bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactions of Crucible Materials With an FeOx–SiO2–Al2O3 Melt and Their Influence on Viscosity Measurements
Authors: Isaksson Jenny , Andersson Anton , Lennartsson Andreas , Samuelsson Caisa
Published: October 2023

Viscosity is a critical parameter during metal extraction, influencing the settling of valuable droplets, slag handling, and mass transfer. The viscosity of oxide melts can be measured with high-temperature rheometers. During such measurements, interactions between the crucible and the oxide system can change the chemical composition, melt structure, and thus the viscosity. For increased reliability of viscosity measurements, the influence of crucible and spindle materials on viscosity must be studied. In this study, the viscosity of a synthetic FeOx–SiO2–Al2O3 melt was measured using the rotating spindle technique and three different crucible and spindle materials (Mo, Fe, and Ni) to determine the interactions with the melt and the influence on viscosity. The interaction was evaluated by comparing the post-experimental chemical analyses, the Fe/Fe2+/Fe3+ content, visual observations, and using scanning electron microscopy–energy dispersive spectroscopy (SEM–EDS). The results showed that all the crucibles partially dissolved into the melt, affecting the melt structure, composition, and, thus, the viscosities. The viscosity data obtained using the Mo setup interacted the least with the melt, was the most stable, and with the best reproducibility.

Graphical Abstract
Sanitizing data for analysis: Designing systems for data understanding
Authors: Holstein Joshua , Schemmer Max , Jakubik Johannes , Vössing Michael , Satzger Gerhard
Published: October 2023

As organizations accumulate vast amounts of data for analysis, a significant challenge remains in fully understanding these datasets to extract accurate information and generate real-world impact. Particularly, the high dimensionality of datasets and the lack of sufficient documentation, specifically the provision of metadata, often limit the potential to exploit the full value of data via analytical methods. To address these issues, this study proposes a hybrid approach to metadata generation, that leverages both the in-depth knowledge of domain experts and the scalability of automated processes. The approach centers on two key design principles—semanticization and contextualization—to facilitate the understanding of high-dimensional datasets. A real-world case study conducted at a leading pharmaceutical company validates the effectiveness of this approach, demonstrating improved collaboration and knowledge sharing among users. By addressing the challenges in metadata generation, this research contributes significantly toward empowering organizations to make more effective, data-driven decisions.
Reorganizing the Waterscape: Asymmetric Loss of Wetlands and Gain of Artificial Water Features in a Mixed-use Watershed
Authors: Rains Mark , Schmidt Kurt , Landry Shawn , Kleindl William , Rains Kai
Published: October 2023

Between the 1780 and 1980s, more than half of the wetlands in the conterminous US were lost. As wetlands have been lost, numerous artificial water features (AWFs), such as stormwater retention ponds, golf course water features, and reservoirs, have been constructed. We contrasted the loss of wetland area and perimeter to the gain of AWF area and perimeter and further explored how this transformation has altered the spatial characteristics of the waterscape. We conducted this analysis in the Tampa Bay Watershed, a large coastal watershed that lost 33% of its wetland area between the 1950s-2007. Trends have been towards fewer, smaller wetlands and more, smaller AWFs. The loss of wetland area far exceeds the gain in AWF area, leading to an overall loss of 23% of the combined wetland and AWF area. However, the loss of wetland perimeter almost equals the gain in AWF perimeter, leading to an overall loss of just 2% of the combined wetland and AWF perimeter. The loss of wetlands and gain of AWFs have predominantly occurred in different geographic locations, with the loss of wetlands predominantly in the headwaters and the gain in AWFs predominantly adjacent to Tampa Bay. Wetlands became further apart, though generally retained their natural distribution, while AWFs became closer to one another and now mirror the more natural wetland distribution. Overall, the physical structure of the waterscape of today is different than in the past, which likely reflects a change in functions performed and related ecological services provided at local and landscape scales.
Myths, Fallacies and "Machismo" Prejudices in the Practice of Sex: A Study on Attitudes and Knowledge for Sexual Life in a Large Spanish Sample
Authors: Monterde-i-Bort Hector , Herrera Inés , Guardiola Carmen
Published: October 2023

Introduction

Many of the sexual problems of the couples that come to psychology and sexology consultations are due to erroneous beliefs surrounding the topic of sex. Beliefs that have been turned into widespread sexual myths and fallacies in society. In this study, we conducted a survey on knowledge and fallacies related to sexual intercourse with a large Spanish random sample. Our aim was to evaluate the presence of these fallacies and myths in today's modern society.

