jeremy
Published: October 2024

Geometric Langlands predicts an isomorphism between Whittaker coefficients of Eisenstein series and functions on the moduli space of

$\check {N}$

-local systems. We prove this formula by interpreting Whittaker coefficients of Eisenstein series as factorization homology and then invoking Beilinson and Drinfeld’s formula for chiral homology of a chiral enveloping algebra.
Recurrent colonization with methicillin-susceptible Staphylococcus aureus after successful decolonization in a neonatal intensive care unit
Authors: Balamohan Archana , Annavajhala Medini K. , Boyar Vitaliya , Chong Alexander , Uhlemann Anne-Catrin , Rubin Lorry G.
Published: October 2024

Recurrent methicillin-susceptible Staphylococcus aureus colonization following successful decolonization in a neonatal intensive care unit (NICU) has been observed. Of 17 recolonization events, 53% were due to concordant strains; 19 different spa types were identified. Results of this study support sources of re-acquisition both intrinsic and extrinsic to the NICU.
Predicting initial microlayer thickness in nucleate boiling using Landau–Levich theory
Authors: Zhang Xiaolong , El Mellas Ismail , Magnini Mirco
Published: October 2024

A phenomenological model is proposed to estimate the initial thickness of the liquid microlayer forming beneath a vapour bubble growing on a solid surface upon nucleate boiling. The model employs an analogy between the microlayer formation and the classic plate withdrawal problem. It calculates the microlayer thickness by considering it as a Landau–Levich film, where the thickness is a function of the meniscus speed and radius of curvature. Given the nearly hemispherical shape of the bubble during the early growth stage when the microlayer is first deposited, we assume that the meniscus speed can be approximated by the bubble expansion rate, and estimate the meniscus curvature using the Rayleigh equations. Unlike previous theories that assume that the bubble radius growth is proportional to the square root of time, the proposed model does not rely on any specific law of growth for vapour bubbles. The model is validated for predicting the microlayer thickness in water and ethanol, showing good agreement with experimental measurements and empirical correlations. Subsequent analyses of the microlayer interface profile address inconsistent reports – some described a wedge-like shape, whereas others reported a slight outward curvature with decreasing thickness in the outer region. This discrepancy is attributed to a reduction in the expansion rate of the microlayer's outer edge, particularly when the bubble reaches its maximum width. Our model provides insights into microlayer dynamics, essential to boiling heat transfer, as the evaporative heat flux through the microlayer is very sensitive to its initial thickness.
Flow state transition induced by emergence of orbiting satellite eddies in two-dimensional turbulent Rayleigh–Bénard convection
Authors: Gao Zhen-Yuan , Tao Xin , Huang Shi-Di , Bao Yun , Xie Yi-Chao
Published: October 2024

We report a numerical investigation of a previously noticed but less explored flow state transition in two-dimensional turbulent Rayleigh–Bénard convection. The simulations are performed in a square domain over a Rayleigh number range of

$10^7 \leq Ra \leq 2 \times 10^{11}$

and a Prandtl number range of

$0.25 \leq Pr \leq 20$

. The transition is characterized by the emergence of multiple satellite eddies with increasing

$Ra$

, which orbit around and interact with the main vortex roll in the system. Consequently, the main roll is squeezed to a smaller size compared with the domain and wanders around in the bulk region irregularly and extensively. This is in sharp contrast to the flow state before the transition, which is featured by a domain-sized circulatory roll with its vortex centre ‘condensed’ near the domain's centre. Detailed velocity field analysis reveals that there exists an abrupt increase in the energy fluctuations of the Fourier modes during the transition. Based on this phase-transition-like signal, the critical condition for the transition is found to follow a scaling relation as

$Ra_t \sim Pr^{1.41}$

where

$Ra_t$

is the critical Rayleigh number for the transition. This scaling relation is quantitatively explained by a phenomenological model grounded on the bistability behaviour (i.e. spontaneous and stochastic switching between the two flow states) observed at the edge of the transition. The model can also account for the effects of aspect ratio on the transition reported in the literature (van der Poel et al., Phys. Fluids, vol. 24, 2012).
Identifying bilingual reference profiles: a cluster-analysis approach to reference production among Greek–Italian bilingual children
Authors: Vogelzang Margreet , Torregrossa Jacopo
Published: October 2024

