bluuebunny/crossref_metadata_2025 huggingface dataset:
Meyer Schapiro, the Jewish Museum, and Living Artists: A Scholar’s Overlooked Activism
Authors: Abt Jeffrey
Published: June 2023

Meyer Schapiro was among a handful of New York’s most prominent Jewish thinkers writing about modern art during the post-Second World War period, just as the international center of new art had shifted there from Paris. Unlike his contemporaries Clement Greenberg and Harold Rosenberg, however, Schapiro is thought to have “seldom” or only “subliminally” addressed questions of Jewish identity, suggesting that he avoided or suppressed the matter. Yet his nearly four-decade-long relationship with the Jewish Museum of New York tells a different story. Schapiro’s unpublished correspondence, memoranda, and addresses reveal his role in transforming the Jewish Museum into a venue for avant-garde art and his urging Jewish acceptance of modern art, including works that were not visibly Jewish or that were created by non-Jews. These efforts reflect the ways his kinship with the Jewish community prompted his articulation of universal values of humanitarianism and social justice that he associated with Judaism, values that coincided with his social activism. The archival materials also show how Schapiro engaged with questions of Jewish identity as he drew on his scholarly knowledge and his affinity with the Jewish community to further the appreciation of modern art for the benefit of Jewish and non-Jewish artists and audiences.
A crystallizing white dwarf in a sirius-like quadruple system
Authors: Venner Alexander , Blouin Simon , Bédard Antoine , Vanderburg Andrew
Published: June 2023

The observational signature of core crystallization of white dwarfs has recently been discovered. However, the magnitude of the crystallization-powered cooling delay required to match observed white dwarfs is larger than predicted by conventional models, requiring additional mechanisms of energy release in white dwarf interiors. The most ideal benchmarks for understanding this discrepancy would be bright and nearby crystallizing white dwarfs with total ages that can be externally constrained. In this work, we report that a recently discovered white dwarf is a bound companion to the triple star HD 190412, forming a new Sirius-like system in the solar neighbourhood. The location of HD 190412 C on the Teff − mass diagram implies it is undergoing crystallization, making this the first confirmed crystallizing white dwarf whose total age can be externally constrained. Motivated by the possibility that a cooling delay caused by crystallization can be directly detected for this white dwarf we employ a variety of methods to constrain the age of the system; however, our empirical age anomaly of +3.1 ± 1.9 Gyr is ultimately too imprecise to reach statistical significance, preventing us from making strong constraints to models of white dwarf crystallization. Our results are none the less compatible with the recent hypothesis that 22Ne phase separation is responsible for the excess cooling delay of crystallizing white dwarfs. The discovery of this system at only 32 parsecs suggests that similar benchmark systems are likely to be common; future discoveries may therefore provide powerful tests for models of white dwarf crystallization.
Discovery of magnetospheric interactions in the doubly magnetic hot binary ϵ Lupi
Authors: Biswas Ayan , Das Barnali , Chandra Poonam , Wade Gregg A , Shultz Matthew E , Cavallaro Francesco , Petit Veronique , Woudt Patrick A , Alecian Evelyne
Published: June 2023

Magnetic fields are extremely rare in close, hot binaries, with only 1.5 per cent of such systems known to contain a magnetic star. The eccentric ϵ Lupi system stands out in this population as the only close binary in which both stars are known to be magnetic. We report the discovery of strong variable radio emission from ϵ Lupi using the upgraded Giant Metrewave Radio Telescope (uGMRT) and the MeerKAT radio telescope. The light curve exhibits striking unique characteristics including sharp high-amplitude pulses that repeat with the orbital period, with the brightest enhancement occurring near periastron. The characteristics of the light curve point to variable levels of magnetic reconnection throughout the orbital cycle, making ϵ Lupi the first known high-mass, main sequence binary embedded in an interacting magnetosphere. We also present a previously unreported enhancement in the X-ray light curve obtained from archival XMM–Newton data. The stability of the components’ fossil magnetic fields, the firm characterization of their relatively simple configurations, and the short orbital period of the system make ϵ Lupi an ideal target to study the physics of magnetospheric interactions. This system may thus help us to illuminate the exotic plasma physics of other magnetically interacting systems such as moon–planet, planet–star, and star–star systems including T Tauri binaries, RS CVn systems, and neutron star binaries.
TRLS-05. PRELIMINARY RESULTS FROM A PHASE I TRIAL TO EVALUATE INTRAVENTRICULAR DELIVERY OF IL13RΑ2-TARGETING CAR T CELLS AFTER LYMPHODEPLETION IN PEDIATRIC BRAIN TUMORS PATIENTS
Authors: Davidson Tom , Oill Angela , Wu Melody , Egelston Colt , Natri Heini , Sepulveda Sean , Hibbard Jonathan , Wagner Jamie , Nisis Monica , Kilpatrick Julie , Stiller Tracey , Georges Joseph , Munoz Margarita , Oliver-Cervantes Cheryl , Shepphird Jennifer , Ressler Julie , D’Apuzzo Massimo , Aftabizadeh Maryam , Blanchard M Suzette , Badie Behnam , Brown Christine , Banovich Nicholas , Wang Leo
Published: June 2023

