bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning based heart murmur detection and classification
Authors: Fernando Ishan , Kannangara Dileesha , Kodituwakku Santhusha , Sirithunga Asiri , Gayan Samiru , Herath Tharupraba , Lokunarangoda Niroshan , Liyanaarachchi Rukshani
Published: December 2024

Cardiovascular diseases rank among the leading causes of mortality worldwide and the early identification of diseases is of paramount importance. This work focuses on developing a novel machine learning-based framework for early detection and classification of heart murmurs by analysing phonocardiogram signals. Our heart murmur detection and classification pipeline encompasses three classification settings. We first develop a set of methods based on transfer learning to determine the existence of heart murmurs and categorize them as present, absent, or unknown. If a murmur is present it will be classified as normal or abnormal based on its clinical outcome by using 1D convolution and audio spectrogram transformers. Finally, we use Wav2Vec encoder with raw audio data and AdaBoost abstain classifier for heart murmur quality identification. Heart murmurs are categorized based on their specific attributes, including murmur pitch, murmur shape, and murmur timing which are important for diagnosis. Using the PhysioNet 2022 dataset for training and validation, we achieve an 81.08% validation accuracy for murmur presence classification and a 68.23% validation accuracy for clinical outcome classification with 60.52% sensitivity and 74.46% specificity. The suggested approaches provide a promising framework for using phonocardiogram signals for the detection, classification, and quality analysis of heart murmurs. This has significant implications for the diagnosis and treatment of cardiovascular diseases.
Rethinking CIGS solar cells for rear illumination applications
Authors: Choubrac Léo , Pineau Fabien , Bertin Eugène , Arzel Ludovic , Barreau Nicolas
Published: December 2024

This study introduces a chalcogenide-based thin-film solar cell structure optimized for rear illumination, featuring a thinner, wide-bandgap Cu(In,Ga)S2 chalcopyrite absorber. Matching the performance of traditional front-illuminated designs, this configuration paves the way for further photoelectrochemical advances thanks to its metallic top layer, which can serve as a versatile grafting platform that is resistant to their operating conditions.
The examination of impact testing performed on SS-316L specimens fabricated utilizing selective laser melting 3D printer machine
Authors: Abu Zaki Muhammad Syafiq Syazwan , Taib Mohd Taufik , Rahman Irfan Ur , Abu Bakar Mohd Hadzley , Ab Wahab Norfariza Binti
Published: December 2024

The research regarding additive manufacturing methods (AM) is popular among new researchers from industrial workers or university students since this technology is most likely to pioneer manufacturing industries in the future. Almost all the studies conducted by past researchers are related to the material properties of the 3D printing machine regardless of the type of material including Selective Laser Melting (SLM) 3D printing machines which utilize metal powder as the primary material. Plus, there is a study on the difference between virgin and recycled powder material in terms of material properties for SLM 3D printing machines. In this study, we conducted Charpy impact tests on metal specimens fabricated from both virgin and recycled powders, varying the print thicknesses in accordance with ASTM E23 standards. For each thickness parameter, three specimens were produced, irrespective of the material state. The selective laser melting (SLM) machine maintained consistent printing parameters for both virgin and recycled materials, while permitting flexibility in the adjustment of specimen coordinates within the production bed. Therefore, the impact test result will determine which material condition delivers the best result of the specimens’ absorbed energy (J) and impact toughness (J/cm²).
Optimal sizing and allocation of multiple distribution generations for radial distribution networks enhancement using advanced metaheuristic-based osprey optimization algorithm
Authors: Adebayo Isaiah , Sun Yanxia , Ikeh Emmanuel , Salimon Sunday , Aborisade David , Adebiyi Oluwaseyi
Published: December 2024

Due to transmission over a long distance from the point of generation to the consumer residence, the distribution station is faced with various challenges which include but not limited to high-power losses, voltage instability and voltage deviation. Thus, it becomes imperative to mitigate these. In this paper, a metaheuristic optimization approach called Osprey Optimization Algorithm (OOA) is proposed to evaluate the best sites and sizes of multiple Distributed Generations (DGs) on radial distribution networks. The suggested OOA is inspired based on the intelligent conduct of ospreys during hunting. The incorporation of multiple DGs at unity, 0.95, optimal power factor was evaluated, and various scenarios were examined. The effectiveness of OOA was scrutinized on the standard IEEE 33-bus distribution system and validated on a practical distribution network, Ayepe 11 KV 34- bus feeder of the Ibadan Electricity Distribution Company (IBEDC). The results obtained from the simulations depicts that three DG units operating at optimal power factor produced the best outcome when considering total active power loss (TAPL) and total reactive power loss (TRPL) on both networks. A 92.87% reduction on TAPL as well a 91.60% reduction on TRPL was attained on the 33-bus system while on the Ayepe 34-bus system both the TAPL and TRPL reduced by 98.51% when juxtaposing them with their respective base cases. The outcomes obtained corroborate the efficacy and superiority of OOA when comparing them to outcomes from recent optimization approach.
Experimental studies on heat transfer performance of a heat exchanger with drilled twisted tape inserts
Authors: Kumbhar Dnyaneshwar G , Sutar Kailasnath B , Kumar Archit , Lavate Roheshkumar S , Pawar Sanjay R
Published: December 2024