Methods

A total of 1162 participants of different genders (female, male, and non-binary), different sexual orientation (mostly heterosexual) and different ages (from 14 –two cases- to 64 with mean of 24.62 and SD of 8.96), answered an online questionnaire, developed ad hoc for this study, during the years 2019, 2020 and 2021. This questionnaire or survey collects the different fallacies, myths and “machismo” attitudes collected in clinical practice (psychology/sexology) that have caused couples or individuals to request professional therapeutic help, as well as knowledge related to sexual practices.

Results

The results show that the current level of knowledge is in general good (between 99 and 73% of adequate responses, with some exceptions mainly related to anatomy), higher among women (reaching their highest percentage of correct answers at 99%) than men (reaching their highest percentage of correct answers at 97%), and independent of age. In addition, we observe the weight and relationship that certain myths and traditional cultural fallacies have, as well as the presence of false expectations and beliefs about what the "ideal" sexual relationship should be, which are still very present in modern Spanish society, and which are responsible for the majority of clinical consultations and alleged disorders related to couples’ sexual life.

Conclusions

These myths, false beliefs, and unrealistic expectations, as well as the subtle attitudes of "machismo" (that people are not aware that they possess), must be combated (information, campaigns) since they are responsible for many of the apparent disorders and dysfunctions in the human sexual response (which are mostly attributed to women), and in the sexual life, in general, of couples.

Policy Implications

This study presents the level that these fallacies and negative attitudes are present in a large sample in Spain, and the questionnaire developed will allow evaluating the level of presence of these fallacies and negative attitudes, both in different societies/ groups and in particular individuals. Information that will be of great help to professional therapists who treat dysfunctions and sexual problems in couple/marital life, which are based on these fallacies, on attitudes of “machismo” and/or on the lack of knowledge on the one's own sex and that of their partner.
Federated machine learning for predicting acute kidney injury in critically ill patients: a multicenter study in Taiwan
Authors: Huang Chun-Te , Wang Tsai-Jung , Kuo Li-Kuo , Tsai Ming-Ju , Cia Cong-Tat , Chiang Dung-Hung , Chang Po-Jen , Chong Inn-Wen , Tsai Yi-Shan , Chu Yuan-Chia , Liu Chia-Jen , Chen Cheng-Hsu , Pai Kai-Chih , Wu Chieh-Liang
Published: October 2023

Purpose

To address the contentious data sharing across hospitals, this study adopted a novel approach, federated learning (FL), to establish an aggregate model for acute kidney injury (AKI) prediction in critically ill patients in Taiwan.

Methods

This study used data from the Critical Care Database of Taichung Veterans General Hospital (TCVGH) from 2015 to 2020 and electrical medical records of the intensive care units (ICUs) between 2018 and 2020 of four referral centers in different areas across Taiwan. AKI prediction models were trained and validated thereupon. An FL-based prediction model across hospitals was then established.

Results

The study included 16,732 ICU admissions from the TCVGH and 38,424 ICU admissions from the other four hospitals. The complete model with 60 features and the parsimonious model with 21 features demonstrated comparable accuracies using extreme gradient boosting, neural network (NN), and random forest, with an area under the receiver-operating characteristic (AUROC) curve of approximately 0.90. The Shapley Additive Explanations plot demonstrated that the selected features were the key clinical components of AKI for critically ill patients. The AUROC curve of the established parsimonious model for external validation at the four hospitals ranged from 0.760 to 0.865. NN-based FL slightly improved the model performance at the four centers.

Conclusion

A reliable prediction model for AKI in ICU patients was developed with a lead time of 24 h, and it performed better when the novel FL platform across hospitals was implemented.
Temporal downscaling of glaciological mass balance using seasonal observations
Authors: Zemp Michael , Welty Ethan
Published: October 2023

Glaciological mass-balance measurements have been the backbone of internationally coordinated glacier monitoring. The resulting annual observations have been used to understand glacier reactions to climate change, and to assess both regional and global glacier mass changes and related contributions to runoff and sea-level rise. However, the comparability of annual observations is hampered by differences in survey periods and mass-balance amplitudes between glaciers, regions and hemispheres. This study presents a simple approach to temporally downscale glaciological mass balance using seasonal observations and sine functions. The proposed analytical model allows reconstruction of the seasonal course of glacier mass balance at weekly to monthly resolution from only annual or seasonal observations. Strengths and limitations of this analytical approach are discussed and compared with results from numerical mass-balance modelling. Potential applications include seasonal corrections of glaciological and geodetic observations and comparisons to monthly results from spaceborne gravimetry and altimetry.
Sending “our brothers” back “home”: Continuity and change in President Erdoğan’s discourse on Syrian refugees
Authors: Morgül Kerem
Published: October 2023