Brain tumors are the leading cause of cancer death in children, and outcomes for patients with recurrent or aggressive disease remain poor. We have previously shown that locoregionally-delivered chimeric antigen receptor (CAR) T cells targeting the high-affinity IL13 receptor IL13Rα2 are safe and well-tolerated in adults, and that they can mediate a remarkable clinical response. This antigen is also expressed on roughly half of pediatric neuromalignancies. Here, we present the clinical experience from the first patients treated with IL13BBζ-CAR T cells on our trial. Patients received four doses of CAR T cells, delivered weekly through an indwelling CNS catheter; the first dose was 1e7 CAR T cells and subsequent doses were 5e7 cells. The first three patients received CAR T cells alone; the rest received lymphodepletion with cyclophosphamide and fludarabine before CAR T cell infusion. After follow-up imaging at the end of the dose-limiting toxicity (DLT) period, patients were given the option to continue therapy. Six patients have been treated without DLTs; one patient on the lymphodepletion arm did not complete the four infusions due to a Grade 3 catheter-related infection. Other patients experienced occasional Grade 3 AEs that were not attributed to CAR T therapy, with the exception of headache, muscle weakness, and ALT elevation. Otherwise, AEs were Grade 1-2. Five patients completed four infusions and were evaluable at the end of the DLT period. Of those, three experienced radiographic and/or clinical benefit, although none met protocol criteria for a partial response. Specific cytokines were increased in the cerebrospinal fluid (CSF) of patients during radiographic response periods. Additionally, single-cell transcriptomic analysis paired with TCR sequencing of CSF cells demonstrated characteristic immune signatures correlated with response. These preliminary results support combining lymphodepletion and repeated intraventricular CAR T cell delivery as a promising therapy in children with brain tumors.
ECCE Homo
Authors: Nietzsche Friedrich
Published: June 2023

Ecce Homo is an autobiography like no other. Deliberately provocative, Nietzsche subverts the conventions of the genre and pushes his philosophical positions to combative extremes, constructing a genius-hero whose life is a chronicle of incessant self-overcoming. Written in 1888, a few weeks before his descent into madness, the book sub-titled ‘How To Become What You Are’ passes under review all Nietzsche’s previous works so that we, his ‘posthumous’ readers, can finally understand him aright, on his own terms. He reaches final reckonings with his many enemies - Richard Wagner, German nationalism, ‘modern men’ in general - and above all Christianity, proclaiming himself the Antichrist. Ecce Homo is the summation of an extraordinary philosophical career, a last great testament to Nietzsche’s will.
CO multi-line imaging of nearby galaxies (COMING). XII. CO-to-H2 conversion factor and dust-to-gas ratio
Authors: Yasuda Atsushi , Kuno Nario , Sorai Kazuo , Muraoka Kazuyuki , Miyamoto Yusuke , Kaneko Hiroyuki , Yajima Yoshiyuki , Tanaka Takahiro , Morokuma-Matsui Kana , Takeuchi Tsutomu T , Kobayashi Masato I N
Published: June 2023

We simultaneously measured the spatially resolved CO-to-H2 conversion factor (αCO) and dust-to-gas ratio (DGR) in nearby galaxies on a kiloparsec scale. In this study, we used 12CO(J = 1–0) data obtained by the Nobeyama 45 m radio telescope with H i and dust mass surface densities. We obtained the values of global αCO and DGR in 22 nearby spiral galaxies, with averages of 2.66 ± 1.36 M⊙ pc−2 (K km s−1)−1 and 0.0052 ± 0.0026, respectively. Furthermore, the radial variations of αCO and DGR in four barred spiral galaxies (IC 342, NGC 3627, NGC 5236, and NGC 6946) were obtained by dividing them into inner and outer regions with a boundary of 0.2 R25, where R25 is the isophotal radius at 25 mag arcsec−2 in the B band. The averages of αCO and DGR in the inner region (≤0.2 R25) are 0.36 ± 0.08 M⊙ pc−2 (K km s−1)−1 and 0.0199 ± 0.0058, while those in the outer region (>0.2 R25) are 1.49 ± 0.76 M⊙ pc−2 (K km s−1)−1 and 0.0084 ± 0.0037, respectively. The value of αCO in the outer region is 2.3 to 5.3 times larger than that of the inner region. When separated into the inner and outer regions, we find that αCO and DGR correlate with the metallicity and the star formation rate surface density. The value of αCO derived in this study tends to be smaller than those obtained in previous studies for the Milky Way and nearby star-forming galaxies. This fact can be attributed to our measurements being biased toward the inner region; we measured αCO at 0.85 and 0.76 times smaller in radius than the previous works for nearby star-forming galaxies and the Milky Way, respectively.
On the well-posed variational principle in degenerate point particle systems using embeddings of the symplectic manifold
Authors: Tomonari Kyosuke
Published: June 2023

