bluuebunny/crossref_metadata_2025 huggingface dataset:
Methods of Contemporary Gauge Theory
Authors: Makeenko Yuri
Published: July 2023

This book introduces the quantum theory of gauge fields, emphasising four non-perturbative methods which have important applications: path integrals, lattice gauge theories, the 1/N expansion, and reduced matrix models. Written as a textbook, it assumes a knowledge of quantum mechanics and elements of perturbation theory, while many relevant concepts are introduced at a basic level in the first half of the book. The second half comprehensively covers large-N Yang–Mills theory. The book uses an approach to gauge theories based on path-dependent phase factors known as Wilson loops, and contains problems with detailed solutions to aid understanding. Suitable for advanced graduate courses in quantum field theory, the book will also be of interest to researchers in high energy theory and condensed matter physics as a survey of recent developments in gauge theory. Originally published in 2002, this title has been reissued as an Open Access publication on Cambridge Core.
On the formation of coastal rogue waves in water of variable depth
Authors: Li Yan , Chabchoub Amin
Published: July 2023

Wave transformation is an intrinsic dynamic process in coastal areas. An essential part of this process is the variation of water depth, which plays a dominant role in the propagation features of water waves, including a change in wave amplitude during shoaling and de-shoaling, breaking, celerity variation, refraction and diffraction processes. Fundamental theoretical studies have revolved around the development of analytical frameworks to accurately describe such shoaling processes and wave group hydrodynamics in the transition between deep- and shallow-water conditions since the 1970s. Very recent pioneering experimental studies in state-of-the-art water wave facilities provided proof of concept validations and improved understanding of the formed extreme waves’ physical characteristics and statistics in variable water depth. This review recaps the related most significant theoretical developments and groundbreaking experimental advances, which have particularly thrived over the last decade.
Examining the ontogeny of the Pennsylvanian cladid crinoid Erisocrinus typus Meek and Worthen, 1865
Authors: Hernandez Gomez Noel J. , Melendez Lisette E. , Lapic Whitney A. , Sheffield Sarah L. , Lewis Ronald D.
Published: July 2023

Crinoids were major constituents of late Carboniferous (Pennsylvanian) marine ecosystems, but their rapid disarticulation rates after death result in few well-preserved specimens, limiting the study of their growth. This is amplified for cladids, who had among the highest disarticulation rates of all Paleozoic crinoids due to the relatively loose suturing of the calyx plates. However, Erisocrinus typus Meek and Worthen, 1865 has been found in unusually large numbers, most preserved as cups but some as nearly complete crowns, in the Barnsdall Formation in Oklahoma. The Barnsdall Formation, a Koncentrat Lagerstätte, is composed predominantly of fine- to medium-grained sandstone, overlain by mudstone and shale; severe compaction of the fossils in the mudstone and shale layer in this formation allowed for exceptional preservation of the plates. Herein, we summarize a growth study based on 10 crowns of E. typus, showcasing a well-defined growth series of this species from the Barnsdall Formation, including fossils from juvenile stages of development, which are rarely preserved. We used high-resolution photographs imported into ImageJ and recorded measurements of the cup and arms for all nondistorted or disarticulated plates. Results show that the plates of the cup grew anisometrically with both positive and negative allometry. The primibrachial plates of E. typus grew with positive allometry. The brachial plates started as uniserial (i.e., cuneiform) as juveniles but shifted to be biserial. Erisocrinus typus broadly shares similar growth trajectories with other cladids. These growth patterns provide insight into feeding strategies and can aid in understanding crinoid evolutionary paleoecological trends.
Ideology and Historiographic License in Chinese Legal Scholarship
Authors: Seppänen Samuli
Published: July 2023

Chinese legal historians and Chinese Communist Party ideologues engage with historical materials in order to advance various ideological projects, including subversive ideological perspectives. At the same time, historical scholarship appeals to many Chinese legal scholars because it is not seen and experienced as being as ideologically sensitive a field as other branches of Chinese legal scholarship. Chinese legal historians themselves have acknowledged their ability to discuss controversial topics—their “historiographic license”—through legal historical research. This article describes Chinese legal scholars’ historiographic license through the tools of rhetorical theory. The subversive elements of Chinese legal historiography can be attributed to the use of figurative language, which conveys forbidden meanings through innocuous surface text. Figurative language allows Chinese legal scholars to subtly question ideological doctrines—which they may support in other social contexts—without having to negate these doctrines explicitly. Historiography arguably even offers Chinese legal scholars a means to question their own ideological beliefs.
Regional variation in articulation rate in French spoken in Canada
Authors: Cichocki Wladyslaw , Kaminskaïa Svetlana , Hagar Luke
Published: July 2023