Considerable research has examined Turkey’s discursive governance of the Syrian refugee crisis, identifying the central themes and metaphors in top officials’ refugee-related messages. However, since they tend to rely on qualitative analyses based on convenience or purposive samples, prior studies have failed to assess the relative frequency of these themes and fall short of reliably gauging the shifts and continuities in the official discourse on refugees. Moreover, while several studies have noted the growing emphasis on the repatriation of Syrian refugees in recent years, no research has yet explored how the Turkish government has sought to reconcile this with its pro-refugee posturing. This paper addresses these limitations via a mixed methods analysis of 382 speeches President Erdoğan gave from September 2014 through December 2022. Quantitative findings show that Islamist and neo-Ottomanist themes have played a major role in Erdoğan’s refugee discourse throughout his presidency. However, since 2018, there has been a sharp increase in Erdoğan’s remarks about repatriating Syrian refugees. A critical discourse analysis of these remarks indicates that Erdoğan has appropriated the language of international law and standards on refugee returns so that he can continue to claim the moral high ground while simultaneously advocating mass repatriation of the Syrians.
THE LIFTING PROBLEM FOR UNIVERSAL QUADRATIC FORMS OVER SIMPLEST CUBIC FIELDS
Authors: GIL-MUÑOZ DANIEL , TINKOVÁ MAGDALÉNA
Published: October 2023

The lifting problem for universal quadratic forms over a totally real number field K consists of determining the existence or otherwise of a quadratic form with integer coefficients (or
$\mathbb {Z}$
-form) that is universal over K. We prove the nonexistence of universal
$\mathbb {Z}$
-forms over simplest cubic fields for which the integer parameter is big enough. The monogenic case is already known. We prove the nonexistence in the nonmonogenic case by using the existence of a totally positive nonunit algebraic integer in K with minimal (codifferent) trace equal to one.
The effect of homogenisation pressure on the microstructure of milk during evaporation and drying: particle-size distribution, electronic scanning microscopy, water activity and isotherm
Authors: Zacaron Thiago Medeiros , Francisquini Júlia d'Almeida , Perrone Ítalo Tuler , Stephani Rodrigo
Published: October 2023

Homogenisation is a widely used technique in manufacturing powdered milk with a direct impact on product solubility, and the homogenisation pressure is a central attribute of this process. We aimed to understand the effect of increasing homogenisation pressures (0/0, 15/5, and 75/5 MPa, 1st/2nd stages) on particle-size distribution during homogenised whole milk powder manufacture and rehydration of the final product. The fluid milk was thermally treated, homogenised, concentrated by rotary evaporation, and then dried using a spray dryer. Particle size (Dv90) was monitored at all stages of the manufacturing process. The final product (milk powder) was analysed using particle-size distribution, electronic scanning microscopy, water activity, and isotherms. The results demonstrated that increasing the homogenisation pressure leads to milk powder with smaller particle size when rehydrated (Dv90 values: 6.08, 1.48 and 0.64 μm for 0, 20 and 80 MPa, respectively). Furthermore, the volume (%) of the particles in the ‘sub-micro’ region (smaller than 1.0 μm) presented an inversely proportional profile to the homogenisation pressure (homogenised fluid milk: 86.1, 29.3 and 2.4%; concentrated milk: 86.1, 26.5 and 5.7%, and reconstituted milk powder: 84.2, 31.8 and 10.9%). Surprisingly, this pattern was not observed in the SPAN value (which corresponds to the width or range of the size distribution based on the volume). Additionally, the increase in the homogenisation pressure did not affect the sorption isotherm pattern. These results demonstrate that increasing the homogenisation pressure decreases the particle size of the reconstituted powdered milk, indicating the potential for future studies on how this phenomenon affects its physicochemical and final product properties.
Image-guided and sialendoscopy-assisted transoral approach for parotid duct stenosis and megaduct
Authors: Gaffuri Michele , Battilocchi Ludovica , Pignataro Lorenzo , Capaccio Pasquale
Published: October 2023

Objective

The aim of this communication was to introduce a novel combined image (magnetic resonance and computed tomography-guided and sialendoscopy-assisted transoral approach for the treatment of a parotid duct stenosis with megaduct.

Methods

A 46-year-old woman was referred to our department for recurrent infections of the right parotid gland following unsuccessful multiple transoral surgical approaches for a Stensen's duct stricture with megaduct. An image (magnetic resonance and computed tomography)-guided and sialendoscopy-assisted transoral sialodochoplasty was planned and performed.

Results

No complications occurred. The patient was discharged 2 days after surgery. No more swelling or infections occurred. The patient is currently symptom-free after a follow up of 11 months.

