bluuebunny/crossref_metadata_2025 huggingface dataset:
Annotation-free multi-organ anomaly detection in abdominal CT using free-text radiology reports: A multi-center retrospective study
Authors: Sato Junya , Sugimoto Kento , Suzuki Yuki , Wataya Tomohiro , Kita Kosuke , Nishigaki Daiki , Tomiyama Miyuki , Hiraoka Yu , Hori Masatoshi , Takeda Toshihiro , Kido Shoji , Tomiyama Noriyuki
Published: June 2024

Background

Artificial intelligence (AI) systems designed to detect abnormalities in abdominal computed tomography (CT) could reduce radiologists’ workload and improve diagnostic processes. However, development of such models has been hampered by the shortage of large expert-annotated datasets. Here, we used information from free-text radiology reports, rather than manual annotations, to develop a deep-learning-based pipeline for comprehensive detection of abdominal CT abnormalities.

Methods

In this multicenter retrospective study, we developed a deep-learning-based pipeline to detect abnormalities in the liver, gallbladder, pancreas, spleen, and kidneys. Abdominal CT exams and related free-text reports obtained during routine clinical practice collected from three institutions were used for training and internal testing, while data collected from six institutions were used for external testing. A multi-organ segmentation model and an information extraction schema were used to extract specific organ images and disease information, CT images and radiology reports, respectively, which were used to train a multiple-instance learning model for anomaly detection. Its performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 score against radiologists’ ground-truth labels.

Findings

We trained the model for each organ on images selected from 66,684 exams (39,255 patients) and tested it on 300 (295 patients) and 600 (596 patients) exams for internal and external validation, respectively. In the external test cohort, the overall AUC for detecting organ abnormalities was 0·886. Whereas models trained on human-annotated labels performed better with the same number of exams, those trained on larger datasets with labels auto-extracted via the information extraction schema significantly outperformed human-annotated label-derived models.

Interpretation

Using disease information from routine clinical free-text radiology reports allows development of accurate anomaly detection models without requiring manual annotations. This approach is applicable to various anatomical sites and could streamline diagnostic processes.

Funding

Japan Science and Technology Agency.
Routine data collection in home care: A national survey of home care providers in England
Authors: Davey V , Healey J , Liddle J , Beresford B , Rand S , Goodman C , Spilsbury K , Hanratty B
Published: June 2024

Purpose

Mandatory digital social care records and a standardised schedule for collecting information on home care clients are proposed for regulated adult social care providers in England. This is akin to a minimum dataset (MDS). This study aimed to understand current data collection practices in home care, and identify where support for implementation of an MDS is needed.

Design

An online survey of English home care providers was conducted in 2023, asking about the information they collect, store, and share about their clients. Data were analysed using descriptive statistics and logistic regression.

Findings

One hundred and fifty-five responses were received from home care providers in all regions of England, a majority were for-profit organisations (89%). All collected a range of data on client characteristics and observations about care delivered. Monitoring of changes in client wellbeing and use of standardised measurement tools (e.g. functioning, mood or quality of life) were uncommon. Over two-thirds (71%) reported that they reviewed the content of care packages at least every six months. Providers with a majority of self-funding clients were more likely to regularly update information on care needs and client/ family preferences.

Originality

To the best of our knowledge, this is the first national survey of home care providers on their routine data collection practices.

Practical implications

Data collection in UK home care will require expansion, to implement an MDS, which has resource implications for providers. Home care staff will need the skills to collect and use data to enhance client care.
The impact of heat stress on the human plasma lipidome
Authors: Estevao Igor L. , Kazman Josh B. , Bramer Lisa M. , Nicora Carrie , Ren Ming Qiang , Sambuughin Nyamkhishig , Munoz Nathalie , Kim Young-Mo , Bloodsworth Kent , Richert Maile , Teeguarden Justin , Burnum-Johnson Kristin , Deuster Patricia A. , Nakayasu Ernesto S. , Many Gina
Published: June 2024