A methodology on making the variational principle well-posed in degenerate systems is constructed. In the systems including higher-order time derivative terms being compatible with Newtonian dynamics, we show that a set of position variables of a coordinate system of a given system has to be fixed on the boundaries and that such systems are always Ostrogradski stable. For these systems, Frobenius integrability conditions are derived in explicit form. Relationships between integral constants indicated from the conditions and boundary conditions in a given coordinate system are also investigated by introducing three fundamental correspondences between Lagrange and Hamilton formulation. Based on these ingredients, we formulate problems that have to be resolved to realize the well-posedness in the degenerate systems. To resolve the problems, we compose a set of embeddings that extract a subspace holding the symplectic structure of the entire phase space in which the variational principle should be well-posed. Using these embeddings, we establish a methodology to set appropriate boundary conditions that the well-posed variational principle demands. Finally, we apply the methodology to examples and summarize this work as a three-step procedure such that one can use just by following it.
Non-SUSY lepton flavor model with the three Higgs doublet model
Authors: Izawa Yukimura , Shimizu Yusuke , Takei Hironori
Published: June 2023

We propose a simple non-supersymmetric lepton flavor model with A4 symmetry. The A4 group is a minimal one that includes triplet irreducible representation. We introduce three Higgs doublets, which are assigned as a triplet of the A4 symmetry. It is natural that there are three generations of the Higgs fields, as with the standard model fermions. We analyze the potential and find the vacuum expectation values for the local minimum. In the vacuum expectation values, we obtain the charged lepton, Dirac neutrino, and right-handed Majorana neutrino mass matrices. By using the type-I seesaw mechanism, we get the left-handed Majorana neutrino mass matrix. In the NuFIT 5.1 data, we predict the Dirac CP phase and the Majorana phases for the only inverted neutrino mass hierarchy. In particular, the Dirac CP phase and lepton mixing angle θ23 are strongly correlated. If θ23 is more precisely measured, the Dirac CP phase is more precisely predicted, and vice versa. We also predict the effective mass for neutrinoless double beta decay mee ≃ 47.1 [meV] and the lightest neutrino mass m3 ≃ 0.789–1.43 [meV]. This will be testable with our model in near-future neutrino experiments.
Three instability stratifications of the stack of Higgs bundles on a smooth projective curve
Authors: Hamilton Eloise
Published: June 2023

We study three instability stratifications of the stack of twisted Higgs bundle of a fixed rank and degree on a smooth complex projective curve. The first is the Harder–Narasimhan (HN) stratification, defined by the instability type of the Higgs bundle. The second is the bundle Harder–Narasimhan (bHN) stratification, defined by the instability type of the underlying bundle. While an unstable HN stratum fibres over the stack parameterizing Higgs bundles which are isomorphic to their HN graded, this is not true for Higgs bundles of unstable bHN type. Obtaining such a fibration requires refining the bHN stratification; this is the third instability stratification. After introducing these three stratifications, we establish comparison results. In particular, we obtain explicit criteria for determining semistability of a Higgs bundle of low rank with unstable underlying bundle. Then we show how the HN and bHN stratifications can be used to filter the stack of Higgs bundles by global quotient stacks in two different ways. Finally, we use these filtrations to relate the HN and bHN stratifications to GIT instability stratifications and the refined bHN stratification to a Bialynicki–Birula stratification.
Early Outcomes of Operative Versus Nonoperative Management of Stress-Positive Minimally Displaced Lateral Compression Type 1 Pelvic Ring Injuries
Authors: Tucker Nicholas J. , Scott Bryan L. , Heare Austin , Stacey Stephen , Mauffrey Cyril , Parry Joshua A.
Published: June 2023

Objectives:

To compare the early outcomes of patients with stress-positive minimally displaced lateral compression type 1 (LC1b) pelvic ring injuries managed with or without operative fixation.

Design:

Retrospective comparison study.

Setting:

Level 1 trauma center.

Patients/Participants:

Forty-three patients with LC1b injuries.

Intervention:

Operative versus nonoperative.

Main Outcome Measurements:

Discharge to subacute rehabilitation (SAR); 2- and 6-week pain visual analog score, opioid use, assistive device use, percentage of normal single assessment numerical evaluation, SAR status; fracture displacement; and complications.

Results:

The operative group did not differ in age, gender, body mass index, high-energy mechanism, dynamic displacement stress radiographs, complete sacral fractures, Denis sacral fracture classification, Nakatani rami fracture classification, follow-up length, or American Society of Anesthesiologists classification. The operative group was less likely to be using an assistive device at 6 weeks [observed difference (OD) −53.9%, 95% confidence interval (CI) −74.3% to −20.6%, OD/CI 1.00, P = 0.0005], less likely to remain in an SAR at 2 weeks (OD −27.5%, CI, −50.0% to −2.7%, OD/CI 0.58, P = 0.02), and had less fracture displacement at follow-up radiographs (OD −5.0 mm, CI, −9.2 to −1.0 mm, OD/CI 0.61, P = 0.02). There were no other differences in outcomes between treatment groups. Complications occurred in 29.6% (n = 8/27) of the operative group compared with 25.0% (n = 4/16) of the nonoperative group resulting in 7 and 1 additional procedures, respectively.