Conclusion

Although imaging navigation means more technical effort and costs, this novel approach can be considered a viable surgical opportunity for distal and mid-third parotid duct stenosis with concomitant megaduct, particularly in cases of persistent inflammation or iatrogenic scars due to previous surgery.
Female diaconate in medieval Nubia: evidence from a wall inscription from Faras
Authors: Ochała Grzegorz
Published: October 2023

This paper offers a re-edition and reinterpretation of a Greek inscription painted on a wall at the Rivergate Church at Faras in medieval Nubia and dated to the thirteenth–fourteenth centuries. This dedicatory prayer is the first evidence for the existence of the female diaconate in the entire Nile Valley. While the close reading of the text in its architectural and art-historical settings allows us to formulate some hypotheses about the functions of Nubian deaconesses, in a broader perspective, the inscription is also a valuable piece of evidence for the high position of Nubian women on the one hand and the “Byzantineness” of Christian Nubian culture on the other.
On Bohr compactifications and profinite completions of group extensions
Authors: BEKKA BACHIR
Published: October 2023

Let
$G= N\rtimes H$
be a locally compact group which is a semi-direct product of a closed normal subgroup N and a closed subgroup H. The Bohr compactification
${\rm Bohr}(G)$
and the profinite completion
${\rm Prof}(G)$
of G are, respectively, isomorphic to semi-direct products
$Q_1 \rtimes {\rm Bohr}(H)$
and
$Q_2 \rtimes {\rm Prof}(H)$
for appropriate quotients
$Q_1$
of
${\rm Bohr}(N)$
and
$Q_2$
of
${\rm Prof}(N).$
We give a precise description of
$Q_1$
and
$Q_2$
in terms of the action of H on appropriate subsets of the dual space of N. In the case where N is abelian, we have
${\rm Bohr}(G)\cong A \rtimes {\rm Bohr}(H)$
and
${\rm Prof}(G)\cong B \rtimes {\rm Prof}(H),$
where A (respectively B) is the dual group of the group of unitary characters of N with finite H-orbits (respectively with finite image). Necessary and sufficient conditions are deduced for G to be maximally almost periodic or residually finite. We apply the results to the case where
$G= \Lambda\wr H$
is a wreath product of discrete groups; we show in particular that, in case H is infinite,
${\rm Bohr}(\Lambda\wr H)$
is isomorphic to
${\rm Bohr}(\Lambda^{\rm Ab}\wr H)$
and
${\rm Prof}(\Lambda\wr H)$
is isomorphic to
${\rm Prof}(\Lambda^{\rm Ab} \wr H),$
where
$\Lambda^{\rm Ab}=\Lambda/ [\Lambda, \Lambda]$
is the abelianisation of
$\Lambda.$
As examples, we compute
${\rm Bohr}(G)$
and
${\rm Prof}(G)$
when G is a lamplighter group and when G is the Heisenberg group over a unital commutative ring.
Modelling Age-Varying Associations among Group Memberships, Neighborhood Connectedness, and Well-Being
Authors: Evans M. Blair , Li Zhuo , Benson Alex
Published: October 2023

Individuals who maintain group memberships in their community tend to experience improved well-being relative to those who participate in few or no groups. There are, however, few investigations targeting variability in the correlates of group membership across the lifespan. The present examination probed age-related variability in the association between group memberships and subjective connectedness as well as well-being. Participants included 3,940 (mean age = 45.61 years, standard deviation [SD] = 15.62) Canadian and American respondents who completed an online survey during August of 2020 (i.e., amidst the COVID-19 pandemic). Time-varying effects modelling was used to estimate coefficients for group membership at each age within the sample. Memberships in social groups positively predicted connectedness, and this association was strongest in middle-to-older age; a similar association was also evident when predicting well-being. Connectedness was also a positive predictor of well-being throughout most ages. These findings build on emerging research conveying how group memberships have significance for people currently in middle-to-older age.
COMmunity-Based Nutrition RISK Screening in Older Adults Living Independently (COMRISK): Feasibility, Acceptability, and Appropriateness of Community Partnership Models in Alberta, Canada
Authors: Geary Rebecca , Mantik Jessica , Moore Valerie , Schuller Jessica , Fedoruk Rani , Atkins Marlis , Chan Catherine B.
Published: October 2023