Empirical studies on bilingual children’s reference production have often focussed on comparisons with monolingual peers. In this study, we introduce the concept of ‘reference profiles’: Speakers may exhibit similar or different behaviours in reference production, independently of whether they belong to a specific group (e.g., monolinguals or bilinguals) or whether their production adheres to some norm. Thirty-seven Greek–Italian bilingual children (Mage = 9;4, range 7;10–11;6) performed narrative retelling tasks in both of their languages, as well as vocabulary tasks and various cognitive tasks. The results show that the children had a good mastery of reference (i.e., appropriately using null pronouns, full pronouns or full nouns) in both of their languages. Using cluster analyses, we identified two distinct reference profiles. Further investigation showed that these profiles differed in both their sustained attention and in the use of overspecified referring expressions in contexts where reference to the same referent was maintained. These results are interpreted in light of current cognitive theories of (bilingual) reference processing and emphasise the potential of reference profiles for the study of other domains beyond bilingual reference production.
The national network of US state legislators on Twitter
Authors: Gopal Ishita , Kim Taegyoon , Nakka Nitheesha , Boehmke Frederick J. , Harden Jeffrey J. , Desmarais Bruce A.
Published: October 2024

Networks among legislators shape politics and policymaking within legislative institutions. In past work on legislative networks, the ties between legislators have been defined on those who serve in the same legislature or chamber. Online information networks, which have been found to play important roles in legislative communication at the national level, are not bounded by individual legislative bodies. We collect original data for over four thousand US state legislators and study patterns of connection among them on Twitter. We look at three types of Twitter networks—follower, retweets, and mentions. We describe these networks and estimate the relationships between ties and salient attributes of legislators. We find that networks are organized largely along geographic and partisan lines and that identity attributes—namely gender and race—exhibit strong associations with the formation of ties.
Allies at Heart? A Study of Ideational Continentalism in Canadians’ Foreign Policy Attitudes
Authors: Jiang Diya , Toettoe Benjamin , Turcsanyi Richard
Published: October 2024

The United States has long represented one of Canada's primary international allies. This partnership has remained strong despite turbulent times in the relationship, such as the one brought forth by the Trump presidency. Our article seeks to understand the sources of such continuity through the lens of continentalism. While historical accounts of continentalism have portrayed it as a passive force stemming from Canada's material self-interest, scholars have recently identified the emergence of an evolved form of continentalism that represents a dominant idea and a coherent analytical framework in Canadian foreign policy. Has this new form of continentalism indeed gained widespread acceptance among Canadians? We answer this question by considering continentalism in the ideational realm. Using novel public opinion data, our analysis investigates whether continentalist attitudes have become embedded in Canadians’ national identity and foster closer alignment preferences vis-à-vis the United States. We find significant and robust evidence of such effects.
Priests and their Wigs in Eighteenth-Century Rome
Authors: Pattenden Miles
Published: October 2024

The wig was the quintessential accessory of eighteenth-century European culture, but the wearing of wigs by clerics became a subject of heated controversy across Catholic societies. Critics of clerical wig-wearing pointed to its inherent vanity, to Paul's proscription against men covering their heads in Church in 1 Corinthians 11, and to its apparent denial of the tonsure's importance as the visible outward sign of clerical status. However, defenders pointed to arguments about the need to cover up imperfections in the priest's body and avoid scandal. Various bishops moved to restrict the use of wigs amongst their diocesan clergy. However, no bishop was more active in legislating than the bishops of Rome themselves. Popes from Clement IX (r. 1667–69) to Pius VI (r. 1775–99) all issued instructions about clerical wig-wearing and their legislation betrays shifting attitudes and approaches. The most zealous rules from the 1720s gradually gave way to more pragmatic ones which attest to the persistent desire of Roman clerics to engage in male status competition and to the growing difficulty that the Church's leadership had in persuading them of the intrinsic superiority of their clerical status.
Storm in an Ice Cream Cone: Was Ben & Jerry's Decision to End Ice Cream Sales in Israeli Settlements a Responsible Corporate Exit from Occupied Territories?
Authors: Kolieb Jonathan
Published: October 2024