Heat exchangers are vital components in various systems where the crucial process of heat exchange takes place. This process typically occurs across the copper wall of a tube, facilitating the transfer of thermal energy between fluids. However, the efficiency of this heat exchange is fundamentally limited by the geometry of the components of the heat exchanger. To enhance the performance and efficiency it is necessary to increase the rate of heat transfer. By optimizing this process, industries can achieve better energy efficiency, reduced operational costs, and improved system reliability. In the present study experimental study of the heat exchanger was accomplished using the drilled twisted tapes. A simple copper tube was equipped with inserts of twist ratios 2.5, 3.33, and 5.0. Additionally, both a classic type insert and a perforated type insert with perforation diameters of 5 mm and 8 mm were fitted inside the copper tube for experimental testing, analysis, and comparison with the heat exchanger without inserts. Overall, the study confirmed that both the classic twisted and perforated inserts can substantially improve heat exchanger performance, with larger perforations being especially effective in optimizing heat transfer. No single combination of the twist ratio and perforation diameter for an insert demonstrated the highest thermal performance factor across all the Reynolds number values. The heat exchanger with an insert featuring a twist ratio of 2.5 and a perforation diameter of 8 mm exhibited a high thermal performance factor in the lower Reynolds number range. In contrast, an insert with a twist ratio of 3.3 and a perforation diameter of 5 mm showed a high thermal performance factor in the higher Reynolds number range. The highest thermal performance factor recorded was 2.37 for the insert with a twist ratio of 2.5 and a perforation diameter of 8 mm.
UPLC-MS/MS Combined with Microdialysis for Determination of Two Active Components of Chuanxiong Rhizoma Extracts in Rat Brain: Application in Pharmacokinetic Study
Authors: Wang Yu , Jin Liang , Liu Xinhua , Shu Bing , Xu Jia , Pan Lingyun
Published: December 2024

Chuanxiong Rhizoma (Chuanxiong), a traditional Chinese medicine, has been widely used to treat various nervous and cardiovascular system-related conditions. Its active components, senkyunolide A (SA) and 3-n-butylphthalide (NBP), have been proven effective in treating nervous system diseases. A new method was established based on microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to estimate the concentrations of these components in brain extracellular fluid. Chromatographic separation was achieved using an Acquity UPLC BEH C8 column (2.1 × 100 mm, 1.7 μm) with acetonitrile and 0.1% formic acid as mobile phase. The calibration curves of SA and NBP were linear in the concentration ranges of 0.25–100.00 and 0.12–48.00 ng/mL, respectively, with a correlation coefficient above 0.9992. All validation parameters, including intra- and inter-day precision, accuracy, matrix effect and stability, were within the acceptance limits of bioanalytical guidelines. The validated method was successfully applied to study the pharmacokinetics of SA and NBP in rat brain microdialysis after oral administration of Chuanxiong extracts. The results showed that both components penetrated the brain and reached maximum concentrations in the microdialysates of 72.31 and 9.93 ng/mL at 1.50 and 1.58 h, respectively.
Impact on Quality of Life of Full-Time and Night-Time Braces in Adolescent Idiopathic Scoliosis
Authors: Peiro-Garcia Alejandro , Garcia Rocio G. , Martin-Gorgojo Victor , Vilalta-Vidal Inmaculada , Gonzalez-Gonzalez Luis , Martin-Moreno Jose M. , Silvestre-Muñoz Antonio
Published: December 2024

Study Design.

Randomized clinical trial.

Objective.

To compare the effect on quality of life of night-time (NT) and full-time (FT) brace treatment for adolescent idiopathic scoliosis (AIS).

Summary of Background Data.

Conservative treatment of adolescent idiopathic scoliosis (AIS) with full-time (FT) braces has proven to prevent the risk of progression and the need for surgery, with an inversely proportional relationship to the number of hours worn. However, therapeutic adherence and its effect on quality of life continue to pose a clinical challenge.

Materials and Methods.

Open-label clinical trial including AIS patients with curves between 25-45 degrees randomized to either NT or FT brace group. Follow-up occurred over two years, assessing treatment efficacy through radiographs and quality of life using SRS-22 and visual analog scale (VAS) questionnaires scores at baseline, 6 months, and 12 months. Compliance was monitored with thermal sensors every three months. Statistical analyses were conducted, with significance set at P < 0.05.

Results.

78 AIS patients, predominantly females (85.9%), were recruited, including 35 (44.87%) in FT group and 43 (55.13%) in NT. Initial Cobb angles were comparable between groups. Nine patients were excluded, and eight required surgery (NT 12.82%, FT 10%). After two years, both braces showed similar effectiveness in preventing curve progression. No differences on SRS-22 nor VAS scores were found before treatment. At six-month follow-up, NT group reported significantly better outcomes in “Self-image” compared to FT (P=0.047). After one year, NT patients reported less pain compared to baseline (P=0.048)

Conclusions.

