bluuebunny/crossref_metadata_2025 huggingface dataset:
Click-Gap, paternalism, and tech giants’ relationships with their users
Authors: Donohue J. L. A.
Published: November 2023

The spread of misinformation and fake news raises important problems for our society and for our democracy. From the January 6 attack on the U.S. Capitol to vaccine hesitancy, from suppressing voter turnout to peddling conspiracy theories, we know that these problems are real and need to be taken seriously. While misinformation is not a new problem for democracy, it can spread more quickly and easily because of new media’s design and popularity. Given these problems, it is encouraging that some technology companies are taking steps to reduce the spread of misinformation and fake news on the platforms they manage. Despite this seemingly positive development, some scholars have criticized some interventions designed to combat the spread of misinformation and fake news as paternalistic. For example, a 2019 Facebook intervention called Click-Gap aimed to reduce the amount of low-quality content (including fake news and misinformation) that users see on their NewsFeed. Click-Gap has been criticized as an instance of epistemic paternalism because it was adopted (1) with the goal of improving the epistemic status of its users and (2) irrespective of what the company believed the wishes of its users to be. If interventions like Click-Gap are problematic because paternalistic, those of us interested in the ethics of technology would face a dilemma—either endorse technology companies treating their users paternalistically or endorse their failing to act to combat the spread of misinformation and fake news on their platforms. Both options seem to me to be problematic. While paternalism may sometimes be permissible, I think we should be very hesitant to endorse a paternalistic relationship between technology companies and their users. The relationship does not seem to bear the right sort of structure to one in which paternalism might be appropriate, if it ever is. The second option seems, if anything worse: surely technology companies should not stand by and change nothing about their platforms despite the spread of misinformation and fake news in those spaces. In this paper, I argue that Click-Gap and interventions like it are not paternalistic, contrary to the conclusion of other scholars. Further, I will argue that the focus on paternalism itself is actually a red herring here. While not just any intervention or strategy that purports to reduce fake news and misinformation is permissible, we should want technology companies to take user well-being seriously and be able to take that well-being as a direct reason for action. Their doing so is not paternalistic nor even morally problematic, and it should not be criticized as such.
Using a data driven approach for comprehensive Life Cycle Assessment and effective eco design of the Internet of Things: taking LoRa-based IoT systems as examples
Authors: Quisbert-Trujillo Ernesto , Morfouli Panagiota
Published: November 2023

As we reach the limits of our current technologies and the number of connected devices grows, scientists put more efforts to estimate and reduce the ecological damage of the Internet of Things. Unfortunately, recent literature related to Life Cycle Assessment and eco design of IoT systems suffers from a major inconvenience so far: it does not put sensor data in the focus of attention. This paper aims to point out explicitly the essential role of this aspect for modeling reference flows, and demonstrate its relevance for appropriate environmental assessment and practical eco design. Also, it aims to illustrate that such modeling process must happen in a comprehensive way. For this, our work relies on a case study addressing smart metering, and we proceed as follows: based on available documentation and inspired by certain aspects of different technologies, we deduce the maximal capacities of key electronic components and construct an unfavorable data flow scenario, to get a rough idea of the reference flow and the long-term impact of our system during its use phase. Results from this procedure are later contrasted with results obtained from a packet traffic analysis, in which local and internet data flow are examined carefully. At the end, we verify the importance of sensor data theoretically and empirically, and we conclude that the reference flow and the impact contributors of a system could be affected not only by the local data transit but also by the complex interactions between edge devices and cloud resources. All our findings are discussed to nourish the state-of-the-art around the environmental impact of using full IoT systems and their sustainable design.
Examples of Riesz Bases of Exponentials for Multi-tiling Domains and Their Duals
Authors: Frederick Christina , Yacoubou Djima Karamatou
Published: November 2023

A well-studied problem in sampling theory is to find an expansion of a function in terms of a Riesz basis of exponentials for $$L^2(\Omega )$$

L
2

(
Ω
)

, where $$\Omega $$
Ω
is a bounded, measurable set. For such a basis, we are guaranteed the existence of a unique biorthogonal dual basis that can be used to calculate the expansion coefficients. Much attention has been paid to the existence of Riesz bases of exponentials for various domains; however, the sampling and reconstruction problems in these cases are less understood. Recently, explicit formulas for the corresponding dual Riesz bases were introduced in Frederick and Okoudjou in [Appl Comput Harmon Anal 51:104–117, 2021; Frederick and Mayeli in J Fourier Anal Appl 27(5):1–21, 2021] for a class of multi-tiling domains. In this paper, we further this work by presenting explicit examples of a finite co-measurable union of intervals or multi-rectangles. In the higher-dimensional case, we also discuss how different sampling strategies lead to different Riesz bounds.
Contamination of Resin-Matrix Composites on Chairside Handling Using Latex or Nitrile Gloves: An In Vitro Study
Authors: Cunha Ivana , Torres Orlanda , Fidalgo-Pereira Rita , Henriques Bruno , Özcan Mutlu , Souza Júlio C. M.
Published: November 2023