Ben & Jerry's – the famous ice cream brand known for its quirky flavours and social justice ethos – announced in 2021 that it would withdraw its products from Israeli settlements in the Occupied Palestinian Territory (OPT). This announcement sparked controversy, with an impact on the company and its parent, Unilever. While the UN Guiding Principles on Business and Human Rights (2011) (UNGP) have established themselves as the leading international governance framework for the social responsibilities of businesses, their application to conflict-affected areas lacks clarity. Questions remain, including when is a company legally complicit in violations of international humanitarian law (IHL), and when is a corporate exit from an area under military occupation the appropriate and responsible thing to do. This article uses Ben & Jerry's withdrawal from the OPT as the basis for investigating these questions. It finds that while it is unlikely that Ben & Jerry's would be exposed to any legal liability for violating IHL through its product sales in Israeli settlements in the OPT, its withdrawal aligns with its responsibilities under the UNGP as a reasonable and prudent corporate action in response to its activities being linked to enduring and severe IHL violations.
How can you help us, Mr Darwin? Social Darwinism in the history of Chinese international thought
Authors: Wojciuk Anna , Górecki Maciej A. , Kowalski Bartosz
Published: October 2024

Social Darwinism was a pathbreaker in the history of Chinese international thought. In this study, we explore the hitherto sparsely discussed process of the reception of social Darwinism in China, which led to a fundamental transformation in Chinese thinking about the international order and the position of China vis-à-vis Western powers. Drawing on the work of three leaders of that intellectual transformation – Yan Fu, Kang Youwei, and Liang Qichao – we analyse issues such as the struggle for existence and survival, national and racial competition, and statism. We demonstrate how the three aforementioned thinkers modified the original Darwinist thought, enriching it with voluntarism and radical collectivism, all in order for the emerging set of ideas to suit China’s historically determined needs. Overall, our analysis contributes to both the history of International Relations thought in China and the broader debate on the globalisation of IR theory and IR knowledge production.
Best Practices and the Need for Research on MA Degree Programs in Political Science
Authors: De Maio Jennifer L. , Macias Alexandra
Published: October 2024

Recent research suggests that master’s (MA) education in the United States could be restructured to better meet the expectations of students who seek nonacademic careers. This article considers the state of terminal MA degree programs in political science to assess whether they are preparing students to enter the workforce. We examine programs across various dimensions and supplement this analysis with survey data to gain additional information about the purpose of terminal MA degree programs. The results suggest that their reconceptualization is needed in the discipline of political science.
Adjustments to Climate Perturbations—Mechanisms, Implications, Observational Constraints
Authors: Quaas Johannes , Andrews Timothy , Bellouin Nicolas , Block Karoline , Boucher Olivier , Ceppi Paulo , Dagan Guy , Doktorowski Sabine , Eichholz Hannah Marie , Forster Piers , Goren Tom , Gryspeerdt Edward , Hodnebrog Øivind , Jia Hailing , Kramer Ryan , Lange Charlotte , Maycock Amanda C. , Mülmenstädt Johannes , Myhre Gunnar , O’Connor Fiona M. , Pincus Robert , Samset Bjørn Hallvard , Senf Fabian , Shine Keith P. , Smith Chris , Stjern Camilla Weum , Takemura Toshihiko , Toll Velle , Wall Casey J.
Published: October 2024