According to our results, both braces are equally effective in avoiding the progression of the deformity and need for surgery. However, FT brace has a higher impact on self-image and pain compared to NT brace.
Rates, Risk Factors and Outcomes of Complications After COVID-19 in Children
Authors: Rattanawijit Mallika , Samutpong Arisara , Apiwattanakul Nopporn , Assawawiroonhakarn Surapat , Techasaensiri Chonnamet , Boonsathorn Sophida , Chaisavaneeyakorn Sujittra
Published: December 2024

Background:

Coronavirus disease 2019 (COVID-19) can lead to various complications, including multisystem inflammatory syndrome in children (MIS-C) and post-COVID-19 conditions (long COVID). This study aimed to determine the rates, risk factors and outcomes of MIS-C and long COVID in children previously diagnosed with COVID-19.

Methods:

This study was a combined retrospective and prospective cohort study. Patients 0–18 years of age diagnosed with COVID-19 or another respiratory virus infection were enrolled between October 2021 and April 2022. Demographic and clinical data were reviewed. Information on persisting symptoms and their impacts were recorded at 1–3, 3–6 and 6–12 months after infection. Laboratory investigations and chest imaging examinations were performed during follow-up. MIS-C and long COVID were defined according to the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) definitions.

Results:

A total of 618 patients were enrolled, comprising 437 (70.7%) with COVID-19 and 181 (29.3%) with another respiratory virus infection. At 1–3 months, the rate of persisting symptoms was 16.5% in patients with COVID-19, compared with 1.1% in patients with another respiratory virus infection. The rate of MIS-C was 0.7%. The rate of long COVID according to the CDC and WHO definitions were 20.4% and 13.0%, respectively. Respiratory systems were most affected in long COVID. Age 5–18 years, anosmia during COVID-19, history of pneumonia and infection during the delta and omicron waves were associated with long COVID in children.

Conclusions:

Long COVID after COVID-19 in children is uncommon. Children with anosmia and a history of pneumonia during COVID-19 require follow-up for long COVID.
Opportunistic Quantitative Computed Tomography Assessing Bone Mineral Density in Patients With Laparoscopic Roux-En-Y-Gastric Bypass Metabolic Surgery Throughout a 5-Year Observation Window
Authors: Noser Mark-Stefan , Boll Daniel T. , Lazaridis Ioannis I. , Delko Tarik , Koestler Thomas , Zingg Urs , Potthast Silke
Published: December 2024

Background

Bariatric surgery is associated with decreasing bone mineral density (BMD).

Objective

To assess the long-term vertebral BMD, measured by opportunistic quantitative CT (QCT), and body mass index (BMI) in patients undergoing proximal laparoscopic Roux-en-Y surgery (LRYGB).

Methods

In 62 patients undergoing LRYGB, opportunistic QCT measurements were performed extracting BMD and BMI on day 1 and years 1, 3, and 5 postoperatively.

Primarily, one-way analyses of variance were performed on dependent variables BMI and BMD, with imaging interval defined as an independent factor. Student-Newman-Keuls tests performed pairwise comparisons of imaging interval permutations for BMI/BMD.

Secondarily, analyses of covariance were used on dependent variables BMI and BMD, with imaging interval as an independent factor and gender/age as well as BMD/BMI, respectively, as covariates.

Results

A total of 227 opportunistic QCT measurements in 62 patients were performed without the need of a phantom or extra software.

The BMD decreased substantially and continuously during 1-, 3-, and 5-year follow-up observations, reaching statistical significance in pairwise comparisons for 3- and 5-year follow-up visits compared to initial BMD values as well as the 5-year follow-up visit compared to the 1-year BMD values, P < 0.001. Age and BMI were significant covariates, P < 0.001.

The BMI decreased within 1 year and stayed constant until a slight increase at 5 years was observed. Statistical significance in pairwise comparisons for first-year and 3- and 5-year follow-up visits was reached compared to initial BMI values, P < 0.001. For the BMI assessment, none of the covariates reached statistical significance.

Conclusion

Opportunistic QCT is suited for the calculation and follow-up of BMD. There was a continuous decrease of BMD after LRYGB over 5 years post-surgery, whereas BMI decreased in the first year and stayed constant thereafter. Older patients with lower BMI seem particularly prone to an accelerated BMD loss.
Reducing the Risk
Authors: Jordan Kathleen S. , Steelman Sara H. , McInnis Elizabeth C.
Published: December 2024

Fever is the most common complaint for children of all ages who present to an emergency department (ED) for evaluation and treatment. Although most children with fever have a self-limiting viral illness, the infant less than 60 days of age with fever poses a higher risk for an underlying serious bacterial illness (SBI) including urinary tract infections, bacteremia and bacterial meningitis, or an invasive bacterial infection (IBI) including bacteremia. This case is a discussion of a high-risk febrile infant that was evaluated in the emergency department and was ultimately diagnosed with Streptococcus B meningitis. This case emphasizes the importance of heightened vigilance in this high-risk age group for the risk of infection. To prevent mortality and long term morbidities that may result from inadequate treatment or delayed diagnosis and treatment, it is critical to know and strictly adhere to the clinical practice guidelines.
Universal differential equations for systems biology: Current state and open problems
Authors: Philipps Maren , Schmid Nina , Hasenauer Jan
Published: December 2024