Conclusions:

Operative treatment was associated with early benefits over nonoperative management, including shorter time using assistive devices, less SAR use, and less fracture displacement at follow-up.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Data Heterogeneity in Meta-Analyses
Authors: Yalla Goutham R. , Lambrechts Mark J.
Published: June 2023

Data heterogeneity determines whether sufficiently strong conclusions can be derived from synthesizing and aggregating the available literature. Multiple tools are available to calculate data heterogeneity, but each tool has pros and cons. Providing a prediction interval may be the most beneficial since it allows readers to quantify heterogeneity in a clear and clinically relevant form. However, the ultimate decision on which tool to use is left to the discretion of the researcher. This decision should be decided upon during the study inception.
A novel biodegradable polymer-coated sirolimus-eluting stent: the 1-year results of the HELIOS registry
Authors: Zheng Bo , Liu Yi , Zhang Ruining , Yang Wangwei , Su Fangju , Wang Rutao , Chen Dapeng , Shen Guidong , Qiu Yumin , Wang Lianmin , Chen Chang , Wu Zhongwei , Li Fei , Li Jiayi , Li Chengxiang , Gao Chao , Tao Ling
Published: June 2023

Background:

The HELIOS stent is a sirolimus-eluting stent with a biodegradable polymer and titanium oxide film as the tie-layer. The study aimed to evaluate the safety and efficacy of HELIOS stent in a real-world setting.

Methods:

The HELIOS registry is a prospective, multicenter, cohort study conducted at 38 centers across China between November 2018 and December 2019. A total of 3060 consecutive patients were enrolled after application of minimal inclusion and exclusion criteria. The primary endpoint was target lesion failure (TLF), defined as a composite of cardiac death, non-fatal target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (TLR) at 1-year follow-up. Kaplan–Meier methods were used to estimate the cumulative incidence of clinical events and construct survival curves.

Results:

A total of 2998 (98.0%) patients completed the 1-year follow-up. The 1-year incidence of TLF was 3.10% (94/2998, 95% closed interval: 2.54%–3.78%). The rates of cardiac death, non-fatal target vessel MI and clinically indicated TLR were 2.33% (70/2998), 0.20% (6/2998), and 0.70% (21/2998), respectively. The rate of stent thrombosis was 0.33% (10/2998). Age ≥60 years, diabetes mellitus, family history of coronary artery disease, acute myocardial infarction at admission, and device success were independent predictors of TLF at 1 year.

Conclusion:

The 1-year incidence rates of TLF and stent thrombosis were 3.10% and 0.33%, respectively, in patients treated with HELIOS stents. Our results provide clinical evidence of the HELIOS stent for the evaluation of Interventional Cardiologists and Policymakers.

Clinical trial registration:

ClinicalTrials.gov, NCT03916432
Intraspecific variation of two duckweed species influences response to microcystin-LR exposure
Authors: Rzodkiewicz Lacey D. , Turcotte Martin M.
Published: June 2023

Cyanotoxins produced by harmful cyanobacteria blooms can damage freshwater ecosystems and threaten human health. Floating macrophytes may be used as a means of biocontrol by limiting light and resources available to cyanobacteria. However, genetic variation in macrophyte sensitivity to cyanotoxins could influence their suitability as biocontrol agents. We investigated the influence of such intraspecific variation on the response of two rapidly growing duckweed species,Lemna minorandSpirodela polyrhiza, often used in nutrient and metal bioremediation. We assessed two biomarkers related to productivity (biomass and chlorophyll A production) and two related to fitness measures (population size and growth rate). Fifteen genetic lineages of each species were grown in media containing common cyanotoxin microcystin-LR at ecologically relevant concentrations or control media for a period of twelve days. Genotype identity had a strong impact on all biomarker responses. Microcystin concentration did impact the final population sizes of both macrophyte species with a marginal effect on growth rate ofL. minorand the chlorophyll A production ofS. polyrhiza, but overall these species were very tolerant of microcystin. The strong tolerance supports the potential use of these plants as bioremediators of cyanobacterial blooms. The differential impact of microcystin exposure discovered in single lineage models among genotypes indicates a potential for cyanotoxins to act as selective forces and reduce local macrophyte genetic diversity.

Highlights

Ecotoxicology often uses standard genotypes of plants in testing.

We tested the influence of clonal variation in duckweeds on their response to common cyanotoxin, microcystin-LR.

Microcystin impacts were often masked by genotypic variation in response.

Results imply that genotype identity may be important to bioremediation and local evolutionary dynamics.
Improving patient clustering by incorporating structured label relationships in similarity measures
Authors: Lambert Judith , Leutenegger Anne-Louise , Baudot Anaïs , Jannot Anne-Sophie
Published: June 2023

Context

Patient stratification is the cornerstone of numerous health studies, serving to enhance medicine efficacy estimation and facilitate patient matching. To stratify patients, similarity measured between patients can be computed from medical health records databases, such as medico-administrative databases. Importantly, the variables included in medico-administrative databases can be associated with labels, which can be organized in ontologies or other classification systems. However, to the best of our knowledge, the relevance of considering such label classification in the computation of patient similarity measures has been poorly studied.

Objective

We propose and evaluate several weighted versions of the Cosine similarity that consider structured label relationships to compute patient similarities from a medico-administrative database.