The year of 2023 displayed the highest average global temperatures since it has been recorded—the duration and severity of extreme heat are projected to increase. Rising global temperatures represent a major public health threat, especially to occupations exposed to hot environments, such as construction and agricultural workers, and first responders. Despite efforts of the scientific community, there is still a need to characterize the pathophysiological processes leading to heat related illness and develop biomarkers that can predict its onset. Here, we performed a plasma lipidomic analysis on male and female subjects who underwent heat tolerance testing (HTT), consisting of a 2-h treadmill walk at 5 km/h with 2% inclination at a controlled temperature of 40°C. We identified 995 lipids from 27 classes, with nearly half of all detected lipids being responsive to HTT. Lipid classes related to substrate utilization were predominantly affected by HTT, with a downregulation of triacylglycerols and upregulation of free fatty acids and acyl-carnitines (CARs). We additionally examined correlations between changes in plasma lipids by using the physiological strain index (PSI). Here, even chain CAR 4:0, 14:0 and 16:1, suggested by-products of incomplete beta oxidation, and diacylglycerols displayed the highest correlation to PSI. PSI did not correlate with plasma lactate levels, suggesting that correlations between even chain CARs and PSI is related to metabolic efficiency versus physical exertion. Overall, our results show that HTT has a strong impact on the plasma lipidome and that metabolic inefficiencies may underlie heat intolerance.
Comparison of Glomerular Filtration Rate Equations in a Rural New Mexico Cohort: Results from the COMPASS Study
Authors: Balasch Monica Moya , Roumelioti Maria-Eleni , Argyropoulos Christos P
Published: June 2024

Rationale and Objective

The NKF-ASN Task Force recommends accurate kidney function estimation avoiding biases through racial adjustments. We explored the use of multiple kidney function biomarkers and hence estimated glomerular filtration rate (eGFR) equations to improve kidney function calculations in an ethnically diverse patient population.

Study design

Prospective community cohort study.

Setting and Participants

Rural New Mexico clinic with patients > 18 yo.

Methods

Markers of kidney function, IDMS-Creatinine (SCr), chemiluminescence Beta-2 Microglobulin (B2M), Nephelometry-calibrated ELISA Cystatin C (CysC), inflammation, glucose tolerance, demographics, BUN/UACR from the baseline visit of the COMPASS cohort, were analyzed by Kernel-based Virtual Machine learning methods.

Results

Among 205 participants, the mean age was 50.1, 62% were female, 54.1% Hispanic American and 30.2% Native American. Average kidney function biomarkers were: SCr 0.9 mg/dl, B2M 1.8 mg/L, and CysC 0.7 mg/dl. The highest agreement was observed between SCr and B2M-based eGFR equations [mean difference in eGFRs: (4.48 ml/min/1.73m2], and the lowest agreement between B2M and CysC-based eGFR equations (−24.75 ml/min/1.73m2). There was no pattern of association between the differences in eGFR measures and gender. In the continuous analyses, the absolute eGFR value (p<2 × 10-16) and serum albumin (p =6.4 × 10-5) predicted the difference between B2M- and SCr-based e-GFR. The absolute eGFR value (p<2 × 10-16) and age (p =7.6 x 10-5) predicted the difference between CysC- and SCr-based e-GFR.

Limitations

Relatively small sample size, elevated inflammatory state in majority of study participants and no inulin excretion rate measurements.

Conclusion

B2M should be strongly considered as a kidney function biomarker fulfilling the criteria for the NKF-ASN. B2M’s eGFR equation does not need adjustment for gender or race and showed the highest agreement with SCr-based eGFR equations.
Integrating immunophenotypes reveals causal relationship between tuberculosis and lung cancer: Mendelian randomization study
Authors: Li Xianwen , Huang Dayin , Liu Chang , Yu Wei , Bi Lijun
Published: June 2024

Background

Tuberculosis (TB) and lung cancer (LC) are major respiratory diseases causing significant deaths worldwide. Both primarily affect the lungs and share similar clinical symptoms. The comorbidity rate between TB and LC is high, and epidemiological data suggest a potential association between the two diseases. However, the detailed causal relationships and potential mediators remain underexplored due to limited evidence from observational studies. This study aims to elucidate the relationship between TB and LC, including the pathological subtypes of LC, and to investigate the potential mediating effects of immune cells.