Since the 5th Assessment Report of the Intergovernmental Panel on Climate Change (AR5) an extended concept of the energetic analysis of climate change including forcings, feedbacks and adjustment processes has become widely adopted. Adjustments are defined as processes that occur in response to the introduction of a climate forcing agent, but that are independent of global‐mean surface temperature changes. Most considered are the adjustments that impact the Earth energy budget and strengthen or weaken the instantaneous radiative forcing due to the forcing agent. Some adjustment mechanisms also impact other aspects of climate not related to the Earth radiation budget. Since AR5 and a following description by Sherwood et al. (2015, https://doi.org/10.1175/bams‐d‐13‐00167.1), much research on adjustments has been performed and is reviewed here. We classify the adjustment mechanisms into six main categories, and discuss methods of quantifying these adjustments in terms of their potentials, shortcomings and practicality. We furthermore describe aspects of adjustments that act beyond the energetic framework, and we propose new ideas to observe adjustments or to make use of observations to constrain their representation in models. Altogether, the problem of adjustments is now on a robust scientific footing, and better quantification and observational constraint is possible. This allows for improvements in understanding and quantifying climate change.
The Pivotal Role of Evaporation in Lake Water Isotopic Variability Across Space and Time in a High Arctic Periglacial Landscape
Authors: Akers Pete D. , Kopec Ben G. , Klein Eric S. , Bailey Hannah , Welker Jeffrey M.
Published: October 2024

Rapidly changing climate is disrupting the High Arctic's water systems. As tracers of hydrological processes, stable water isotopes can be used for high quality monitoring of Arctic waters to better reconstruct past changes and assess future environmental threats. However, logistical challenges typically limit the length and scope of isotopic monitoring in High Arctic landscapes. Here, we present a comprehensive isotopic survey of 535 water samples taken in 2018 and 2019 of the lakes and other surface waters of the periglacial Pituffik Peninsula in far northwest Greenland. The δ18O, δ2H, and deuterium‐excess values of these samples, representing 196 unique sites, grant unprecedented insight into the environmental drivers of the regional hydrology and water isotopic variability. We find that the spatial variability of lake water isotopes can best be explained through evaporation and the hydrological ability of a lake to replace evaporative water losses with precipitation and snowmelt. Temporally, summer‐long evaporation can drive lake water isotopes beyond the isotopic range observed in precipitation, and wide interannual changes in lake water isotopes reflect annual weather differences that influenced evaporation. Following this, water isotope samples taken at individual times or sites in similar periglacial landscapes may have limited regional representativeness, and increasing the spatiotemporal extent of isotopic sampling is critical to producing accurate and informative High Arctic paleoclimate reconstructions. Overall, our survey highlights the diversity of isotopic compositions in Pituffik surface waters, and our complete isotopic and geospatial database provides a strong foundation for future researchers to study hydrological changes at Pituffik and across the Arctic.
The Critical Role of Hydrological Distance in Shaping Nutrient Dynamics Along the Watershed‐Lake Continuum
Authors: Huang Jiacong , Arhonditsis George B. , Zhang Yinjun , Zhang Shuai , Ji Yulai , Paerl Hans W. , Jeppesen Erik , Gao Junfeng
Published: October 2024

Terrestrial hydrological and nutrient cycles are subjected to major disturbances by agricultural operations and urbanization that profoundly influence freshwater resources. Non‐point source pollution is one of the primary causes for water quality deterioration, and thus an emerging imperative in limnology is establishing empirical models that connect watershed attributes and hydrological drivers with lake nutrient dynamics. Here, we compiled three nation‐wide nutrient, meteorological, and watershed‐landscape data sets, to develop Generalized Linear Models that predict lake phosphorus and nitrogen concentrations as a function of the surrounding watershed characteristics within various hydrological distances across 104 Chinese lakes and reservoirs. Our national‐scale investigation revealed that lake nutrient concentrations can be satisfactorily predicted by proxies of natural drivers and anthropogenic activities, reflecting the properties of the surrounding watershed. Counter to previous studies, we found that China's lake nutrient concentrations strongly depend on watershed characteristics within a hydrological distance of less than 45 km rather than the entire watershed. Furthermore, extensive human activities in watersheds not only compromise our predictive capacity, but also increase the hydrological distance that is relevant to predict lake nutrients. This national‐scale characterization can inform one of the most contentious issues in the context of China's lake management, that is, the determination of the extent of the nearshore area, where nutrient control should be prioritized. As far as we know, our study represents the first attempt to apply the concept of hydrological distance and establish statistical models that can delineate the critical spatial domain primarily responsible for the nutrient conditions along the watershed‐lake continuum.
Modeling Sediment Fluxes From Debris‐Rich Basal Ice Layers
Authors: Pierce Ethan , Overeem Irina , Jouvet Guillaume
Published: October 2024

