bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring the effect of RFID and marker recognition tags on cockroach (Blattodea: Blaberidae) behavior using AI-aided tracking
Authors: McLean Callum J , Fisher David N
Published: January 2025

Radio frequency identification (RFID) technology and marker recognition algorithms can offer an efficient and non-intrusive means of tracking animal positions. As such, they have become important tools for invertebrate behavioral research. Both approaches require fixing a tag or marker to the study organism, and so it is useful to quantify the effects such procedures have on behavior before proceeding with further research. However, frequently studies do not report doing such tests. Here, we demonstrate a time-efficient and accessible method for quantifying the impact of tagging on individual movement using open-source automated video tracking software. We tested the effect of RFID tags and tags suitable for marker recognition algorithms on the movement of Argentinian wood roaches (Blapicta dubia, Blattodea: Blaberidae) by filming tagged and untagged roaches in laboratory conditions. We employed DeepLabCut on the resultant videos to track cockroach movement and extract measures of behavioral traits. We found no statistically significant differences between RFID tagged and untagged groups in average speed over the trial period, the number of unique zones explored, and the number of discrete walks. However, groups that were tagged with labels for marker recognition had significantly higher values for all 3 metrics. We therefore support the use of RFID tags to monitor the behavior of B. dubia but note that the effect of using labels suitable for label recognition to identify individuals should be taken into consideration when measuring B.dubia behavior. We hope that this study can provide an accessible and viable roadmap for further work investigating the effects of tagging on insect behavior.
Feeling out-of-sync: navigating new rhythms in places of settlement
Authors: Kale Amber , Kindon Sara , Stupples Polly
Published: January 2025

In this article, we draw upon Lefebvre’s method of rhythmanalysis to analyse themes emerging from a participatory research project with former refugees in Aotearoa New Zealand. Specifically, we explore how participants navigate everyday rhythms, routines, and cycles in new places, and the nuanced ways in which these repetitive time structures influence their sense of place attachment and well-being. While resettlement discourse prioritizes abstract, linear framings of time, our research suggested that concrete temporal experiences (such as the pace-of-life and changing seasonal cycles) are also important to consider. Being out-of-sync with everyday rhythms evoked disorientation and discomfort for participants, while synchronizing and/or syncopating with local rhythms helped them to maintain important habits and routines and regain a sense of stability. We therefore argue for a broader conceptualization of time in resettlement, which considers how everyday rhythms are embodied and felt by former refugees in ways that influence their well-being and wider resettlement outcomes.
A lipoxygenase gene modulates jasmonate biosynthesis to enhance blast resistance in rice
Authors: Wang Lanlan , Chen Yumeng , Deng Fan , Jin Gaochen , Gong Xue , Wu Gengwei , Zhang Chi , Li Ran , Wang Hua
Published: January 2025

Inhibition of jasmonic acid (JA) signaling renders plants more susceptible to biotic stresses. Pathogen infection can induce an increase in JA levels. However, our understanding of the mechanisms mediating pathogen-induced JA accumulation in rice (Oryza sativa) remains limited. We characterized OsLOX9, a lipoxygenase gene of the 13-LOX subfamily involved in JA biosynthesis, which is induced upon infection by the rice blast fungus Magnaporthe oryzae. Two independent lox9 mutants exhibited increased susceptibility to M. oryzae infection, a phenotype that was fully restored by methyl jasmonate treatment, and showed reduced pathogen-induced accumulation of 12-oxo-phytodienoic acid, JA, and its bioactive form JA-Ile. RNA sequencing-based expression analysis in response to M. oryzae infection revealed an essential role of OsLOX9-produced jasmonates in up-regulating terpenoid phytoalexin pathway genes. Furthermore, we found that the JA core transcription factor, OsMYC2, can bind to the promoter of OsLOX9 and activate its expression, creating a positive feedback loop during pathogenesis. This study reveals that OsLOX9 is a key blast fungus-induced JA biosynthesis gene and contributes to resistance to blast disease in rice.
The AIRI plug-and-play algorithm for image reconstruction in radio-interferometry: variations and robustness
Authors: Terris Matthieu , Tang Chao , Jackson Adrian , Wiaux Yves
Published: January 2025

Plug-and-play (PnP) algorithms are appealing alternatives to proximal algorithms when solving inverse imaging problems. By learning a Deep Neural Network (DNN) denoiser behaving as a proximal operator, one waives the computational complexity of optimization algorithms induced by sophisticated image priors, and the sub-optimality of handcrafted priors compared to DNNs. Such features are highly desirable in radio-interferometric (RI) imaging, where precision and scalability of the image reconstruction process are key. In previous work, we introduced AIRI (‘AI Regularization in radio-interferometric Imaging’), PnP counterpart to the unconstrained variant of the SARA (Sparsity Averaging Reweighted Analysis) optimization algorithm, relying on a forward–backward algorithmic backbone. Here, we introduce variations of AIRI towards a more general and robust PnP paradigm in RI imaging. First, we show that the AIRI denoisers can be used without any alteration to instantiate a PnP counterpart to the constrained SARA optimization algorithm itself, relying on a primal-dual forward–backward algorithmic backbone, thus extending the remit of the AIRI paradigm. Secondly, we show that AIRI algorithms are robust to strong variations in the nature of the training data set, with denoisers trained on medical images yielding similar reconstruction quality to those trained on astronomical images. Thirdly, we develop a functionality to quantify the model uncertainty introduced by the randomness in the training process. We validate the image reconstruction and uncertainty quantification functionality of AIRI algorithms against the SARA family and CLEAN, both in simulation and on real data of the ESO 137-006 galaxy acquired with the MeerKAT telescope. AIRI code is available in the BASPLib code library$^\dagger$ on GitHub.
The Gefion Asteroid Family: parent body puzzles and ordinary chondrite pieces
Authors: McGraw Allison , Reddy Vishnu , Sanchez Juan A
Published: January 2025