Universal Differential Equations (UDEs) combine mechanistic differential equations with data-driven artificial neural networks, forming a flexible framework for modelling complex biological systems. This hybrid approach leverages prior knowledge and data to uncover unknown processes and deliver accurate predictions. However, UDEs face challenges in efficient and reliable training due to stiff dynamics and noisy, sparse data common in biology, and in ensuring the interpretability of the parameters of the mechanistic model. We investigate these challenges and evaluate UDE performance on realistic biological scenarios, providing a systematic training pipeline. Our results demonstrate the versatility of UDEs in systems biology and reveal that noise and limited data significantly degrade performance, but regularisation can improve accuracy and interpretability. By addressing key challenges and offering practical solutions, this work advances UDE methodology and underscores its potential in tackling complex problems in systems biology.
The effect of age and sex hormones on female neuromuscular function across the adult lifespan
Authors: O’Bryan Steven J. , Critchlow Annabel , Fuchs Cas , Hiam Danielle , Lamon Séverine
Published: December 2024

Neuromuscular ageing is characterized by neural and/or skeletal muscle degeneration that decreases maximal force and power. Female neuromuscular ageing occurs earlier in life compared to males, potentially due to sex hormone changes during the menopausal transition. We quantified neuromuscular function in 88 healthy females represented equally over each decade from 18-80 years of age and investigated the potential role of decreased ovarian hormone concentrations following menopause. Neuromuscular assessment included quadriceps maximal voluntary and evoked isometric torque and surface electromyography measurements, plus one-repetition maximum leg press. Voluntary and evoked torques and one-repetition maximum decreased non-linearly with age, with accelerated reductions starting during the fourth decade. An absence of changes in volitional recruitment of existing quadriceps motor units and Ia afferent facilitation of spinal motoneurons suggests that functional decline was largely mediated by impairment in intrinsic muscle function and/or neuromuscular transmission. Maximal muscle compound action potential amplitude decreased with increasing age for rectus femoris only, indicating increased vulnerability to neuromuscular degeneration compared to vastus lateralis and medialis. In postmenopausal females, some variance in data was explained by inter-individual differences in body composition and physical activity level, however, changes in total or free concentrations of oestrogen, progesterone and/or testosterone were correlated with all age-related decreases in neuromuscular variables. In conclusion, we demonstrate an accelerated onset of neuromuscular degeneration of muscular origin around menopause onset, which is associated with changes in sex hormone concentrations. Interventions aimed at mitigating declines in ovarian hormones and their subsequent effects on neuromuscular function postmenopause should be further explored.

Key Points

Neuromuscular deterioration with age is associated with poor physical function and quality of life in older adults, but female-specific trajectories and mechanisms remain unclear.

This study is the first to map neuromuscular function across each decade of the adult lifespan in 88 healthy females from 18 to 80 years old and to examine the potential role of hormonal changes after menopause

We show an accelerated reduction in neuromuscular function, primarily of muscular origin, that occurs between 40 and 50 years of age, coinciding with the onset of menopause.

In postmenopausal females, age-related reductions in neuromuscular function can be explained by differences in body composition, physical activity, and sex hormone concentrations.

These findings help us better understand the factors that contribute to the loss of neuromuscular function with age in females, enabling the identification of potential therapeutic interventions to prolong the female health span.
Sensitivity to temozolomide of cell lines derived from brain tumours and melanomas: relationship to MGMT gene expression
Authors: Baguley Bruce C , Joseph Wayne R , Murray Pamela M , Stowell Kathryn M , Leung Euphemia Y , Marshall Elaine S
Published: December 2024

Background

We have developed a series of low-passage melanoma and glioma cell lines and are using them to study responses to antitumour drugs. Here we have assessed responses to temozolomide, a commonly used clinical drug used for the treatment of glioblastoma and melanoma. Temozolomide acts mainly by methylation of DNA guanine and lesions can be removed by the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Low expression of MGMT is one of the main features associated with sensitivity to temozolomide and is usually associated with CpG methylation of the MGMT promoter. We wished to determine whether temozolomide sensitivity in these lines was related to MGMT promoter methylation and MGMT mRNA synthesis. Methods: 63 melanoma and 37 glioblastoma lines were derived from developed from surgical samples, using atmosphere of 5% oxygen for development and propagation in order to minimise oxygen toxicity. Temozolomide sensitivity (IC50data) was analysed by its effect on3H-thymidine incorporation in 5-day assays. MGMT promoter methylation status was assessed by the methylation-specific polymerase chain reaction (PCR). MGMT mRNA expression was assessed using reverse transcription and PCR. Results: 40% of the melanoma lines and 24% of the glioblastoma showed some sensitivity to temozolomide. Of the 79 cell lines analysed for MGMT mRNA expression, a good correlation was found to temozolomide resistance (p < 0.0001). Of the 100 cell lines assessed for MGMT promoter status, 12 showed methylation of both promoter sequences and were all temozolomide-sensitive; 50 lines showed no MGMT promoter methylation and 90% of these were temozolomide resistant; 30 lines showed partial promoter methylation and 53% of these were temozolomide resistant. Conclusion: Temozolomide sensitivity matched MGMT mRNA expression well but only partially matched MGMT promoter methylation. Other factors, such as loss of DNA mismatch repair capacity, may contribute to resistance.
Trade-offs associated with higher winter wheat yields in low soil organic matter cropping systems under climate change
Authors: Michel Jennifer , Leemans Vincent , Weinmann Markus , Balanzategui-Guijarro Iñaki , Bin Jimmy , Biver Simon , Blum Adrien , Börger Rachel , Cao Da , Him Sok-Lay , Kirbas Gaëlle , Le Gouis Jacques , Moya-Laraño Jordi , Persyn Mayliss , Pierreux Jérome , Quenon Alice , Sanchez-Moreno Sara , Symanczik Sarah , Brande Florian Vanden , Van Der Straeten Dominique , Wagner Markus , Waibel Matthias , Xayphrarath Anna , Vanderschuren Hervé , Thonar Cécile , Delaplace Pierre
Published: December 2024