This study examines articulation rate in three varieties of Canadian French and includes consideration of speaking style (reading vs. spontaneous), speaker’s age and gender, and length of inter-pause intervals. The varieties are spoken in different geographic areas of Canada – Quebec City (Quebec), Tracadie (New Brunswick), and Windsor (Ontario) – where there are different degrees of French–English contact. The main research question asks how these different contact situations are related to variation in articulation rate. Results show that in both reading and spontaneous speech articulation rates were faster among Quebec City speakers, where French is in a low-contact setting, and slower among speakers from Tracadie and Windsor, where there are greater degrees of contact. The effects of other factors are the same across the three regions: AR was faster in spontaneous productions than in reading; AR decreased with age in the reading task; AR was faster as the length of the inter-pausal intervals increased. The discussion points to similarities and differences with varieties of French spoken in Europe and underscores the importance of language contact in accounting for variation in articulation rate.
Power relations in the music teaching studio
Authors: Burwell Kim
Published: July 2023

Power relations operate in any educational setting, and there may be particular vulnerabilities in a tradition conducted in the relative isolation of the music teaching studio. These vulnerabilities have been highlighted dramatically in recent years through high-profile cases of power abuse, but power is implicated in a wide range of contexts related to the studio, including cultural, gendered, pedagogical, artistic, institutional and interpersonal issues. It may be impossible to divest power of its negative connotations, but there is a good deal of theory focused on power, even if its terms are broadly political or philosophical, and subject to debate. This theoretical paper explores power relations with regard to the music studio, investigating popular conceptions and everyday usage before turning to scholarship focused on interpersonal and broader social perspectives. Some reflections are offered on the uses and abuses of power in the studio. A better understanding of its dimensions and usage can support the ongoing development of studio practices and contribute to the conversation that we need to have about power.
Les retraités au Canada : portrait comparatif selon le statut d’immigrant
Authors: Silva-Ramirez Rafael , Carrière Yves , Gagnon Alain
Published: July 2023

La retraite au Canada a fait l’objet de plusieurs recherches, mais peu d’études ont comparé le passage de la vie active à la retraite des natifs et des immigrants ainsi que leurs caractéristiques une fois à la retraite, une lacune importante compte tenu de l’augmentation de la part des immigrants parmi les futures cohortes canadiennes de retraités. Cette étude descriptive vise à pallier cette lacune à l’aide des données de l’Enquête sociale générale de 2016. Les résultats montrent, entre autres, que les femmes et les hommes natifs ont plus de chances de prendre leur retraite que les immigrants, quel que soit le groupe d’âge étudié, et que l’âge moyen à la retraite des femmes et hommes immigrants est de deux ans supérieur à celui des natifs. Cette étude suggère que le statut d’immigrant implique une transition vers la retraite différente de celle vécue par les natifs ; différence qui devrait être considérée dans la structure du système de revenus de retraite.
The role of cognitive control in bilingual language comprehension: An event-related potential study of dense code-switching sentences
Authors: Jiang Siyi , Ma Lvheng , Chen Baoguo
Published: July 2023

This study investigated the engagement of domain-general cognitive control during the comprehension of dense code-switching sentences. Stimulus-locked event-related potentials (ERPs) were measured while L1-dominant Chinese–English bilinguals read switch and non-switch sentences. The results of the reading task revealed language dominance effects on the N400, left anterior negativity (LAN) and late positive component (LPC). The language dominance effects at lexical level (i.e., on the N400 and LAN) were modulated by individual differences in monitoring capacity. In contrast, inhibition capacity predicted code-switching costs at the sentence level (i.e., for the LPC component). The results suggest that proactive monitoring and reactive inhibition affect different processing stages during the comprehension of dense code-switching sentences. These findings partially align with processing models of code-switching incorporating a dual control mode perspective and contribute new insight into the dynamic interplay between reactive and proactive control processes.
Assessing risk for nonmedical opioid use among patients with cancer: Stability of the CAGE-AID questionnaire across clinical care settings
Authors: Edwards Tonya , Arthur Joseph , Joy Manju , Lu Zhanni , Dibaj Seyedeh , Bruera Eduardo , Zhukovsky Donna
Published: July 2023

Objectives

The Cut down, Annoyed, Guilty, and Eye opener- Adapted to Include Drugs (CAGE-AID) questionnaire (CA) is a validated screening tool used to assess risk for nonmedical opioid use (NMOU) in patients receiving opioids for cancer pain. Data on consistencies and variations in responses to the CA between different clinical settings are lacking. We evaluated the frequency and consistency in scoring of the CA among patients seen between the first inpatient consult (T1) and the first outpatient follow-up (T2) visits.