Asteroid families provide critical clues to the nature of their original parent bodies. Ordinary chondrites, the most common meteorites to reach Earth, consist of three subtypes: H, L, and LL chondrites, offering valuable insights into the Solar system’s geochemical history. The Gefion Asteroid Family (GAF) has been proposed as a source for some L chondrites. In this study, we present the results of a spectroscopic campaign on dynamically defined members of the GAF, testing the hypothesis that L chondrites may originate from this family. Our new observations, combined with near-infrared (NIR) spectra from previous work, provide data for 18 asteroids. Compositional analysis reveals a range of meteorite analogues, including H (1 object, 6 per cent), L (8 objects, 43 per cent), and LL (1 object, 6 per cent). Objects with L chondrite-like compositions were the most common in our sample. Accounting for uncertainties, we also observed intermediate subtypes, such as H/L (5 objects, 28 per cent) and L/LL (3 objects, 17 per cent). Based on these results, we conclude that the GAF is a viable source for some L chondrite meteorites. However, further investigations are needed to fully understand the family’s contribution to the broader meteorite population.
Protest Chants as Public Music Theory
Authors: Manabe Noriko
Published: January 2025

This article recounts a music theorist’s experience with transcribing and analyzing protest chants as a form of public music theory, drawing from over a decade of fieldwork at demonstrations in Japan and the United States, including antinuclear protests in Japan, the Women’s March, Black Lives Matter demonstrations, and protests related to reproductive freedom and gun control. While exploring how music analysis can serve public needs, the project also raises important methodological and ethical questions. The transcriptions demonstrate how protesters use rhythmic patterns, intonation, and musical structures to build solidarity and amplify their message, often drawing on historical precedents and popular culture. By publishing analyses through open-access platforms and social media, I make musical transcriptions and insights available to activists and the public. However, this approach also reveals tensions between academic and public-facing scholarship, including questions about notation methods, the limitations of transcription, recognition of the work as scholarship by colleagues, and the role of social media in knowledge dissemination. The article ultimately considers how music theorists can meaningfully engage with contemporary social movements while navigating the challenges of public scholarship in a digital age.
c-JUN: a chromatin repressor that limits mesoderm differentiation in human pluripotent stem cells
Authors: Zhang Ran , Li Guihuan , Zhang Qi , Wang Zhenhua , Xiang Dan , Zhang Xiaofei , Chen Jiekai , Hutchins Andrew P , Qin Dajiang , Su Huanxing , Pei Duanqing , Li Dongwei
Published: January 2025

Cell fate determination at the chromatin level is not fully comprehended. Here, we report that c-JUN acts on chromatin loci to limit mesoderm cell fate specification as cells exit pluripotency. Although c-JUN is widely expressed across various cell types in early embryogenesis, it is not essential for maintaining pluripotency. Instead, it functions as a repressor to constrain mesoderm development while having a negligible impact on ectoderm differentiation. c-JUN interacts with MBD3–NuRD complex, which helps maintain chromatin in a low accessibility state at mesoderm-related genes during the differentiation of human pluripotent stem cells into mesoderm. Furthermore, c-JUN specifically inhibits the activation of key mesoderm factors, such as EOMES and GATA4. Knocking out c-JUN or inhibiting it with a JNK inhibitor can alleviate this suppression, promoting mesoderm cell differentiation. Consistently, knockdown of MBD3 enhances mesoderm generation, whereas MBD3 overexpression impedes it. Overexpressing c-JUN redirects differentiation toward a fibroblast-like lineage. Collectively, our findings suggest that c-JUN acts as a chromatin regulator to restrict the mesoderm cell fate.
Genomic clustering tendency of transcription factors reflects phase-separated transcriptional condensates at super-enhancers
Authors: Wang Shengyuan , Wang Zhenjia , Zang Chongzhi
Published: January 2025

Many transcription factors (TFs) have been shown to bind to super-enhancers, forming transcriptional condensates to activate transcription in various cellular systems. However, the genomic and epigenomic determinants of phase-separated transcriptional condensate formation remain poorly understood. Questions regarding which TFs tend to associate with transcriptional condensates and what factors influence their association are largely unanswered. Here we systematically analyzed 571 DNA sequence motifs across the human genome and 6650 TF binding profiles across different cell types to identify the molecular features contributing to the formation of transcriptional condensates. We found that the genomic distributions of sequence motifs for different TFs exhibit distinct clustering tendencies. Notably, TF motifs with a high genomic clustering tendency are significantly associated with super-enhancers. TF binding profiles showing a high genomic clustering tendency are further enriched at cell-type-specific super-enhancers. TFs with a high binding clustering tendency also possess high liquid–liquid phase separation abilities. Compared to nonclustered TF binding, densely clustered TF binding sites are more enriched at cell-type-specific super-enhancers with higher chromatin accessibility, elevated chromatin interaction and stronger association with cancer outcomes. Our results indicate that the clustered genomic binding patterns and the phase separation properties of TFs collectively contribute to the formation of transcriptional condensates.
Proximity-activated guide RNA of CRISPR–Cas12a for programmable diagnostic detection and gene regulation
Authors: Hu Zhian , Ling Shen , Duan Jialin , Yu Zixiao , Che Yanfei , Wang Song , Zhang Sichun , Zhang Xinrong , Li Zhengping
Published: January 2025