Materials and Methods

The genetic variants for TB and LC were sourced from the IEU Open GWAS Project, while the data for the 731 immunocyte phenotypes were obtained from their genome-wide association studies (GWAS). The inverse variance-weighted (IVW), MR-Egger, weighted median, simple mode and weighted mode were used to evaluate the causal relationship between TB and LC. We then applied a two-step Mendelian randomization (MR) analysis to examine the roles of immunocyte phenotypes as mediators. Additionally, multiple sensitivity analyses were conducted to ensure the reliability of the MR results.

Results

The results of the IVW methods of the MR analysis indicated a causal relationship between TB and LC, demonstrating a positive correlation (OR = 1.072, 95% CI: 1.010–1.137,P< 0.05). The immune phenotype CD4 on CD39+ resting regulatory T cell is implicated in the linkage between TB and LC as well (mediation proportion: 9.09%). Additionally, no evidence was found to support a reverse causal relationship between TB and LC, nor a causal relationship between TB and the pathological subtypes of LC. There was no observed heterogeneity or horizontal pleiotropy in our MR results.

Conclusion

Our study suggests the causal effect of TB on increased LC risk, with immune phenotype playing a mediating role. These insights provide a significant basis for the prevention and concurrent management of LC and TB.
Impact of Language Models on Healthcare in Thailand: Benefits, Challenges, and Future Opportunities
Authors: Moongthin Chanakan
Published: June 2024

This study explores the use of Artificial Intelligence (AI), specifically Large Language Models (LLMs) in the Thai healthcare sector, focusing on applications such as diagnosis, patient monitoring, and automated question-and-answer systems. While AI has the potential to improve diagnosis accuracy, reduce the time required for appointment, and enhance patient care, several challenges prevent widespread adoption of LLMs in healthcare, including significant computational resources required for deployment, data privacy and security concerns, and Thai language being a low-resource language. Through a comprehensive analysis of publicly available online data and literature, this study examines the current state of AI adoption in Thai healthcare, identifying key barriers to adoption and providing recommendations for overcoming these challenges, including targeted training and education for healthcare professionals, strategic government initiatives, and investments in infrastructure. By addressing these issues, Thailand can harness the full potential of AI technologies to enhance its healthcare system, ensuring better patient outcomes and operational efficiencies.
Predictive coding model can detect novelty on different levels of representation hierarchy
Authors: Li T. Ed , Tang Mufeng , Bogacz Rafal
Published: June 2024

Novelty detection, also known as familiarity discrimination or recognition memory, refers to the ability to distinguish whether a stimulus has been seen before. It has been hypothesized that novelty detection can naturally arise within networks that store memory or learn efficient neural representation, because these networks already store information on familiar stimuli. However, computational models instantiating this hypothesis have not been shown to reproduce high capacity of human recognition memory, so it is unclear if this hypothesis is feasible. This paper demonstrates that predictive coding, which is an established model previously shown to effectively support representation learning and memory, can also naturally discriminate novelty with high capacity. Predictive coding model includes neurons encoding prediction errors, and we show that these neurons produce higher activity for novel stimuli, so that the novelty can be decoded from their activity. Moreover, the hierarchical predictive coding networks uniquely perform novelty detection at varying abstraction levels across the hierarchy, i.e., they can detect both novel low-level features, and novel higher-level objects. Overall, we unify novelty detection, associative memory, and representation learning within a single computational framework.
Artificial intelligence and species distribution ensemble models inform resource interactions with offshore wind development
Authors: Ingram Evan C. , Dunton Keith J. , Frisk Michael G. , Butler Liam
Published: June 2024

Development of offshore wind energy resources has led to growing concerns for marine wildlife. However, significant uncertainty remains regarding the technology’s potential to impact species of interest that may occupy planned development sites. This is further compounded by the difficulty of monitoring highly migratory or data-poor species in marine waters, making practical assessment of site- or species-specific threats that could require additional management intervention particularly problematic. Here, I identify a highly generalizable framework to inform species interactions in marine habitats allocated for offshore resource exploitation, using telemetry-derived artificial intelligence species distribution models. Results from a case study of the federally protected Atlantic Sturgeon (Acipenser oxyrinchus) demonstrate excellent discriminatory capacity (i.e., AUC ≥ 0.9) at a relatively fine scale (raster resolution = 1 km2), while providing critical information on predicted occurrence over a broad swath of unmonitored marine habitats (i.e., the Atlantic OCS region of the US; area > 620,000 km2). Furthermore, ensemble map products developed from these models are readily scalable to ongoing management needs and, when overlaid with offshore wind energy lease areas, can feed directly into management strategies to inform best practices for potential habitat influences on Atlantic Sturgeon, as well as other species of commercial or conservation interest.
Social cues on stone tools outweigh raw material properties in wild primates
Authors: Henke-von der Malsburg J , Reeves J , Proffitt T , Falótico T , Rufo HP , Luncz LV
Published: June 2024

1.