Methods

A retrospective chart review of 333 consecutive patients seen at both T1 and T2 within 3 months between August 2016 and March 2017 was reviewed.

Results

Median age was 58 years (range, 18–87 years); 53% were female. CA was completed for 88% of patients at T1 and 94% at T2. Of these, 10% and 13% were CAGE-AID positive, respectively. CA score changed from negative to positive in 4% and from positive to negative in 1% of patients between T1 and T2. Kappa coefficient for agreement of CA between T1 and T2 was 0.74 (95% CI: 0.62–0.86, p = 0.02).

Significant of results

Completion rate and consistency of patient responses to the CA were high irrespective of clinical setting. Of these patients, 10% and 13% were CA positive which is suggestive of high risk for NMOU. Further studies are needed to evaluate ways to ensure more consistency in the completion of the CA and enhance its utilization in routine clinical practice.
Seasonal Flow Types of Glaciers in Sermilik Fjord, Greenland, Over 2016–2021
Authors: Poinar K.
Published: July 2023

Greenland glaciers have three primary seasonal ice flow patterns, or “types”: terminus‐driven, runoff‐driven, and runoff‐adapting. To date, glacier types have been identified by analyzing flow at a single location near the terminus; information at all other locations is discarded. Here, we use principal component (PC)/empirical orthogonal function (EOF) analysis to decompose multi‐year time series of glacier speed, combined from three satellite‐derived products at four glaciers feeding Sermilik Fjord, Greenland. This improves on single‐point methods by yielding spatial patterns (EOFs), which ensure the result reflects data at all locations on the glacier, and associated temporal patterns (PCs), which allow identification of glacier type. We find that the leading EOF is uniformly signed over the entire glacier domain, that this mode explains the majority of the variance in speed, and therefore that glacier type can be inferred from the leading PC. We find that Helheim Glacier was terminus‐driven, Fenris Glacier and Midgard Glacier were runoff‐adapting, and Pourquoi Pas Glacier was runoff‐driven over 2016–2021. Our classification agrees with previous work for Helheim and Midgard Glaciers, but differs at the other two. At all but Fenris Glacier, the leading PC correlates significantly with the speed pattern observed at the single point used in previous analyses. Thus, Fenris Glacier has more complex flow patterns than single‐point analysis can capture, and wider spatial analysis techniques such as EOF/PC are required. We suggest that, due to its low computational cost and inclusion in standard analysis packages, EOF/PC analysis should be used for assessing glacier type.
Transient Response and Adjustment Timescales of Channel Width and Angle of Valley‐Side Slopes to Accelerated Incision
Authors: Takahashi Naoya O. , Shyu J. Bruce H. , Toda Shinji , Matsushi Yuki , Ohta Ryoga J. , Matsuzaki Hiroyuki
Published: July 2023

Studying bedrock rivers during their transient states helps understand the response of a fluvial system to the changing boundary conditions. Although theoretical studies predict how river form adjusts to changes in incision or rock uplift rates, field constraints on the timescale of this adjustment are limited. We investigated the transient behavior of channels and hillslopes and estimated the adjustment times of channel width and angle of valley‐side slopes to accelerated incision based on knickpoint travel time. We documented channel slopes, channel widths, and hillslope angles along six rivers around an active normal fault in Iwaki, Japan, and identified river sections in a transient state. Channel slopes and basin‐averaged erosion rates determined from 10Be concentrations are distinct between rivers near and distant from the fault, suggesting that past increases in fault throw rates triggered the knickpoint formation and the observed transient response. Adjustment time for width is at least 105 years and can take 106 years after the knickpoint passage. Adjustment time for hillslope angles is generally shorter than for channel width. However, the hillslope adjustment may take longer than previously reported if the effect of width adjustment on hillslope angles is significant or the complete adjustment of hillslope angles is considered. The fact that channel slope, channel width, and hillslope angle have distinct adjustment times underlines the importance of correctly identifying river sections that are fully adjusted to the new boundary conditions when inferring erosion or relative uplift rates for bedrock rivers.
Research on the Effect of Data Assimilation for Three‐Dimensional MHD Simulation of Solar Wind
Authors: Zhang Hanke , Shen Fang , Yang Yi
Published: July 2023