The flexibility and programmability of CRISPR–Cas technology have made it one of the most popular tools for biomarker diagnostics and gene regulation. Especially, the CRISPR–Cas12 system has shown exceptional clinical diagnosis and gene editing capabilities. Here, we discovered that although the top loop of the 5′ handle of guide RNA can undergo central splitting, deactivating CRISPR–Cas12a, the segments can dramatically restore CRISPR function through nucleic acid self-assembly or interactions with small molecules and aptamers. This discovery forms the basis of an engineered Cas12a system with a programmable proximity-activated guide RNA (PARC–Cas12a) that links targets of interest to dsDNA. Leveraging the efficient trans- and cis-cleavage of Cas12, our findings further inspired a detection platform design for RNAs or non-nucleic acid biomarkers, enabling highly sensitive and multiplexed analysis. We further demonstrated the feasibility of RNA-controllable gene knockout/knockdown in Escherichia coli. Notably, we successfully validated the gene regulatory capabilities of the PARC–Cas12a system within mammalian cell systems by utilizing the classical theophylline molecule–aptamer system. Our results introduce a programmable toolbox for precise diagnostics and cell regulation, allowing the development of versatile diagnostic tools, complex synthetic biological circuits, and cellular biosensors.
Unveiling the power duo: agriculture and social science take center stage in the evolution of climate change adaptation research in South Africa
Authors: Nondlazi Basanda Xhantilomzi , Mantlana Brain Khanyisa , Naidoo Sasha , Ramoelo Abel
Published: January 2025

Global changes in climatic conditions threaten the world’s socio-economic development, including South Africa (SA). Climate change adaptation (CCA) research in SA has grown in number (publication rate) and importance (influence on different sectors) over time. A growing body of research uses systematic literature reviews to examine themes within this rapidly evolving field. However, there is still a lack of analysis on the current state of CCA science literature in SA and its evolution over time. This paper fills this gap by providing a cross-validated bibliometric review of scientific literature on CCA in SA using Scopus and Web of Science (WoS) databases. The review is constructed across time, between databases, within databases and on most preferred journals. This transdisciplinary analysis of CCA literature and dominant research themes and priorities spanning 1966–2022 examines how they relate to SA’s adaptation strategy in response to climate change. CCA research has evolved in South Africa. Since 2011/12, publication rates have grown exponentially, averaging between 5% and 26% yearly. Term diversity peaked in 2018 when the publication rate reached 100 publications per year. This exponential development can be explained using themes of clustered terms over time, i.e. biodiversity emerging around 2015/16, Climate & Yield around 2017, and Agriculture & CCA, respectively, in 2018, with 41% similarity between Scopus and Web of Science. Future research needs to advance the monitoring of activities and outcomes on adaptation throughout the thematic evolution period.
Nitro-fatty acids modulate germination onset through S-nitrosothiol metabolism
Authors: Mata-Pérez Capilla , Begara-Morales Juan C , Padilla María N , Chaki Mounira , Sánchez-Calvo Beatriz , Carreras Alfonso , Aranda-Caño Lorena , Melguizo Manuel , Valderrama Raquel , Sánchez-Vicente Inmaculada , Lorenzo Óscar , Barroso Juan B
Published: January 2025

Nitro-fatty acids (NO2-FAs) have emerged as key components of nitric oxide (NO) signaling in eukaryotes. We previously described how nitro-linolenic acid (NO2-Ln), the major NO2-FA detected in plants, regulates S-nitrosoglutathione (GSNO) levels in Arabidopsis (Arabidopsis thaliana). However, the underlying molecular mechanisms remain undefined. Here, we used a combination of physiological, biochemical, and molecular approaches to provide evidence that NO2-Ln modulates S-nitrosothiol (SNO) content through S-nitrosylation of S-nitrosoglutathione reductase1 (GSNOR1) and its impact on germination onset. The aer mutant (a knockout mutant of the alkenal reductase enzyme; AER) exhibits higher NO2-Ln content and lower GSNOR1 transcript levels, reflected by higher SNO content and S-nitrosylated proteins. Given its capacity to release NO, NO2-Ln mediates the S-nitrosylation of GSNOR1, demonstrating that NO2-FAs can indirectly modulate total SNO content in plants. Moreover, the ectopic application of NO2-Ln to dormant seeds enhances germination success similarly to the aer germination rate, which is mediated by the degradation of master regulator ABSCISIC ACID INSENSITIVE 5 (ABI5). Our results establish that NO2-FAs regulate plant development through NO and SNO metabolism and reveal a role of NO2-FAs in plant physiology.
Officer-Involved: The Media Language of Police Killings
Authors: Moreno-Medina Jonathan , Bayer Aurelie Ouss Patrick , Ba Bocar A
Published: January 2025