Sediment erosion, transport, and deposition by glaciers and ice sheets play crucial roles in shaping landscapes, provide important nutrients to downstream ecosystems, and preserve key indicators of past climate conditions in the geologic record. While previous work has quantified sediment fluxes from subglacial meltwater, we also observe sediment entrained within basal ice, transported by the flow of the glacier itself. However, the formation and evolution of these debris‐rich ice layers remains poorly understood and rarely represented in landscape evolution models. Here, we identify a characteristic sequence of basal ice layers at Mendenhall Glacier, Alaska. We develop a numerical model of frozen fringe and regelation processes that describes the co‐evolution of this sequence and explore the sensitivity of the model to key properties of the subglacial sedimentary system, using the Instructed Glacier Model to parameterize ice dynamics. Then, we run numerical simulations over the spatial extent of Mendenhall Glacier, showing that the sediment transport model can predict the observed basal ice stratigraphy at the glacier's terminus. From the model results, we estimate basal ice layers transport between 23,300 and 39,800 of sediment, mostly entrained in the lowermost ice layers nearest to the bed, maximized by high effective pressures and slow, convergent flow fields. Overall, our results highlight the role of basal sediment entrainment in delivering eroded material to the glacier terminus and indicate that this process should not be ignored in broader models of landscape evolution.
Realizing Orthogonal Modes in Compact Cavity‐Backed Dual‐Polarized Antenna Through Simple Feeding Structures for Millimeter‐Wave AiP Applications
Authors: Huang Tzu‐Ming , Lin Yi‐Cheng
Published: October 2024

This paper presents a dual‐polarized cavity‐backed antenna designed for mm‐wave applications, featuring simple feeding structures with a high‐isolation for 60 GHz compact AiP applications. The dual‐polarization design relies on two separate feed ports that excite two orthogonal modes within the same resonant cavity, achieving very high port isolation of up to 40 dB over the entire band. We conducted a detail analysis of the antenna, including its working principles and parametric studies. For verification, we fabricated an antenna test kit using standard printed process on substrates and measured the kit from the back‐side of a GSG probing platform. The proposed antenna demonstrates a wide impedance bandwidth, stable radiation patterns, very low cross‐polarization levels, and a high radiation efficiency. The co‐located cavity‐backed design ensures the compactness and facilitates easy integration with ICs in a very small AiP module. These features make the proposed antenna highly suitable for 60 GHz AiP applications, such as high‐data‐rate wireless communication and mmW polarimetric radar systems.
Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma
Authors: Fortuna Gliceida Galarza , Banerjee Rahul , Savid-Frontera Constanza , Song Jinming , Morán-Segura Carlos M. , Nguyen Jonathan V. , Lekakis Lazaros , Fernandez-Pol Sebastian , Samraj Annie N. , Naresh Kikkeri N. , Vazquez-Martinez Mariola , Baz Rachid C. , Spiegel Jay Y. , Mikkilineni Lekha , Gubatan John M. , Sidana Surbhi , de Menezes Silva Corraes Andre , Kalariya Nilesh M. , Patel Krina K. , Shim Kevin G. , Fonseca Rafael , Ferreri Christopher , Voorhees Peter M. , Richard Shambavi , Valdes Cesar Rodriguez , Sireesha Asoori  , Wolf Jeffrey L. , Cowan Andrew J. , Sborov Douglas W. , Locke Frederick L. , Lin Yi , Wang Yinghong , Hansen Doris K.
Published: October 2024

We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22–210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1–3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.
Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine
Authors: Tambe Mahesh , Unterberger Sarah , Kriegbaum Mette C. , Vänttinen Ida , Olgac Ezgi June , Vähä-Koskela Markus , Kontro Mika , Wennerberg Krister , Heckman Caroline A.
Published: October 2024