As an important part of space weather forecasting, the prediction of solar wind parameters in the near‐Earth space is particularly significant. The introduction of data assimilation (DA) method can improve the reliability of numerical prediction. In this study, we use a three‐dimensional (3D) magnetohydrodynamics (MHD) numerical model with Kalman filter to infer the impact of the DA on solar wind modeling. We use the 3D MHD numerical model with near‐Earth in situ observations from the OMNI database to reconstruct solar wind parameters between 21.5 solar radii and 1 AU. The period from 2018 to 2021 is simulated, when the solar activity in the decay of the 24th solar cycle to the rising of 25th solar cycle. The numerical model generates two separate results, one without DA and one with DA directly performed on the model‐only results. Statistical analysis of observed, modeled and assimilated solar wind parameters at 1 AU reveals that assimilating simulations provide a more accurate forecast than the model‐only results with a sharp reduction in the root mean square error and an increase of correlation coefficient.
Sex differences in placenta-derived markers and later autistic traits in children
Authors: Tsompanidis A. , Blanken L. , Broere-Brown Z. A. , van Rijn B. B. , Baron-Cohen S. , Tiemeier H.
Published: July 2023

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean= 13.5 [SD = 2.0] weeks gestation) and 2nd trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, compared to female pregnancies. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2nd: n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd: n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2nd trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.
B cell-derived IL-10 promotes the resolution of lipopolysaccharide-induced acute lung injury
Authors: Sun Zhun , Chen Anning , Fang Hongwei , Sun Donglin , Huang Meiying , Cheng Erdeng , Luo Mengyuan , Zhang Xiaoren , Fang Hao , Qian Guojun
Published: July 2023

Inflammation resolution is critical for acute lung injury (ALI) recovery. Interleukin (IL)-10 is a potent anti-inflammatory factor. However, its role in ALI resolution remains unclear. We investigated the effects of IL-10 during the ALI resolution process in a murine lipopolysaccharide (LPS)-induced ALI model. Blockade of IL-10 signaling aggravates LPS-induced lung injury, as manifested by elevated pro-inflammatory factors production and increased neutrophils recruitment to the lung. Thereafter, we used IL-10 GFP reporter mice to discern the source cell of IL-10 during ALI. We found that IL-10 is predominantly generated by B cells during the ALI recovery process. Furthermore, we used IL-10-specific loss in B-cell mice to elucidate the effect of B-cell-derived IL-10 on the ALI resolution process. IL-10-specific loss in B cells leads to increased pro-inflammatory cytokine expression, persistent leukocyte infiltration, and prolonged alveolar barrier damage. Mechanistically, B cell-derived IL-10 inhibits the activation and recruitment of macrophages and downregulates the production of chemokine KC that recruits neutrophils to the lung. Moreover, we found that IL-10 deletion in B cells leads to alterations in the cGMP–PKG signaling pathway. In addition, an exogenous supply of IL-10 promotes recovery from LPS-induced ALI, and IL-10-secreting B cells are present in sepsis-related ARDS. This study highlights that B cell-derived IL-10 is critical for the resolution of LPS-induced ALI and may serve as a potential therapeutic target.
The Road from AKI to CKD: Molecular Mechanisms and Therapeutic Targets of Ferroptosis
Authors: Guo Runzhi , Duan Jiayu , Pan Shaokang , Cheng Fei , Qiao Yingjin , Feng Qi , Liu Dongwei , Liu Zhangsuo
Published: July 2023

Acute kidney injury (AKI) is a prevalent pathological condition that is characterized by a precipitous decline in renal function. In recent years, a growing body of studies have demonstrated that renal maladaptation following AKI results in chronic kidney disease (CKD). Therefore, targeting the transition of AKI to CKD displays excellent therapeutic potential. However, the mechanism of AKI to CKD is mediated by multifactor, and there is still a lack of effective treatments. Ferroptosis, a novel nonapoptotic form of cell death, is believed to have a role in the AKI to CKD progression. In this study, we retrospectively examined the history and characteristics of ferroptosis, summarized ferroptosis’s research progress in AKI and CKD, and discussed how ferroptosis participates in regulating the pathological mechanism in the progression of AKI to CKD. Furthermore, we highlighted the limitations of present research and projected the future evolution of ferroptosis. We hope this work will provide clues for further studies of ferroptosis in AKI to CKD and contribute to the study of effective therapeutic targets to prevent the progression of kidney diseases.
α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure
Authors: Zhang Naijin , Zhang Ying , Xu Jiaqi , Wang Pengbo , Wu Boquan , Lu Saien , Lu Xinxin , You Shilong , Huang Xinyue , Li Mohan , Zou Yuanming , Liu Mengke , Zhao Yuanhui , Sun Guozhe , Wang Wenbin , Geng Danxi , Liu Jingwei , Cao Liu , Sun Yingxian
Published: July 2023

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC–Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC–Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC–Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.
Deep structured learning for variant prioritization in Mendelian diseases
Authors: Danzi Matt C. , Dohrn Maike F. , Fazal Sarah , Beijer Danique , Rebelo Adriana P. , Cintra Vivian , Züchner Stephan
Published: July 2023

