bluuebunny/crossref_metadata_2025 huggingface dataset:
New Diagnoses of Juvenile Idiopathic Arthritis Early in the COVID-19 Pandemic
Authors: Rege Sanika , Parlett Lauren E. , Neikirk Amanda , Iizuka Alicia , Yang Yiling , Huang Cecilia , Crystal Stephen , Davidow Amy , Haynes Kevin , Gerhard Tobias , Rose Carlos D. , Strom Brian L. , Horton Daniel B.
Published: November 2024

Background/Objective

Little is known about the rates of rheumatic disease diagnosis among children during the COVID-19 pandemic. We examined the impact of the pandemic on the diagnosis of juvenile idiopathic arthritis (JIA) in the United States.

Methods

We performed a historical cohort study using US commercial insurance data (2016–2021) to identify children aged <18 years without prior JIA diagnosis or treatment in the prior ≥12 months. New JIA diagnoses were identified using a combination of ICD-10-CM diagnosis codes, location, and timing of medical services. Crude rates with 95% confidence intervals (CIs) of JIA diagnosis per 100,000 enrolled children per quarter were estimated and stratified by age group, sex, region, JIA type, and uveitis. The incidence rate ratio (95% CI) for JIA diagnosis was estimated using Poisson regression, adjusted for various demographic variables.

Results

From 2018–2021, 643 children were diagnosed with JIA. Crude new JIA diagnoses per 100,000 children per quarter dropped from 2.62 (95% CI, 2.39–2.87) prepandemic to 1.94 (95% CI, 1.66–2.25) during the pandemic. Declines in JIA diagnosis were more apparent in the US Northeast and West regions and among children aged 6–11 years. After adjustment for covariates, JIA diagnoses fell by 30% during the pandemic compared with the prior 3 years (IRR, 0.70; 95% CI, 0.59–0.83).

Conclusions

Compared with the prepandemic period, JIA was diagnosed 30% less often during the early pandemic among commercially insured children in the United States. More research is needed to understand the underlying reasons for these changes in JIA diagnosis and more recent trends.
Preliminary Evaluation for the Development of a Scoring System to Predict Homozygous M694V Genotype in Familial Mediterranean Fever Patients
Authors: Tunce Eray , Uçar Sıla Atamyıldız , Coşkuner Taner , Baykal Gülcan Özomay , Yiğit Ramazan Emre , Türkmen Şeyma , Pirim Gülşah , Ulu Kadir , Sözeri Betül
Published: November 2024

Objective

The aim of this study was to identify key parameters of a scoring system to be developed to predict the homozygous M694V genotype in patients clinically diagnosed with familial Mediterranean fever.

Methods

This study was a cross-sectional analysis of 472 pediatric familial Mediterranean fever patients with a homozygous genotype on exon 10, followed at our tertiary pediatric rheumatology clinic between June 2016 and June 2023. The patients were categorized into 2 groups based on their genotypes: group 1 comprised 402 patients (85.2%) with the homozygous M694V genotype, whereas group 2 consisted of 70 patients (14.8%) with other homozygous genotypes. Demographic information, clinical manifestations, MEFV (Mediterranean fever) gene variant analysis, and treatment responses were recorded from the patients' medical charts.

Results

The odds ratios for age at disease onset, arthritis, and chest pain were 0.892 (95% confidence interval [CI]: 0.832–0.958, p = 0.002), 2.565 (95% CI: 1.109–5.934, p = 0.028), and 2.351 (95% CI: 1.123–4.922, p = 0.023), respectively. A total of 60.7% of patients in group 1 had arthralgia, and 25% had erysipelas-like erythema, with these percentages were higher in group 1 compared with group 2 (p = 0.002, p = 0.001, respectively). Protracted febrile myalgia syndrome was detected in 1.5% of patients, all of whom had homozygous M694V genotype. Colchicine resistance was detected in 13.3% of patients, and all had homozygous M694V genotype.

Conclusions

This preliminary evaluation identified key parameters for a scoring system designed to predict the homozygous M694V genotype. A multicenter national study will further refine these parameters and develop the scoring system, which will aid clinicians in disease prognosis and therapeutic decision-making.
Papillary Tumor of the Pineal Gland With Discordant FDG and FAPi Uptake
Authors: Preet Komal , Purohit Priyavrat , Mittal Bhagwant Rai , Kumar Rajender , Singh Harmandeep , Shukla Jaya , Bal Amanjit , Madan Renu
Published: November 2024

In recent years, 68Ga-FAP inhibitor has emerged as a possible substitute radiotracer to FDG for imaging of most of the tumors. Here, we report a 7-year-old girl diagnosed with recurrent papillary tumor of the pineal gland, presenting with complaints of headache and vomiting. 18F-FDG PET/CT revealed an FDG-avid enhancing lesion in the posterior part of the third ventricle. Negligible FAPI uptake was noted on the corresponding 68Ga-FAPI-46 PET/CT images, highlighting the scope of 18F-FDG PET/CT in this realm.
Local Delivery of Melatonin Along With Bone Grafts to Improve Osteogenesis
Authors: Ahmadpour Ehsan , Azizi Bita , Behradfar Melika , Javadi Sanaz , Jabbari Hagh Elaheh , Ahmadpour Farzin
Published: November 2024

