bluuebunny/crossref_metadata_2025 huggingface dataset:
AN EFFECTIVE BOUND FOR GENERALISED DIOPHANTINEm-TUPLES
Authors: BHATTACHARJEE SAUNAK , DIXIT ANUP B. , SAIKIA DISHANT
Published: November 2023

For$k\geq 2$and a nonzero integern, a generalised Diophantinem-tuple with property$D_k(n)$is a set ofmpositive integers$S = \{a_1,a_2,\ldots , a_m\}$such that$a_ia_j + n$is akth power for$1\leq i< j\leq m$. Define$M_k(n):= \text {sup}\{|S| : S$having property$D_k(n)\}$. Dixitet al. [‘Generalised Diophantinem-tuples’,Proc. Amer. Math. Soc.150(4) (2022), 1455–1465] proved that$M_k(n)=O(\log n)$, for a fixedk, asnvaries. In this paper, we obtain effective upper bounds on$M_k(n)$. In particular, we show that for$k\geq 2$,$M_k(n) \leq 3\,\phi (k) \log n$ifnis sufficiently large compared tok.
“Une pièce d’étoffe que nous aurons à faire”: Louis Riel's Utopia: Between Prophecy and Politics
Authors: Barter Moulaison Luc
Published: November 2023

This article offers a re-evaluation of Louis Riel's political, philosophical and religious writings by reconstructing these writings along utopian lines. In so doing, it supplements the existing literature on Riel's writings that tends to see Riel as either a prophetic figure or a practical man of action, but rarely, if ever, both. In its reconstruction of Riel's utopian vision, this article focuses on three aspects of his writings. First, it addresses his critical conception of Métis self-government before Confederation. Second, it examines his proposals for the overthrow of what he perceived as Anglo-Canadian tyranny in the North-West. Third, it considers his visions of an ideal—that is, utopian—society in the North-West. The article concludes by examining the implications of this reading of Riel's utopian vision for his legacy in Canadian political science.
Genotype–environment interplay in associations between maternal drinking and offspring emotional and behavioral problems
Authors: Hannigan Laurie John , Lund Ingunn Olea , Dahl Askelund Adrian , Ystrom Eivind , Corfield Elizabeth C. , Ask Helga , Havdahl Alexandra
Published: November 2023

Background

While maternal at-risk drinking is associated with children's emotional and behavioral problems, there is a paucity of research that properly accounts for genetic confounding and gene–environment interplay. Therefore, it remains uncertain what mechanisms underlie these associations. We assess the moderation of associations between maternal at-risk drinking and childhood emotional and behavioral problems by common genetic variants linked to environmental sensitivity (genotype-by-environment [G × E] interaction) while accounting for shared genetic risk between mothers and offspring (GE correlation).

Methods

We use data from 109 727 children born to 90 873 mothers enrolled in the Norwegian Mother, Father, and Child Cohort Study. Women self-reported alcohol consumption and reported emotional and behavioral problems when children were 1.5/3/5 years old. We included child polygenic scores (PGSs) for traits linked to environmental sensitivity as moderators.

Results

Associations between maternal drinking and child emotional (β1 = 0.04 [95% confidence interval (CI) 0.03–0.05]) and behavioral (β1 = 0.07 [0.06–0.08]) outcomes attenuated after controlling for measured confounders and were almost zero when we accounted for unmeasured confounding (emotional: β1 = 0.01 [0.00–0.02]; behavioral: β1 = 0.01 [0.00–0.02]). We observed no moderation of these adjusted exposure effects by any of the PGS.

Conclusions

The lack of strong evidence for G × E interaction may indicate that the mechanism is not implicated in this kind of intergenerational association. It may also reflect insufficient power or the relatively benign nature of the exposure in this sample.
The validation crisis in the L2 motivational self system tradition
Authors: Al-Hoorie Ali H. , Hiver Phil , In’nami Yo
Published: November 2023

Concerns have recently been raised about the validity of scales used in the L2 motivational self system tradition, particularly in relation to sufficient discriminant validity among some of its scales. These concerns highlight the need to systematically examine the validity of scales used in this tradition. In this study, we therefore compiled a list of 18 scales in widespread use and administered them to Korean learners of English (N = 384). Testing the factorial structure of these scales using multiple exploratory and confirmatory factor-analytic criteria revealed severe discriminant validity issues. For example, the ideal L2 self was not discriminant from linguistic self-confidence, suggesting that participant responses to such ideal L2 self items is not driven by actual–ideal discrepancies as previously presumed but more likely by self-efficacy beliefs. We discuss these results in the context of the need to encourage systematic psychometric validation research in the language motivation field.
Mapping the predictive role of MLAT subtests for L2 achievement through regression commonality analysis
Authors: Dale Philip S. , Sparks Richard L.
Published: November 2023