Effective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify a wide range of protein-altering single nucleotide variants (SNVs) and indels and assesses whether a variant would be pathogenic in the context of dominant or recessive inheritance. We demonstrate that MAVERICK outperforms all other major programs that assess pathogenicity in a Mendelian context. In a cohort of 644 previously solved patients with Mendelian diseases, MAVERICK ranks the causative pathogenic variant within the top five variants in over 95% of cases. Seventy-six percent of cases were solved by the top-ranked variant. MAVERICK ranks the causative pathogenic variant in hitherto novel disease genes within the first five candidate variants in 70% of cases. MAVERICK has already facilitated the identification of a novel disease gene causing a degenerative motor neuron disease. These results represent a significant step towards automated identification of causal variants in patients with Mendelian diseases.
Hidden modes of DNA binding by human nuclear receptors
Authors: Bhimsaria Devesh , Rodríguez-Martínez José A. , Mendez-Johnson Jacqui L. , Ghoshdastidar Debostuti , Varadarajan Ashwin , Bansal Manju , Daniels Danette L. , Ramanathan Parameswaran , Ansari Aseem Z.
Published: July 2023

Human nuclear receptors (NRs) are a superfamily of ligand-responsive transcription factors that have central roles in cellular function. Their malfunction is linked to numerous diseases, and the ability to modulate their activity with synthetic ligands has yielded 16% of all FDA-approved drugs. NRs regulate distinct gene networks, however they often function from genomic sites that lack known binding motifs. Here, to annotate genomic binding sites of known and unexamined NRs more accurately, we use high-throughput SELEX to comprehensively map DNA binding site preferences of all full-length human NRs, in complex with their ligands. Furthermore, to identify non-obvious binding sites buried in DNA–protein interactomes, we develop MinSeq Find, a search algorithm based on the MinTerm concept from electrical engineering and digital systems design. The resulting MinTerm sequence set (MinSeqs) reveal a constellation of binding sites that more effectively annotate NR-binding profiles in cells. MinSeqs also unmask binding sites created or disrupted by 52,106 single-nucleotide polymorphisms associated with human diseases. By implicating druggable NRs as hidden drivers of multiple human diseases, our results not only reveal new biological roles of NRs, but they also provide a resource for drug-repurposing and precision medicine.
Threat gates visual aversion via theta activity in Tachykinergic neurons
Authors: Tsuji Masato , Nishizuka Yuto , Emoto Kazuo
Published: July 2023

Animals must adapt sensory responses to an ever-changing environment for survival. Such sensory modulation is especially critical in a threatening situation, in which animals often promote aversive responses to, among others, visual stimuli. Recently, threatened Drosophila has been shown to exhibit a defensive internal state. Whether and how threatened Drosophila promotes visual aversion, however, remains elusive. Here we report that mechanical threats to Drosophila transiently gate aversion from an otherwise neutral visual object. We further identified the neuropeptide tachykinin, and a single cluster of neurons expressing it (“Tk-GAL42 ∩ Vglut neurons”), that are responsible for gating visual aversion. Calcium imaging analysis revealed that mechanical threats are encoded in Tk-GAL42 ∩ Vglut neurons as elevated activity. Remarkably, we also discovered that a visual object is encoded in Tk-GAL42 ∩ Vglut neurons as θ oscillation, which is causally linked to visual aversion. Our data reveal how a single cluster of neurons adapt organismal sensory response to a threatening situation through a neuropeptide and a combination of rate/temporal coding schemes.
Inhibition of AXL receptor tyrosine kinase enhances brown adipose tissue functionality in mice
Authors: Efthymiou Vissarion , Ding Lianggong , Balaz Miroslav , Sun Wenfei , Balazova Lucia , Straub Leon G. , Dong Hua , Simon Eric , Ghosh Adhideb , Perdikari Aliki , Keller Svenja , Ghoshdastider Umesh , Horvath Carla , Moser Caroline , Hamilton Bradford , Neubauer Heike , Wolfrum Christian
Published: July 2023