The ability to select appropriate tool material enabled early hominins access to new resources and environments. The underlying mechanisms driving tool selection effectively remain unknown. Observations of extant primates have demonstrated strong selectivity for specific tools, offering analogous insight into technological decision-making. However, whether tool selection is determined by individual experience alone or social information plays a role remained difficult to disentangle. Here, we used an experimental approach to investigate decision-making factors for tool selection in non-human primates. We provided naturalistic nut-cracking opportunities to wild capuchin monkeys, one of the most prolific extant tool users. We offered standardized stones varying in asocial (material properties) and social cues (evidence of previous use) to two populations, differing in their previous experience of natural materials. Our results show that both populations persistently selected tools based on their material properties when only asocial cues were provided. However, when provided with both asocial and social cues combined, they consistently selected previously used material regardless of material properties. These findings suggest that wild capuchin monkeys discriminate between raw material properties; however, prioritize social cues when present. Tool selection behaviors are therefore shaped by indirect social processes and highlight the importance of culturally transmitted information for skill acquisition in technological primates.
Cholesterol inhibits assembly and activation of the EphA2 receptor
Authors: Schuck Ryan J , Ward Alyssa E , Sahoo Amita R , Rybak Jennifer A , Pyron Robert J , Trybala Thomas N , Simmons Timothy B , Baccile Joshua A , Sgouralis Ioannis , Buck Matthias , Lamichhane Rajan , Barrera Francisco N
Published: June 2024

The receptor tyrosine kinase EphA2 drives cancer malignancy by facilitating metastasis. EphA2 can be found in different self-assembly states: as a monomer, dimer, and oligomer. However, our understanding remains limited regarding which EphA2 state is responsible for driving pro-metastatic signaling. To address this limitation, we have developed SiMPull-POP, a single-molecule method for accurate quantification of membrane protein self-assembly. Our experiments revealed that a reduction of plasma membrane cholesterol strongly promoted EphA2 self-assembly. Indeed, low cholesterol caused a similar effect to the EphA2 ligand ephrinA1-Fc. These results indicate that cholesterol inhibits EphA2 assembly. Phosphorylation studies in different cell lines revealed that low cholesterol increased phospho-serine levels, the signature of oncogenic signaling. Investigation of the mechanism that cholesterol uses to inhibit the assembly and activity of EphA2 indicate an in-trans effect, where EphA2 is phosphorylated by protein kinase A downstream of beta-adrenergic receptor activity, which cholesterol also inhibits. Our study not only provides new mechanistic insights on EphA2 oncogenic function, but also suggests that cholesterol acts as a molecular safeguard mechanism that prevents uncontrolled self-assembly and activation of EphA2.
The transcriptional response to low temperature is weakly conserved across theEnterobacteriaceae
Authors: Hoang Johnson , Stoebel Daniel M
Published: June 2024

Bacteria respond to changes in their external environment, such as temperature, by changing the transcription of their genes. We know little about how these regulatory patterns evolve. We used RNA-seq to study the transcriptional response to a shift from 37°C to 15°C in wild-typeEscherichia coli, Salmonella enterica, Citrobacter rodentium, Enterobacter cloacae, Klebsiella pneumoniae,andSerratia marcescens, as well as ΔrpoSstrains ofE. coliandS. enterica.We found that these species change the transcription of between 626 and 1057 genes in response to the temperature shift, but there were only 16 differentially expressed genes in common among the six species. Species-specific transcriptional patterns of shared genes were a prominent cause of this lack of conservation. GO enrichment of regulated genes suggested many species-specific phenotypic responses to temperature changes, but enriched terms associated with iron metabolism, central metabolism, and biofilm formation were implicated in at least half of the species. The alternative sigma factor RpoS regulated about 200 genes between 37°C and 15°C in bothE. coliandS. enterica, with only 83 genes in common between the two species. Overall, there was limited conservation of the response to low temperature generally, or the RpoS-regulated part of the response specifically. This study suggests that species-specific patterns of transcription of shared genes, rather than horizontal acquisition of unique genes, are the major reason for the lack of conservation of the transcriptomic response to low temperature.