Empirical data is key to anticipate the impact of climate change on cropping systems and develop land management strategies that are sustainable while ensuring food security. Here, the combined effects of projected increases in temperature, atmospheric CO2-concentrations, solar irradiation and altered precipitation patterns on winter wheat cropping systems were investigated using an Ecotron. Experimental plant-soil systems were subjected to three different climatic conditions representing a gradient of ongoing climate change implementing the weather patterns of the years 2013, 2068, and 2085 respectively. The wheat plants were grown in two differentially manged agricultural soil types: one with long-term low organic matter (OM) inputs and the other one with long-term high OM inputs. In the low OM system, the risk for plant diseases and nitrate leaching was increased, but it outperformed the high OM system with higher yields and lower CO2-emissions. Developing high-yielding cropping systems leveraging the CO2-fertilisation effect without sacrificing environmental health will therefore require further refined of management practices to improve nutrient cycling and reduce greenhouse gas emissions. One possibility is adapting crop rotations and cover crops to the shorter wheat cycle observed in the future climates to replenish soil nutrients and break disease cycles. Further, in both here studied soil types the wheat plants developed natural coping mechanisms against environmental stressors, such as enhanced root growth and increased levels of proline and silicon. Unravelling the molecular mechanisms that trigger such inherent plant defences is a further interesting target for breeding future crops.

Graphical abstract
ProtSpace: a tool for visualizing protein space
Authors: Senoner Tobias , Olenyi Tobias , Heinzinger Michael , Spannagl Anton , Bouras George , Rost Burkhard , Koludarov Ivan
Published: December 2024

Protein language models (pLMs) generate high-dimensional representations of proteins, so called embeddings, that capture complex information stored in the set of evolved sequences. Interpreting these embeddings remains an important challenge.ProtSpaceprovides one solution through an open-source Python package that visualizes protein embeddings interactively in 2D and 3D. The combination of embedding space with protein 3D structure view aids in discovering functional patterns readily missed by traditional sequence analysis.

We present two examples to showcaseProtSpace. First, investigations of phage data sets showed distinct clusters of major functional groups and a mixed region, possibly suggesting bias in today’s protein sequences used to train pLMs. Second, the analysis of venom proteins revealed unexpected convergent evolution between scorpion and snake toxins; this challenges existing toxin family classifications and added evidence refuting theaculeatoxin family hypothesis.

ProtSpaceis freely available as a pip-installable Python package (source code & documentation) with examples on GitHub (https://github.com/tsenoner/protspace) and as a web interface (https://protspace.rostlab.org). The platform enables seamless collaboration through portable JSON session files.
Joint analysis of RNA-DNA and DNA-DNA interactomes reveals their strong association
Authors: Zvezdin Dmitry S. , Tyukaev Artyom A. , Zharikova Anastasia A. , Mironov Andrey A.
Published: December 2024

At the moment, many non-coding RNAs that perform a variety of functions in the regulation of chromatin processes are known. An increasing number of protocols allow researchers to study RNA-DNA interactions and shed light on new aspects of the RNA-chromatin interactome. The Hi-C protocol, which enables the study of chromatin’s three-dimensional organization, has already led to numerous discoveries in the field of genome 3D organization. We conducted a comprehensive joint analysis of the RNA-DNA interactome and chromatin structure across different human and mouse cell lines. We have shown that these two phenomena are closely related in many respects, with the nature of this relationship being both tissue-specific and conserved across human and mouse.
Shifts in honeybee worker metabolism immediately post-eclosion
Authors: Verbinnen Gilles , Roald-Arbøl Mikkel , Niven Jeremy Edward , Nicholls Elizabeth
Published: December 2024

The metabolic rate of an organism is intrinsically linked to key traits such as reproductive output and lifespan. While the drivers of individual differences in metabolic rate are poorly understood, previous research in insects has shown that metabolic rate can change substantially in the initial hours and days post-eclosion as adults.

Here we repeatedly measured the resting and active metabolic rate of individual adult honeybees (Apis mellifera) for up to 48 hours from the time of eclosion. We combined flow-through respirometry with automated behaviour tracking, permitting us to obtain ‘active’ (AMR) and true ‘resting’ metabolic rate (RMR) from freely moving animals. We compared these recordings to the more conventional approach of obtaining resting metabolic rate by restraining animals.

Both active and resting metabolic rates and mass-specific metabolic rates increased significantly in the first 48-hours post-eclosion, whereas metabolic scope did not change. Mass-specific water loss was highest in active bees and changed non-linearly with time post-eclosion, increasing in the first 24 hours before decreasing again. A similar quadratic relationship with time was also observed for bees’ movement speed. Speed- and mass-specific metabolic rate and scope increased with time post-emergence, whereas speed- and mass-specific water loss did not.