The aim of this study was to evaluate the effect of different gloves and clinical environment on the contamination of resin-matrix composites for restorative dentistry. Specimens of nano-hybrid resin-matrix composite (n = 6) were divided in groups regarding the handling with (A) clinical spatula; (B) latex gloves; (C) latex or (D) nitrile gloves with human saliva; (E) latex or (F) nitrile gloves with human blood. After light curing, groups of specimens were analyzed by optical microscopy at magnification ranging from x30 up to x500 and by scanning electron microscopy at different magnification ranging from x50 up to x8000. Handling of resin-matrix composites with unpowdered nitrile gloves or clinical spatulas avoided the presence of contaminants. However, agglomerates of the resin-matrix composite itself became entrapped leading to a heterogenous morphological aspect. SEM images revealed the presence of corn-derived starch released from the powdered gloves. Also, the formation of micro-spaces (voids) occurred after handling with powdered latex gloves. Specimens handled with both type of gloves contaminated with saliva showed a conditioning layer composed of glycoproteins rolls and compounds including calcium-based chlorides, phosphates, and carbonates. Also, blood products were transferred from the contaminated gloves to the resin-matrix composites after handling. Thus, resin-matrix composite restorations are susceptible to contamination with debris from powdered gloves. Also, saliva or blood debris become adsorbed and entrapped in the resin-matrix composites during clinical handling leading to the presence of defects such macro- and micro-scale voids or contaminant agglomerates.
Physical characteristics, nutritional composition and acceptability of gluten-free crackers produced from germinated pearl millet (Pennisetum glaucum), defatted-sesame seed (Sesamum indicum) and defatted-tigernut (Cyperus esculentus) composite flours
Authors: Akeem Sarafa Adeyemi , Mustapha Balikis Oluwakemi , Ayinla Ridwan Opeyemi , Ajibola Oluwaseun , Johnson Winnifred Oluwaseyi , Akintayo Olaide Akinwunmi
Published: November 2023

Crackers are flat, crispy, baked snacks typically prepared from wheat flour. Recently, increasing efforts are being made towards the use of novel ingredients with health, economic and nutritional benefits in the production of crackers. In this study, physical, chemical and sensory characteristics of gluten-free crackers (GFCs) developed from germinated pearl millet, defatted-sesame seed and defatted-tigernut composite flours (90:0:10, 80:10:10, 70:20:10, 60:30:10) against those of 100% wheat cracker (WHFC) were investigated. Compared to wheat flour, formulated composite flours demonstrated higher water and oil absorption capacities but swelling indices were comparable. While WHFC showed higher (P < 0.05) colour characteristics (L*, a* and b*) as well as higher weight, thickness and diameter, the GFCs exhibited improved spread ratio. The developed GFCs were also higher in ash (2.41–2.71%), fibre (3.63–4.18%), protein (9.14–12.21%), and energy (376.82–381.58 kCal/100 g) but lower in carbohydrates (67.60–69.76%). Phytates were generally low in all the crackers, whereas WHFC showed highest trypsin inhibitors (8.8 mg/100 g). GFCs containing defatted-sesame seeds had the highest calcium (2.81 mg/100 g) and lowest iron (0.17 mg/100 g) contents, respectively. In vitro protein digestibility was generally higher (P < 0.05) in the developed GFCs than wheat cracker. Mean sensory scores of > 6 on a 9-point Hedonic scale indicated that the GFCs were generally accepted by the panellists. The study revealed the potentials of composite flours prepared from germinated pearl millet, defatted-sesame seed, and defatted-tigernut flours in the production of acceptable, nutritious and healthy crackers.
Developing innovative and cost-effective UAS-PPK module for generating high-accuracy digital surface model
Authors: Lu Cheng-Hao , Tsai Shu-Min , Wu Ming-Tien , Lin Di-Yi
Published: November 2023

Traditional indirect georeferencing requires time-consuming and labor-intensive field surveys to obtain ground control points (GCPs), making it challenging to apply in high-risk areas with limited accessibility. This study proposes a novel and low-cost system for direct georeferencing using unmanned aerial system post-processing kinematics (UAS-PPK), which is less than a quarter of the price of commercially available products. To evaluate the accuracy of the aerial surveys of the custom-built module and digital surface models, we used 15 checkpoints (CPs) and 99 validation points (VPs). The results showed that this UAS-PPK module could deliver high-precision aerial surveys with a root mean square error (RMSE) of less than 4 cm for three dimensions without using control points. After adding one GCP, the RMSE of three dimensions was close to that of traditional aerial survey methods using 12 GCPs, having a vertical accuracy of 2.51 cm. The same 99 VPs were used to evaluate the accuracy of the digital surface model produced using UAS-PPK. The results showed that the accuracy was close to that of traditional aerial survey methods, having an average error of less than 3 cm. We demonstrated the self-made attachable UAS-PPK module to be a reliable and accurate survey tool in geoscience applications.
The ACTIV-6 Stakeholder Advisory Committee: a model for virtual engagement in decentralized clinical trials
Authors: Hamm Megan E. , Arnold Jonathan , Denson Josh , Edwards Talethia , Merritt Greg , McCarthy Matthew , Nelson Danielle , Phillips Kirk T. , Thicklin Florence , Vasey Andrew , McTigue Kathleen
Published: November 2023