This review is an attempt to investigate the effects of local delivery of melatonin along with bone grafts to improve osteogenesis. A systematic literature search was done from January 1970 to December 2023 using PubMed following PRISMA instructions. A structured search was carried out to identify in vivo and in vitro studies. After screening the articles based on the abstract and title, 24 articles were included. The included studies were animal/human in vivo studies or in vitro studies. In total, 91.7% of the studies reported better outcomes in comparison with the control groups. Melatonin potentially can affect many signaling molecules and pathways promoting osteoblastic differentiation, such as activating pathways including Wnt, Nrf2/HO-1, PI3K/AKT, MAPK, NFkB, SIRT/SOD, BMP/Smad, PERK/ATF4. In conclusion, locally administered melatonin may stimulate bone healing in surgical bone defects and enhance peri-implant bone response.
Open abdomen versus primary closure in nontrauma patients: A weighted analysis of a single-center experience
Authors: Bunino Francesca Margherita , Zulian Davide , Famularo Simone , Persichetti Giorgia Willy Ladini , Mauri Giulia , Del Fabbro Daniele
Published: November 2024

INTRODUCTION

The open abdomen (OA) technique is nowadays a worldwide strategy both for trauma and emergency general surgery. Despite the attempt at conducting prospective studies, a high level of evidence is far from established. The aim of this study was to investigate if we overused this strategy and if it improved the postoperative course of our patients.

METHODS

Emergency laparotomies from 2017 and 2023 were reviewed and stratified according to OA and closed abdomen (CA). Differences were balanced by inverse probability weighting, and the 90-day mortality was estimated. Subgroup analysis was carried out for patients with a Mannheim Peritonitis Index (MPI) of >26, bowel obstruction, bowel ischemia (BI) and gastrointestinal perforation.

RESULTS

Of the 320 patients, 167 were CA and 153 were OA. Groups were different for American Society of Anesthesiologists, comorbidities, transfusion rate, Physiologic and Operative Severity Score for the Study of Mortality and Morbidity score, MPI, Clinical Frailty Scale score, diagnosis, and resection. Two balanced pseudo-populations were created. The 90-day survival rate was 50.8% for CA and 60.8% for OA (hazard ratio [HR], 0.79; confidence interval [CI], 0.40–1.55; p = 0.502). At the Cox regression, the Clinical Frailty Scale score (HR, 1.125; 95% CI, 1.01–1.25; p = 0.033) and BI (HR, 5.531; 95% CI, 2.37–12.89; p < 0.001) were independent risk factors for mortality. Transfusion rate (odds ratio [OR], 3.44; 95% CI, 1.44–8.23; p < 0.006) and length of stay in the intensive care unit (OR, 1.13; 95% CI, 1.07–1.20; p < 0.001) were associated with major complications. Open abdomen did not modify mortality in the case of bowel obstruction, MPI >26, or gastrointestinal perforation. Finally, OA (HR, 0.056; 95% CI, 0.01–0.22; p = 0.001) and large bowel resection (HR, 6.442; 95% CI, 1.28–32.31; p = 0.040) were predictors of longer survival in the subgroup of patients with BI.

CONCLUSION

Open abdomen was not associated with a higher complication rate or higher mortality but did result in a longer in-hospital stay. The only setting where OA seemed to be advantageous was in the BI population.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level III.
Hospital-based violence intervention programs: An analysis of costs and key components
Authors: O'Toole Megan J. , Schnippel Kathryn , Larson Bruce
Published: November 2024

BACKGROUND

Firearm assaults contribute to nearly 18,000 deaths and at least twice as many injuries annually, with immense human and financial costs. Gun violence survivors especially face unique and long-term physical, mental, economic, and safety-related challenges. Hospital-based violence intervention programs (HVIPs) connect survivors with violence prevention professionals at their hospital bedsides, then provide them with wraparound services in the months to come. Promising research shows that HVIPs reduce risks of reinjury, retaliation, and recidivism.

METHODS

This report provides a cost analysis of HVIPs, to inform researchers and implementers of the budget and key resources necessary for the first three years of implementation. Researchers employ an ingredients-based costing approach and base-case assumptions for a hospital-linked HVIP situated in a mid-sized city emergency department, serving 100 participants annually.

RESULTS

Results indicate that this base-case HVIP costs an estimated $1.1 million annually, or just under $10,800 per participant. Staffing accounts for the majority of HVIP budgets, followed by operations, crisis support, and finally transportation. Upfront costs are limited to technical assistance, first-time equipment, and accreditation courses, leaving annual costs relatively stable across the first 3 years of implementation. A customizable workbook is provided, through which users can adjust this study’s assumptions to reflect their own program’s specifications, which may vary.

CONCLUSION

While a full cost-savings analysis remains needed, HVIP enrollment costs less per person than a single year of medical fees for nonfatal firearm assault-related injuries. This research can inform future cost, benefit, and savings analyses, and empower more communities to implement lifesaving HVIPs.