The metabolic rate of restrained bees was consistently significantly higher than the true RMR at all time points, likely due to the stress associated with being restrained. Therefore, we recommend future studies of insect resting metabolic rates avoid restraining organisms to restrict movement and consider employing behaviour tracking as a means to extract metabolic rate data from periods of true rest.

This study provides important insights into the previously overlooked changes in metabolism exhibited by newly emerged honeybee workers. The high mortality rate beyond 48 hours, coupled with significant changes in metabolic rates, body mass, and water loss, underscores the importance of this early post-eclosion period for survival and metabolic stabilization.
Impact of force field polarization on the collective motions of proteins
Authors: Milinski Ana , Dejaegere Annick , Stote Roland H.
Published: December 2024

Correlated motions of proteins underpin many physiological mechanisms, such as substrate binding, signal transduction, enzymatic activity and allostery. These motions arise from low frequency collective movements of biomolecules and have mostly been studied using molecular dynamics simulations. Here, we present the effects of two different empirical energy force fields used for molecular dynamics simulations on correlated motions – the non-polarizable CHARMM 36m additive force field and the polarizable Drude force field. The study was conducted on two proteins, ubiquitin - a small protein with a well-described dynamic - and the nuclear receptor protein PPARγ. The ligand binding domain of PPARγ was of particular interest since its function is to regulate transcription through ligand and coregulator protein binding. It has been previously shown that a dynamical network of correlated motions ensures the transmission of information related to ligand binding. We present the results of classical MD simulations where we analyze the results in terms of residue fluctuations, correlation maps, community network analysis and Shortest Path Method analysis. We find that the RMS fluctuations tend to be greater and that the correlated motions are less intense when using the Drude force field than when using the non-polarizable all atom additive force field. Our results provide the first quantification of the impact of using a polarizable force field in computational studies that focus on collective motions.
The Landscape of Sex- and APOE Genotype-Specific Transcriptional Changes in Alzheimer’s Disease at the Single Cell Level
Authors: Yu Gefei , Thorpe Abigail , Zeng Qi , Wang Erming , Cai Dongming , Wang Minghui , Zhang Bin
Published: December 2024

Alzheimer’s disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients are females. Basic and clinical research studies show evidence supporting sex-specific differences contributing to the complexity of AD. There is also strong evidence supporting sex-specific interaction between the primary genetic risk factor of AD,APOE4and AD-associated neurodegenerative processes. Recent studies by us and others have identified sex and/or APOE4 specific differentially expressed genes in AD based on the bulk tissue RNA-sequencing data of postmortem human brain samples in AD. However, there lacks a comprehensive investigation of the interplay between sex and APOE genotypes at the single cell level. In the current study, we systematically explore sex and APOE genotype differences in single cell transcriptomics in AD. Our work provides a comprehensive overview of sex and APOE genotype-specific transcriptomic changes across 54 high-resolution cell types in AD and highlights individual genes and brain cell types that show significant differences between sexes and APOE genotypes. This study lays the groundwork for exploring the complex molecular mechanisms of AD and will inform the development of effective sex- and APOE-stratified interventions for AD.
Abnormal eNK cells contribute to endometrial fibrosis in intrauterine adhesions patients
Authors: Zhou Zhenhua , Weng Qiao , Liu Dan , Yao Simin , Zou Xueqin , Wang Huiyan , Zhou Zihan , Zhu Hui , Zhang Xier , Chen Ling , Zhang Xiwen , Zhao Guangfeng , Hu Yali
Published: December 2024

Endometrial natural killer cells (eNK) at the proliferative phase are one of the major lymphocytes in the endometrium, but their phenotype and function remain elucidated. Here, we demonstrated that eNK cells had three subtypes and were different from peripheral blood NK (pbNK) and decidual NK (dNK) cells. They played an important role in maintaining the homeostasis of the endometrium through preventing endometrial stromal cells (ESCs) from the differentiation into myofibroblasts physiologically. However, in the fibrotic endometria of patients with intrauterine adhesions (IUA), eNK cells were significantly decreased and highly negatively correlated with an increase in myofibroblasts. In vitro experiments showed that eNK cells could inhibit the differentiation of ESCs into myofibroblasts and promote the dedifferentiation of myofibroblasts, in which the main effector molecules from eNK cells was Prostaglandin D2 (PGD2). PGD2 downregulated the expression of ZNF521 to decrease profibrotic protein synthesis. Furthermore, we confirmed the anti-endometrial fibrosis effect of eNK cells and its mechanism in an IUA-like murine model. These findings reveal an important role of eNK cells in endometrial homeostasis and provide potential therapeutic approaches for IUA patients.
A Novel Efficient Algorithm for Common Variants Genotyping from Low-Coverage Sequencing Data
Authors: Zhang Shixuan , Xiao Kanglong , He Xinyi , Hao Meng , Ma Yanyun , Tian Yuxin , Jin Li , Li Yi , Wang Jiucun , Wang Yi
Published: December 2024