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.
All-optical reporting of inhibitory receptor driving force in the nervous system
Authors: Selfe Joshua S. , Steyn Teresa J. S. , Shorer Eran F. , Burman Richard J. , Düsterwald Kira M. , Kraitzick Ariel Z. , Abdelfattah Ahmed S. , Schreiter Eric R. , Newey Sarah E. , Akerman Colin J. , Raimondo Joseph V.
Published: October 2024

Ionic driving forces provide the net electromotive force for ion movement across receptors, channels, and transporters, and are a fundamental property of all cells. In the nervous system, fast synaptic inhibition is mediated by chloride permeable GABAA and glycine receptors, and single-cell intracellular recordings have been the only method for estimating driving forces across these receptors (DFGABAA). Here we present a tool for quantifying inhibitory receptor driving force named ORCHID: all-Optical Reporting of CHloride Ion Driving force. We demonstrate ORCHID’s ability to provide accurate, high-throughput measurements of resting and dynamic DFGABAA from genetically targeted cell types over multiple timescales. ORCHID confirms theoretical predictions about the biophysical mechanisms that establish DFGABAA, reveals differences in DFGABAA between neurons and astrocytes, and affords the first in vivo measurements of intact DFGABAA. This work extends our understanding of inhibitory synaptic transmission and demonstrates the potential for all-optical methods to assess ionic driving forces.
Genetic architecture of routinely acquired blood tests in a British South Asian cohort
Authors: Jacobs Benjamin M. , Stow Daniel , Hodgson Sam , Zöllner Julia , Samuel Miriam , Kanoni Stavroula , Bidi Saeed ,   Genes & Health Research Team, Akhtar Shaheen , Anwar Mohammad , Arciero Elena , Asgar Omar , Ashraf Samina , Bidi Saeed , Breen Gerome , Broster James , Chung Raymond , Collier David , Curtis Charles J. , Chaudhary Shabana , Clinch Megan , Colligan Grainne , Deloukas Panos , Durham Ceri , Durrani Faiza , Eto Fabiola , Finer Sarah , Gafton Joseph , Garcia Ana Angel , Griffiths Chris , Harvey Joanne , Heng Teng , Hodgson Sam , Huang Qin Qin , Hurles Matt , Hunt Karen A. , Hussain Shapna , Islam Kamrul , Iyer Vivek , Jacobs Ben , Khan Ahsan , Lavery Cath , Lee Sang Hyuck , Lerner Robin , MacArthur Daniel , Malawsky Daniel , Martin Hilary , Mason Dan , Mathur Rohini , Mazid Mohammed Bodrul , McDermott John , Morton Caroline , Newman Bill , Owor Elizabeth , Qureshi Asma , Rahman Samiha , Ramachandrappa Shwetha , Reza Mehru , Russell Jessry , Safa Nishat , Samuel Miriam , Simpson Michael , Solly John , Spreckley Marie , Stow Daniel , Taylor Michael , Trembath Richard C. , Tricker Karen , Uddin Nasir , van Heel David A. , Walter Klaudia , Winckley Caroline , Wood Suzanne , Wright John , Zollner Julia , Walter Klaudia , Langenberg Claudia , Dobson Ruth , Finer Sarah , Morton Caroline , Siddiqui Moneeza K. , Martin Hilary C. , Pietzner Maik , Mathur Rohini , van Heel David A.
Published: October 2024

Understanding the genetic basis of routinely-acquired blood tests can provide insights into several aspects of human physiology. We report a genome-wide association study of 42 quantitative blood test traits defined using Electronic Healthcare Records (EHRs) of ~50,000 British Bangladeshi and British Pakistani adults. We demonstrate a causal variant within the PIEZO1 locus which was associated with alterations in red cell traits and glycated haemoglobin. Conditional analysis and within-ancestry fine mapping confirmed that this signal is driven by a missense variant - chr16-88716656-G-TT - which is common in South Asian ancestries (MAF 3.9%) but ultra-rare in other ancestries. Carriers of the T allele had lower mean HbA1c values, lower HbA1c values for a given level of random or fasting glucose, and delayed diagnosis of Type 2 Diabetes Mellitus. Our results shed light on the genetic basis of clinically-relevant traits in an under-represented population, and emphasise the importance of ancestral diversity in genetic studies.
On-chip phonon-enhanced IR near-field detection of molecular vibrations
Authors: Bylinkin Andrei , Castilla Sebastián , Slipchenko Tetiana M. , Domina Kateryna , Calavalle Francesco , Pusapati Varun-Varma , Autore Marta , Casanova Fèlix , Hueso Luis E. , Martín-Moreno Luis , Nikitin Alexey Y. , Koppens Frank H. L. , Hillenbrand Rainer
Published: October 2024