This paper examines language patterns in US television news coverage of police killings. We first document that the media use semantic structures—such as passive voice, nominalizations, and intransitive verbs—that obscure responsibility more often in cases of police killings than in cases of civilian killings. Through an online experiment, we demonstrate the significance of these semantic differences, revealing that participants are less likely to hold police officers morally responsible and demand penalties when exposed to obfuscatory language, particularly in cases involving unarmed victims. Further analysis of news data shows greater use of obfuscatory language when the victims are unarmed or video footage is available—situations where obfuscation may have the greatest impact. Exploring the causes of this differential obfuscation, we do not find evidence that it is driven by either demand-side factors or supply-side factors associated with TV station ownership and political leaning. Instead, our results suggest that narratives crafted by police departments are a more likely driver of media obfuscation. Our study underscores the importance of semantic structures in how media shape perceptions, extending beyond considerations of coverage volume and bias.
The Impact of Being Denied a Wanted Abortion on Women and Their Children
Authors: Londoño-Vélez Juliana , Saravia Estefanía
Published: January 2025

This article examines the impact of denying a wanted abortion on women and children in Colombia using high-quality administrative microdata and credibly exogenous variation in abortion access. Women can seek legal abortions through a tutela, with cases randomly assigned to judges. Female judges are 20 percentage points (32%) less likely to deny abortion cases than are male judges, and we use the judge’s sex as an instrument for abortion denial. Denial of a wanted abortion has both immediate and lasting effects. It increases a woman’s risk of death by 2.5 percentage points within nine months, mainly due to unsafe abortion procedures, and raises the likelihood of carrying the pregnancy to term by 31 percentage points. Tracking outcomes up to 15 years later, we find that women denied an abortion experience more health issues, lower educational attainment, reduced labor force participation, and higher rates of single motherhood, poverty, and reliance on government assistance. Existing children, born before their mother sought an abortion, are less likely to attend school and are more likely to work.
Utilization of Potentially Inappropriate Sedative-Hypnotic and Atypical Antipsychotic Medications among Elderly Individuals with Insomnia and Alzheimer’s Disease
Authors: Chekani Farid , Mirchandani Kirti , Zaki Saba , Goswami Swarnali , Sharma Manvi
Published: January 2025

Study Objectives

This study assessed the utilization of potentially inappropriate medications (PIM) including oral sedative-hypnotic and atypical antipsychotic (OSHAA), healthcare resource utilization (HCRU), and costs among elderly individuals with insomnia and in the subpopulation with Alzheimer’s Disease (AD) who also had a diagnosis of insomnia.

Methods

Using claims database containing International Classification of Diseases, 10th Revision (ICD-10) codes, the cohort included individuals aged ≥ 65 with incident insomnia (EI, N=152,969) and AD insomnia subpopulation (ADI, N=4,888). Proportion of patients utilizing atypical antipsychotics or oral sedative-hypnotic medications, namely z-drugs, benzodiazepines, doxepin, Dual Orexin Receptor Antagonists (DORAs), and melatonin agonists, were assessed. Inappropriate OSHAA utilization was defined as per the American Geriatrics Society (AGS) Beers criteria. Multivariable models were utilized to compare HCRU and costs between PIM-OSHAA and no PIM-OSHAA groups.

Results

Among the EI cohort, z-drugs (13.39%) were the most commonly utilized OSHAA, and in the ADI cohort, it was AAPs (29.97%). PIM-OSHAA was utilized by 20% of the EI and 35% of the ADI cohorts. Patients with PIM-OSHAA use among the EI cohort had a higher annualized adjusted mean HCRU (pharmacy visits: 31.21 vs. 23.68; ambulatory & outpatient visits: 18.55 vs. 16.85) and costs, primarily due to medical costs (mean total cost: $36,676.08 vs. $31,346.54) compared to those without.

Conclusions

Substantial utilization of PIM-OSHAA was observed in EI and ADI cohorts. PIM-OSHAA use was associated with higher HCRU and costs. These findings underscore the importance of appropriate treatment strategies for insomnia in the elderly population especially in those with concurrent AD.
Effects of administering local anesthesia immediately before surgical castration on indicators of pain and discomfort of beef calves
Authors: Bernier Amanda F , Erickson Nathan , Campbell John , Moya Diego
Published: January 2025

Forty Hereford cross calves (mean and SD of 47.9 ± 10.43 d old) were used to assess the efficacy of lidocaine administered immediately before surgical castration on physiological and behavioral indicators of pain and discomfort. Calves were assigned by age to one of two treatments: surgical castration following subcutaneous injection of 2.5 mL/100 kg body weight of meloxicam (Metacam 20 mg/mL, Boehringer Ingelhein, Burlington, ON, Canada) per kg body weight (MEX, n = 19); or the same treatment preceded 90 s before by a nerve block of the spermatic cord using 8 mL of buffered (1 mL:10 mL of 8.4% sodium bicarbonate USP, Hospira Inc., Lake Forest, IL, USA) lidocaine (4 mL per cord; 20 mg/mL, LIDO-2 with epinephrine, Rafter Products, Calgary, AB, Canada) (LID, n = 21). During the castration procedure, two observers scored how much pain each animal was experiencing (visual analog score, VAS), number of body shakes and leg kicks for each calf. Blood samples and exit scores were collected the day of castration and on d 7, and 14 to assess the neutrophil-to-lymphocyte ratio (N:L) and calf temperament, respectively. Hair samples were collected the day of castration and on d 14 to determine cortisol levels. Scrotal circumference, swelling, and healing scores were determined on d 7 and 14 to assess healing. An accelerometer (HOBO Pendant® G Data Logger, Onset, Cape Cod, MA) was placed on the left hind leg to measure lying behavior until d 6 after castration. Calves were video recorded for 1 hour after the castration procedure to observe behaviors indicative of pain and discomfort. Surveillance cameras were also used to assess the mobility of the calves when cow-calf pairs were moved from the holding pen to the pasture. The VAS, number of tail flicks and foot stamps were greater (P < 0.01) in MEX than in LID calves. During the first hour after castration, LID calves spent more time lying (P = 0.03) and less time standing (P = 0.01) than MEX calves. When moved from the holding pen, LID calves moved faster (P < 0.01) and closer to their dams (P < 0.05) than MEX calves. Hair cortisol was greater (P < 0.05) in LID than MEX calves on d 14. Results suggest that using lidocaine for local anesthesia immediately before surgical castration reduced behaviors indicative of pain and improved mobility post-castration.
Phylogenetic systematics of the keratin-feeding genus Polynoncus Burmeister, 1876 (Coleoptera: Scarabaeoidea: Trogidae)
Authors: da Costa-Silva Vinícius , Strümpher Werner P , Thyssen Patricia J , Vaz-de-Mello Fernando Z
Published: January 2025