Despite the widespread use and effectiveness of the Modern Language Aptitude Test (MLAT) composite score in predicting individual differences in L2 achievement and proficiency, there has been little examination of MLAT subtests, although they have potential for illuminating components of L2 aptitude and the mechanism of prediction. Here we use regression commonality analysis to decompose the predictive variance from the MLAT into unique components for each subtest alone and for each possible combination of subtests (duos, trios, etc.) that may have shared variance. The results, from a longitudinal study of 307 U.S. secondary students during 2 years of Spanish learning, provide strong evidence for the role of literacy-related skills in all subtests and in predicting all L2 outcomes. These and other results support a view of L1 literacy and language skills leading to metalinguistic development, which in turn leads to stronger L2 aptitude and achievement.
Anaphoriques en première mention : « Épiphénomène », ou modèle pour le fonctionnement de l’anaphore ?
Authors: Cornish Francis
Published: November 2023

Deux manifestations d’anaphoriques fonctionnant « sans antécédent » (l’exophore et l’anaphore indirecte) sont analysées afin de mettre en évidence le fonctionnement véritable de l’anaphore. Nous verrons ainsi la manière dont ceux-ci réalisent une référence dépendante, non par le biais d’un élément particulier de leur co-texte (un « antécédent » conventionnel), mais plutôt en fonction d’une représentation discursive déjà installée en mémoire de travail. Celle-ci aura été évoquée dans l’interaction par les participants dans un événement communicatif, et sera supposée saillante au moment du renvoi.

Seront examinées dans ce sens les contributions des valeurs de genre portées par des pronoms anaphoriques, les propriétés intrinsèques de ceux-ci, la pertinence des « noms de base » pour les pronoms employés ainsi, puis le rôle de la prédication « hôte » dans son ensemble. Ainsi « libérés » de la contrainte d’une mise en relation préalable avec un « antécédent » textuel, leur contribution à la gestion et à l’évolution du discours sera plus aisément perceptible.
Measuring dissociation across adolescence and adulthood: developing the short-form Černis Felt Sense of Anomaly scale (ČEFSA-14)
Authors: Černis Emma , Loe Bao S. , Lofthouse Katie , Waite Polly , Molodynski Andrew , Ehlers Anke , Freeman Daniel
Published: November 2023

Background:

Dissociation may be important across many mental health disorders, but has been variously conceptualised and measured. We introduced a conceptualisation of a common type of dissociative experience, ‘felt sense of anomaly’ (FSA), and developed a corresponding measure, the Černis Felt Sense of Anomaly (ČEFSA) scale.

Aims:

We aimed to develop a short-form version of the ČEFSA that is valid for adolescent and adult respondents.

Method:

Data were collected from 1031 adult NHS patients with psychosis and 932 adult and 1233 adolescent non-clinical online survey respondents. Local structural equation modelling (LSEM) was used to establish measurement invariance of items across the age range. Ant colony optimisation (ACO) was used to produce a 14-item short-form measure. Finally, the expected test score function derived from item response theory modelling guided the establishment of interpretive scoring ranges.

Results:

LSEM indicated 25 items of the original 35-item ČEFSA were age invariant. They were also invariant across gender and clinical status. ACO of these items produced a 14-item short-form (ČEFSA-14) with excellent psychometric properties (CFI=0.992; TLI=0.987; RMSEA=0.034; SRMR=0.017; Cronbach’s alpha=0.92). Score ranges were established based on the expected test scores at approximately 0.7, 1.25 and 2.0 theta (equivalent to standard deviations above the mean). Scores of 29 and above may indicate elevated levels of FSA-dissociation.

Conclusions:

The ČEFSA-14 is a psychometrically valid measure of FSA-dissociation for adolescents and adults. It can be used with clinical and non-clinical respondents. It could be used by clinicians as an initial tool to explore dissociation with their clients.
Dual modality feeders: a group of human milk feeders with unique practices and needs
Authors: Kholina Ksenia , Brady Jennifer , Snelgrove-Clarke Erna , Rossiter Melissa D , Whitfield Kyly C
Published: November 2023

Objective:

Dual modality feeding (DMF) – feeding human milk interchangeably from the breast and from a bottle – comes with unique practical, emotional and relational challenges, as well as support needs. Yet, there is little research that explores the experiences of individuals who use DMF in the Canadian context. The aim of this study is to explore the practices, challenges, reasons and enablers of DMF.

Design:

Repeat, semi-structured one-on-one interviews were conducted at 8 weeks and 22 weeks postpartum. Interview transcripts were thematically analysed using a critical feminist lens.

Setting:

Nova Scotia, Canada.

Participants:

Ten DMF mothers.

Results:

DMF practices were influenced by a mix of social and material circumstances, including breast-feeding challenges, the involvement of support persons, finances and access to lactation support. Individuals who predominantly fed at the breast expressed milk strategically to mitigate transitory breast-feeding challenges, for convenience under specific circumstances, and to share feeding responsibilities with other caregivers for personal and practical reasons. Individuals who mainly bottle-fed did so due to long-term breast-feeding challenges or a need to return to employment. Enablers of successful DMF were consistent between the two groups and included practical, personal and relational aspects.