Material and Methods

As a use case, we analyze medicine reimbursements contained in theÉchantillon Généraliste des Bénéficiaires, a French medico-administrative database. We compute the standard Cosine similarity between patients based on their medicine reimbursement. In addition, we computed a weighted Cosine similarity measure that includes variable frequencies and two weighted Cosine similarity measures that consider label relationships. We construct patient networks from each similarity measure and identify clusters of patients. We evaluate the performance of the different similarity measures with enrichment tests using information on chronic diseases.

Results

The similarity measures that include label relationships perform better to identify similar patients. Indeed, using these weighted measures, we identify distinct patient clusters with a higher number of chronic disease enrichments as compared to the other measures. Importantly, the enrichment tests provide clinically interpretable insights into these patient clusters.

Conclusion

Considering label relationships when computing patient similarities improves stratification of patients regarding their health status.
Derivation of an Outcome-Driven Threshold for Aortic Pulse Wave Velocity: An Individual-Participant Meta-Analysis
Authors: An De-Wei , Hansen Tine W. , Aparicio Lucas S. , Chori Babangida , Huang Qi-Fang , Wei Fang-Fei , Cheng Yi-Bang , Yu Yu-Ling , Sheng Chang-Sheng , Gilis-Malinowska Natasza , Boggia José , Wojciechowska Wiktoria , Niiranen Teemu J. , Tikhonoff Valérie , Casiglia Edoardo , Narkiewicz Krzysztof , Stolarz-Skrzypek Katarzyna , Kawecka-Jaszcz Kalina , Jula Antti M. , Yang Wen-Yi , Woodiwiss Angela J. , Filipovský Jan , Wang Ji-Guang , Rajzer Marek W. , Verhamme Peter , Nawrot Tim S. , Staessen Jan A. , Li Yan ,   The International Database of Central Arterial Properties for Risk Stratification Investigators
Published: June 2023

BACKGROUND

Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVE) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using two populations studies, respectively, for derivation (IDCARS) and replication (MONICA).

METHODS

A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mmHg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI).

RESULTS

In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomical pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (HR [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both endpoints was ∼0.75. IDI was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas NRI was not for any outcome.

CONCLUSIONS

PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a person’s lifetime causes stiffening of the elastic arteries as waypoint to CVE and death.
Mosquito surveillance on U.S military installations as part of a Japanese encephalitis virus detection program: 2016 to 2021
Authors: Olson Mark F. , Brooks Caroline , Kakazu Akira , Promma Ploenphit , Sornjai Wannapa , Smith Duncan R. , Davis Timothy J.
Published: June 2023

Japanese encephalitis virus (JEV) continues to circulate throughout Southeast Asia and the Western Pacific where approximately 3 billion people in 24 countries are at risk of infection. Surveillance targeting the mosquito vectors of JEV was conducted at four military installations on Okinawa, Japan, between 2016 and 2021. Out of a total of 10,426 mosquitoes from 20 different species, zero were positive for JEV. The most abundant mosquito species collected wereAedes albopictus(36.4%) followed byCulex sitiens(24.3%) andArmigeres subalbatus(19%). Statistically significant differences in mosquito species populations according to location were observed. Changes in land use over time appear to be correlated with the species and number of mosquitoes trapped in each location. Japanese encephalitis virus appears to be absent from mosquito populations on Okinawa, but further research on domestic pigs and ardeid birds is warranted.

Author summary

Japanese encephalitis (JE) is a vector borne disease of significant public health importance for over one third of the earth’s population. While JE was first reported in Japan, the most significant outbreaks today are occurring in China and India. Since 2015, Japanese encephalitis vaccine became mandatory for United States military personnel assigned to Japan or South Korea. In an effort to evaluate the risk of JE infection to service members stationed on Okinawa, mosquito surveillance was conducted at four military installations between 2016 and 2021. Over ten thousand mosquitoes were collected, identified to species, and subjected to PCR testing. None of these samples were positive for Japanese encephalitis virus, but further research is still necessary.
Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types from 10,983 cancer patients
Authors: Everall Andrew , Tapinos Avraam , Hawari Aliah , Cornish Alex , Sud Amit , Chubb Daniel , Kinnersley Ben , Frangou Anna , Barquin Miguel , Jung Josephine , Church David N ,   Genomics England Research Consortium, Alexandrov Ludmil , Houlston Richard , Gruber Andreas J. , Wedge David C.
Published: June 2023