LEVEL OF EVIDENCE

Economic and Value-Based Evaluation; Level II.
The macroecology of Mesozoic dinosaurs
Authors: Chiarenza Alfio Alessandro
Published: November 2024

Dinosaurs thrived for over 160 million years in Mesozoic ecosystems, displaying diverse ecological and evolutionary adaptations. Their ecology was shaped by large-scale climatic and biogeographic changes, calling for a ‘deep-time’ macroecological investigation. These factors include temperature fluctuations and the break up of Pangaea, influencing species richness, ecological diversity and biogeographic history. Recent improvements in the dinosaur fossil record have enabled large-scale studies of their responses to tectonic, geographic and climatic shifts. Trends in species diversity, body size and reproductive traits can now be analysed using quantitative approaches like phylogenetic comparative methods, machine learning and Bayesian inference. These patterns sometimes align with, but also deviate from, first-order macroecological rules (e.g. species–area relationship, latitudinal biodiversity gradient, Bergmann’s rule). Accurate reconstructions of palaeobiodiversity and niche partitioning require ongoing taxonomic revisions and detailed anatomical descriptions. Interdisciplinary research combining sedimentology, geochemistry and palaeoclimatology helps uncover the environmental conditions driving dinosaur adaptations. Fieldwork in under-sampled regions, particularly at latitudinal extremes, is crucial for understanding the spatial heterogeneity of dinosaur ecosystems across the planet. Open science initiatives and online databases play a key role in advancing this field, enriching our understanding of deep-time ecological processes, and offering new insights into dinosaur macroecology and its broader implications.
Evaluating vaccination timing, hesitancy and effectiveness to prevent future outbreaks: insights from COVID-19 modelling and transmission dynamics
Authors: Tanwar Komal , Kumawat Nitesh , Tripathi Jai Prakash , Chauhan Sudipa , Mubayi Anuj
Published: November 2024

The COVID-19 vaccine has been available in India since January 2021, although many individuals have refused to take the vaccine for various reasons. Vaccination plays a crucial role in disease control by preventing a substantial number of cases and associated disabilities. However, vaccine hesitancy poses a barrier that hinders these efforts. Our article presents a novel approach by proposing a mathematical model for COVID-19 that incorporates vaccine hesitancy, vaccine efficacy and behaviour compensation post-vaccination. The model is calibrated with COVID-19 incidence data for India from 13 February 2021 to 12 January 2022, using the Markov chain Monte Carlo method. The analysis examines the effects of hesitancy and social interventions through a series of practical simulations. The simulation results show that while COVID-19-infected individuals may have natural immunity, vaccination post-recovery is crucial to reduce cases by up to 64.1%. Social interventions, such as face masks and distancing, remain essential to prevent a rise in cases and ensure effective disease control. The model demonstrates that vaccination, combined with continued social interventions, is crucial for effectively reducing COVID-19 cases and preventing future outbreaks. Addressing vaccine hesitancy and maintaining preventive measures are key to successfully controlling the pandemic.
Demographics of co-ageing complex systems: from infected worms to chess games
Authors: Eskin Cagatay , Vural Dervis Can
Published: November 2024

Ageing, as defined in terms of the slope of the probability of death versus time (hazard curve), is a generic phenomenon observed in nearly all complex systems. Theoretical models of ageing predict hazard curves that monotonically increase in time, in discrepancy with the peculiar ups and downs observed empirically. Here we introduce the concept of co-ageing, where the demographic trajectories of multiple cohorts couple together, and show that co-ageing dynamics can account for the anomalous hazard curves exhibited by some species. In our model, multiple interdependency networks inflict damage on one other proportional to their number of functional nodes. We then fit our model predictions to three datasets describing (i) co-ageing worm–pathogen populations and (ii) competing tree species. Lastly, we collect data on the mortality statistics of (iii) chess games to demonstrate that co-ageing dynamics is not exclusive to biological systems.
Langevin dynamics for a heavy particle immersed within a flow of light particles
Authors: Erban Radek , Van Gorder Robert A.
Published: November 2024

A micro-hydrodynamics model based on elastic collisions of light point solvent particles with a heavy solute particle is investigated in the setting where the light particles have velocity distribution corresponding to a background flow. Considering a range of stationary background flows and distributions for the solvent particle velocities, the macroscopic Langevin-type description of the behaviour of the heavy particle is derived in the form of a generalized Ornstein–Uhlenbeck process. At leading order, the drift term in this process depends upon both the geometric structure of the background flow and the size of the heavy particle, while both drift and diffusion terms scale with moments of the light particle velocity distribution. Computational methods for simulating the micro-hydrodynamics model are then designed to confirm the theoretical results. To enable long-time calculations, simulations are performed in a frame co-moving with the heavy particle. Efficient methods for sampling the position and velocity distributions of incoming solvent particles at the boundaries of the co-moving frame are derived for a range of distributions of solvent particles. The simulations show good agreement with the theoretical results.
The principle of compromise-in-competition: understanding mesoscale complexity of different levels
Authors: Li Jinghai
Published: November 2024