Conclusions:

DMF is a unique practice compared to feeding human milk solely from the breast or bottle. Despite the potential growing prevalence of DMF, it is currently understudied and inadequately addressed in existing support programmes in Nova Scotia. Tailored programming and public messaging are needed to support DMF families.
Ultra-processing markers are more prevalent in plant-based meat products as compared to their meat-based counterparts in a German food market analysis
Authors: Metz Kemja-Maria , Neumann Nathalie Judith , Fasshauer Mathias
Published: November 2023

Objective:

To compare ultra-processing markers and nutrient composition in plant-based meat products (PBMP) with equivalent meat-based products (MBP).

Design:

A total of 282 PBMP and 149 MBP within 18 product categories were assessed. Based on the NOVA classification, 33 ultra-processing markers were identified and six ultra-processing bullet categories were defined, that is flavour, flavour enhancer, sweetener, colour, other cosmetic additives and non-culinary ingredients. The ingredient lists were analysed concerning these ultra-processing markers and ultra-processing bullet categories, as well as nutrient composition, for all PBMP and MBP. Differences between PBMP and MBP were assessed using chi-square and Mann-Whitney U tests, respectively.

Setting:

Cross-sectional analysis.

Participants:

282 PBMP and 149 MBP.

Results:

The percentage of ultra-processed food (UPF) items was significantly higher in PBMP (88 %) as compared to MBP (52 %) (P < 0·0001). The proportion of UPF items was numerically higher in 15 out of 18 product categories with differences in six categories reaching statistical significance (P < 0·05). Flavour, flavour enhancer, colour, other cosmetic additives and non-culinary ingredients were significantly more prevalent in PBMP as compared to MBP (P < 0·0001). Concerning nutrient composition, median energy, total fat, saturated fat and protein content were significantly lower, whereas the amounts of carbohydrate, sugar, fibre and salt were significantly higher in PBMP (P < 0·05).

Conclusions:

Ultra-processing markers are significantly more prevalent in PBMP as compared to MBP. Since UPF intake has been convincingly linked to metabolic and CVD, substituting MBP with PBMP might have negative net health effects.
FLUTE: A Python GUI for interactive phasor analysis of FLIM data
Authors: Gottlieb Dale , Asadipour Bahar , Kostina Polina , Ung Thi Phuong Lien , Stringari Chiara
Published: November 2023

Fluorescence lifetime imaging microscopy (FLIM) is a powerful technique used to probe the local environment of fluorophores. The fit-free phasor approach to FLIM data is increasingly being used due to its ease of interpretation. To date, no open-source graphical user interface (GUI) for phasor analysis of FLIM data is available in Python, thus limiting the widespread use of phasor analysis in biomedical research. Here, we present Fluorescence Lifetime Ultimate Explorer (FLUTE), a Python GUI that is designed to fill this gap. FLUTE simplifies and automates many aspects of the analysis of FLIM data acquired in the time domain, such as calibrating the FLIM data, performing interactive exploration of the phasor plot, displaying phasor plots and FLIM images with different lifetime contrasts simultaneously, and calculating the distance from known molecular species. After applying desired filters and thresholds, the final edited datasets can be exported for further user-specific analysis. FLUTE has been tested using several FLIM datasets including autofluorescence of zebrafish embryos and in vitro cells. In summary, our user-friendly GUI extends the advantages of phasor plotting by making the data visualization and analysis easy and interactive, allows for analysis of large FLIM datasets, and accelerates FLIM analysis for non-specialized labs.
Validating Finescale Parameterizations for the Eastern Arctic Ocean Internal Wave Field
Authors: Baumann Till M. , Fer Ilker , Schulz Kirstin , Mohrholz Volker
Published: November 2023

In the Arctic Ocean, vertical transport of heat by turbulent mixing is ultimately coupled to the sea‐ice cover, with immediate and far‐reaching impacts on the climate and ecosystem. Unfortunately, direct observations of mixing are difficult, expensive and sparse. Finescale Parameterization (FS) of turbulent energy dissipation rate (ɛ) allows for the quantification of turbulence from breaking internal waves using standard measurements, such as profiles of hydrography and velocity. While FS proved to be reliable in mid‐latitudes, the Arctic Ocean internal wave field is distinct in terms of composition and energy level, rendering the applicability of FS uncertain. To test FS in a wide range of eastern Arctic conditions, we compiled data from eight cruises. All profiles used to calculate FS were collocated with in‐situ measurements of ɛ obtained from microstructure profilers. FS was applied between 50 and 450 m below the surface. Results show a satisfactory performance of FS, with 84% of FS‐derived ɛ being within a factor of 5 to observations. This improved to 90% when using lower‐noise velocity profiles of lowered current meters instead of ship‐mounted current meters. In our data, FS performance is independent of the shear‐strain ratio (Rω) and internal wave field bandwidth (N/f), but there is evidence that highly stratified environments with large potential energy, low turbulence and substantially non‐white shear spectra are less suitable for FS. A widely used formulation of FS using only hydrography and a prescribed Rω = 7 results in 73% of FS estimates being within a factor of 5 to observations.
Global Mapping of Potential and Climatic Plant‐Available Soil Water
Authors: Gupta Surya , Lehmann Peter , Bickel Samuel , Bonetti Sara , Or Dani
Published: November 2023