Low-coverage whole-genome sequencing (LC-WGS) combined with imputation represents a cost-effective genotyping strategy for genome-wide association studies (GWAS) in population genetics. In this study, the Limpute algorithm was developed specifically for genotyping from low-coverage sequencing data, it extracts variant information from low-coverage sequencing data by the novel virtual probes and subsequently performs imputation through cross-reference between samples. Compared to the currently dominant algorithm for low-coverage sequencing data, GLIMPSE2, Limpute achieved similar imputation performance within common variants (r2>0.87) while the GLIMPSE2 has a runtime approximately five times longer than that of the Limpute. Furthermore, to fully evaluate the accuracy of genotype imputation by Limpute, we utilized high-coverage whole-genome sequencing data (30x), microarray data, and high-coverage whole-exome sequencing data (30x) as validation sets respectively. The results demonstrated that Limpute has a good imputation performance for common variants using low-coverage sequencing data (1x: r2> 0.87; 3x: r2> 0.92; 5x: r2> 0.93). In summary, we present a highly efficient, low-cost algorithm for genotyping from low-coverage sequencing data, offering substantial support for genetic research.
Cystic fibrosis risk variants confer protection against inflammatory bowel disease
Authors: Yu Mingrui , Zhang Qian , Yuan Kai , Sazonovs Aleksejs , Stevens Christine , Fachal Laura ,   the International Inflammatory Bowel Disease Genetics Consortium, Anderson Carl A. , Daly Mark J. , Huang Hailiang
Published: December 2024

Genetic mutations that yield defective cystic fibrosis transmembrane regulator (CFTR) protein cause cystic fibrosis, a life-limiting autosomal recessive Mendelian disorder. A protective role ofCFTRloss-of-function mutations in inflammatory bowel disease (IBD) has been suggested, but its evidence has been inconclusive and contradictory. Here, leveraging the largest IBD exome sequencing dataset to date, comprising 38,558 cases and 66,945 controls in the discovery stage, and 35,797 cases and 179,942 controls in the replication stage, we established a protective role of CF-risk variants against IBD based on evidence from the association test ofCFTRdelF508 (p-value=8.96E-11) and the gene-based burden test of CF-risk variants (p-value=3.9E-07). Furthermore, we assessed variant prioritization methods, including AlphaMissense, using clinically annotated CF-risk variants as the gold standard. Our findings highlight the critical and unmet need for effective variant prioritization in gene-based burden tests.
A robust benchmark for detecting low-frequency variants in the HG002 Genome In A Bottle NIST reference material.
Authors: Daniels Camille , Abdulkadir Adetola , Cleveland Megan H. , McDaniel Jennifer H. , Jaspez David , Rubio-Rodriguez Luis Alberto , Munoz-Barrera Adrian , Lorenzo-Salazar Jose Miguel , Flores Carlos , Yoo Byunggil , Sahraeian Sayed Mohammad Ebrahim , Wang Yina , Rossi Massimiliano , Visvanath Arun , Murray Lisa , Chen Wei-Ting , Catreux Severine , Han James , Mehio Rami , Parnaby Gavin , Carroll Andrew , Chang Pi-Chuan , Shafin Kishwar , Cook Daniel E. , Kolesnikov Alexey , Brambrink Lucas , Mootor Mohammed Faizal Eeman , Patel Yash , Yamaguchi Takafumi N. , Boutros Paul C. , Sienkiewicz Karolina , Foox Jonathan , Mason Christopher E. , Lajoie Bryan , Ruiz-Perez Carlos A. , Kruglyak Semyon , Zook Justin M. , Olson Nathan D.
Published: December 2024

Somatic mosaicism is an important cause of disease, but mosaic and somatic variants are often challenging to detect because they exist in only a fraction of cells. To address the need for benchmarking subclonal variants in normal cell populations, we developed a benchmark containing mosaic variants in the Genome in a Bottle Consortium (GIAB) HG002 reference material DNA from a large batch of a normal lymphoblastoid cell line. First, we used a somatic variant caller with high coverage (300x) Illumina whole genome sequencing data from the Ashkenazi Jewish trio to detect variants in HG002 not detected in at least 5% of cells from the combined parental data. These candidate mosaic variants were subsequently evaluated using >100x BGI, Element, and PacBio HiFi data. High confidence candidate SNVs with variant allele fractions above 5% were included in the HG002 draft mosaic variant benchmark, with 13/85 occurring in medically relevant gene regions. We also delineated a 2.45 Gbp subset of the previously defined germline autosomal benchmark regions for HG002 in which no additional mosaic variants >2% exist, enabling robust assessment of false positives. The variant allele fraction of some mosaic variants is different between batches of cells, so using data from the homogeneous batch of reference material DNA is critical for benchmarking these variants. External validation of this mosaic benchmark showed it can be used to reliably identify both false negatives and false positives for a variety of technologies and detection algorithms, demonstrating its utility for optimization and validation. By adding our characterization of mosaic variants in this widely-used cell line, we support extensive benchmarking efforts using it in simulation, spike-in, and mixture studies.
A lineage-resolved multimodal single-cell atlas reveals the genomic dynamics of earlyC. elegansdevelopment
Authors: van der Burght Servaas N. , Carelli Francesco N. , Appert Alex , Dong Yan , Hill Matthew , Buttress Toby , Butler Richard , Ahringer Julie
Published: December 2024