This perspective is not meant to be a complete summary of the full series of our studies over decades, rather it aims to look back across the entire process to outline: What inspired this work at its beginning? How did the mindset gradually evolve from a solely engineering study to the new concept of Mesoscience? And where is the research currently being focused and to be extended? This approach elucidates the central importance of correlating precise engineering problems to be resolved with associated missing links in the underlying, fundamental science while exploring a notable commonality, namely, the universality of Mesoscience. Inspired by the physical phenomenon of the coexistence and interaction between a gas-rich dilute phase and a solid-rich dense phase with different physical mechanisms dominating the behaviour for each phase in gas–solid fluidization, it was recognized that an underlying compromise-in-competition (CIC) exists between these two physically dominant mechanisms. This, then, is the CIC principle. We believe that this is the origin of inherent structural complexity in these and other systems. We have shown that this CIC principle can be formulated as a multi-objective optimization problem through the so-called energy-minimization multi-scale model, leading to a massive improvement in both the accuracy and scalability of computation and its wide application in both academia and industries. Furthermore, this approach was extended to formulate and understand other complex systems in many apparently disparate fields, indicating the wide applicability of the CIC principle and then resulting in the proposition and advancement of the concept of Mesoscience. Furthermore, within the main body of this perspective article, future directions for identifying, developing and applying the concept of Mesoscience will be prospected. This includes extending its possible generality and applications in many different disciplines and fields, even to analysing global challenging issues and promoting CIC-informed AI. In this way, many challenging problems in engineering—identified through their underlying mesoscale complexity—will be closely correlated with the development of future fundamental science. Through this approach, we hope to illustrate that fundamental research can now tackle the intrinsic complexity existing in a multitude of engineering problems. Through the concept of Mesoscience, we aim to explore the possible commonality from complexity. The deduction of commonality from diversity is possible in resolving global challenges, shifting paradigms in science and filling in the existing gaps at the mesoscales of different levels of our knowledge, though there are difficulties and uncertainty coming from diversity.
Fine-tuning the evolutionary stability of recombinant herpesviral transmissible vaccines
Authors: Chan Baca , Nuismer Scott L. , Alqirbi Hujaz , Nichols Jenna , Remien Christopher H. , Davison Andrew J. , Jarvis Michael A. , Redwood Alec J.
Published: November 2024

Spillover of infectious diseases from wild animal populations constitutes a long-standing threat to human health for which few globally viable solutions have been developed. The use of oral baits laden with conventional vaccines distributed
en masse
represents one success story but is costly and practicable primarily for rabies risk reduction in North American and European carnivores. Efforts to expand vaccination to control pathogens within less accessible wildlife populations have raised interest in a new kind of vaccine capable of spreading pathogen-specific immunity through autonomous spread. However, such ‘transmissible’ vaccines raise concerns about the irrevocable release of genetically modified viruses into the environment. Herein, we explore the feasibility of an intrinsic strategy for transgene control within these vaccines based on the genetic destabilizing effect of
cis
-acting sequences flanking the heterologous transgene of interest. While suitable for the control of transgene stability within all types of DNA-viral vectored vaccines, this strategy has particular applicability to transmissible vaccines. Using a combination of experiments, mathematical modelling and whole-genome sequencing, we show that the rate of transgene loss can be controlled by varying the lengths of the direct repeat sequences. This opens a way for fine-tuning the lifespan of a transmissible vaccine in the wild.
Large language models (LLMs) as agents for augmented democracy
Authors: Gudiño Jairo F. , Grandi Umberto , Hidalgo César
Published: November 2024

We explore an augmented democracy system built on off-the-shelf large language models (LLMs) fine-tuned to augment data on citizens’ preferences elicited over policies extracted from the government programmes of the two main candidates of Brazil’s 2022 presidential election. We use a train-test cross-validation set-up to estimate the accuracy with which the LLMs predict both: a subject’s individual political choices and the aggregate preferences of the full sample of participants. At the individual level, we find that LLMs predict out of sample preferences more accurately than a ‘bundle rule’, which would assume that citizens always vote for the proposals of the candidate aligned with their self-reported political orientation. At the population level, we show that a probabilistic sample augmented by an LLM provides a more accurate estimate of the aggregate preferences of a population than the non-augmented probabilistic sample alone. Together, these results indicate that policy preference data augmented using LLMs can capture nuances that transcend party lines and represents a promising avenue of research for data augmentation.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Complex systems perspective in assessing risks in artificial intelligence
Authors: Kondor Daniel , Hafez Valerie , Shankar Sudhang , Wazir Rania , Karimi Fariba
Published: November 2024

In this article, we identify challenges in the complex interaction between artificial intelligence (AI) systems and society. We argue that AI systems need to be studied in their socio-political context to be able to better appreciate a diverse set of potential outcomes that emerge from long-term feedback between technological development, inequalities and collective decision-making processes. This means that assessing the risks from the deployment of any specific technology presents unique challenges. We propose that risk assessments concerning AI systems should incorporate a complex systems perspective, with adequate models that can represent short- and long-term effects and feedback, along with an emphasis on increasing public engagement and participation in the process.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Co-designing transport models as a heuristic planning tool
Authors: Maheshwari Tanvi , Fourie Pieter
Published: November 2024

Recently the transportation sector has witnessed several new technologically driven disruptions that have amplified the complexity of city planning and policymaking. Traditional well-established processes of decision-making in urban planning and transportation are proving insufficient to deal with this degree of complexity and uncertainty. This paper proposes an alternative approach, combining qualitative and normative urban design, with quantitative and predictive transport modelling. This requires urban designers and transport modellers to co-create goal-driven and agile transport models that act as a heuristic tool to guide planning decisions in early design stages. Heuristic modelling is informed by design optioning and vice versa in an iterative loop. A case study is presented to demonstrate how this approach is operationalized to study the impacts of automated vehicles on urban planning. Design workshops are used as a method to elicit responses from stakeholders, which are used to co-create the simulation models. This collaborative process grounds the research in real-world practice and enhances the communication of design proposals and research findings across disciplines. By integrating design thinking methods with agent-based transport simulations, this approach provides a better understanding of emergent effects in complex urban systems and improves stakeholder engagement in the planning process.