Introduction:

Engaging patients, caregivers, and other stakeholders to help guide the research process is a cornerstone of patient-centered research. Lived expertise may help ensure the relevance of research questions, promote practices that are satisfactory to research participants, improve transparency, and assist with disseminating findings.

Methods:

Traditionally engagement has been conducted face-to-face in the local communities in which research operates. Decentralized platform trials pose new challenges for the practice of engagement. We used a remote model for stakeholder engagement, relying on Zoom meetings and blog communications.

Results:

Here we describe the approach used for research partnership with patients, caregivers, and clinicians in the planning and oversight of the ACTIV-6 trial and the impact of this work. We also present suggestions for future remote engagement.

Conclusions:

The ACTIV-6 experience may inform proposed strategies for future engagement in decentralized trials.
Continuous gradient fusion class activation mapping: segmentation of laser-induced damage on large-aperture optics in dark-field images
Authors: Han Yueyue , Huang Yingyan , Dong Hangcheng , Chen Fengdong , Zeng Fa , Peng Zhitao , Zhu Qihua , Liu Guodong
Published: November 2023

Segmenting dark-field images of laser-induced damage on large-aperture optics in high-power laser facilities is challenged by complicated damage morphology, uneven illumination and stray light interference. Fully supervised semantic segmentation algorithms have achieved state-of-the-art performance but rely on a large number of pixel-level labels, which are time-consuming and labor-consuming to produce. LayerCAM, an advanced weakly supervised semantic segmentation algorithm, can generate pixel-accurate results using only image-level labels, but its scattered and partially underactivated class activation regions degrade segmentation performance. In this paper, we propose a weakly supervised semantic segmentation method, continuous gradient class activation mapping (CAM) and its nonlinear multiscale fusion (continuous gradient fusion CAM). The method redesigns backpropagating gradients and nonlinearly activates multiscale fused heatmaps to generate more fine-grained class activation maps with an appropriate activation degree for different damage site sizes. Experiments on our dataset show that the proposed method can achieve segmentation performance comparable to that of fully supervised algorithms.
The Interrelationship between Freedom of Thought, Conscience, and Religion and the Rule of Law
Authors: Giles Jessica
Published: November 2023

The article explores the connection between the rule of law and the right to freedom of thought, conscience, and religion from an empirical and theoretical perspective. The author posits that the two are not merely interdependent, but that freedom of thought, conscience, and religion is foundational for embedding the rule of law because a state needs to facilitate freedom of thought, conscience, and religion to encourage the exploration of virtue to inform consensus around society’s common norms. This virtue-building role of freedom of thought, conscience, and religion gives the human right its foundational role for creating the conditions required for embedding the rule of law. This conclusion is drawn from Martin Krygier’s analysis of the sociological conditions necessary to embed the rule of law and a comparison of the worldwide rule of law, religious freedom, and happiness indexes. To support a universal approach to the human right and to underpin the identified essentiality of it, the author proposes a theoretical approach grounded in the theory of common grace; Rowan Williams’s other-regarding communal approach to rights; and the framework for plural living together proposed by Herman Dooyeweerd. The author posits that this approach could be adapted with a plural metanarrative to accommodate dialogue around virtue building and dispute resolution within societies with very different outlooks.
How do adolescents classify foods as healthy and unhealthy?: A qualitative inquiry from rural India
Authors: Kansal Sangeeta , Raj Aryan , Smita Kumari , Worsley Anthony , Rathi Neha
Published: November 2023

Indian adolescents exhibit obesogenic dietary habits including low intake of fruits and vegetables and increasing consumption of fast food and carbonated beverages. Adolescents’ classification of healthy and unhealthy foods is likely to have significant implications for their dietary behaviour, and consequently, their health. However, there is limited evidence about the ways Indian adolescents classify foods as healthy or unhealthy. Hence, this qualitative study was designed to explore how Indian adolescents classify nutritious or non-nutritious food choices. Convenience sampling was used to recruit the study participants from Tikari village in Uttar Pradesh, India. Underpinned by the social constructivist lens, the adolescents were interviewed face-to-face in Hindi. All the interactions were digitally recorded, transcribed verbatim, and translated into English prior to data analysis. Transcribed data were analysed thematically using inductive as well as deductive coding, and subsequently, conceptual themes were extracted. A total of thirty-nine adolescents (twenty boys; nineteen girls) aged 10–19 years participated in this qualitative inquiry. The adolescents classified healthy and unhealthy foods based on the following six themes: (i) Food groups and nutrients; (ii) Health and immunity; (iii) Type of ingredient; (iv) Place and time of food preparation; (v) Packaging; and (vi) Parental influence. These findings can inform school-based food literacy interventions to foster healthy dietary habits and cooking skills among Indian adolescents.
Effects of pre-exercise high and low glycaemic index meals on substrate metabolism and appetite in middle-aged women
Authors: Sakazaki Miki , Yoshikawa Yoshie , Kamemoto Kayoko , Tataka Yusei , Yamada Yoshiki , Wu Ching-Lin , Miyashita Masashi
Published: November 2023