Importance

We studied how different species of bacteria from the same Family (Enterobacteriacae) change the expression of their genes in response to a decrease in temperature. Using de novo-generated parallel RNA-seq datasets, we found that the six species in this study change the level of expression of many of their genes in response to a shift from human body temperature (37°C) to a temperature that might be found out of doors (15°C). Surprisingly, there were very few genes that change expression in all six species. This was due in part to differences in gene content, and in part due to shared genes with distinct expression profiles between the species. This study is important to the field because it illustrates that closely related species can share many genes but not use those genes in the same way in response to the same environmental change.
Exploring aggregation genes in aP. aeruginosachronic infection model
Authors: Gannon Alexa D. , Matlack Jenet , Darch Sophie E.
Published: June 2024

Bacterial aggregates are observed in both natural and artificial environments. In the context of disease, aggregates have been isolated from both chronic and acute infections.Pseudomonas aeruginosa(Pa) aggregates contribute significantly to chronic infections, particularly in the lungs of people with cystic fibrosis (CF). Unlike the large biofilm structures observedin vitro, Pain CF sputum forms smaller aggregates (∼10-1000 cells), and the mechanisms behind their formation remain underexplored. This study aims to identify genes essential and unique toPaaggregate formation in a synthetic CF sputum media (SCFM2). We culturedPastrain PAO1 in SCFM2 and LB, both with and without mucin, and used RNA sequencing (RNA-seq) to identify differentially expressed genes. The presence of mucin revealed hundreds of significantly differentially expressed (DE) genes, predominantly downregulated, with 40% encoding hypothetical proteins unique to aggregates. Using high-resolution microscopy, we assessed the ability of mutants to form aggregates and identified 13 that were unable to form WT aggregates. Notably, no mutant exhibited a completely planktonic phenotype. Instead, we identified multiple spatial phenotypes described as ‘normal,’ ‘entropic,’ or ‘impaired.’ Entropic mutants displayed tightly packed, raft-like structures, while impaired mutants had loosely packed cells. Predictive modeling linked the prioritized genes to metabolic shifts, iron acquisition, surface modification, and quorum sensing. Co-culture experiments with wild-type PAO1 revealed further spatial heterogeneity and the ability to ‘rescue’ some mutant phenotypes, suggesting cooperative interactions during growth. This study enhances our understanding ofPaaggregate biology, specifically the genes and pathways unique to aggregation in CF-like environments. Importantly, it provides insights for developing therapeutic strategies targeting aggregate-specific pathways.

Importance

This study identifies genes essential for the formation ofPseudomonas aeruginosa(Pa) aggregates in cystic fibrosis (CF) sputum, filling a critical gap in understanding their specific biology. Using a synthetic CF sputum model (SCFM2) and RNA sequencing, 13 key genes were identified, whose disruption led to distinct spatial phenotypes observed through high-resolution microscopy. The addition of wild-type cells either rescued the mutant phenotype or increased spatial heterogeneity, suggesting cooperative interactions are involved in aggregate formation. This research advances our knowledge ofPaaggregate biology, particularly the unique genes and pathways involved in CF-like environments, offering valuable insights for developing targeted therapeutic strategies against aggregate-specific pathways.
Bred for affection: The canine anterior ectosylvian gyrus responds selectively to social reinforcement
Authors: Miller Kai J. , Lampert Frederik , Mivalt Filip , Kim Inyong , Ince Nuri , Kim Jiwon , Kremen Vaclav , Baker Matthew R. , Van den Boom Max A. , Hermes Dora , Coenen Volker A. , Schalk Gerwin , Brunner Peter , Worrell Gregory A.
Published: June 2024