Multimodal single-cell profiling provides a powerful approach for unravelling the gene regulatory mechanisms that drive development, by simultaneously capturing cell-type- specific transcriptional and chromatin states. However, its inherently destructive nature hampers the ability to trace regulatory dynamics between mother and daughter cells. Taking advantage of the invariant cell lineage of Caenorhabditis elegans, we constructed a lineage- resolved single-cell multimodal map of pre-gastrulation development, which allows the tracing of chromatin and gene expression changes across cell divisions and regulatory cascades. We characterise the early dynamics of genome regulation, revealing that zygotic genome activation occurs on an accessible chromatin landscape pre-patterned both maternally and zygotically, and we identify a redundant family of transcriptional regulators that drive a transient pre-gastrulation program. Our findings demonstrate the power of a lineage-resolved atlas for dissecting the genome regulatory events of development.
Downregulation of Gankyrin/PSMD10 affects cancer cell growth and proliferation in glioblastoma:in vitroandin vivostudy
Authors: Travnikova Daria , Shashkovskaya Vera , Kordyukova Maria , Nosova Irina , Kudryashova Olga , Zatsepin Timofei , Belousov Vsevolod , Abakumova Tatiana
Published: December 2024

The oncoprotein Gankyrin/PSMD10 is upregulated in various cancers, including glioblastoma multiforme (GBM), the most difficult tumor to treat. The heterogeneity of this type of tumor requires a multi-targeted approach to overcome radio- and chemoresistance. Here we aim to investigate the effects of Gankyrin inhibition on glioma cell proliferation and its impact on sensitivity to chemotherapy bothin vitroandin vivo. We have employed the RNA interference approach as a valuable tool to downregulate the expression of target genes. Small interfering RNA (siRNA) were formulated into lipid nanoparticles (LNP) to facilitate delivery and overcome challenges, including RNase activity. We demonstrate that knockdown of Gankyrin promotes cell growth arrest of murine (GL261, CT-2А) and human (U87, GBM23, GBM24) glioma cells and induces the generation of reactive oxygen species and apoptosis. Importantly, Gankyrin inhibition enhances the therapeutic effect of temozolomide in murine glioma cell lines and decreases the IC50 of doxorubicin and cisplatin for U87 and GL261 cells. The therapeutic potential of Gankyrin inhibition was shown in patient-derived glioblastoma stem cells, which are responsible for tumor initiation and resistance to therapy. We showed that downregulation of Gankyrin led to decreased cell proliferationin vitroand improved survival in xenograft glioma model mice. Our results suggest that harnessing siRNA against Gankyrin may serve as a novel therapeutic strategy for glioblastoma therapy in a multi-drug approach and address challenges in current treatment by sensitizing glioma cells to chemotherapy.

Highlights

siRNA-mediated knockdown of Gankyrin reduced cell proliferation of murine and human glioma cells, induced ROS generation and promoted apoptosis.

Inhibition of Gankyrin increased the therapeutic effect of temozolomide in resistant CT- 2A glioma cells and decreased the IC50 concentration of doxorubicin and cisplatin in U87 and GL261 cells.

Downregulation of Gankyrin inhibited the growth of patient-derived glioma stem cells and increased the survival of NOD/SCID xenograft glioma model mice
CoLaML: Inferring latent evolutionary modes from heterogeneous gene content
Authors: Yamanouchi Shun , Fukunaga Tsukasa , Iwasaki Wataru
Published: December 2024

Motivation

Estimating the history of gene content evolution provides insights into genome evolution on a macroevolutionary timescale. Previous models did not consider heterogeneity in evolutionary patterns among gene families across different periods and/or clades.

Results

We introduce CoLaML (joint inference of gene COntent evolution and its LA-tent modes using Maximum Likelihood), which considers heterogeneity using a Markov-modulated Markov chain. This model assumes that internal states determine evolutionary patterns (i.e., latent evolutionary modes) and attributes heterogeneity to their switchover during the evolutionary timeline. We developed a practical algorithm for model inference and validated its performance through simulations. CoLaML outperformed previous models in fitting empirical datasets and estimated plausible evolutionary histories, capturing heterogeneity among clades and gene families without prior knowledge.

Availability

CoLaML is freely available athttps://github.com/mtnouchi/colaml.

Contact

yamanouchi@bs.s.u-tokyo.ac.jp
Target cell tension regulates macrophage trogocytosis
Authors: Cornell Caitlin E. , Chorlay Aymeric , Krishnamurthy Deepak , Martin Nicholas R. , Baldauf Lucia , Fletcher Daniel A.
Published: December 2024

Macrophages are known to engulf small membrane fragments, or trogocytose, target cells and pathogens, rather than fully phagocytose them. However, little is known about what causes macrophages to choose trogocytosis versus phagocytosis. Here, we report that cortical tension of target cells is a key regulator of macrophage trogocytosis. At low tension, macrophages will preferentially trogocytose antibody-opsonized cells, while at high tension they tend towards phagocytosis. Using model vesicles, we demonstrate that macrophages will rapidly switch from trogocytosis to phagocytosis when membrane tension is increased. Stiffening the cortex of target cells also biases macrophages to phagocytose them, a trend that can be countered by increasing antibody surface density and is captured in a mechanical model of trogocytosis. This work suggests that a distinct molecular pathway for trogocytosis is not required to explain differences in trogocytosis among target cell types and points to a mechanism for target cells to modulate trogocytosis.