The estimation of plant‐available soil water (PASW) is essential to quantify transpiration fluxes, the onset of heatwaves, irrigation water management, land‐use decisions, vegetation ecology, and land surface memory in climate models. PASW is the amount of stored water available for plant use. It is broadly defined as the difference between soil water content at field capacity (FC) and wilting point (WP) in the root zone. The limiting states of FC and WP are linked to gravitational drainage and plant physiology and are often deduced from soil water characteristics at prescribed matric potentials (−3.3 and −150 m for FC and WP, respectively). Evidence suggests that static definition of FC at a constant matric potential ignores dynamic effects on FC attainment affected by soil and climate. Here, we revise the definition of PASW by considering (a) soil‐specific dynamic effects and (b) local climate effects of evaporation and rainfall frequency on PASW. The new global PASW maps benefit from state‐of‐the‐art soil maps, water characteristic parameterization, and incorporation of dynamic definition of FC. For completeness we provide static and dynamic PASW estimates. Globally, ice‐free soils store up to 19,941 km3 of water in the top 1 m (representing 18% of annual terrestrial precipitation). Adjusted for local climatic conditions, global PASW storage rarely exceeds 14,853 km3 per year highlighting the need for multiple refilling of soil profiles. Differences between potential and climatic PASW are manifested primarily in arid regions (where soil profiles are rarely filled to capacity) whereas in humid regions differences in PASW storage are minor.
Seafloor Investigations of the Kemp Caldera, the Southernmost Arc Caldera Volcano From the South Sandwich Island Arc
Authors: Kürzinger Victoria , Römer Miriam , Lichtschlag Anna , Bohrmann Gerhard
Published: November 2023

Kemp Caldera, situated in the south of the intra‐oceanic South Sandwich arc, is one of the least explored submarine calderas that hosts hydrothermally active vent sites. The caldera was discovered in 2009. Since then, the focus has been primarily on biological studies. During the R/V Polarstern cruise PS119 in 2019, we gained new insights into the morphology, petrology and the formation of the Kemp Caldera. The ship's multibeam data provide an overview of the caldera bathymetry and backscatter characteristics. The new data revealed that the caldera is nested with two or possibly three concentric calderas. TV‐sled and remotely operated vehicle (ROV) observations provide detailed visual data for the hydrothermally active sites of the vent field at the central resurgent cone and flare site at the NNW caldera rim. The central vent field is dominated by white smokers, where clams, sponges and other fauna thrive, while at the flare site inactive as well as actively venting chimneys have been found. The latter are characterized by metal‐enriched fluids of temperatures ≥200°C. During ROV dives, rock samples were collected from the cone, providing the first information about the Kemp Caldera rock composition. The caldera rocks are dacitic, in contrast to the basalts and andesites of the neighboring Kemp Seamount. This suggests that the dacitic cone was formed by one or more later eruptions of differentiated magma, probably stored in shallow intrusions which are driving hydrothermal activity.
Coral Reveals a Transition in Sources of Seawater Vanadium From Submarine Groundwater Discharge to Upwelling in the Northern South China Sea
Authors: Guo Ning , Jiang Wei , Yu Kefu , Zhao Jian‐xin , Song Yinxian , Feng Yue‐xing , Han Yansong , Gu Tingwu
Published: November 2023

In recent decades, vanadium (V) levels in the environment have dramatically increased and will continue to rise alarmingly in the future. Conventional methods for assessing oceanic V typically only involved the collection of seawater and sediments, which significantly limited our understanding of the dynamics of oceanic V and its relationship to environment and climate. Here, the interannual temporal variations in surface seawater V levels in the northern South China Sea, were reconstructed utilizing a 137‐year record of V/Ca ratios from Porites lutea coral from Xiaodonghai Bay off Sanya. We observed that anthropogenic activities had a limited impact on the V levels of surface seawater in the study area, whereas V variability exhibited significant disparities across different time periods. Precipitation‐related submarine groundwater discharge (SGD) recharge was the primary driver of V variation prior to 1990, with tropical cyclones (TCs) playing a detectable role in total precipitation during this period. Conversely, changes in surface seawater V levels after 1990 were predominantly linked to increasingly intense upwelling driven by summer winds. The recharge processes in unconfined groundwater systems within the study area might generate favorable oxic and alkaline conditions, which facilitated mineral dissolution and/or desorption reactions that elevated V concentrations along the groundwater flow path, which were recorded in coral skeletal V/Ca ratios. This study confirmed the seawater V was dominated by SGD and upwelling near Sanya, providing essential evidence for comprehending the geochemical behavior of V and the impact of ocean‐atmospheric climate interactions on long‐term variations in seawater V levels.
Removal of the rate table: MEMS gyrocompass with virtual maytagging
Authors: Miao Tongqiao , Li Qingsong , Chen Liangqian , Li Junjian , Hu Xiaoping , Wu Xuezhong , Wu Wenqi , Xiao Dingbang
Published: November 2023