Among the five known Trogidae genera, Polynoncus is the only one endemic to South America. Although the systematics within Trogidae is well established, the evolutionary relationships among Polynoncus species remain poorly understood. Here, we conducted a phylogenetic analysis based on maximum parsimony, using the equal and implicit weighting algorithm with all characters, in TNT v.1.5 software. The assembled data matrix consisted of 98 morphological characters scored for 48 taxa. Our results corroborate the monophyletic status of Polynoncus and its sister-group relationship with the genus Omorgus, both within Omorginae. In Polynoncus, three main lineages were recovered: (i) clade ‘pedestris’, with four species occurring mostly in the Andes; (ii) clade ‘pilularius’, whose species have been most reported in the temperate zone of South America; and (iii) clade ‘brevicollis’, whose species are distributed from the arid zones of Argentina and Chile to Peru, following through the Andes. This is the first species-level phylogeny presented for Trogidae.
Mitochondrial respiration in white adipose tissue is dependent on body mass index and tissue location in patients undergoing oncological or parietal digestive surgery
Authors: Guerrier Lisa , Bacoeur‐Ouzillou Ophélie , Touron Julianne , Mezher Sami , Cassagnes Lucie , Vieille‐Marchiset Aurélie , Chanon Stéphanie , Pereira Bruno , Pezet Denis , Pinel Alexandre , Gagnière Johan , Malpuech‐Brugère Corinne , Richard Ruddy
Published: January 2025

Adipose tissue (AT), is a major endocrine organ that plays a key role in health and disease. However, adipose dysfunctions, especially altered energy metabolism, have been under‐investigated as white adipocytes have relatively low mitochondrial density. Nevertheless, recent studies suggest that mitochondria could play a major role in AT disorders and that AT mitochondrial activity could depend on adiposity level and location. This clinical study aimed to evaluate mitochondrial respiration and metabolism in human visceral (vAT) and subcutaneous (scAT) AT and their relationship with body mass index (BMI). This clinical study enrolled 67 patients (30 females/37 males) scheduled for digestive surgery without chemotherapy and parietal infection. BMI ranged from 15.4 to 51.9 kg·m−2 and body composition was estimated by computed tomographic images. Mitochondrial respiration was measured in situ in digitonin‐permeabilized AT using high‐resolution respirometry and a substrate/inhibitor titration approach. Protein levels of mitochondrial and lipid metabolism key elements were evaluated by Western blot. Maximal mitochondrial respiration correlated negatively with BMI (p < .01) and AT area (p < .001) regardless of the anatomical location. However, oxidative phosphorylation respiration was significantly higher in vAT (2.22 ± 0.15 pmol·sec−1·mg−1) than scAT (1.79 ± 0.17 pmol·sec−1·mg−1) (p < 0.001). In line with oxygraphy results, there were higher levels of mitochondrial respiratory chain complexes in low‐BMI patients and vAT. Mitochondrial respiration decreased with increasing BMI in both scAT and vAT, without sex‐associated difference. Mitochondrial respiration appeared to be higher in vAT than scAT. These differences were both qualitative and quantitative. Clinical Trials Registration IDNCT05417581.
Industrial air emissions and breast cancer incidence in a United States-wide prospective cohort
Authors: Ish Jennifer L. , Madrigal Jessica M. , Pearce John L. , Keil Alexander P. , Fisher Jared A. , Jones Rena R. , Sandler Dale P. , White Alexandra J.
Published: January 2025

Background:

We evaluated air emissions of industrial compounds, many of which have carcinogenic or endocrine disrupting properties, in relation to breast cancer incidence.

Methods:

Using the United States Environmental Protection Agency’s Toxics Release Inventory, we quantified air emissions of 28 compounds near Sister Study participants’ residences during the 10 years leading up to study enrollment (2003-2006; n=46,150). We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of residential emission levels of single pollutants with incident breast cancer. We assessed pollutant mixtures using an Exposure Continuum Mapping (ECM) framework and characterized associations using a joint-exposure response function.

Results:

During follow-up (median=13.4 years), we identified 4,155 breast cancer cases. We observed non-monotonic but elevated associations with breast cancer for emissions within 3km of the residence for nickel compounds (HRquintile5vs.none = 1.3; 95% CI 1.0, 1.6) and trichloroethylene (HRquintile5vs.none = 1.3; 95% CI 1.0, 1.6). ECM identified 25 mixture profiles that explained 72% of the variance in emissions patterns, with most participants experiencing relatively low emissions profiles. The joint-exposure response function suggested that higher incidence of breast cancer occurred among individuals with relatively rare, high emissions profiles; however, the overall trend was not associated with breast cancer (p=0.09).