Few studies have examined the influence of pre-exercise meals with different glycaemic indices (GIs) on substrate oxidation and non-homeostatic appetite (i.e. food reward) in adults of various ages and ethnicities. We aimed to examine the effects of pre-exercise high and low GI meals on substrate oxidation and food reward in middle-aged Japanese women. This randomised crossover trial included fifteen middle-aged women (aged 40⋅9 ± 6⋅5 years, mean ± sd). The participants consumed a high or low GI breakfast at 09.00 and rested until 11.00. Thereafter, participants performed a 60-min walk at 50 % of their estimated maximum oxygen uptake (11.00–12.00) and rested until 13.00. Expired gas samples were collected every 30 min prior to walking, and samples were collected continuously throughout the walking and post-walking periods. Blood samples and subjective appetite ratings were collected every 30 min, except during walking. The Leeds Food Preference Questionnaire in Japanese (LFPQ-J) was used to assess food reward at 09.00, 10.00, and 13.00 h. The cumulative fat oxidation during exercise was higher in the low GI trial than in the high GI trial (P = 0⋅03). The cumulative carbohydrate oxidation during walking was lower in the low GI trial than in the high GI trial (P = 0⋅01). Trial-by-time interactions were not found for any food-reward parameters between trials. Low GI meals elicited enhanced fat oxidation during a subsequent 60-min walk in middle-aged women. However, meals with different GIs did not affect food reward evaluated over time in the present study.
Interplay between endocannabinoid and endovanilloid mechanisms in fear conditioning
Authors: Briânis Rayssa C. , Andreotti Julia P. , Moreira Fabrício A. , Iglesias Lia P.
Published: November 2023

Objective:

The transient receptor potential cation channel, subfamily V (vanilloid), member 1 (TRPV1) mediates pain perception to thermal and chemical stimuli in peripheral neurons. The cannabinoid receptor type 1 (CB1), on the other hand, promotes analgesia in both the periphery and the brain. TRPV1 and CB1 have also been implicated in learned fear, which involves the association of a previously neutral stimulus with an aversive event. In this review, we elaborate on the interplay between CB1 receptors and TRPV1 channels in learned fear processing.

Methods:

We conducted a PubMed search for a narrative review on endocannabinoid and endovanilloid mechanisms on fear conditioning.

Results:

TRPV1 and CB1 receptors are activated by a common endogenous agonist, arachidonoyl ethanolamide (anandamide), Moreover, they are expressed in common neuroanatomical structures and recruit converging cellular pathways, acting in concert to modulate fear learning. However, evidence suggests that TRPV1 exerts a facilitatory role, whereas CB1 restrains fear responses.

Conclusion:

TRPV1 and CB1 seem to mediate protective and aversive roles of anandamide, respectively. However, more research is needed to achieve a better understanding of how these receptors interact to modulate fear learning.
Systematic review and meta-analysis of laryngeal reinnervation techniques in adults with unilateral and bilateral vocal fold palsies
Authors: Onifade Anjola , Vincent Elizabeth , Tolley Neil
Published: November 2023

Objective

To evaluate the outcomes of reinnervation techniques for the treatment of adult unilateral vocal fold paralysis and bilateral vocal fold paralysis.

Methods

A literature review was conducted in the Embase and Medline databases in English, with no limitations on the publication date. The outcome parameters of interest included visual, subjective perceptual, acoustic, aerodynamic analysis and electromyography. A meta-analysis with a random-effects model and inverse variance was calculated.

Results

The systematic Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach resulted in 27 studies, totalling 803 patients (747 unilateral cases and 56 bilateral cases). Thyroid cancer and/or surgery had caused unilateral vocal fold paralysis in 74.8 per cent of cases and bilateral vocal fold paralysis in 69.6 per cent of cases. Statistically significant improvements in patients were observed for voice, deglutition and decannulation (bilateral vocal fold paralysis). Meta-analysis of 10 reinnervation techniques was calculated for the maximum phonation time of 184 patients.