This article is part of the theme issue ‘Co-creating the future: participatory cities and digital governance’.
Quantifying body size estimation accuracy and body dissatisfaction in body dysmorphic disorder using a digital avatar
Authors: Karsan Sameena , Diaz-Fong Joel P. , Ly Ronald , Hellemann Gerhard , Feusner Jamie D.
Published: November 2024

A core feature of body dysmorphic disorder (BDD) is body image disturbance. Many with BDD misperceive and are dissatisfied with the sizes and shapes of body parts, but detailed quantification and analysis of this has not yet been performed. To address this gap, we appliedSomatomap 3D,a digital avatar tool, to quantify body image disturbances by assessing body size estimation (BSE) accuracy and body dissatisfaction. Sixty-one adults (31 with BDD, 30 healthy controls) created avatars to reflect their perceived current body and ideal body by altering 23 body part sizes and lengths usingSomatomap 3D.Physical measurements of corresponding body parts were recorded for comparison. BSE accuracy (current minus actual) and body dissatisfaction (ideal minus current) were compared between groups and in relation to BDD symptom severity using generalized estimating equations. Individuals with BDD significantly over-and under-estimated certain body parts compared to healthy controls. Individuals with BDD overall desired significantly thinner body parts compared to healthy controls. Moreover, those with worse BSE accuracy had greater body dissatisfaction and poorer insight. In sum, this digital avatar tool revealed disturbances in body image in individuals with BDD that may have perceptual and cognitive/affective components.
Cross-sectional, interventional, and causal investigation of insulin sensitivity using plasma proteomics in diverse populations
Authors: Kho Pik Fang , Wary Neil , Zanetti Daniela , Abbasi Fahim , Knowles Joshua W. , Panyard Daniel J. , Watson Katie T. , Stell Laurel , Lazzeroni Laura C. , Gustafsson Stefan , Lind Lars , Petrie John R , Assimes Themistocles L.
Published: November 2024

Background

We previously reported significant correlations between a direct measure of insulin sensitivity (IS) and blood levels of proteins measured using the Proximity Extension Assay (PEA) in two European cohorts. However, protein correlations with IS within non-European populations, in response to short-term interventions that improve IS, and any causal associations with IS have not yet been established.

Methods

We measured 1,470 proteins using the PEA in the plasma of 1,015 research participants at Stanford University who underwent one or more direct measures of IS. Association analyses were carried out with multivariable linear regression within and across Stanford subgroups and within each of the two European cohorts. Association statistics were also meta-analyzed after transformation and harmonization of the two direct measures of IS. Lastly, we performed genome-wide association studies of IS and used genetic instruments of plasma proteins from the UK Biobank to identify candidate causal proteins for IS through Mendelian Randomization (MR) analysis.

Results

In age and sex adjusted model, 810 proteins were associated with baseline IS among 652 self-reported European participants in the Stanford cohort at a false discovery rate (FDR) < 0.05. Effect sizes for these proteins were highly correlated with those observed in 122 South Asian, 92 East Asian, 85 Hispanic, and 52 Black/African American persons (r= 0.68 to 0.83, all P≤4.3×10-113). Meta-analysis of the full Stanford cohort with the two European cohorts (N=2,945) yielded 247 significant protein associations (FDR < 0.05), with 75 remaining significant after further adjustment for body mass index. In a subset of Stanford participants undergoing insulin sensitizing interventions (N=53 taking thiazolidinediones, N=66 with weight loss), 79.6% of protein level changes were directionally consistent with the respective baseline association (observed/expected p=6.7x10-16). MR analyses identified eight candidate causal proteins for IS, among which were SELE and ASGR1, proteins with established drug targets currently under investigation.

Conclusion

Plasma proteins measured using the PEA provide a robust signature for IS across diverse populations and after short-term insulin sensitizing interventions highlighting their potential value as universal biomarkers of insulin resistance. A small subset of markers provided insights into potential causal molecular mechanisms and therapeutic targets.

Highlights

Insulin sensitivity-related plasma proteins are consistent across diverse populations.

Protein changes from interventions align with baseline, aiding insulin sensitivity tracking.

SELE and ASGR1 are potential targets for insulin sensitivity.
Master regulators governing protein abundance across ten human cancer types
Authors: Wang Zishan , Wojciechowicz Megan , Rosen Jordan , Elmas Abdulkadir , Song Won-Min , Liu Yansheng , Huang Kuan-lin
Published: November 2024