High-performance micro-electro-mechanical system (MEMS) gyrocompasses for north-finding systems have been very popular for decades. In this paper, a MEMS north-finding system (NFS) based on virtual maytagging (VM) is presented for the first time. In stark contrast to previous schemes of MEMS-based NFSs (e.g., carouseling, maytagging) and the abandoning rate table, we developed a honeycomb disk resonator gyroscope (HDRG) and two commercial accelerometers for azimuth detection. Instead of the physical rotation of the integrated turntable in traditional NFSs, the vibratory working modes of the HDRG are rotated periodically with electronic control to reduce the uncertainty in the azimuth. After systematically analyzing the principle of NFSs with VM, we designed tests to verify the practicability at the sensor level. A bias instability of 0.0078°/h can be obtained during one day with VM in an HDRG. We also implemented comparative north-finding experiments to further check our strategy at the system level. The accuracy in the azimuth can reach 0.204° for 5 min at 28.2° latitude with VM and 0.172° with maytagging. The results show that without any mechanical turning parts, VM technology makes it possible to develop high-precision handheld MEMS NFSs.
Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance
Authors: Yan Gang , Dai Meiou , Poulet Sophie , Wang Ni , Boudreault Julien , Daliah Girija , Ali Suhad , Lebrun Jean-Jacques
Published: November 2023

Triple negative breast cancer (TNBC) is defined as lacking the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC patients exhibit relatively poor clinical outcomes due to lack of molecular markers for targeted therapies. As such chemotherapy often remains the only systemic treatment option for these patients. While chemotherapy can initially help shrink TNBC tumor size, patients eventually develop resistance to drug, leading to tumor recurrence. We report a combined in vitro/in vivo genome-wide CRISPR synthetic lethality screening approach in a relevant TNBC cell line model to identify several targets responsible for the chemotherapy drug, paclitaxel resistance. Computational analysis integrating in vitro and in vivo data identified a set of genes, for which specific loss-of-function deletion enhanced paclitaxel resistance in TNBC. We found that several of these genes (ATP8B3, FOXR2, FRG2, HIST1H4A) act as cancer stemness negative regulators. Finally, using in vivo orthotopic transplantation TNBC models we showed that FRG2 gene deletion reduced paclitaxel efficacy and promoted tumor metastasis, while increasing FRG2 expression by means of CRISPR activation efficiently sensitized TNBC tumors to paclitaxel treatment and inhibited their metastatic abilities. In summary, the combined in vitro/in vivo genome-wide CRISPR screening approach proved effective as a tool to identify novel regulators of paclitaxel resistance/sensitivity and highlight the FRG2 gene as a potential therapeutical target overcoming paclitaxel resistance in TNBC.
Mesenchymal stem cells under epigenetic control – the role of epigenetic machinery in fate decision and functional properties
Authors: Walewska Alicja , Janucik Adrian , Tynecka Marlena , Moniuszko Marcin , Eljaszewicz Andrzej
Published: November 2023

Mesenchymal stem cells (mesenchymal stromal cells, MSC) are multipotent stem cells that can differentiate into cells of at least three mesodermal lineages, namely adipocytes, osteoblasts, and chondrocytes, and have potent immunomodulatory properties. Epigenetic modifications are critical regulators of gene expression and cellular differentiation of mesenchymal stem cells (MSCs). Epigenetic machinery controls MSC differentiation through direct modifications to DNA and histones. Understanding the role of epigenetic machinery in MSC is crucial for the development of effective cell-based therapies for degenerative and inflammatory diseases. In this review, we summarize the current understanding of the role of epigenetic control of MSC differentiation and immunomodulatory properties.
PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity
Authors: Liu Rui , Zeng Lin-Wen , Li Hui-Fang , Shi Jun-Ge , Zhong Bo , Shu Hong-Bing , Li Shu
Published: November 2023

Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γc). PD-1 ligation also activates SHP2, which dephosphorylates γcY357, leading to impairment of γc family cytokine-triggered signaling. Conversely, PD-1 blockade restores γc level and activity, thereby sensitizing CD8+ T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γc family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.
A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis
Authors: Newsome Philip N. , Sanyal Arun J. , Neff Guy , Schattenberg Jörn M. , Ratziu Vlad , Ertle Judith , Link Jasmin , Mackie Alison , Schoelch Corinna , Lawitz Eric ,   BI 1467335 NASH Phase IIa trial team
Published: November 2023

Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg (n = 16), 3 mg (n = 16), 6 mg (n = 17), 10 mg (n = 32) or placebo (n = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks’ treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo; n = 32), 26.5% (1 mg; n = 16), 10.4% (3 mg; n = 16), 5.0% (6 mg; n = 16), 3.3% (10 mg; n = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition ( < 20% activity) at Week 4. At Week 12 following doses of BI 1467335 ≥ 3 mg, ALT and CK-18 caspase decreased dose-dependently. All tested BI 1467335 doses were well tolerated, with no clinically relevant treatment-emergent safety signals. BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83).
Validation of MSIntuit as an AI-based pre-screening tool for MSI detection from colorectal cancer histology slides
Authors: Saillard Charlie , Dubois Rémy , Tchita Oussama , Loiseau Nicolas , Garcia Thierry , Adriansen Aurélie , Carpentier Séverine , Reyre Joelle , Enea Diana , von Loga Katharina , Kamoun Aurélie , Rossat Stéphane , Wiscart Corentin , Sefta Meriem , Auffret Michaël , Guillou Lionel , Fouillet Arnaud , Kather Jakob Nikolas , Svrcek Magali
Published: November 2023

Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is now recommended, but contributes to increased workload for pathologists and delayed therapeutic decisions. Deep learning has the potential to ease dMMR/MSI testing and accelerate oncologist decision making in clinical practice, yet no comprehensive validation of a clinically approved tool has been conducted. We developed MSIntuit, a clinically approved artificial intelligence (AI) based pre-screening tool for MSI detection from haematoxylin-eosin (H&E) stained slides. After training on samples from The Cancer Genome Atlas (TCGA), a blind validation is performed on an independent dataset of 600 consecutive CRC patients. Inter-scanner reliability is studied by digitising each slide using two different scanners. MSIntuit yields a sensitivity of 0.96–0.98, a specificity of 0.47-0.46, and an excellent inter-scanner agreement (Cohen’s κ: 0.82). By reaching high sensitivity comparable to gold standard methods while ruling out almost half of the non-MSI population, we show that MSIntuit can effectively serve as a pre-screening tool to alleviate MSI testing burden in clinical practice.
Nodal band-off-diagonal superconductivity in twisted graphene superlattices
Authors: Christos Maine , Sachdev Subir , Scheurer Mathias S.
Published: November 2023

The superconducting state and mechanism are among the least understood phenomena in twisted graphene systems. Recent tunneling experiments indicate a transition between nodal and gapped pairing with electron filling, which is not naturally understood within current theory. We demonstrate that the coexistence of superconductivity and flavor polarization leads to pairing channels that are guaranteed by symmetry to be entirely band-off-diagonal, with a variety of consequences: most notably, the pairing invariant under all symmetries can have Bogoliubov Fermi surfaces in the superconducting state with protected nodal lines, or may be fully gapped, depending on parameters, and the band-off-diagonal chiralp-wave state exhibits transitions between gapped and nodal regions upon varying the doping. We demonstrate that band-off-diagonal pairing can be the leading state when only phonons are considered, and is also uniquely favored by fluctuations of a time-reversal-symmetric intervalley coherent order motivated by recent experiments. Consequently, band-off-diagonal superconductivity allows for the reconciliation of several key experimental observations in graphene moiré systems.
Dual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes
Authors: Silale Augustinas , Zhu Yiling , Witwinowski Jerzy , Smith Robert E. , Newman Kahlan E. , Bhamidimarri Satya P. , Baslé Arnaud , Khalid Syma , Beloin Christophe , Gribaldo Simonetta , van den Berg Bert
Published: November 2023

The outer membrane (OM) in diderm, or Gram-negative, bacteria must be tethered to peptidoglycan for mechanical stability and to maintain cell morphology. Most diderm phyla from the Terrabacteria group have recently been shown to lack well-characterised OM attachment systems, but instead have OmpM, which could represent an ancestral tethering system in bacteria. Here, we have determined the structure of the most abundant OmpM protein from Veillonella parvula (diderm Firmicutes) by single particle cryogenic electron microscopy. We also characterised the channel properties of the transmembrane β-barrel of OmpM and investigated the structure and PG-binding properties of its periplasmic stalk region. Our results show that OM tethering and nutrient acquisition are genetically linked in V. parvula, and probably other diderm Terrabacteria. This dual function of OmpM may have played a role in the loss of the OM in ancestral bacteria and the emergence of monoderm bacterial lineages.
Tracing cancer evolution and heterogeneity using Hi-C
Authors: Erdmann-Pham Dan Daniel , Batra Sanjit Singh , Turkalo Timothy K. , Durbin James , Blanchette Marco , Yeh Iwei , Shain Hunter , Bastian Boris C. , Song Yun S. , Rokhsar Daniel S. , Hockemeyer Dirk
Published: November 2023