Whole genome sequencing (WGS) allows exploration of the complete compendium of oncogenic processes generating characteristic patterns of mutations. Mutational signatures provide clues to tumour aetiology and highlight potentially targetable pathway defects. Here, alongside single base substitution (SBS), double base substitution (DBS), small insertions and deletions (ID) and copy number aberration (CN) signatures covered by the Catalogue of Somatic Mutations in Cancer (COSMIC) we report signatures from an additional mutation type, structural variations (SV), all extractedde-novofrom WGS in 10,983 patients across 16 tumour types recruited to the 100,000 genomes project. Across the five mutation classes we report 137 signatures, with 29 signatures new to COSMIC, including the first COSMIC SV signature reference set. We relate the signatures to clinical outcomes and likely response to therapy, demonstrating the role of signature analysis in delivering the vision of precision oncology.
Trajectory of plasma lipidomes associated with the risk of late-onset Alzheimer’s disease pathogenesis: a longitudinal study in the ADNI cohort
Authors: Wang Tingting , Arnold Matthias , Huynh Kevin , Weinisch Patrick , Giles Corey , Mellett Natalie A , Duong Thy , Marella Bharadwaj , Nho Kwangsik , De Livera Alysha , Han Xianlin , Blach Colette , Saykin Andrew J , Kastenmüller Gabi , Meikle Peter J , Kaddurah-Daouk Rima ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Comprehensive lipidomic studies have demonstrated strong cross-sectional associations between the blood lipidome and late-onset Alzheimer’s disease (AD) and its risk factors. However, the longitudinal relationship between the lipidomic variations and progression of AD remains unknown. Here, we employed longitudinal lipidomic profiling on 4,730 plasma samples from 1,517 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to investigate the temporal evolution of lipidomes among diagnostic groups. At baseline, there were 1,393 participants including 437 cognitively normal (CN), 713 with mild cognitive impairment (MCI), and 243 AD cases. During follow up, 329 individuals (29 CN and 300 MCI) developed clinical AD (AD converters). We developed an AD-CN classification model to stratify the non-converting MCI group into AD-like and non AD-like MCI based on their lipidomics profiles at baseline. Longitudinal analysis identified associations between the change in ether lipid species (including alkylphosphatidylcholine, alkenylphosphatidylcholine, lysoalkylphosphatidylcholine, and lysoalkenylphosphatidylcholine) in converters relative to non-converting CN and MCI groups. Further, the AD-CN model efficiently classified MCI into low AD risk and high AD risk, with the high AD risk group having two times higher risk of conversion to AD than the low risk group. These findings suggest that the lipidomic profile can serve as a potential biomarker to identify individuals at higher risk for progressing to AD.
Outcome Prediction in Aneurysmal Subarachnoid Hemorrhage with World Federation of Neurological Societies grade V(OPAS-V)
Authors: Yamada Shuhei , Nishida Takeo , Takenaka Tomofumi , Yamazaki Hiroki , Nakagawa Ryota , Takagaki Masatoshi , Yano Yoshihiro , Nakamura Hajime , Toyota Shingo , Fujinaka Toshiyuki , Taki Takuyu , Fujita Toshiaki , Kishima Haruhiko
Published: June 2023

Background

Aneurysmal subarachnoid hemorrhage (aSAH) with World Federation of Neurological Societies (WFNS) grade V has a high mortality rate and poor prognosis. Some patients with WFNS grade V aSAH have had good outcomes after aggressive treatment; however, outcome predictions based on routine examinations and findings obtained at admission are yet to be reported. This study aimed to develop a decision tree model for predicting outcomes of patients with WFNS grade V aSAH to aid decision-making for treatment strategy.

Methods

A multicenter study with retrospective and prospective data collected from 201 (derivation cohort) and 12 (validation cohort) patients with WFNS grade V aSAH, respectively, was conducted. Clinical outcomes were divided into good (Modified Rankin Scale [mRS] score at the time of discharge: 0–2) and poor (mRS score: 3–6) outcomes. A decision tree model was developed for the derivation cohort using the classification and regression tree method with clinical data including laboratory findings; it was named OPAS-V (Outcome Prediction in Aneurysmal Subarachnoid hemorrhage with WFNS grade V). The performance of the model was evaluated by area under the curve (AUC) and overall accuracy in both cohorts.

Results

OPAS-V comprised 3 metrics; the percentage of lymphocytes (<49.9% or not), age (>50 yrs or not), and glucose to potassium ratio (≥3.2 or not). The model achieved an AUC of 0.828 (95% confidence interval: 0.712–0.944) and overall accuracy of 0.930. Moreover, the model performed well in the validation cohort with an AUC of 0.700 (95% confidence interval: 0.200–1) and overall accuracy of 0.833.

Conclusions

This study developed the first decision tree model for predicting outcomes of patients with WFNS grade V aSAH, based on simple findings obtained at admission. This may aid clinicians in determining treatment strategies for severe conditions such as WFNS grade V aSAH.
Fostering transparent medical image AI via an image-text foundation model grounded in medical literature
Authors: Kim Chanwoo , Gadgil Soham U. , DeGrave Alex J. , Cai Zhuo Ran , Daneshjou Roxana , Lee Su-In
Published: June 2023