Studying mammalian brain function aids our understanding of human brain evolution. We implanted a beagle with a prototype human neuromodulation platform that measures activity from the brain surface. One year later, a set of simple sensory tasks was performed, finding visual and somatosensory representation in the canine homologs of the expected areas in humans. Surprisingly, the canine anterior ectosylvian gyrus, which is anatomically homologous to human receptive speech areas, was selectively active during independent social reinforcement tasks. This suggests that human speech understanding may have evolved from more general mammalian brain structures that are specialized for social reinforcement.
Fdo1, Fkh1, Fkh2 and the Swi6-Mbp1 MBF complex regulate Mcd1 levels to impact eco1 rad61 cell growth in Saccharomyces cerevisiae
Authors: Singh Gurvir , Skibbens Robert V.
Published: June 2024

Cohesins promote proper chromosome segregation, gene transcription, genomic architecture, DNA condensation, and DNA damage repair. Mutations in either cohesin subunit or regulatory genes can give rise to severe developmental abnormalities (such as Robert Syndrome and Cornelia de Lange Syndrome) and also are highly correlated with cancer. Despite this, little is known about cohesin regulation. Eco1 (ESCO2/EFO2 in humans) and Rad61 (WAPL in humans) represent two such regulators but perform opposing roles. Eco1 acetylation of cohesin during S phase, for instance, stabilizes cohesin-DNA binding to promote sister chromatid cohesion. On the other hand, Rad61 promotes the dissociation of cohesin from DNA. While Eco1 is essential,ECO1andRAD61co-deletion results in yeast cell viability, but only within a limited temperature range. Here, we report thateco1 rad61cell lethality is due to reduced levels of the cohesin subunit Mcd1. Results from a suppressor screen further reveals thatFDO1deletion rescues the temperature sensitive (ts) growth defects exhibited byeco1 rad61double mutant cells by increasing Mcd1 levels. Regulation ofMCD1expression, however, appears more complex. Elevated expression ofMBP1, which encodes a subunit of the MBF transcription complex, also rescueseco1 rad61cell growth defects. Elevated expression ofSWI6, however, which encodes the Mbp1-binding partner of MBF, exacerbateseco1 rad61cell growth and also abrogates the Mpb1-dependent rescue. Finally, we identify two additional transcription factors, Fkh1 and Fkh2, that impactMCD1expression. In combination, these findings provide new insights into the nuanced and multi-faceted transcriptional pathways that impactMCD1expression.
Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice
Authors: Yang Yang , Jeng Jing-Yi , Murtha Kaitlin , Climer Leslie K. , Ceriani Federico , Sese Weintari D. , Hornak Aubrey J. , Liberman M. Charles , Marcotti Walter , Simmons Dwayne D.
Published: June 2024

Tight regulation of Ca2+is crucial for the function of cochlear outer hair cells (OHCs). Dysregulation of Ca2+homeostasis in OHCs is associated with impaired hearing function and contributes to increased vulnerability to environmental insults, such as noise exposure. Ca2+signaling in developing OHCs can be modulated by oncomodulin (OCM), an EF-hand calcium-binding protein. Here, we investigated whether the lack of OCM disrupts the control of intracellular Ca2+in mature OHCs, and influences vulnerability to noise. Using young adult CBA/CaJ mice, we found that OHCs fromOcm-knockout (Ocm-/-) mice exhibited normal biophysical profiles and electromotile responses compared to littermate control OHCs. Moderate noise exposure (95 dB SPL, 2 hrs) caused temporary hearing threshold shifts inOcm+/+andOcm-/-mice but the loss of hearing was permanent forOcm-/-mice. However, whileOcm+/+fully recovered their hearing 2 weeks after noise exposure,Ocm-/-mice showed permanent threshold shifts. Using a genetically encoded Ca2+sensor (GCaMP6s) expressed inOcm+/+andOcm-/-OHCs, we found that chronic noise exposure (95 dB SPL, 9 hrs) increased ATP-induced Ca2+signaling inOcm-/-OHCs compared toOcm+/+OHCs. Chronic noise exposures also caused higher hearing threshold shifts inOcm-/-mice. Prior to noise exposure, P2X2 expression was already upregulated inOcm-/-mice compared toOcm+/+mice. Following chronic noise, P2X2 receptors were upregulated in theOcm+/+cochlea but not in theOcm-/-cochlea, which retains their pre-noise high expression level. We propose that the lack of OCM increases susceptibility to noise. Increased purinergic signaling and dysregulation of cytosolic Ca2+homeostasis could contribute to early onset hearing loss in theOcm-/-mice.
Tool skill impacts the archaeological evidence across technological primates
Authors: Luncz Lydia V. , Slania Nora E. , Almeida-Warren Katarina , Carvalho Susana , Falótico Tiago , Malaivijitnond Suchinda , Arroyo Adrián , de la Torre Ignacio , Proffitt Tomos
Published: June 2024