Conclusions:

In our study, breast cancer incidence was associated with air emissions of certain industrial carcinogens. Although the overall emissions mixture did not show a trend related to breast cancer, this may not reflect the importance of individual compounds or specific emissions sources.
New therapies in celiac disease
Authors: Santonicola Antonella , Soldaini Carlo , Ciacci Carolina
Published: January 2025

Purpose of review

Celiac disease (CeD) is a chronic autoimmune disorder of the small intestine triggered by gluten ingestion in genetically predisposed individuals. The cornerstone of CeD management remains a strict adherence to a lifelong gluten-free diet (GFD), although such a dietary restriction can lead to an altered quality of life and may not be easy to follow for many patients. These challenges highlighted the need for alternative therapies. This review aims to explore the latest advancements in these therapeutic avenues, emphasizing mechanisms of action, clinical efficacy, and safety profiles of drugs currently in advanced stages of clinical testing.

Recent findings

Recent advances in the understanding of CeD pathophysiology have catalyzed the development of new therapeutic approaches, which include strategies to modify gluten processing in the gut, block gluten-triggered immune responses, or restore immune tolerance to gluten.

While these therapies are not poised to take the place of GFD, they represent promising treatment alternatives that could enhance the quality of life and minimize long-term consequences in CeD patients. Further research, as well as phase III clinical trials of those already conducted, are needed to establish the feasibility of integrating these novel drugs in the clinical management of CeD.
Selective degradation of BRD9 by a DCAF16-recruiting targeted glue: mode of
action elucidation and in vivo proof of concept
Authors: Hughes Scott J. , Stec Wojciech J. , Davies Colin T. R. , McGarry David , Williams Alicia , Del Barco Barrantes Ivan , Harris Rebecca , Owens Dominic D. G. , Fawcett Alexander , Hellicar John , Meier Gregor P. , Runcie Andrew C. , Greger Liliana , O’Rourke Martin , Churcher Ian , Pass Martin , Brown Giles A. , Ciulli Alessio , Modis Louise K. , Testa Andrea
Published: January 2025

Prospective discovery of molecular glues degraders for a specific
therapeutic target protein of interest is an emerging strategy in drug
discovery. Modification of pre-existing ligands with fragments that can alter
the protein surface can lead to the creation of novel compounds (‘’targeted
glues’’) able to induce neo-interactions between the target and an E3 ligase,
resulting in targeted protein degradation. By screening a library of potential
BRD9 targeted glue compounds, we have discovered a potent and selective,
reversibly covalent BRD9 degrader,AMPTX-1.
Co-immunoprecipitation-mass spectrometry experiments demonstrated that cell
treatment withAMPTX-1induces selective recruitment of
BRD9 to the E3 ligase DCAF16. Degradation is dependent on the engagement of the
surface Cys58 of DCAF16 and formation of a covalent adduct to DCAF16 is
facilitated by the ternary complex formation with BRD9. BRD9 degradation is
achievedin vivo after oral dosing, demonstrating
that covalent recruitment of DCAF16 is a viable strategy for targeted protein
degradation and can be achieved with drug-like, orally bioavailable compounds
with promisingin vivoactivity.
Exploring the kinetics and mechanism of phase separation in ternary lipid
mixtures containing APP C99 using atomistic vs coarse-grained MD
simulations
Authors: Pantelopulos George A. , Prusty Sangram , Bandara Asanga , Straub John E.
Published: January 2025

The phase separation of lipid bilayers, composed of mixtures of saturated
and unsaturated lipids and cholesterol, is a topic of fundamental importance in
membrane biophysics and cell biology. The formation of lipid domains, including
liquid-disordered domains enriched in unsaturated lipids and liquid-ordered
domains enriched in saturated lipids and cholesterol is believed to be essential
to the function of many membrane proteins. Experiment, theory, and simulation
have been used to develop a general understanding of the thermodynamic driving
forces underlying phase separation in ternary and quaternary lipid mixtures.
However, the kinetics of early events in lipid phase separation in the presence
of transmembrane proteins remain relatively understudied. Using large-scale
all-atom and coarse-grained simulations, we explore the kinetics and phase
separation of ternary lipid mixtures of saturated lipid, unsaturated lipid, and
cholesterol. Order parameters employed in the Cahn-Hilliard theory provide
insight into the kinetics and mechanism of lipid phase separation. We observe
three distinct time regimes in the phase separation process: a shorter time
exponential phase followed by a power law phase followed by a longer time
plateau phase. Comparison of lipid, protein and lipid-protein dynamics between
all-atom and coarse-grained models identifies both quantitative and qualitative
differences and similarities in the phase separation kinetics. Moreover,
timescaling of dynamics of AA and CG simulation yields a similar kinetic
mechanism of phase separation. The findings of this study elucidate fundamental
aspects of membrane biophysics and the ongoing efforts to define the role of
lipid rafts in the structure and function of cellular membrane.
Protection Against Pneumonia Induced By Vaccination With Fimbriae Subunits
FromKlebsiella pneumoniae
Authors: Assoni Lucas , Ciaparin Isabelle , Trentini Monalisa , Baboghlian Juliana , Rodrigo Gabriel , Ferreira Brenda Vieira , Pereira José Aires , Martinez Carlos Augusto Real , Caldas Ferraz Lucio Fabio , Girardello Raquel , de Carvalho Lucas Miguel , Hakansson Anders P. , Converso Thiago Rojas , Darrieux Michelle
Published: January 2025