The current obesity epidemic and high prevalence of metabolic diseases necessitate efficacious and safe treatments. Brown adipose tissue in this context is a promising target with the potential to increase energy expenditure, however no pharmacological treatments activating brown adipose tissue are currently available. Here, we identify AXL receptor tyrosine kinase as a regulator of adipose function. Pharmacological and genetic inhibition of AXL enhance thermogenic capacity of brown and white adipocytes, in vitro and in vivo. Mechanistically, these effects are mediated through inhibition of PI3K/AKT/PDE signaling pathway, resulting in induction of nuclear FOXO1 localization and increased intracellular cAMP levels via PDE3/4 inhibition and subsequent stimulation of the PKA-ATF2 pathway. In line with this, both constitutive Axl deletion as well as inducible adipocyte-specific Axl deletion protect animals from diet-induced obesity concomitant with increases in energy expenditure. Based on these data, we propose AXL receptor as a target for the treatment of obesity.
Atomic structure of a nudivirus occlusion body protein determined from a 70-year-old crystal sample
Authors: Keown Jeremy R. , Crawshaw Adam D. , Trincao Jose , Carrique Loïc , Gildea Richard J. , Horrell Sam , Warren Anna J. , Axford Danny , Owen Robin , Evans Gwyndaf , Bézier Annie , Metcalf Peter , Grimes Jonathan M.
Published: July 2023

Infectious protein crystals are an essential part of the viral lifecycle for double-stranded DNA Baculoviridae and double-stranded RNA cypoviruses. These viral protein crystals, termed occlusion bodies or polyhedra, are dense protein assemblies that form a crystalline array, encasing newly formed virions. Here, using X-ray crystallography we determine the structure of a polyhedrin from Nudiviridae. This double-stranded DNA virus family is a sister-group to the baculoviruses, whose members were thought to lack occlusion bodies. The 70-year-old sample contains a well-ordered lattice formed by a predominantly α-helical building block that assembles into a dense, highly interconnected protein crystal. The lattice is maintained by extensive hydrophobic and electrostatic interactions, disulfide bonds, and domain switching. The resulting lattice is resistant to most environmental stresses. Comparison of this structure to baculovirus or cypovirus polyhedra shows a distinct protein structure, crystal space group, and unit cell dimensions, however, all polyhedra utilise common principles of occlusion body assembly.
Dynamic imaging of interfacial electrochemistry on single Ag nanowires by azimuth-modulated plasmonic scattering interferometry
Authors: Wu Gang , Qian Chen , Lv Wen-Li , Zhao Xiaona , Liu Xian-Wei
Published: July 2023

Direct visualization of surface chemical dynamics in solution is essential for understanding the mechanisms involved in nanocatalysis and electrochemistry; however, it is challenging to achieve high spatial and temporal resolution. Here, we present an azimuth-modulated plasmonic imaging technique capable of imaging dynamic interfacial changes. The method avoids strong interference from reflected light and consequently eliminates the parabolic-like interferometric patterns in the images, allowing for a 67-fold increase in the spatial resolution of plasmonic imaging. We demonstrate that this optical imaging approach enables comprehensive analyses of surface chemical dynamics and identification of previously unknown surface reaction heterogeneity by investigating electrochemical redox reactions over single silver nanowires as an example. This work provides a general strategy for high-resolution plasmonic imaging of surface electrochemical dynamics and other interfacial chemical reactions, complementing existing surface characterization methods.
Discovering functionally important sites in proteins
Authors: Cagiada Matteo , Bottaro Sandro , Lindemose Søren , Schenstrøm Signe M. , Stein Amelie , Hartmann-Petersen Rasmus , Lindorff-Larsen Kresten
Published: July 2023

Proteins play important roles in biology, biotechnology and pharmacology, and missense variants are a common cause of disease. Discovering functionally important sites in proteins is a central but difficult problem because of the lack of large, systematic data sets. Sequence conservation can highlight residues that are functionally important but is often convoluted with a signal for preserving structural stability. We here present a machine learning method to predict functional sites by combining statistical models for protein sequences with biophysical models of stability. We train the model using multiplexed experimental data on variant effects and validate it broadly. We show how the model can be used to discover active sites, as well as regulatory and binding sites. We illustrate the utility of the model by prospective prediction and subsequent experimental validation on the functional consequences of missense variants in HPRT1 which may cause Lesch-Nyhan syndrome, and pinpoint the molecular mechanisms by which they cause disease.
Conductance stable and mechanically durable bi-layer EGaIn composite-coated stretchable fiber for 1D bioelectronics
Authors: Lee Gun-Hee , Lee Do Hoon , Jeon Woojin , Yoon Jihwan , Ahn Kwangguk , Nam Kum Seok , Kim Min , Kim Jun Kyu , Koo Yong Hoe , Joo Jinmyoung , Jung WooChul , Lee Jaehong , Nam Jaewook , Park Seongjun , Jeong Jae-Woong , Park Steve
Published: July 2023