Building trustworthy and transparent image-based medical AI systems requires the ability to interrogate data and models at all stages of the development pipeline: from training models to post-deployment monitoring. Ideally, the data and associated AI systems could be described using terms already familiar to physicians, but this requires medical datasets densely annotated with semantically meaningful concepts. Here, we present a foundation model approach, named MONET (Medical cONcept rETriever), which learns how to connect medical images with text and generates dense concept annotations to enable tasks in AI transparency from model auditing to model interpretation. Dermatology provides a demanding use case for the versatility of MONET, due to the heterogeneity in diseases, skin tones, and imaging modalities. We trained MONET on the basis of 105,550 dermatological images paired with natural language descriptions from a large collection of medical literature. MONET can accurately annotate concepts across dermatology images as verified by board-certified dermatologists, outperforming supervised models built on previously concept-annotated dermatology datasets. We demonstrate how MONET enables AI transparency across the entire AI development pipeline from dataset auditing to model auditing to building inherently interpretable models.
Myeloid-derived suppressor cells exacerbate poly(I:C)-induced lung inflammation in mice with renal injury and older mice
Authors: Xie Zhiqi , Zhou Haoyang , Obana Masanori , Fujio Yasushi , Okada Naoki , Tachibana Masashi
Published: June 2023

Viral pneumonia is a global health burden with a high mortality rate, especially in the elderly and in patients with underlying diseases. Recent studies have found that myeloid-derived suppressor cells (MDSCs) are abundant in these patient groups; however, their roles in the progression of viral pneumonia remain unclear. In this study, we observed a substantial increase in MDSCs in a mouse model of renal ischemia/reperfusion (I/R) injury and in older mice. When intranasal polyinosinic- polycytidylic acid (poly(I:C)) administration was used to mimic viral pneumonia, we found that mice with renal I/R injury exhibited more severe lung inflammation than sham mice when challenged with poly(I:C). In addition, MDSC depletion attenuated lung inflammation in mice with I/R injury. Similar results were obtained in older mice compared with those in young mice. Furthermore, we found that the adoptive transfer ofin vitro-differentiated MDSCs exacerbated poly(I:C)-induced lung inflammation. Taken together, these experimental results suggest that the increased proportion of MDSCs in mice with renal I/R injury and in older mice exacerbates poly(I:C)-induced lung inflammation. These findings have important implications for the treatment and prevention of severe lung inflammation caused by viral pneumonia.
Proteomic insights into mental health status: plasma markers in young adults
Authors: Afonin Alexey M. , Piironen Aino-Kaisa , de Sousa Maciel Izaque , Ivanova Mariia , Alatalo Arto , Whipp Alyce M , Pulkkinen Lea , Rose Richard J , van Kamp Irene , Kaprio Jaakko , Kanninen Katja M.
Published: June 2023

Global emphasis on enhancing prevention and treatment strategies necessitates increased understanding of biological mechanisms of psychopathology. Plasma proteomics is a powerful tool that has been applied in the context of specific mental disorders for biomarker identification. The p-factor, also known as the “general psychopathology factor”, is a concept in psychopathology suggesting that there is a common underlying factor that contributes to the development of various forms of mental disorders. It has been proposed that the p-factor can be used to understand the overall mental health status of an individual. Here we aimed to discover plasma proteins associated with the p-factor in 775 young adults in the FinnTwin12 cohort. Using liquid chromatography–tandem mass spectrometry, 14 proteins with a significant connection with the p-factor were identified, 9 of which were linked to epidermal growth factor receptor (EGFR) signalling. This exploratory study provides new insight into biological alterations associated with mental health status in young adults.
Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer
Authors: Zhang Linan , Cascio Sandra , Mellors John W , Buckanovich Ronald J , Osmanbeyoglu Hatice Ulku
Published: June 2023

High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a high stromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. Single-cell transcriptomics of the HGSOC TME from public and in-house datasets revealed a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors had a lower fraction of certain T cells, natural killer (NK) cells, and macrophages and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicated that epithelial cancer cells and CA-MSCs secreted CXCL12 that interacted with the CXCR4 receptor, which was overexpressed on NK and CD8+T cells. CXCL12 and/or CXCR4 antibodies confirmed the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.
A Deep Neural Network Two-part Model and Feature Importance Test for Semi-continuous Data
Authors: Zou Baiming , Mi Xinlei , Xenakis James G. , Wu Di , Hu Jianhua , Zou Fei
Published: June 2023

Semi-continuous data frequently arise in clinical practice. For example, while many surgical patients suffer from varying degrees of acute postoperative pain (POP) post surgery (i.e., POP score>0), others experience none (i.e., POP score = 0), indicating the existence of two distinct data processes at play. Existing parametric or semi-parametric two-part modeling methods for this type of semicontinuous data can fail to appropriately model these two underlying data processes as such methods rely heavily on (generalized) linear additive assumptions. However, many factors may interact to jointly influence the experience of POP non-additively and non-linearly. Motivated by this challenge and inspired by the flexibility of deep neural networks (DNN) to accurately approximate complex functions universally, we derive a DNN-based two-part model by adapting the conventional DNN methods by adding two additional components: a bootstrapping procedure along with a filtering algorithm to boost the stability of the conventional DNN, an approach we denote as sDNN. To improve the interpretability and transparency of sDNN, we further derive a feature importance testing procedure to identify important features contributing to the outcome measurements of the two data processes, denoting this approach fsDNN. We show that fsDNN not only offers a valid feature importance test but also that using the identified features can further improve the predictive performance of sDNN. The proposed sDNN- and fsDNN-based twopart models are applied to the analysis of real data from a POP study, in which application they clearly demonstrate advantages over the existing parametric and semi-parametric two-part models. Further, we conduct extensive numerical studies to demonstrate that sDNN and fsDNN consistently outperform the existing two-part models regardless of the data complexity. An R package implementing the proposed methods has been developed and deposited on GitHub (https://github.com/SkadiEye/fsDNN).
Dopamine activation modulates oscillatory synchrony in the hippocampal-prefrontal cortex circuitry
Authors: de Oliveira-Júnior Benedito Alves , Leite João Pereira , Ruggiero Rafael Naime
Published: June 2023