The archaeological record offers insights into our evolutionary past by revealing ancient behaviour through stone and fossil remains. Percussive foraging is suggested to be particularly relevant for the emergence of tool-use in our lineage, yet early hominin percussive behaviours remain largely understudied compared to flaked technology. Stone tool-use of extant primates allows the simultaneous investigation of their artefacts and the associated behaviours. This is important for understanding the development of tool surface modification, and crucial for interpreting damage patterns in the archaeological record. Here, we compare the behaviour and the resulting material record across stone tool-using primates. We investigate the relationship of nut-cracking technique and stone tool modification across chimpanzees, capuchins, and long-tailed macaques by conducting standardized field experiments with comparable raw materials. We show that different techniques likely emerged in response to diverse nut hardness, leading to variation in foraging success across species. Our experiments further demonstrate a correlation between techniques and the intensity of visible percussive damage on the tools. Tools used with more precision and efficiency as demonstrated by macaques, show fewer use wear traces. This suggests that some percussive techniques may be less readily identified in the archaeological record.
Direct Genome-Scale Screening ofGluconobacter oxydansB58 for Rare Earth Element Bioleaching
Authors: Marecos Sabrina , Pian Brooke , Medin Sean A. , Schmitz Alexa , Wu Mingming , Balta J. Brian , Gazel Esteban , Holycross Megan , Reid Matthew C. , Barstow Buz
Published: June 2024

The transition to a sustainable energy economy will require an enormous increase in the supply of rare earth elements (REE). Bioleaching offers a promising alternative to conventional hydrometallurgical methods for REE extraction from low-grade ores. However, exploiting this potential remains challenging due to large gaps in our understanding of the genetics involved, and inadequate biological tools to address them. We generated a highly non-redundant whole genome knockout collection for the bioleaching microbeGluconobacter oxydansB58, reducing redundancy by 85% compared to the previous best collection. This new collection was directly screened for bioleaching neodymium from a synthetic monazite powder, identifying 89 genes important for bioleaching, 68 of which have not previously been associated with this mechanism. We conducted bench-scale experiments to validate the extraction efficiency of promising strains: 8 demonstrated significant increases in bioleaching by up to 111% (G. oxydansδGO_1598, a disruption of the gene encoding the orotate phosphoribosyltransferase enzyme PyrE), and one strain significantly reduced it by 97% (δGO_1096, a disruption of the gene encoding the GTP-binding protein TypA). Notable changes in biolixiviant pH were only observed for 3 strains, suggesting an important role for non-acid mechanisms in bioleaching. These findings provide valuable insights into further enhancing REE-bioleaching byG. oxydans’ through targeted genetic engineering.
Targeted mutagenesis of specific genomic DNA sequences in animals for thein vivogeneration of variant libraries
Authors: Falo-Sanjuan Julia , Diaz-Tirado Yuliana , Turner Meghan A. , Rourke Olivia , Davis Julian , Medrano Claudia , Haines Jenna , McKenna Joey , Karshenas Arman , Eisen Michael B. , Garcia Hernan G.
Published: June 2024

Understanding how the number, placement and affinity of transcription factor binding sites dictates gene regulatory programs remains a major unsolved challenge in biology, particularly in the context of multicellular organisms. To uncover these rules, it is first necessary to find the binding sites within a regulatory region with high precision, and then to systematically modulate this binding site arrangement while simultaneously measuring the effect of this modulation on output gene expression. Massively parallel reporter assays (MPRAs), where the gene expression stemming from 10,000s of in vitro-generated regulatory sequences is measured, have made this feat possible in high-throughput in single cells in culture. However, because of lack of technologies to incorporate DNA libraries, MPRAs are limited in whole organisms. To enable MPRAs in multicellular organisms, we generated tools to create a high degree of mutagenesis in specific genomic lociin vivousing base editing. Targeting GFP integrated in the genome ofDrosophilacell culture and whole animals as a case study, we show that the base editor AIDevoCDA1stemming from sea lamprey fused to nCas9 is highly mutagenic. Surprisingly, longer gRNAs increase mutation efficiency and expand the mutating window, which can allow the introduction of mutations in previously untargetable sequences. Finally, we demonstrate arrays of >20 gRNAs that can efficiently introduce mutations along a 200bp sequence, making it a promising tool to test enhancer functionin vivoin a high throughput manner.
Immunity and bacterial recruitment in plant leaves are parallel processes whose link shapes sensitivity to temperature stress
Authors: Jose Jisna , Teutloff Erik , Naseem Simrat , Barth Emanuel , Halitschke Rayko , Marz Manja , Agler Matthew T.
Published: June 2024