This feasibility study of routine nutrition risk screening in community-dwelling older adults using a partnership between health care and community-based organizations (CBO) aimed to (1) evaluate the ability of community-based partnerships to provide screening for nutrition risk, and appropriately refer at-risk individuals for follow-up care and (2) determine the barriers to and facilitators of screening. Adults 65 years of age and older were screened by staff in two primary care and one CBO setting using the Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN)-8 nutrition risk screening tool. Screeners, organization administrators, and registered dietitians responded to surveys regarding SCREEN-8 administration, referral processes, and partnership interactions. All found the SCREEN-8 initiative feasible, acceptable, and appropriate. Sustainability requires strengthening of community resources, referral processes, and telephone assessments. The partnership added value despite limitations in communications. We conclude that broader implementation of this program using community-based partnerships has the potential to aid in the prevention of malnutrition in older adults.
RER-LX: A new scale to measure reduced emotional resonance in bilinguals’ later learnt language
Authors: Toivo Wilhelmiina , Scheepers Christoph , Dewaele Jean-Marc
Published: October 2023

In two online survey studies (N = 688 and N = 247, respectively) we developed and validated a new psychometric scale for measuring emotional resonance reduction in bilinguals’ LX (“later learnt language”) relative to their L1 (“first language”). The final scale, dubbed RER-LX (for Reduced Emotional Resonance in LX), comprises 15 items and possesses a number of desirable psychometric properties. It yields good test reliability (expected alpha between 0.8 and 0.9), produces near-normally distributed test scores, and exhibits content validity in terms of its underlying factor structure. Moreover, it correlates well with the only other instrument previously used for the same purpose (BEQ subscale comprising BEQ-swearing, BEQ-feelings and BEQ-anger). However, compared to the BEQ items, RER-LX has significantly better discriminant validity in relation to LexTALE, a widely used measure of proficiency in English as a second language. Our new scale will be useful to researchers studying bilingualism and emotion.
Islands in a sea of sand: The role of Tarim Basin polities in global trade during late antiquity
Authors: Høisæter Tomas Larsen
Published: October 2023

Much of the literature on the Ancient Silk Road has examined its operation through the prism of empires and East-West connections. Yet in the last few decades several scholars have sought to re-examine this framework, with a number suggesting that the roots of the Silk Road exchange network should be sought instead in the many polities which lay along its routes. This article similarly seeks to challenge the traditional ‘Silk Road of Empires’ concept by applying approaches from global history and examining both archaeological and written sources from the third- and fourth-century kingdom of Kroraina in the south-eastern Tarim Basin in Xinjiang, Western China. The first goal of this article is to consider Kroraina’s inclusion in the wider Silk Roads network and how this network influenced local elite consumption. The second is to examine Kroraina’s role in the Silk Road network. It is argued that polities like Kroraina played a crucial role in facilitating and maintaining trans-Eurasian trade in Late Antiquity.
Postcolonial Pessimisms and Alternative Spatial Practices: Critical Interpretation of the concept of the Third Space through the Case of Fatahillah Square, Indonesia
Authors: Park Junyoung
Published: October 2023

Spatial practice is at the core of postcolonial geography's response to the geography of colonialism. However, the methodology of postcolonial spatial practice is linked to pessimisms within the postcolonial debate. This study aims to overcome pessimisms of postcolonialism by analysing a case of postcolonial spatial practice through literature review, expert interview, and field study. The case under investigation is Fatahillah Square in Jakarta, which has been transformed through postcolonial spatial practices from a space that symbolised the tragedy of colonialism into one of culture and art. Here, the characteristics of Homi K. Bhabha's “third space” are apparent, but this case may also be interpreted as an extension of the concept. Through the hybrid and emancipatory plurality of its spatial practice, it refutes the pessimisms of postcolonialism and calls for further postcolonial practice and analysis.
PI3K/mTOR inhibitors promote G6PD autophagic degradation and exacerbate oxidative stress damage to radiosensitize small cell lung cancer
Authors: Deng Huan , Chen Yamei , Wang Li , Zhang Yibi , Hang Qingqing , Li Peijing , Zhang Peng , Ji Jing , Song Hai , Chen Ming , Jin Ying
Published: October 2023

Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.
Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer
Authors: Jiang Cen , Zhu Youzhi , Chen Huaying , Lin Junyu , Xie Ruiwang , Li Weiwei , Xue Jiajie , Chen Ling , Chen Xiangjin , Xu Sunwang
Published: October 2023

Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzymatic activity was enhanced in TamR cells. Mechanistically, the transcription factor c-Jun was activated by JNK kinase-mediated phosphorylation. Activated c-Jun bound to the TRE motif in the CPT1A promoter to drive CPT1A transcription and recruited CBP/P300 to chromatin, catalysing histone H3K27 acetylation to increase chromatin accessibility, which ensured more effective transcription of CPT1A and an increase in the FAO rate, eliminating the cytotoxic effects of tamoxifen in ER-positive BC cells. Pharmacologically, inhibiting CPT1A enzymatic activity with the CPT1 inhibitor etomoxir or blocking c-Jun phosphorylation with a JNK inhibitor restored the tamoxifen sensitivity of TamR cells. Clinically, high levels of phosphorylated c-Jun and CPT1A were observed in ER-positive BC tissues in patients with recurrence after tamoxifen therapy and were associated with poor survival. These results indicate that the assessment and targeting of the JNK/c-Jun-CPT1A-FAO axis will provide promising insights for clinical management, increased tamoxifen responses and improved outcomes for ER-positive BC patients.
Concurrently mapping quantitative trait loci associations from multiple subspecies within hybrid populations
Authors: Warburton Christie L. , Costilla Roy , Engle Bailey N. , Moore Stephen S. , Corbet Nicholas J. , Fordyce Geoffry , McGowan Michael R. , Burns Brian M. , Hayes Ben J.
Published: October 2023

Many of the world’s agriculturally important plant and animal populations consist of hybrids of subspecies. Cattle in tropical and sub-tropical regions for example, originate from two subspecies, Bos taurus indicus (Bos indicus) and Bos taurus taurus (Bos taurus). Methods to derive the underlying genetic architecture for these two subspecies are essential to develop accurate genomic predictions in these hybrid populations. We propose a novel method to achieve this. First, we use haplotypes to assign SNP alleles to ancestral subspecies of origin in a multi-breed and multi-subspecies population. Then we use a BayesR framework to allow SNP alleles originating from the different subspecies differing effects. Applying this method in a composite population of B. indicus and B. taurus hybrids, our results show that there are underlying genomic differences between the two subspecies, and these effects are not identified in multi-breed genomic evaluations that do not account for subspecies of origin effects. The method slightly improved the accuracy of genomic prediction. More significantly, by allocating SNP alleles to ancestral subspecies of origin, we were able to identify four SNP with high posterior probabilities of inclusion that have not been previously associated with cattle fertility and were close to genes associated with fertility in other species. These results show that haplotypes can be used to trace subspecies of origin through the genome of this hybrid population and, in conjunction with our novel Bayesian analysis, subspecies SNP allele allocation can be used to increase the accuracy of QTL association mapping in genetically diverse populations.
Taphonomic experiments reveal authentic molecular signals for fossil melanins and verify preservation of phaeomelanin in fossils
Authors: Slater Tiffany S. , Ito Shosuke , Wakamatsu Kazumasa , Zhang Fucheng , Sjövall Peter , Jarenmark Martin , Lindgren Johan , McNamara Maria E.
Published: October 2023

Melanin pigments play a critical role in physiological processes and shaping animal behaviour. Fossil melanin is a unique resource for understanding the functional evolution of melanin but the impact of fossilisation on molecular signatures for eumelanin and, especially, phaeomelanin is not fully understood. Here we present a model for the chemical taphonomy of fossil eumelanin and phaeomelanin based on thermal maturation experiments using feathers from extant birds. Our results reveal which molecular signatures are authentic signals for thermally matured eumelanin and phaeomelanin, which signatures are artefacts derived from the maturation of non-melanin molecules, and how these chemical data are impacted by sample preparation. Our model correctly predicts the molecular composition of eumelanins in diverse vertebrate fossils from the Miocene and Cretaceous and, critically, identifies direct molecular evidence for phaeomelanin in these fossils. This taphonomic framework adds to the geochemical toolbox that underpins reconstructions of melanin evolution and of melanin-based coloration in fossil vertebrates.
Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment
Authors: Vinikoor Tra , Dzidotor Godwin K. , Le Thinh T. , Liu Yang , Kan Ho-Man , Barui Srimanta , Chorsi Meysam T. , Curry Eli J. , Reinhardt Emily , Wang Hanzhang , Singh Parbeen , Merriman Marc A. , D’Orio Ethan , Park Jinyoung , Xiao Shuyang , Chapman James H. , Lin Feng , Truong Cao-Sang , Prasadh Somasundaram , Chuba Lisa , Killoh Shaelyn , Lee Seok-Woo , Wu Qian , Chidambaram Ramaswamy M. , Lo Kevin W. H. , Laurencin Cato T. , Nguyen Thanh D.
Published: October 2023