Interaction between brain networks forms the functional unit that sustains cognition and behavior. It has been proposed that oscillatory activity can synchronize distant neuronal populations. One crucial aspect to elucidate brain function and its emergent properties is to understand how functional connectivity is modulated in different time scales according to environmental or physiological demand. Modulatory neurotransmitters such as dopamine have been implicated in changes in membrane excitability, modulation of oscillatory power, and coherence in crucial circuits for cognition, such as the hippocampus-prefrontal cortex (HPC-PFC) pathway. However, it is not known how dopaminergic release modulates specifically the phase synchrony of HPC-PFC or which specific dopaminergic receptors are responsible for the effects. In this context, our objective was to investigate the influence of dopaminergic activity on HPC-PFC synchrony and to assess whether the observed effects are receptor-specific. Our results show that dopamine induces HPC-PFC theta synchrony dose-dependently. This effect is not reproduced by apomorphine unspecific agonism or by SKF and quinpirole agonists, which act respectively on D1- and D2-like receptors. Additionally, we observed a late effect with peak activity between 30 and 40 minutes after dopamine 100 nmol, apomorphine 0.75 mg/kg, or quinpirole administration in which the HPC-PFC delta synchrony increased. Together, these results evidence the participation of dopaminergic neurotransmission in regulating HPC-PFC oscillatory dynamics, Influencing the synchronization in slow frequency oscillation and long-distant brain communication.
Montane rain forest dynamics under changes in climate and human impact during the past millennia in northern Madagascar
Authors: Montade Vincent , Bremond Laurent , Teixeira Helena , Kasper Thomas , Daut Gerhard , Rasoamanana Elysée , Ramavovolona Perle , Favier Charly , Arnaud Fabien , Radespiel Ute , Behling Hermann
Published: June 2023

Madagascar comprises one of the Earth’s biologically richest, but also one of most endangered, terrestrial ecoregions. Although it is obvious that humans substantially altered its natural ecosystems during the past decades, the timing of arrival of humans on Madagascar as well as their environmental impact is not well resolved. In this context, this research aims to study and compare the influence of early human impact and climate change on rain forests and wildlife in northern Madagascar during the past Millennia. By using palaeoenvironmental reconstructions from lake sediment cores in a montane environment (Montagne d’Ambre), results indicate a major drought, starting approximately 1,100 years ago. This drought caused significant changes in lake levels and vegetation dynamics. Human impact, evidenced by fires, started a few decades later. Anthropogenic burning, limited to the low-altitude areas, was therefore not the driving force behind these early changes observed in the lake catchment areas. Although this does not dismiss the strong impacts humans had subsequently on these ecosystems, this work demonstrates that the late Holocene natural drought that intensified regionally about one thousand years ago, significantly impacted the ecosystems independently and prior to anthropogenic activities. At a regional scale, a review of demographic studies revealed a substantial number of inferred population bottlenecks in various wildlife species during the last millennia, likely resulting from this combination of both human-related impact and natural environmental changes (i.e., precipitation decline). This research highlights that the current state of ecosystems in northern Madagascar results from both human impact and natural climate changes. It also points to the importance of a multi-site and multi-proxy comparison for deciphering the nature and succession of past environmental changes.
Heritable epigenetic changes are constrained by the dynamics of regulatory architectures
Authors: Jose Antony M
Published: June 2023

Interacting molecules create regulatory architectures that can persist despite turnover of molecules. Although epigenetic changes occur within the context of such architectures, there is limited understanding of how they can influence the heritability of changes. Here I develop criteria for the heritability of regulatory architectures and use quantitative simulations of interacting regulators parsed as entities, their sensors and the sensed properties to analyze how architectures influence heritable epigenetic changes. Information contained in regulatory architectures grows rapidly with the number of interacting molecules and its transmission requires positive feedback loops. While these architectures can recover after many epigenetic perturbations, some resulting changes can become permanently heritable. Such stable changes can (1) alter steady-state levels while preserving the architecture, (2) induce different architectures that persist for many generations, or (3) collapse the entire architecture. Architectures that are otherwise unstable can become heritable through periodic interactions with external regulators, which suggests that the evolution of mortal somatic lineages with cells that reproducibly interact with the immortal germ lineage could make a wider variety of regulatory architectures heritable. Differential inhibition of the positive feedback loops that transmit regulatory architectures across generations can explain the gene-specific differences in heritable RNA silencing observed in the nematodeC. elegans, which range from permanent silencing to recovery from silencing within a few generations and subsequent resistance to silencing. More broadly, these results provide a foundation for analyzing the inheritance of epigenetic changes within the context of the regulatory architectures implemented using diverse molecules in different living systems.