Deformable semi-solid liquid metal particles (LMP) have emerged as a promising substitute for rigid conductive fillers due to their excellent electrical properties and stable conductance under strain. However, achieving a compact and robust coating of LMP on fibers remains a persistent challenge, mainly due to the incompatibility of conventional coating techniques with LMP. Additionally, the limited durability and absence of initial electrical conductivity of LMP restrict their widespread application. In this study, we propose a solution process that robustly and compactly assembles mechanically durable and initially conductive LMP on fibers. Specifically, we present a shearing-based deposition of polymer-attached LMP followed by additional coating with CNT-attached LMP to create bi-layer LMP composite with exceptional durability, electrical conductivity, stretchability, and biocompatibility on various fibers. The versatility and reliability of this manufacturing strategy for 1D electronics are demonstrated through the development of sewn electrical circuits, smart clothes, stretchable biointerfaced fiber, and multifunctional fiber probes.
Colloidal transport by light induced gradients of active pressure
Authors: Pellicciotta Nicola , Paoluzzi Matteo , Buonomo Dario , Frangipane Giacomo , Angelani Luca , Di Leonardo Roberto
Published: July 2023

Active fluids, like all other fluids, exert mechanical pressure on confining walls. Unlike equilibrium, this pressure is generally not a function of the fluid state in the bulk and displays some peculiar properties. For example, when activity is not uniform, fluid regions with different activity may exert different pressures on the container walls but they can coexist side by side in mechanical equilibrium. Here we show that by spatially modulating bacterial motility with light, we can generate active pressure gradients capable of transporting passive probe particles in controlled directions. Although bacteria swim faster in the brighter side, we find that bacteria in the dark side apply a stronger pressure resulting in a net drift motion that points away from the low activity region. Using a combination of experiments and numerical simulations, we show that this drift originates mainly from an interaction pressure term that builds up due to the compression exerted by a layer of polarized cells surrounding the slow region. In addition to providing new insights into the generalization of pressure for interacting systems with non-uniform activity, our results demonstrate the possibility of exploiting active pressure for the controlled transport of microscopic objects.
Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?
Authors: Yu Jing , da Silva Edaise M. , La Hae-Sun , Clark Beth Z. , Fine Jeffrey L. , Carter Gloria J. , Villatoro Tatiana M. , Soong T. Rinda , Lee Adrian V. , Oesterreich Steffi , Basili Thais , Blanco-Heredia Juan , Selenica Pier , Ye Qiqi , Da Cruz Paula Arnaud , Dopeso Higinio , Gazzo Andrea , Marra Antonio , Pareja Fresia , Reis-Filho Jorge S. , Bhargava Rohit
Published: July 2023

This study describes “lobular-like invasive mammary carcinomas” (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management.
The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets
Authors: Chung Jeeyun , Park Joongkyu , Lai Zon Weng , Lambert Talley J. , Richards Ruth C. , Zhang Jiuchun , Walther Tobias C. , Farese Robert V.
Published: July 2023

Lipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular mechanisms mediating LD degradation by selective autophagy (lipophagy) are unknown. Here we identify spartin as a receptor localizing to LDs and interacting with core autophagy machinery, and we show that spartin is required to deliver LDs to lysosomes for triglyceride mobilization. Mutations in SPART (encoding spartin) lead to Troyer syndrome, a form of complex hereditary spastic paraplegia1. Interfering with spartin function in cultured human neurons or murine brain neurons leads to LD and triglyceride accumulation. Our identification of spartin as a lipophagy receptor, thus, suggests that impaired LD turnover contributes to Troyer syndrome development.
Real-time microscopy of the relaxation of a glass
Authors: Ruiz-Ruiz Marta , Vila-Costa Ana , Bar Tapas , Rodríguez-Tinoco Cristian , Gonzalez-Silveira Marta , Plaza Jose Antonio , Alcalá Jorge , Fraxedas Jordi , Rodriguez-Viejo Javier
Published: July 2023

The understanding of the dynamics of a glass above its devitrification temperature remains incomplete. Here, we build a spatio-temporal map of the relaxation dynamics of a highly stable glass into its supercooled liquid using real-time atomic force microscopy imaging. This methodology enables direct visualization of the progression of the liquid phase and clarifies and quantifies the presence of localized fast mobility regions separated by giant length scales. Our data establish a clear correlation between dynamic length and time scales in glasses. This approach may also be applicable to unveil the microscopic structure and dynamics of other glass-forming systems with much shorter length and time scales, including liquid-cooled glasses.
Molecular basis for ubiquitin/Fubi cross-reactivity in USP16 and USP36
Authors: O’Dea Rachel , Kazi Nafizul , Hoffmann-Benito Alicia , Zhao Zhou , Recknagel Sarah , Wendrich Kim , Janning Petra , Gersch Malte
Published: July 2023