Osteoarthritis affects millions of people worldwide but current treatments using analgesics or anti-inflammatory drugs only alleviate symptoms of this disease. Here, we present an injectable, biodegradable piezoelectric hydrogel, made of short electrospun poly-L-lactic acid nanofibers embedded inside a collagen matrix, which can be injected into the joints and self-produce localized electrical cues under ultrasound activation to drive cartilage healing. In vitro, data shows that the piezoelectric hydrogel with ultrasound can enhance cell migration and induce stem cells to secrete TGF-β1, which promotes chondrogenesis. In vivo, the rabbits with osteochondral critical-size defects receiving the ultrasound-activated piezoelectric hydrogel show increased subchondral bone formation, improved hyaline-cartilage structure, and good mechanical properties, close to healthy native cartilage. This piezoelectric hydrogel is not only useful for cartilage healing but also potentially applicable to other tissue regeneration, offering a significant impact on the field of regenerative tissue engineering.
Hyper-cores promote localization and efficient seeding in higher-order processes
Authors: Mancastroppa Marco , Iacopini Iacopo , Petri Giovanni , Barrat Alain
Published: October 2023

Going beyond networks, to include higher-order interactions of arbitrary sizes, is a major step to better describe complex systems. In the resulting hypergraph representation, tools to identify structures and central nodes are scarce. We consider the decomposition of a hypergraph in hyper-cores, subsets of nodes connected by at least a certain number of hyperedges of at least a certain size. We show that this provides a fingerprint for data described by hypergraphs and suggests a novel notion of centrality, the hypercoreness. We assess the role of hyper-cores and nodes with large hypercoreness in higher-order dynamical processes: such nodes have large spreading power and spreading processes are localized in central hyper-cores. Additionally, in the emergence of social conventions very few committed individuals with high hypercoreness can rapidly overturn a majority convention. Our work opens multiple research avenues, from comparing empirical data to model validation and study of temporally varying hypergraphs.
Mucosal application of the broadly neutralizing antibody 10-1074 protects macaques from cell-associated SHIV vaginal exposure
Authors: Suphaphiphat Karunasinee , Desjardins Delphine , Lorin Valérie , Dimant Nastasia , Bouchemal Kawthar , Bossevot Laetitia , Galpin-Lebreau Maxence , Dereuddre-Bosquet Nathalie , Mouquet Hugo , Le Grand Roger , Cavarelli Mariangela
Published: October 2023

Passive immunization using broadly neutralizing antibodies (bNAbs) is investigated in clinical settings to inhibit HIV-1 acquisition due to the lack of a preventive vaccine. However, bNAbs efficacy against highly infectious cell-associated virus transmission has been overlooked. HIV-1 transmission mediated by infected cells present in body fluids likely dominates infection and aids the virus in evading antibody-based immunity. Here, we show that the anti-N-glycans/V3 loop HIV-1 bNAb 10-1074 formulated for topical vaginal application in a microbicide gel provides significant protection against repeated cell-associated SHIV162P3 vaginal challenge in non-human primates. The treated group has a significantly lower infection rate than the control group, with 5 out of 6 animals fully protected from the acquisition of infection. The findings suggest that mucosal delivery of potent bnAbs may be a promising approach for preventing transmission mediated by infected cells and support the use of anti-HIV-antibody-based strategies as potential microbicides in human clinical trials.
In-situ electro-responsive through-space coupling enabling foldamers as volatile memory elements
Authors: Li Jinshi , Shen Pingchuan , Zhuang Zeyan , Wu Junqi , Tang Ben Zhong , Zhao Zujin
Published: October 2023

Voltage-gated processing units are fundamental components for non-von Neumann architectures like memristor and electric synapses, on which nanoscale molecular electronics have possessed great potentials. Here, tailored foldamers with furan‒benzene stacking (f-Fu) and thiophene‒benzene stacking (f-Th) are designed to decipher electro-responsive through-space interaction, which achieve volatile memory behaviors via quantum interference switching in single-molecule junctions. f-Fu exhibits volatile turn-on feature while f-Th performs stochastic turn-off feature with low voltages as 0.2 V. The weakened orbital through-space mixing induced by electro-polarization dominates stacking malposition and quantum interference switching. f-Fu possesses higher switching probability and faster responsive time, while f-Th suffers incomplete switching and longer responsive time. High switching ratios of up to 91 for f-Fu is realized by electrochemical gating. These findings provide evidence and interpretation of the electro-responsiveness of non-covalent interaction at single-molecule level and offer design strategies of molecular non-von Neumann architectures like true random number generator.
The pan-genome and local adaptation of Arabidopsis thaliana
Authors: Kang Minghui , Wu Haolin , Liu Huanhuan , Liu Wenyu , Zhu Mingjia , Han Yu , Liu Wei , Chen Chunlin , Song Yan , Tan Luna , Yin Kangqun , Zhao Yusen , Yan Zhen , Lou Shangling , Zan Yanjun , Liu Jianquan
Published: October 2023