Protein abundance correlates only moderately with mRNA levels, and are modulated post-transcriptionally by a network of regulators including ribosomes, RNA-binding proteins (RBPs), and the proteasome. Here, we identifiedMasterProtein abundanceRegulators (MaPRs) across ten cancer types by devising a new computational pipeline that jointly analyzed transcriptomes and proteomes from 1,305 tumor samples. We identified 232 to 1,394 MaPRs per cancer type, mediating up to 79% of post- transcriptional regulatory networks. MaPRs exhibit high network connectivity, strong genetic dependency in cancer cells, and significant enrichment for RBPs. Combining tumor up-regulation, druggability, and target network analyses identified cancer-specific vulnerabilities. MaPRs predict tumor proteomic subtypes more accurately than other proteins. Finally, significant portions of RBP MaPR-target relationships were validated by experimental evidence from eCLIP binding and knockdown assays. Our findings uncover central MaPRs that govern post-transcriptional networks, highlighting diverse processes underlying human proteome regulation and identifying key regulators in cancer biology.
Perspectives on Codebook: sequence specificity of uncharacterized human transcription factors
Authors: Jolma Arttu , Laverty Kaitlin U. , Fathi Ali , Yang Ally W.H. , Yellan Isaac , Vorontsov Ilya E. , Inukai Sachi , Kribelbauer-Swietek Judith F. , Gralak Antoni J. , Razavi Rozita , Albu Mihai , Brechalov Alexander , Patel Zain M. , Nozdrin Vladimir , Meshcheryakov Georgy , Kozin Ivan , Abramov Sergey , Boytsov Alexandr ,   The Codebook Consortium, Fornes Oriol , Makeev Vsevolod J. , Grau Jan , Grosse Ivo , Bucher Philipp , Deplancke Bart , Kulakovskiy Ivan V. , Hughes Timothy R.
Published: November 2024

We describe an effort (“Codebook”) to determine the sequence specificity of 332 putative and largely uncharacterized human transcription factors (TFs), as well as 61 control TFs. Nearly 5,000 independent experiments across multiplein vitroandin vivoassays produced motifs for just over half of the putative TFs analyzed (177, or 53%), of which most are unique to a single TF. The data highlight the extensive contribution of transposable elements to TF evolution, both incisandtrans, and identify tens of thousands of conserved, base-level binding sites in the human genome. The use of multiple assays provides an unprecedented opportunity to benchmark and analyze TF sequence specificity, function, and evolution, as further explored in accompanying manuscripts. 1,421 human TFs are now associated with a DNA binding motif. Extrapolation from the Codebook benchmarking, however, suggests that many of the currently known binding motifs for well-studied TFs may inaccurately describe the TF’s true sequence preferences.
Targeting synthetic lethality between non-homologous end joining and radiation in very high-risk SHH medulloblastoma
Authors: DeCarlo Alexandria , MacLeod Graham , Fernandes da Silva Carolina , Shen Lily , Aragao Lucas , Sie Mariska , Termini Deborah , Magee Jon , Gudenas Brian , Sukumaran Sneha , Charron Frederic , Marcellus Richard , Al-Awar Rima , Aman Ahmed , Tabori Uri , Nör Carolina , Northcott Paul A. , Dirks Peter , Angers Stephane , Ramaswamy Vijay
Published: November 2024

Specific and biologically informed treatments for medulloblastoma, especially the highly lethalTP53mutant SHH subgroup, remain elusive, where radiotherapy is the primary treatment option. Applying genome-wide CRISPR-Cas9 screening in combination with lethal doses of radiotherapy, we identified the main driver of radiation resistance in SHH medulloblastoma is loss of p53. A negative selection CRISPR-Cas9 screen across multiple models ofTrp53-deficient SHH medulloblastoma revealed a strong synthetic lethal interaction between components of the non-homologous end-joining pathway and radiation, particularly DNA protein kinase (DNA-PK) and its binding partners. Both genetic and pharmacological perturbation of DNA-PK enhanced radiosensitivity inTP53-deficient SHH medulloblastoma, leading to cell death.In vivotreatment of somatic and germlineTP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improved survival when combined with radiotherapy, strongly supporting further clinical investigation.
Human single-neuron activity is modulated by intracranial theta burst stimulation of the basolateral amygdala
Authors: Campbell Justin M. , Cowan Rhiannon L. , Wahlstrom Krista L. , Hollearn Martina K. , Jensen Dylan , Davis Tyler , Rahimpour Shervin , Shofty Ben , Arain Amir , Rolston John D. , Hamann Stephan , Wang Shuo , Eisenman Lawrence N. , Swift James , Xie Tao , Brunner Peter , Manns Joseph R. , Inman Cory S. , Smith Elliot H. , Willie Jon T.
Published: November 2024

Direct electrical stimulation of the human brain has been used for numerous clinical and scientific applications. Previously, we demonstrated that intracranial theta burst stimulation (TBS) of the basolateral amygdala (BLA) can enhance declarative memory, likely by modulating hippocampal-dependent memory consolidation. At present, however, little is known about how intracranial stimulation affects activity at the microscale. In this study, we recorded intracranial EEG data from a cohort of patients with medically refractory epilepsy as they completed a visual recognition memory task. During the memory task, brief trains of TBS were delivered to the BLA. Using simultaneous microelectrode recordings, we isolated neurons in the hippocampus, amygdala, orbitofrontal cortex, and anterior cingulate cortex and tested whether stimulation enhanced or suppressed firing rates. Additionally, we characterized the properties of modulated neurons, patterns of firing rate coactivity, and the extent to which modulation affected memory task performance. We observed a subset of neurons (∼30%) whose firing rate was modulated by TBS, exhibiting highly heterogeneous responses with respect to onset latency, duration, and direction of effect. Notably, location and baseline activity predicted which neurons were most susceptible to modulation, although the impact of this neuronal modulation on memory remains unclear. These findings advance our limited understanding of how focal electrical fields influence neuronal firing at the single-cell level and motivate future neuromodulatory therapies that aim to recapitulate specific patterns of activity implicated in cognition and memory.
Systematic benchmarking of mass spectrometry-based antibody sequencing reveals methodological biases
Authors: Chernigovskaya Maria , Lê Quý Khang , Stensland Maria , Singh Sachin , Nelson Rowan , Yilmaz Melih , Kalogeropoulos Konstantinos , Sinitcyn Pavel , Patel Anand , Castellana Natalie , Bonissone Stefano , Foss Stian , Andersen Jan Terje , Sandve Geir Kjetil , Jenkins Timothy Patrick , Noble William S. , Nyman Tuula A. , Snapkow Igor , Greiff Victor
Published: November 2024