Conclusion

Reinnervation was shown to improve voice, swallowing and decannulation, but studies lacked control groups, limiting generalisability. Larger studies with controls are needed.
Metabolic syndrome after childhood trauma: a 9-year longitudinal analysis
Authors: Souama Camille , Milaneschi Yuri , Lamers Femke , Vinkers Christiaan H. , Giltay Erik J. , Liemburg Edith J. , Penninx Brenda W. J. H.
Published: November 2023

Background

Childhood trauma (CT) has been cross-sectionally associated with metabolic syndrome (MetS), a group of biological risk factors for cardiometabolic disease. Longitudinal studies, while rare, would clarify the development of cardiometabolic dysregulations over time. Therefore, we longitudinally investigated the association of CT with the 9-year course of MetS components.

Methods

Participants (N = 2958) from the Netherlands Study of Depression and Anxiety were assessed four times across 9 years. The CT interview retrospectively assessed childhood emotional neglect and physical, emotional, and sexual abuse. Metabolic outcomes encompassed continuous MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, blood pressure [BP], and glucose) and count of clinically elevated MetS components. Mixed-effects models estimated sociodemographic- and lifestyle-adjusted longitudinal associations of CT with metabolic outcomes over time. Time interactions evaluated change in these associations.

Results

CT was reported by 49% of participants. CT was consistently associated with increased waist (b = 0.32, s.e. = 0.10, p = 0.001), glucose (b = 0.02, s.e. = 0.01, p < 0.001), and count of MetS components (b = 0.04, s.e. = 0.01, p < 0.001); and decreased HDL cholesterol (b = −0.01, s.e.<0.01, p = .020) and systolic BP (b = −0.33, s.e. = 0.13, p = 0.010). These associations were mainly driven by severe CT and unaffected by lifestyle. Only systolic BP showed a CT-by-time interaction, where CT was associated with lower systolic BP initially and with higher systolic BP at the last follow-up.

Conclusions

Over time, adults with CT have overall persistent poorer metabolic outcomes than their non-maltreated peers. Individuals with CT have an increased risk for cardiometabolic disease and may benefit from monitoring and early interventions targeting metabolism.
Are dynamic measurements of central venous pressure in Fontan circulation during exercise or volume loading superior to resting measurements?
Authors: Venna Alyssia , Deshpande Shriprasad , Downing Tacy , John Anitha , d’Udekem Yves
Published: November 2023

Background:

The main objective measure to assess the health of the Fontan circulation is the pressure measurement of the superior vena cava or pulmonary arteries. We reviewed the literature for benefits of measuring resting pressure in the Fontan circuit and explored whether dynamic measurement by volume loading or exercise has the potential to refine this diagnostic tool.

Methods:

PubMed was searched for articles showing a relationship between resting post-operative central venous pressure or pulmonary artery pressure and Fontan failure. Relationships between post-operative central venous pressure or pulmonary artery pressure and volume loading changes, such as during exercise or volume loading during cardiac catheterization, were also queried.

Results:

A total of 44 articles mentioned relationships between resting central venous pressure or pulmonary artery pressure and Fontan failure. Only 26 included an analysis between the variables and only seven of those articles found pressure to be predictive of Fontan failure. Ten articles examined the relationship between exercise or volume loading and outcomes and demonstrated a large individual variation of pressures under these dynamic conditions.

Conclusions:

Based on current literature, there is not a lot of strong evidence to show that elevated resting central venous pressure or pulmonary artery pressure is predictive of Fontan failure. Some individuals experience dramatic increases in central venous pressure or pulmonary artery pressure under increased loading conditions with exercise or bolus fluid infusion, while others experience increases closer to that of a healthy control population. Further studies are needed to examine whether more dynamic and continuous monitoring of systemic venous pressures might better predict outcomes in patients with Fontan circulation.
Ratgeber Selbstverletzendes Verhalten
Authors: Hepp Johanna , Schmahl Christian , Stiglmayr Christian
Published: November 2023

Selbstverletzendes Verhalten wie Ritzen oder Schneiden tritt vor allem im Jugendalter und im jungen Erwachsenenalter auf. Für die Betroffenen und deren Angehörige stellt es eine große Belastung dar. Häufig bekommt das Umfeld davon wenig oder gar nichts mit, manchmal sind Selbstverletzungen jedoch auch ein Mittel der Kommunikation in schwierigen Lebensphasen.
Dieser Ratgeber beschreibt die verschiedenen Formen sowie die psychologischen und biologischen Hintergründe von Selbstverletzungen. Er geht auf die Faktoren ein, die dazu führen, dass Menschen sich selbst verletzen oder die sie davon abhalten können. Neben der Regulation von Stress und Emotionen haben nichtsuizidale Selbstverletzungen häufig auch eine Funktion in der Kommunikation mit dem sozialen Umfeld, also innerhalb des Freundeskreises, in der Schule oder in der Familie. Ein besonderes Augenmerk legt der Ratgeber zudem auf die Kommunikation über Selbstverletzungen in den sozialen Medien. Weiterhin gibt der Ratgeber konkrete Tipps, wie Betroffene sich selbst helfen können bzw. wie sie Hilfe bekommen können. Schließlich zeigt er Behandlungsmöglichkeiten auf und erläutert die Elemente einer erfolgreichen Behandlung.
Identifying a locus in super-enhancer and its resident NFE2L1/MAFG as transcriptional factors that drive PD-L1 expression and immune evasion
Authors: Shi Conglin , Chen Liuting , Pi Hui , Cui Henglu , Fan Chenyang , Tan Fangzheng , Qu Xuanhao , Sun Rong , Zhao Fengbo , Song Yihua , Wu Yuanyuan , Chen Miaomiao , Ni Wenkai , Qu Lishuai , Mao Renfang , Fan Yihui
Published: November 2023