Klebsiella pneumoniaeinfections pose a great
burden worldwide, causing high morbidity and mortality, which are worsened by
the increase in multidrug resistant strains. New therapeutic/prophylactic
strategies are urgently needed to overcome antibiotic resistance and reduce the
health and economic impacts of diseases caused by this pathogen. Fimbriae are
important virulence factors involved in biofilm formation and adhesion to host
cells. Their exposed location, conservation among clinical isolates and adjuvant
properties make them interesting candidates for inclusion in protein-based
vaccines. Therefore, the present work investigated the immunological potential
of type 1 and 3 fimbriae subunits in a murine model ofK.
pneumoniaelung infection. Subcutaneous immunization with
recombinant FimA and MrkA induced high IgG1 production; the antibodies
efficiently recognized the native proteins at the bacterial surface, promoted C3
deposition and reduced biofilm formation byK. pneumoniae in
vitro. Mice vaccinated with the co-administered proteins
reduced the bacterial loads in the lungs after intranasal challenge, less
inflammation and tissue damage. The results suggest that both type 1 and type 3
fimbriae contribute to protection againstK.
pneumoniaelung infection, inducing antibodies that bind to the
bacteria and favor complement deposition and clearance by the host, while
inhibiting biofilm formation.
An ultra-long heavy chain bovine antibody neutralizes SARS-CoV-2 and reacts
broadly with sarbecoviruses
Authors: Tsoleridis Theocharis , Fan Chengcheng , Park Emily J. , Duncan Joshua D. , Sharma Parul , Wartnaby Sophie , Chappell Joseph G. , Kipar Anja , Bentley Eleanor G. , Kirby Adam , Han Ximeng , Coleman Christopher M. , Flyak Andrew I. , McClure C Patrick , Rho Semi , Johansson Daniel X. , Persson Mats A.A. , Tarr Alexander W. , Haig David , Stewart James P. , Bjorkman Pamela J. , Urbanowicz Richard A. , Ball Jonathan K.
Published: January 2025

The threat of emergence of further SARS-CoV-2 variants, and the future
spillover potential of other sarbecoviruses has prompted continued efforts to
isolate broadly reactive monoclonal antibodies for therapeutic use. In this
study, we generated monoclonal antibodies from immunised cattle, primarily
because of their ability to produce antibodies with ultra-long heavy chain
complementarity determining region 3 (CDRH3) domains. Such antibodies have been
shown to have potent and cross-reactive neutralisation phenotypes in other virus
infections. Following extended immunisation with different forms of spike
protein and using single B-cell sorting and phage display techniques, we
isolated 33 mAbs, including 10 with ultra-long CDRH3s (>50 amino acids). Of
these, mAbs P7 and 99 exhibited remarkable neutralisation breadth and potency.
Notably, mAb P7, which possessed an ultra-long CDRH3, neutralised all tested
variants, including SARS-CoV-1, with IC50values ranging
from 0.01 µg/mL to 1.06 µg/mL. This antibody was also cross-reactive against a
panel of RBDs from diverse sarbecovirus species. Structural studies revealed
that mAb 99 targets a region of the receptor-binding domain (RBD) of the spike
protein that overlaps with the ACE2 binding site. Although the structure of the
P7 Fab-RBD complex was not resolvable, data suggest P7 induces trimer
dissociation by binding to an occluded RBD epitope, likely mediated by the
extended CDRH3 structure. Syrian hamster challenge experiments, using several
VOCs, showed that mAbs P7 and 99 significantly reduced lung viral load. These
findings highlight the potential of bovine-derived, especially those possessing
ultra-long CDRH3s, as effective therapeutics against current and future
sarbecovirus threats.

One Sentence Summary

Monoclonal antibodies derived from SARS-CoV-2 immunised cows exhibit
pan-sarbecovirus reactivity, highlighting their potential use as
therapeutics
Dissection of ergosterol metabolism reveals a pathway optimized for membrane
phase separation
Authors: Juarez-Contreras Israel , Lopes Laura J.S. , Holt Jamie , Yu-Liao Lorena , O’Shea Katherine , Ruiz-Ruiz Jose , Sodt Alexander , Budin Itay
Published: January 2025

Sterols are among the most abundant lipids in eukaryotic cells, yet are
synthesized through notoriously long metabolic pathways. It has been proposed
that the molecular evolution of such pathways must have required each step to
increase the capacity of its product to condense and order phospholipids. Here
we carry out a systematic analysis of the ergosterol pathway that leverages the
yeast vacuole’s capacity to phase-separate as a predictive biophysical readout
for each intermediate. In the post-synthetic steps specific to ergosterol
biosynthesis, we find that successive modifications act to oscillate ordering
capacity, settling on a level that supports phase separation while retaining
fluidity of the resulting domains. Simulations carried out with each
intermediate showed how conformers in the sterol’s alkyl tail are capable of
modulating long-range ordering of phospholipids, which could underlie changes in
phase behavior. Our results indicate that the complexity of sterol metabolism
could have resulted from the need to balance lipid interactions required for
membrane organization.
Development of Severity Index for Oral Epithelial Dysplasia Using Fuzzy Group Decision Making Algorithm
Authors: Nawn Debaleena , Lahiri Pooja , Dey Budhaditya , Pal Mousumi , Paul Ranjan Rashmi , Adhya Debashree Guha , Chakraborty Debjani , Chatterjee Jyotirmoy
Published: January 2025

Background

Oral epithelial dysplasia (OED) grading suffers from several levels of uncertainties and imprecision. An index is preferred in this context to improve reliability and reduce subjectivity in diagnostic decision making. In this study, a fuzzy logic-based disease severity index (SI) is formulated considering standard histopathological features used in OED grading.