The circulating antibody repertoire is crucial for immune protection, holding significant immunological and biotechnological value. While bottom-up mass spectrometry (MS) is the most widely used proteomics technique for profiling the sequence diversity of circulating antibodies (Ab-seq), it has not been thoroughly benchmarked. We quantified the replicability and robustness of Ab-seq using six monoclonal antibodies with known protein sequences in 70 different combinations of concentration and oligoclonality, both with and without polyclonal serum IgG background. Each combination underwent four protease treatments and was analyzed across four experimental and three technical replicates, totaling 3,360 LC-MS/MS runs. We quantified the dependence of MS-based Ab-seq identification on antibody sequence, concentration, protease, background signal diversity, and bioinformatics setups. Integrating the data from experimental replicates, proteases, and bioinformatics tools enhanced antibody identification.De novopeptide sequencing showed similar performance to database-dependent methods for higher antibody concentrations, butde novoantibody reconstruction remains challenging. Our work provides a foundational resource for the field of MS-based antibody profiling.
Connectivity and population structure in a marginal sea – a review
Authors: Henriksson Simon , Jorde Per Erik , Berkström Charlotte , Søvik Guldborg , De Wit Pierre , Knutsen Halvor , Moland Even , André Carl , Jahnke Marlene
Published: November 2024

The current biodiversity crisis calls for conservation measures that limit the negative human impact on important habitats and sensitive wild populations. To effectively protect biodiversity at all levels, including intraspecific diversity, conservation measures should be aligned with the connectivity and genetic structure of wild populations. In this review, we synthesise scientific literature on the connectivity and population structure of marine species in the Skagerrak – a marginal sea in the northeast Atlantic Ocean. We discuss the results in relation to the current management practices in the region, as well as the general transferability of our findings. The Skagerrak is one of the most intensively studied regions within this research field, and our findings show that the overall connectivity with adjacent seas is high, but asymmetric, for most species. Simultaneously, most species have populations in the Skagerrak distinct from both each other, and those in adjacent seas.

Most of this population structure is associated with the convoluted Skagerrak coastline – population structure is common both among coastal populations and between coastal and offshore populations. In many mobile species, multiple populations are temporally sympatric in certain areas, but retain their genetic divergence through natal homing or other barriers to gene flow. The presence of population structure despite high connectivity is a challenge for area-based protection measures, and calls for temporally flexible management that also monitors intraspecific genetic diversity on multiple timescales.
Detection of Unlabeled Micro- and Nanoplastics in Unstained Tissue with Optical Photothermal Infrared Spectroscopy
Authors: Duswald Kristina , Pichler Verena , Kopatz Verena , Limberger Tanja , Karl Verena , Wimberger David , Zimmerleiter Robert , Wadsak Wolfgang , Hettich Mike , Kenner Lukas , Brandstetter Markus
Published: November 2024

In this study, we investigate the efficacy of Optical Photothermal Infrared (O-PTIR) spectroscopy, also known as mid-infrared photothermal (MIP) microscopy, for the detection of micro- and nano plastics (MNPs) down to diameters of 250 nm in mammalian tissues. Experiments with bothin vitro3D cell cultures derived from HTC116 colorectal cancer cell line andin vivomouse tissue models were conducted to evaluate the spatial resolution limits and quality of spectra that formed the basis for label-free and non- destructive identification of MNPs. Our findings demonstrate the superior resolution of O-PTIR in imaging individual particles of 250 nm in mouse kidney tissues, surpassing the capabilities of traditional FTIR spectroscopy, which was applied as a reference technique. Furthermore, we introduce a semi-automated image analysis that incorporates machine learning algorithms to accelerate the detection process, thus improving throughput and minimizing the potential for human error. The results confirm that O-PTIR produces high-quality, artefact-free spectral images in a contact-less manner and significantly outperforms FTIR in terms of spatial resolution and signal-to-noise ratio in complex biological matrices.
QT-WEAVER: Correcting quartet distribution improves phylogenomic analyses despite gene tree estimation error
Authors: Bin Hasan Navid , Sohaib  , Bayzid Md. Shamsuzzoha
Published: November 2024