Although the transcriptional regulation of the programmed death ligand 1 (PD-L1) promoter has been extensively studied, the transcription factor residing in the PD-L1 super-enhancer has not been comprehensively explored. Through saturated CRISPR-Cas9 screening of the core region of the PD-L1 super-enhancer, we have identified a crucial genetic locus, referred to as locus 22, which is essential for PD-L1 expression. Locus 22 is a potential binding site for NFE2:MAF transcription factors. Although genetic silencing of NRF2 (NFE2L2) did not result in a reduction of PD-L1 expression, further analysis reveals that MAFG and NFE2L1 (NRF1) play a critical role in the expression of PD-L1. Importantly, lipopolysaccharides (LPS) as the major component of intratumoral bacteria could greatly induce PD-L1 expression, which is dependent on the PD-L1 super-enhancer, locus 22, and NFE2L1/MAFG. Mechanistically, genetic modification of locus 22 and silencing of MAFG greatly reduce BRD4 binding and loop formation but have minimal effects on H3K27Ac modification. Unlike control cells, cells with genetic modification of locus 22 and silencing of NFE2L1/MAFG failed to escape T cell-mediated killing. In breast cancer, the expression of MAFG is positively correlated with the expression of PD-L1. Taken together, our findings demonstrate the critical role of locus 22 and its associated transcription factor NFE2L1/MAFG in super-enhancer– and LPS-induced PD-L1 expression. Our findings provide new insight into understanding the regulation of PD-L1 transcription and intratumoral bacteria-mediated immune evasion.
RPL22L1, a novel candidate oncogene promotes temozolomide resistance by activating STAT3 in glioblastoma
Authors: Chen Yunping , Mu Yu , Guan Qing , Li Chenlong , Zhang Yangong , Xu Yinzhi , Zhou Chong , Guo Ying , Ma Yanan , Zhao Meiqi , Ji Guohua , Liu Peng , Sun Donglin , Sun Haiming , Wu Nan , Jin Yan
Published: November 2023

Aggressiveness and drug resistance are major challenges in the clinical treatment of glioblastoma (GBM). Our previously research reported a novel candidate oncogene ribosomal protein L22 like 1 (RPL22L1). The aim of this study was to elucidate the potential role and mechanism of RPL22L1 in progression and temozolomide (TMZ) resistance of GBM. Online database, tissue microarrays and clinical tissue specimens were used to evaluate the expression and clinical implication of RPL22L1 in GBM. We performed cell function assays, orthotopic and subcutaneous xenograft tumor models to evaluate the effects and molecular mechanisms of RPL22L1 on GBM. RPL22L1 expression was significantly upregulated in GBM and associated with poorer prognosis. RPL22L1 overexpression enhanced GBM cell proliferation, migration, invasion, TMZ resistance and tumorigenicity, which could be reduced by RPL22L1 knockdown. Further, we found RPL22L1 promoted mesenchymal phenotype of GBM and the impact of these effects was closely related to EGFR/STAT3 pathway. Importantly, we observed that STAT3 specific inhibitor (Stattic) significantly inhibited the malignant functions of RPL22L1, especially on TMZ resistance. RPL22L1 overexpressed increased combination drug sensitive of Stattic and TMZ both in vitro and in vivo. Moreover, Stattic effectively restored the sensitive of RPL22L1 induced TMZ resistance in vitro and in vivo. Our study identified a novel candidate oncogene RPL22L1 which promoted the GBM malignancy through STAT3 pathway. And we highlighted that Stattic combined with TMZ therapy might be an effective treatment strategy in RPL22L1 high-expressed GBM patients.
Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly
Authors: Houghton F. M. , Adams S. E. , Ríos A. S. , Masino L. , Purkiss A. G. , Briggs D. C. , Ledda F. , McDonald N. Q.
Published: November 2023