Chromosomal rearrangements can initiate and drive cancer progression, yet it has been challenging to evaluate their impact, especially in genetically heterogeneous solid cancers. To address this problem we developed HiDENSEC, a new computational framework for analyzing chromatin conformation capture in heterogeneous samples that can infer somatic copy number alterations, characterize large-scale chromosomal rearrangements, and estimate cancer cell fractions. After validating HiDENSEC with in silico and in vitro controls, we used it to characterize chromosome-scale evolution during melanoma progression in formalin-fixed tumor samples from three patients. The resulting comprehensive annotation of the genomic events includes copy number neutral translocations that disrupt tumor suppressor genes such as NF1, whole chromosome arm exchanges that result in loss of CDKN2A, and whole-arm copy-number neutral loss of homozygosity involving PTEN. These findings show that large-scale chromosomal rearrangements occur throughout cancer evolution and that characterizing these events yields insights into drivers of melanoma progression.
Evolutionary design of explainable algorithms for biomedical image segmentation
Authors: Cortacero Kévin , McKenzie Brienne , Müller Sabina , Khazen Roxana , Lafouresse Fanny , Corsaut Gaëlle , Van Acker Nathalie , Frenois François-Xavier , Lamant Laurence , Meyer Nicolas , Vergier Béatrice , Wilson Dennis G. , Luga Hervé , Staufer Oskar , Dustin Michael L. , Valitutti Salvatore , Cussat-Blanc Sylvain
Published: November 2023

An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting “black box” models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches.
Eco-evolutionary feedbacks in the human gut microbiome
Authors: Good Benjamin H. , Rosenfeld Layton B.
Published: November 2023

Gut microbiota can evolve within their hosts on human-relevant timescales, but little is known about how these changes influence (or are influenced by) the composition of their local community. Here, by combining ecological and evolutionary analyses of a large cohort of human gut metagenomes, we show that the short-term evolution of the microbiota is linked with shifts in its ecological structure. These correlations are not simply explained by expansions of the evolving species, and often involve additional fluctuations in distantly related taxa. We show that similar feedbacks naturally emerge in simple resource competition models, even in the absence of cross-feeding or predation. These results suggest that the structure and function of host microbiota may be shaped by their local evolutionary history, which could have important implications for personalized medicine and microbiome engineering.
Microbiome and metabolome features in inflammatory bowel disease via multi-omics integration analyses across cohorts
Authors: Ning Lijun , Zhou Yi-Lu , Sun Han , Zhang Youwei , Shen Chaoqin , Wang Zhenhua , Xuan Baoqin , Zhao Ying , Ma Yanru , Yan Yuqing , Tong Tianying , Huang Xiaowen , Hu Muni , Zhu Xiaoqiang , Ding Jinmei , Zhang Yue , Cui Zhe , Fang Jing-Yuan , Chen Haoyan , Hong Jie
Published: November 2023

The perturbations of the gut microbiota and metabolites are closely associated with the progression of inflammatory bowel disease (IBD). However, inconsistent findings across studies impede a comprehensive understanding of their roles in IBD and their potential as reliable diagnostic biomarkers. To address this challenge, here we comprehensively analyze 9 metagenomic and 4 metabolomics cohorts of IBD from different populations. Through cross-cohort integrative analysis (CCIA), we identify a consistent characteristic of commensal gut microbiota. Especially, three bacteria, namely Asaccharobacter celatus, Gemmiger formicilis, and Erysipelatoclostridium ramosum, which are rarely reported in IBD. Metagenomic functional analysis reveals that essential gene of Two-component system pathway, linked to fecal calprotectin, are implicated in IBD. Metabolomics analysis shows 36 identified metabolites with significant differences, while the roles of these metabolites in IBD are still unknown. To further elucidate the relationship between gut microbiota and metabolites, we construct multi-omics biological correlation (MOBC) maps, which highlights gut microbial biotransformation deficiencies and significant alterations in aminoacyl-tRNA synthetases. Finally, we identify multi-omics biomarkers for IBD diagnosis, validated across multiple global cohorts (AUROC values ranging from 0.92 to 0.98). Our results offer valuable insights and a significant resource for developing mechanistic hypotheses on host-microbiome interactions in IBD.
Bioinspired thermadapt shape-memory polymer with light-induced reversible fluorescence for rewritable 2D/3D-encoding information carriers
Authors: Huang Jinhui , Jiang Yue , Chen Qiuyu , Xie Hui , Zhou Shaobing
Published: November 2023

Fluorescent materials have attracted widespread attention for information encryption owing to their stimuli-responsive color-shifting. However, the 2D encoding of fluorescent images poses a risk of information leakage. Herein, inspired by the mimic octopus capable of camouflage by changing colors and shapes, we develop a thermadapt shape-memory fluorescent film (TSFF) for integrating 2D/3D encoding in one system. The TSFF is based on anthracene group with reversible photo-cross-linking and poly (ethylene-co-vinyl acetate) network with thermadapt shape-memory properties. The reversible photo-cross-linking of anthracene is accompanied by repeatable fluorescence-shifting and enables rewritable 2D encoding. Meanwhile, the thermadapt shape-memory properties not only enables the reconfiguration of the permanent shape for creating and erasing 3D patterns, i.e., rewritable 3D information, but also facilitates recoverable shape programming for 3D encoding. This rewritable 2D/3D encoding strategy can enhance information security because only designated inspectors can decode the information by providing sequential heating for shape recovery and UV exposure. Overall, TSFF capable of rewritable 2D/3D encoding will inspire the design of smart materials for high-security information carriers.
Structure of a heteropolymeric type 4 pilus from a monoderm bacterium
Authors: Anger Robin , Pieulle Laetitia , Shahin Meriam , Valette Odile , Le Guenno Hugo , Kosta Artemis , Pelicic Vladimir , Fronzes Rémi
Published: November 2023