Arabidopsis thaliana serves as a model species for investigating various aspects of plant biology. However, the contribution of genomic structural variations (SVs) and their associate genes to the local adaptation of this widely distribute species remains unclear. Here, we de novo assemble chromosome-level genomes of 32 A. thaliana ecotypes and determine that variable genes expand the gene pool in different ecotypes and thus assist local adaptation. We develop a graph-based pan-genome and identify 61,332 SVs that overlap with 18,883 genes, some of which are highly involved in ecological adaptation of this species. For instance, we observe a specific 332 bp insertion in the promoter region of the HPCA1 gene in the Tibet-0 ecotype that enhances gene expression, thereby promotes adaptation to alpine environments. These findings augment our understanding of the molecular mechanisms underlying the local adaptation of A. thaliana across diverse habitats.
The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging
Authors: Sun Xiaowei , Shen Jie , Perrimon Norbert , Kong Xue , Wang Dan
Published: October 2023

While disorders in lipid metabolism have been associated with aging and age-related diseases, how lipid metabolism is regulated during aging is poorly understood. Here, we characterize the Drosophila endoribonuclease CG2145, an ortholog of mammalian EndoU that we named Age-related lipid regulator (Arlr), as a regulator of lipid homeostasis during aging. In adult adipose tissues, Arlr is necessary for maintenance of lipid storage in lipid droplets (LDs) as flies age, a phenotype that can be rescued by either high-fat or high-glucose diet. Interestingly, RNA-seq of arlr mutant adipose tissues and RIP-seq suggest that Arlr affects lipid metabolism through the degradation of the mRNAs of lipolysis genes – a model further supported by the observation that knockdown of Lsd-1, regucalcin, yip2 or CG5162, which encode genes involved in lipolysis, rescue the LD defects of arlr mutants. In addition, we characterize DendoU as a functional paralog of Arlr and show that human ENDOU can rescue arlr mutants. Altogether, our study reveals a role of ENDOU-like endonucleases as negative regulator of lipolysis.
Intracellular bacteria in cancer—prospects and debates
Authors: Schorr Lena , Mathies Marius , Elinav Eran , Puschhof Jens
Published: October 2023

Recent evidence suggests that some human cancers may harbor low-biomass microbial ecosystems, spanning bacteria, viruses, and fungi. Bacteria, the most-studied kingdom in this context, are suggested by these studies to localize within cancer cells, immune cells and other tumor microenvironment cell types, where they are postulated to impact multiple cancer-related functions. Herein, we provide an overview of intratumoral bacteria, while focusing on intracellular bacteria, their suggested molecular activities, communication networks, host invasion and evasion strategies, and long-term colonization capacity. We highlight how the integration of sequencing-based and spatial techniques may enable the recognition of bacterial tumor niches. We discuss pitfalls, debates and challenges in decisively proving the existence and function of intratumoral microbes, while reaching a mechanistic elucidation of their impacts on tumor behavior and treatment responses. Together, a causative understanding of possible roles played by intracellular bacteria in cancer may enable their future utilization in diagnosis, patient stratification, and treatment.
The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate
Authors: Weisshaar Nina , Ma Sicong , Ming Yanan , Madi Alaa , Mieg Alessa , Hering Marvin , Zettl Ferdinand , Mohr Kerstin , Ten Bosch Nora , Stichling Diana , Buettner Michael , Poschet Gernot , Klinke Glynis , Schulz Michael , Kunze-Rohrbach Nina , Kerber Carolin , Klein Isabel Madeleine , Wu Jingxia , Wang Xi , Cui Guoliang
Published: October 2023

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.
Subretinal timrepigene emparvovec in adult men with choroideremia: a randomized phase 3 trial
Authors: MacLaren Robert E. , Fischer M. Dominik , Gow James A. , Lam Byron L. , Sankila Eeva-Marja K. , Girach Aniz , Panda Sushil , Yoon Dan , Zhao Guolin , Pennesi Mark E.
Published: October 2023

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 1011 vector genomes (vg); n = 69) or low-dose (1.0 × 1010 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41.
ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results
Authors: Anagnostou Valsamo , Ho Cheryl , Nicholas Garth , Juergens Rosalyn Anne , Sacher Adrian , Fung Andrea S. , Wheatley-Price Paul , Laurie Scott A. , Levy Benjamin , Brahmer Julie R. , Balan Archana , Niknafs Noushin , Avrutin Egor , Zhu Liting , Sausen Mark , Bradbury Penelope A. , O’Donnell-Tormey Jill , Gaudreau Pierre Olivier , Ding Keyue , Dancey Janet
Published: October 2023

Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52–97%) and a specificity of 75% (90% CI: 56.5–88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5–2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167.