Methods

Oral onco-pathologists were asked to independently provide weights of different features, according to their clinical significance in the context of dysplasia. Aggregated weight of each feature was calculated from individual assessment of different onco-pathologists by a fuzzy logic-based group decision making algorithm. Confidence levels of experts were also included to improve robustness of the method. SI was generated by integrating abnormality score of each feature with its weight. Abnormality degree of each feature was expressed in linguistic terms by onco-pathologists which were subsequently represented by a triangular fuzzy number. Fuzzy membership function was used as it can capture the ambiguity of experts’ opinion regarding abnormality of individual feature. Finally, defuzzification was used to get a crisp index from weighted sum of all features.

Result

SI was found to be statistically different (p<0.01) for different grades of dysplasia i.e mild, moderate and severe with added advantage of stratifying each grade in low and high subcategory.

Conclusion

Key contribution of our work is that we have developed a fuzzy logic-based group consensus process regarding weights of histopathological features for OED grading. Present methodology of developing SI can be applied to other medical decision-making problems as well.

Highlights

A severity index is proposed to improve reproducibility of oral epithelial dysplasia grading.

Clinical significance of each histopathological and cytopathological feature in the context of dysplasia is reflected by its weight.

A fuzzy logic-based group decision making algorithm is used to reduce subjectivity of features’ weights.

Confidence level of oral onco-pathologists are given due importance in derivation of aggregated weight of each feature.

Abnormality score of each feature is evaluated in fuzzy scale to capture clinicians’ ambiguity.

Present methodology may be useful for developing indices of other diseases.

Abstract Figure

Graphical abstract
Hyperacute Response Proteins (HARPs) synthesized on γ-tubulin-FTO-MARK4 translation microdomains upon exposure to stress, regulate stress response in cancer
Authors: Saleme Bruno , Tejay Saymon , Dembele Paul , Farraj Rabih Abou , Zhang Yongneng , Liu Yongsheng , Boukouris Aristeidis E. , Zervopoulos Sotirios D. , Haromy Alois , Zhao Yuan-Yuan , Braun Shelly , Saleme William , Sun Xuejun , Fahlman Richard , Glover Mark , Kinnaird Adam , Sutendra Gopinath , Michelakis Evangelos D.
Published: January 2025

Compared to normal, cancer cells are particularly resistant to stress, and their immediate response to stress is critical for their subsequent multilayered adaptation programs which pose a major clinical challenge. With unbiased proteomics and transcriptomics analysis, we identified a list of HARPs synthesized from pre-existing mRNAs within 20 min of diverse stresses in A549 cancer cells, despite the known suppressed global translation in stress. HARP mRNAs were translated on microtubule-associated translation microdomains (MATMs) located on γ-tubulin, that host FTO and specialized cytoskeletal ribosomes, structurally and functionally distinct from ER and cytosolic ribosomes. FTO exited the nucleus immediately after stress and was activated by the microtubule-associated stress kinase MARK4 via T6 phosphorylation. Activated FTO demethylated a translation-inhibiting mRNA methylation (m6A) signature, facilitating compartmentalized HARP translation on MATMs, while non-HARP mRNA remained inhibited. FTO or MARK4 inhibition suppressed HARP synthesis and increased apoptosis post various stresses, including chemotherapy. These data were confirmed in 4 additional cancer cell lines and normal fibroblasts. Using the Protein Atlas database, we found that high levels of our identified HARPs had on average a 35% decrease on patient 5-year survival in prevalent and resistant cancers (breast, lung, liver, pancreas). γ-tubulin, FTO and MARK4 are therapeutic targets for many cancers, through their ability to comprehensively promote HARPs translation, a potential Achille’s heel for cancer’s resistance to physiologic or therapeutic stress, offering a new window in stress biology.
Functional interplay between condensin I and topoisomerase IIα in single-molecule DNA compaction
Authors: Tsubota Yuko , Shintomi Keishi , Kinoshita Kazuhisa , Masahara-Negishi Yuki , Aizawa Yuuki , Shima Masami , Hirano Tatsuya , Nishiyama Tomoko
Published: January 2025

Condensin I and topoisomerase IIα (topo IIα) are chromosomal ATPases essential for mitotic chromosome assembly. Mechanistically how the two ATPases cooperate to assemble mitotic chromosomes remains unknown. Here we use total internal reflection fluorescence microscopy to analyze the interplay between condensin I and topo IIα at single-molecule resolution. As observed in previous studies, condensin I alone predominantly forms DNA loops in an ATP-dependent manner. However, when topo IIα is included in the reaction, condensin I forms stable compact structures (termed “lumps”) in a manner dependent on the C-terminal domain of topo IIα. Each of the stable lumps contains a single condensin I complex and a single topo IIα dimer. Remarkably, we find that topo IIα, when catalytically active, renders the lumps resistant to protease treatment. Several lines of evidence show that the protease-resistant lumps contain knotted DNA. A mutant condensin I complex defective in ATP hydrolysis, together with topo IIα, forms smaller lumps in which the probability of DNA knotting is greatly reduced. Our results demonstrate how topo IIα-mediated strand passage is coupled with condensin I-mediated loop extrusion to generate a compact DNA structure. Together with recent studies, we discuss the functional implications of these observations in mitotic chromosome assembly and stabilization.