Summarizing individual gene trees into species phylogenies using coalescent-based methods has become a standard approach in phylogenomics. However, gene tree estimation error (GTEE) arising from a combination of reasons (ranging from analytical factors to more biological causes, as in short gene sequences) can potentially impact the accuracy of phylogenomic inference. We, for the first time, introduce the problem of correcting the quartet distribution induced by a set of estimated gene trees, which involves updating the weights of the quartets to better reflect their relative importance within the gene tree distribution. We present QT-WEAVER, the first method of its kind, which learns the conflicts within the quartet distribution induced by a given set of gene trees and generates an updated quartet distribution by adjusting the weights accordingly. QT-WEAVER is a general- purpose technique needing no explicit modeling of the subject system or reasons for GTEE or gene tree heterogeneity. Experimental studies on a collection of simulated and empirical data sets suggest that QT-WEAVER can effectively account for GTEE, which results in a substantial improvement in the species tree accuracy. Additionally, the concept of quartet conflicts and related algorithmic and combinatorial innovations introduced in this study will benefit various quartet-based computations. Therefore, QT-WEAVER advances the state-of-the-art in species tree estimation from gene trees in the face of GTEE. QT-WEAVER is freely available in open-source form athttps://github.com/navidh86/QT-WEAVER.
The Interaction Of Diet-Induced Obesity And Chronic Stress In A Mouse Model Of Menopause
Authors: Knox Nadja , Yasrebi Ali , Caramico Daniel , Wiersielis Kimberly , Samuels Benjamin A. , Roepke Troy A.
Published: November 2024

Menopause is characterized by the cessation of ovarian hormone production. During postmenopause, cisgender women face increased risks of obesity, cognitive decline, and mood disorder. Mood disorders are associated with exposure to chronic stress. We investigated the combined effects of a high-fat diet (HFD) and chronic stress exposure in a mouse model of menopause using 4-vinylcyclohexene diepoxide (VCD), a selective ovotoxicant that gradually depletes ovarian follicles and hormones. Starting at 6 months, 82 female WT C57BL/6J mice received saline or VCD (130 mg/kg i.p.) 5 days per week for 3 weeks. One month after injection, mice were fed either low-fat diet (LFD) or HFD for 8 weeks followed by 6 weeks of chronic variable mild stress (CVMS). Post-CVMS, mice were either processed for gene expression of the anterodorsal BNST or behavior tests to assess cognitive and anxiety-related behaviors. Plasma samples were collected to analyze metabolic hormones and corticosterone levels. VCD-treated HFD-fed mice had higher fat and body mass, and elevated fasting glucose levels compared to controls and more pronounced avoidance behaviors and cognitive impairments. LFD-fed, VCD-treated mice exhibited less exploration of novel objects and open spaces compared to OIL and HFD counterparts. VCD elevated corticosterone levels on LFD and increased BNSTPacapgene expression on HFD. These findings highlight cognitive repercussions of estrogen deficiency and suggest a potential protective effect of a HFD against some of the adverse outcomes associated with menopause. Our study emphasizes the importance of considering dietary and hormonal interactions in the development of therapeutic strategies.
The transcription factor GABPA is a master regulator of naïve pluripotency
Authors: Zhou Chengjie , Wang Meng , Zhang Chunxia , Zhang Yi
Published: November 2024

The establishment of naïve pluripotency is a continuous process starting with the generation of inner cell mass (ICM) which then differentiating into epiblast (EPI). Recent studies have revealed key transcription factors (TFs) for ICM formation, but which TFs initiate EPI specification remains unknown. Here, using a targeted rapid protein degradation system, we show that GABPA is not only a regulator of major ZGA, but also a master EPI specifier required for naïve pluripotency establishment by regulating 47% of EPI genes during E3.5 to E4.5 transition. Chromatin binding dynamics analysis suggests that GABPA controls EPI formation at least partly by binding to the ICM gene promoters occupied by the pluripotency regulators TFAP2C and SOX2 at E3.5 to establish naïve pluripotency at E4.5. Our study not only uncovers GABPA as a master pluripotency regulator, but also supports the notion that mammalian pluripotency establishment requires a dynamic and stepwise multi-TFs regulatory network.
The Impact of Charge Regulation and Ionic Intranuclear Environment on the Nucleosome Core Particle
Authors: Nap Rikkert J. , Gonzalez Paola Carrillo , Coraor Aria E. , Virk Ranya K. A. , de Pablo Juan , Backman Vadim , Szleifer Igal
Published: November 2024

We theoretically investigate how the intranuclear environment influences the charge of a nucleosome core particle (NCP) - the fundamental unit of chromatin consisting of DNA wrapped around a core of histone proteins. The molecular-based theory explicitly considers the size, shape, conformations, charges, and chemical states of all molecular species - thereby linking the structural state with the chemical/charged state of the system. We investigate how variations in monovalent and divalent salt concentrations, as well as pH, affect the charge distribution across different regions of an NCP and quantify the impact of charge regulation. The effective charge of an NCP emerges from a delicate and complex balance involving the chemical dissociation equilibrium of the amino acids and the DNA-phosphates, the electrostatic interaction between them, and the translational entropy of the mobile solution ions, i.e., counter ion release and ion condensation. From our results, we note the significant effect of divalent magnesium ions on the charge and electrostatic energy as well as the counterion cloud that surrounds an NCP, as a function of magnesium concentration, charge neutralization, and even charge inversion is predicted - in line with experimental observation of NCPs. The strong Mg-dependence of the nucleosome charge state arises from ion bridges between two DNA-phosphates and one Mg+ion. We demonstrate that to describe and predict the charged state of an NCP properly, it is essential to consider molecular details, such as DNA-phosphate ion condensation and the acid-base equilibrium of the amino acids that comprise the core histone proteins.