Ubiquitin and ubiquitin-like proteins typically use distinct machineries to facilitate diverse functions. The immunosuppressive ubiquitin-like protein Fubi is synthesized as an N-terminal fusion to a ribosomal protein (Fubi-S30). Its proteolytic maturation by the nucleolar deubiquitinase USP36 is strictly required for translationally competent ribosomes. What endows USP36 with this activity, how Fubi is recognized and whether other Fubi proteases exist are unclear. Here, we report a chemical tool kit that facilitated the discovery of dual ubiquitin/Fubi cleavage activity in USP16 in addition to USP36 by chemoproteomics. Crystal structures of USP36 complexed with Fubi and ubiquitin uncover its substrate recognition mechanism and explain how other deubiquitinases are restricted from Fubi. Furthermore, we introduce Fubi C-terminal hydrolase measurements and reveal a synergistic role of USP16 in Fubi-S30 maturation. Our data highlight how ubiquitin/Fubi specificity is achieved in a subset of human deubiquitinases and open the door to a systematic investigation of the Fubi system.
CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
Authors: Horie Kanta , Salvadó Gemma , Barthélemy Nicolas R. , Janelidze Shorena , Li Yan , He Yingxin , Saef Benjamin , Chen Charles D. , Jiang Hong , Strandberg Olof , Pichet Binette Alexa , Palmqvist Sebastian , Sato Chihiro , Sachdev Pallavi , Koyama Akihiko , Gordon Brian A. , Benzinger Tammie L. S. , Holtzman David M. , Morris John C. , Mattsson-Carlgren Niklas , Stomrud Erik , Ossenkoppele Rik , Schindler Suzanne E. , Hansson Oskar , Bateman Randall J.
Published: July 2023

Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
GPX4 is a key ferroptosis biomarker and correlated with immune cell populations and immune checkpoints in childhood sepsis
Authors: Qu Guoxin , Liu Hui , Li Jin , Huang Siyuan , Zhao Nannan , Zeng Ling , Deng Jin
Published: July 2023

Sepsis is the uncontrolled reaction of the body to infection-induced inflammation, which results in life-threatening multiple-organ dysfunction (MODS). Although the research on sepsis has advanced significantly in recent years, its pathophysiology remains entirely unknown. Ferroptosis is a new-fashioned type of programmed cell death that may have an impact on sepsis development. However, the precise mechanism still needs to be explored. In this paper, Four pediatric sepsis datasets [training datasets (GSE26378 and GSE26440) and validation datasets (GSE11755 and GSE11281)] were chosen through the GEO (Gene Expression Omnibus) database, and 63 differentially expressions of ferroptosis-relation-genes (DE-FRGs) were eventually discovered using bioinformatics investigation. Functional annotation was performed using GO and KEGG pathway enrichment analysis. Then, four Core-FRGs (FTH1, GPX4, ACSL1, and ACSL6) were extracted after the construction of the protein–protein interaction (PPI) network and the research of the MCODE module. Consequently, Hub-FRG (GPX4) was found using the validation datasets, and correlation exploration of immunity populations (neutrophils, r =  − 0.52; CD8 T-cells, r = 0.43) and immunity checkpoints (CD274, r =  − 0.42) was implemented. The usefulness of GPX4 as a marker in sepsis was assessed in a mouse model of sepsis. The findings demonstrate that GPX4 is a crucial biomarker and a new latent immunotherapy target for the prediction and therapy of pediatric sepsis.
Automated F18-FDG PET/CT image quality assessment using deep neural networks on a latest 6-ring digital detector system
Authors: Schwyzer Moritz , Skawran Stephan , Gennari Antonio G. , Waelti Stephan L. , Walter Joan Elias , Curioni-Fontecedro Alessandra , Hofbauer Marlena , Maurer Alexander , Huellner Martin W. , Messerli Michael
Published: July 2023

To evaluate whether a machine learning classifier can evaluate image quality of maximum intensity projection (MIP) images from F18-FDG-PET scans. A total of 400 MIP images from F18-FDG-PET with simulated decreasing acquisition time (120 s, 90 s, 60 s, 30 s and 15 s per bed-position) using block sequential regularized expectation maximization (BSREM) with a beta-value of 450 and 600 were created. A machine learning classifier was fed with 283 images rated “sufficient image quality” and 117 images rated “insufficient image quality”. The classification performance of the machine learning classifier was assessed by calculating sensitivity, specificity, and area under the receiver operating characteristics curve (AUC) using reader-based classification as the target. Classification performance of the machine learning classifier was AUC 0.978 for BSREM beta 450 and 0.967 for BSREM beta 600. The algorithm showed a sensitivity of 89% and 94% and a specificity of 94% and 94% for the reconstruction BSREM 450 and 600, respectively. Automated assessment of image quality from F18-FDG-PET images using a machine learning classifier provides equivalent performance to manual assessment by experienced radiologists.