Glial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRα1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRα1 complex also supports synaptic cell adhesion independently of RET. Here, we describe the structure of a decameric GDNF-GFRα1 assembly determined by crystallography and electron microscopy, revealing two GFRα1 pentamers bridged by five GDNF dimers. We reconsitituted the assembly between adhering liposomes and used cryo-electron tomography to visualize how the complex fulfils its membrane adhesion function. The GFRα1:GFRα1 pentameric interface was further validated both in vitro by native PAGE and in cellulo by cell-clustering and dendritic spine assays. Finally, we provide biochemical and cell-based evidence that RET and heparan sulfate cooperate to prevent assembly of the adhesion complex by competing for the adhesion interface. Our results provide a mechanistic framework to understand GDNF-driven cell adhesion, its relationship to trophic signalling, and the central role played by GFRα1.
Synaptic mechanisms for associative learning in the cerebellar nuclei
Authors: Broersen Robin , Albergaria Catarina , Carulli Daniela , Carey Megan R. , Canto Cathrin B. , De Zeeuw Chris I.
Published: November 2023

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.
Megakaryocyte- and erythroblast-specific cell-free DNA patterns in plasma and platelets reflect thrombopoiesis and erythropoiesis levels
Authors: Moss Joshua , Ben-Ami Roni , Shai Ela , Gal-Rosenberg Ofer , Kalish Yosef , Klochendler Agnes , Cann Gordon , Glaser Benjamin , Arad Ariela , Shemer Ruth , Dor Yuval
Published: November 2023

Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1–4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.
Controlling crystal-electric field levels through symmetry-breaking uniaxial pressure in a cubic super heavy fermion
Authors: Gati Elena , Schmidt Burkhard , Bud’ko Sergey L. , Mackenzie Andrew P. , Canfield Paul C.
Published: November 2023

YbPtBi is one of the heavy-fermion systems with largest Sommerfeld coefficient γ and is thus classified as a ‘super’-heavy fermion material. In this work, we resolve the long-debated question about the hierarchy of relevant energy scales, such as crystal-electric field (CEF) levels, Kondo and magnetic ordering temperature, in YbPtBi. Through measurements of the a.c. elastocaloric effect and generic symmetry arguments, we identify an elastic level splitting that is unambiguously associated with the symmetry-allowed splitting of a quartet CEF level. This quartet, which we identify to be the first excited state at Δ/kB ≈ 1.6 K above the doublet ground state at ambient pressure, is well below the proposed Kondo temperature TK ≈ 10 K. Consequently, this analysis of the energy scheme can provide support models that predict that the heavy electron mass is a result of an enhanced degeneracy of the CEF ground state, i.e., a quasi-sextet in YbPtBi. At the same time, our study shows the potential of the a.c. elastocaloric effect to control and quantify strain-induced changes of the CEF schemes, opening a different route to disentangle the CEF energy scales from other relevant energy scales in correlated quantum materials.
Distinct distributions of elliptical and disk galaxies across the Local Supercluster as a ΛCDM prediction
Authors: Sawala Till , Frenk Carlos , Jasche Jens , Johansson Peter H. , Lavaux Guilhem
Published: November 2023

Galaxies of different types are not equally distributed in the Local Universe. In particular, the supergalactic plane is prominent among the brightest ellipticals, but inconspicuous among the brightest disk galaxies. This striking difference provides a unique test for our understanding of galaxy and structure formation. Here we use the SIBELIUS DARK constrained simulation to confront the predictions of the standard Lambda Cold Dark Matter (ΛCDM) model and standard galaxy formation theory with these observations. We find that SIBELIUS DARK reproduces the spatial distributions of disks and ellipticals and, in particular, the observed excess of massive ellipticals near the supergalactic equator. We show that this follows directly from the local large-scale structure and from the standard galaxy formation paradigm, wherein disk galaxies evolve mostly in isolation, while giant ellipticals congregate in the massive clusters that define the supergalactic plane. Rather than being anomalous as earlier works have suggested, the distributions of giant ellipticals and disks in the Local Universe and in relation to the supergalactic plane are key predictions of the ΛCDM model.
Spatial metatranscriptomics resolves host–bacteria–fungi interactomes
Authors: Saarenpää Sami , Shalev Or , Ashkenazy Haim , Carlos Vanessa , Lundberg Derek Severi , Weigel Detlef , Giacomello Stefania
Published: November 2023

The interactions of microorganisms among themselves and with their multicellular host take place at the microscale, forming complex networks and spatial patterns. Existing technology does not allow the simultaneous investigation of spatial interactions between a host and the multitude of its colonizing microorganisms, which limits our understanding of host–microorganism interactions within a plant or animal tissue. Here we present spatial metatranscriptomics (SmT), a sequencing-based approach that leverages 16S/18S/ITS/poly-d(T) multimodal arrays for simultaneous host transcriptome- and microbiome-wide characterization of tissues at 55-µm resolution. We showcase SmT in outdoor-grown Arabidopsis thaliana leaves as a model system, and find tissue-scale bacterial and fungal hotspots. By network analysis, we study inter- and intrakingdom spatial interactions among microorganisms, as well as the host response to microbial hotspots. SmT provides an approach for answering fundamental questions on host–microbiome interplay.
Spatial host–microbiome sequencing reveals niches in the mouse gut
Authors: Lötstedt Britta , Stražar Martin , Xavier Ramnik , Regev Aviv , Vickovic Sanja
Published: November 2023