Phonon polaritons – quasiparticles formed by strong coupling of infrared (IR) light with lattice vibrations in polar materials – can be utilized for surface-enhanced infrared absorption (SEIRA) spectroscopy and even for vibrational strong coupling with nanoscale amounts of molecules. Here, we introduce and demonstrate a compact on-chip phononic SEIRA spectroscopy platform, which is based on an h-BN/graphene/h-BN heterostructure on top of a metal split-gate creating a p-n junction in graphene. The metal split-gate concentrates the incident light and launches hyperbolic phonon polaritons (HPhPs) in the heterostructure, which serves simultaneously as SEIRA substrate and room-temperature infrared detector. When thin organic layers are deposited directly on top of the heterostructure, we observe a photocurrent encoding the layer’s molecular vibrational fingerprint, which is strongly enhanced compared to that observed in standard far-field absorption spectroscopy. A detailed theoretical analysis supports our results, further predicting an additional sensitivity enhancement as the molecular layers approach deep subwavelength scales. Future on-chip integration of infrared light sources such as quantum cascade lasers or even electrical generation of the HPhPs could lead to fully on-chip phononic SEIRA sensors for molecular and gas sensing.
Spatial transcriptomics of a parasitic flatworm provides a molecular map of drug targets and drug resistance genes
Authors: Gramberg Svenja , Puckelwaldt Oliver , Schmitt Tobias , Lu Zhigang , Haeberlein Simone
Published: October 2024

The spatial organization of gene expression dictates tissue functions in multicellular parasites. Here, we present the spatial transcriptome of a parasitic flatworm, the common liver fluke Fasciola hepatica. We identify gene expression profiles and marker genes for eight distinct tissues and validate the latter by in situ hybridization. To demonstrate the power of our spatial atlas, we focus on genes with substantial medical importance, including vaccine candidates (Ly6 proteins) and drug resistance genes (glutathione S-transferases, ABC transporters). Several of these genes exhibit unique expression patterns, indicating tissue-specific biological functions. Notably, the prioritization of tegumental protein kinases identifies a PKCβ, for which small-molecule targeting causes parasite death. Our comprehensive gene expression map provides unprecedented molecular insights into the organ systems of this complex parasitic organism, serving as a valuable tool for both basic and applied research.
Evidence of a 4.33 billion year age for the Moon’s South Pole–Aitken basin
Authors: Joy K. H. , Wang N. , Snape J. F. , Goodwin A. , Pernet-Fisher J. F. , Whitehouse M. J. , Liu Y. , Lin Y. T. , Darling J. R. , Tar P. , Tartèse R.
Published: October 2024

The Moon’s farside South Pole–Aitken (SPA) basin is the largest and oldest visible impact basin in the inner Solar System. Determining the timing of this catastrophic event is key to understanding the onset of the lunar basin-forming epoch, with implications for understanding the impact bombardment history of the inner Solar System. Despite this, the formation age of the SPA basin remains poorly constrained. Here we show that the chemical composition of the lunar meteorite Northwest Africa 2995 is in good agreement with lithologies exposed within the southern region of the SPA basin. Radiometric dating of a range of mineral and rock components in Northwest Africa 2995 yielded consistent dates of ~4.32–4.33 billion years old. We interpret these dates as the age of SPA basin formation, inferring that this event occurred ~120 million years before the formation of the main cluster of lunar impact basins between ~4.2 Ga and 3.8 Ga. This weakens support for a narrow period of lunar late heavy impact bombardment and also implies that the earliest formed impact basins on the Moon (that is, >4.33–4.5 Ga old) were erased either by the SPA impact itself when its formation caused massive resurfacing of the lunar surface or through other geological processes.