Type 4 pili (T4P) are important virulence factors, which belong to a superfamily of nanomachines ubiquitous in prokaryotes, called type 4 filaments (T4F). T4F are defined as helical polymers of type 4 pilins. Recent advances in cryo-electron microscopy (cryo-EM) led to structures of several T4F, revealing that the long N-terminal α-helix (α1) – the trademark of pilins – packs in the centre of the filaments to form a hydrophobic core. In diderm bacteria – all available bacterial T4F structures are from diderm species – a portion of α1 is melted (unfolded). Here we report that this architecture is conserved in phylogenetically distant monoderm species by determining the structure of Streptococcus sanguinis T4P. Our 3.7 Å resolution cryo-EM structure of S. sanguinis heteropolymeric T4P and the resulting full atomic model including all minor pilins highlight universal features of bacterial T4F and have widespread implications in understanding T4F biology.
Long-term sea level rise modeling of a basin-tidal inlet system reveals sediment sinks
Authors: Hanegan Kevin C. , FitzGerald Duncan M. , Georgiou Ioannis Y. , Hughes Zoe J.
Published: November 2023

Much of the world’s population lives close to coastlines and this proximity is becoming increasingly impactful because of sea-level rise (SLR). Barrier islands and backbarrier saltmarshes, which comprise >10% of these coasts, are particularly susceptible. To better understand this risk, we model backbarrier morphologic and hydrodynamic evolution over a 200-year period of SLR, incorporating an erodible bed and a range of grain sizes. Here, we show that reduction in intertidal area creates negative feedback, shifting transport of coarse sediment (silt and sand) through the inlet from net export to net import. Imposing a modest marsh vertical accretion rate decreases the period of silt and sand import to 40 years (years 90 to 130) before being exported again. Clay is continuously exported thereby decreasing inorganic deposition on marshes and threatening their sustainability. Simulated marsh loss increases tidal prism and the volume of sand contained in ebb deltas, depleting coastal sand resources.
Realizing a deep reinforcement learning agent for real-time quantum feedback
Authors: Reuer Kevin , Landgraf Jonas , Fösel Thomas , O’Sullivan James , Beltrán Liberto , Akin Abdulkadir , Norris Graham J. , Remm Ants , Kerschbaum Michael , Besse Jean-Claude , Marquardt Florian , Wallraff Andreas , Eichler Christopher
Published: November 2023

Realizing the full potential of quantum technologies requires precise real-time control on time scales much shorter than the coherence time. Model-free reinforcement learning promises to discover efficient feedback strategies from scratch without relying on a description of the quantum system. However, developing and training a reinforcement learning agent able to operate in real-time using feedback has been an open challenge. Here, we have implemented such an agent for a single qubit as a sub-microsecond-latency neural network on a field-programmable gate array (FPGA). We demonstrate its use to efficiently initialize a superconducting qubit and train the agent based solely on measurements. Our work is a first step towards adoption of reinforcement learning for the control of quantum devices and more generally any physical device requiring low-latency feedback.
Dirac-fermion-assisted interfacial superconductivity in epitaxial topological-insulator/iron-chalcogenide heterostructures
Authors: Yi Hemian , Hu Lun-Hui , Zhao Yi-Fan , Zhou Ling-Jie , Yan Zi-Jie , Zhang Ruoxi , Yuan Wei , Wang Zihao , Wang Ke , Hickey Danielle Reifsnyder , Richardella Anthony R. , Singleton John , Winter Laurel E. , Wu Xianxin , Chan Moses H. W. , Samarth Nitin , Liu Chao-Xing , Chang Cui-Zu
Published: November 2023

Over the last decade, the possibility of realizing topological superconductivity (TSC) has generated much excitement. TSC can be created in electronic systems where the topological and superconducting orders coexist, motivating the continued exploration of candidate material platforms to this end. Here, we use molecular beam epitaxy (MBE) to synthesize heterostructures that host emergent interfacial superconductivity when a non-superconducting antiferromagnet (FeTe) is interfaced with a topological insulator (TI) (Bi, Sb)2Te3. By performing in-vacuo angle-resolved photoemission spectroscopy (ARPES) and ex-situ electrical transport measurements, we find that the superconducting transition temperature and the upper critical magnetic field are suppressed when the chemical potential approaches the Dirac point. We provide evidence to show that the observed interfacial superconductivity and its chemical potential dependence is the result of the competition between the Ruderman-Kittel-Kasuya-Yosida-type ferromagnetic coupling mediated by Dirac surface states and antiferromagnetic exchange couplings that generate the bicollinear antiferromagnetic order in the FeTe layer.