Mucosal and barrier tissues, such as the gut, lung or skin, are composed of a complex network of cells and microbes forming a tight niche that prevents pathogen colonization and supports host–microbiome symbiosis. Characterizing these networks at high molecular and cellular resolution is crucial for understanding homeostasis and disease. Here we present spatial host–microbiome sequencing (SHM-seq), an all-sequencing-based approach that captures tissue histology, polyadenylated RNAs and bacterial 16S sequences directly from a tissue by modifying spatially barcoded glass surfaces to enable simultaneous capture of host transcripts and hypervariable regions of the 16S bacterial ribosomal RNA. We applied our approach to the mouse gut as a model system, used a deep learning approach for data mapping and detected spatial niches defined by cellular composition and microbial geography. We show that subpopulations of gut cells express specific gene programs in different microenvironments characteristic of regional commensal bacteria and impact host–bacteria interactions. SHM-seq should enhance the study of native host–microbe interactions in health and disease.
Deep learning-based phenotype imputation on population-scale biobank data increases genetic discoveries
Authors: An Ulzee , Pazokitoroudi Ali , Alvarez Marcus , Huang Lianyun , Bacanu Silviu , Schork Andrew J. , Kendler Kenneth , Pajukanta Päivi , Flint Jonathan , Zaitlen Noah , Cai Na , Dahl Andy , Sankararaman Sriram
Published: November 2023

Biobanks that collect deep phenotypic and genomic data across many individuals have emerged as a key resource in human genetics. However, phenotypes in biobanks are often missing across many individuals, limiting their utility. We propose AutoComplete, a deep learning-based imputation method to impute or ‘fill-in’ missing phenotypes in population-scale biobank datasets. When applied to collections of phenotypes measured across ~300,000 individuals from the UK Biobank, AutoComplete substantially improved imputation accuracy over existing methods. On three traits with notable amounts of missingness, we show that AutoComplete yields imputed phenotypes that are genetically similar to the originally observed phenotypes while increasing the effective sample size by about twofold on average. Further, genome-wide association analyses on the resulting imputed phenotypes led to a substantial increase in the number of associated loci. Our results demonstrate the utility of deep learning-based phenotype imputation to increase power for genetic discoveries in existing biobank datasets.
Phenotype integration improves power and preserves specificity in biobank-based genetic studies of major depressive disorder
Authors: Dahl Andrew , Thompson Michael , An Ulzee , Krebs Morten , Appadurai Vivek , Border Richard , Bacanu Silviu-Alin , Werge Thomas , Flint Jonathan , Schork Andrew J. , Sankararaman Sriram , Kendler Kenneth S. , Cai Na
Published: November 2023

Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.
Large-scale pancreatic cancer detection via non-contrast CT and deep learning
Authors: Cao Kai , Xia Yingda , Yao Jiawen , Han Xu , Lambert Lukas , Zhang Tingting , Tang Wei , Jin Gang , Jiang Hui , Fang Xu , Nogues Isabella , Li Xuezhou , Guo Wenchao , Wang Yu , Fang Wei , Qiu Mingyan , Hou Yang , Kovarnik Tomas , Vocka Michal , Lu Yimei , Chen Yingli , Chen Xin , Liu Zaiyi , Zhou Jian , Xie Chuanmiao , Zhang Rong , Lu Hong , Hager Gregory D. , Yuille Alan L. , Lu Le , Shao Chengwei , Shi Yu , Zhang Qi , Liang Tingbo , Zhang Ling , Lu Jianping
Published: November 2023

Pancreatic ductal adenocarcinoma (PDAC), the most deadly solid malignancy, is typically detected late and at an inoperable stage. Early or incidental detection is associated with prolonged survival, but screening asymptomatic individuals for PDAC using a single test remains unfeasible due to the low prevalence and potential harms of false positives. Non-contrast computed tomography (CT), routinely performed for clinical indications, offers the potential for large-scale screening, however, identification of PDAC using non-contrast CT has long been considered impossible. Here, we develop a deep learning approach, pancreatic cancer detection with artificial intelligence (PANDA), that can detect and classify pancreatic lesions with high accuracy via non-contrast CT. PANDA is trained on a dataset of 3,208 patients from a single center. PANDA achieves an area under the receiver operating characteristic curve (AUC) of 0.986–0.996 for lesion detection in a multicenter validation involving 6,239 patients across 10 centers, outperforms the mean radiologist performance by 34.1% in sensitivity and 6.3% in specificity for PDAC identification, and achieves a sensitivity of 92.9% and specificity of 99.9% for lesion detection in a real-world multi-scenario validation consisting of 20,530 consecutive patients. Notably, PANDA utilized with non-contrast CT shows non-inferiority to radiology reports (using contrast-enhanced CT) in the differentiation of common pancreatic lesion subtypes. PANDA could potentially serve as a new tool for large-scale pancreatic cancer screening.