Rising global temperatures necessitate developing climate-resilient crops with better adaptability to changing climates. Under elevated temperatures, plant immunity is downregulated, putting them at risk of foliar pathogen attack. Manipulating plant defense hormones is one way to mitigate this detrimental effect. However, it is unclear how plant immunity interacts with plant microbiome assembly and how temperature will thus affect overall plant health and stability. We used chemical mutagenesis to identify a phenotypically healthy genotype ofA. thaliana, “CLLF”,that compared to the wild type naturally recruits an altered leaf bacteriome, including unusually high bacteria loads. Simultaneously, CLLF hyperaccumulates salicylic acid (SA) and jasmonates, has constitutively upregulated systemic and innate defenses, and has increased resistance to necrotrophic fungal and hemi-biotrophic bacterial pathogens, indicating that pathogen immunity and non-pathogen recruitment function in parallel. Growth of specific non-pathogenic leaf bacteria on SA as a carbon source suggests the same hormones may even link the two processes. CLLF also showed high tolerance to heat stress in comparison to the wild type, but SA-associated defense processes are not downregulated under heat. Synthetic community (SynCom) experiments showed that when the taxonomic diversity of bacteria available to CLLF is artificially reduced, resilience to heat stress is compromised, leading to dysbiosis, but this does not occur with the full SynCom or in the wild type with any SynCom. Thus, the downregulation of defenses in response to heat may contribute to avoidance of dysbiosis caused by some leaf bacteria, but full bacteriome taxonomic diversity can restore balance.

Significance Statement

Plants are living ecosystems colonized by diverse microorganisms who strongly shape host health. Understanding how balance arises in host-associated microbiomes is a key step to understanding how to preserve, manage and possibly optimize these complex ecosystems, especially in a changing climate. Using a random mutagenesis approach in a naturalA. thalianaecotype, we find that constitutively upregulated defenses are associated with both tolerance to (a)biotic threats and healthy recruitment of leaf bacteria, very likely in a direct manner. Thus, immunity and bacterial recruitment in leaves operate in parallel. Synthetic community experiments show further that this link plays important roles in shaping plant resilience to heat stress, an important consideration in developing plants more stable to climate change.
Induction of a Müller glial-specific protective pathway safeguards the retina from diabetes induced damage
Authors: Lin Cheng-Hui , Wu Man-Ru , Tanasa Bogdan , Prakhar Praveen , Davis Alexander E. , Li Liang , Xia Alexander , Shan Yang , Fort Patrice E. , Wang Sui
Published: June 2024

Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomic analyses, we profiled the transcriptional changes induced by diabetes in different retinal cell types in diabetic rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Müller glial cells exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Müller glial cells initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect as the disease progressed. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depletingZfp36in rat Müller glial cells in vivo using AAV-based tools exacerbated early diabetes-induced phenotypes, including gliosis, neurodegeneration, and vascular defects. Notably, the over-expression ofZfp36slowed the development of phenotypes associated with diabetic retinopathy. In summary, this work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Müller glial cells can mount protective responses throughZfp36. The failure to maintainZfp36levels contributes to the development of diabetic retinopathy.
Association between APOE genotypes and Metabolic Syndrome in a Middle Aged and Elderly Urban Indian Population
Authors: Azhuvalappil Shilna , Prasad Raghav , Sahadevan Pravin , Chatterjee Priya , Pradhan Hitesh , Rai Pooja , Gupta Anant , Kommaddi Reddy Peera , Issac Thomas G. , Sundarakumar Jonas S.
Published: June 2024

Background

This study examines the association between apolipoprotein E (APOE) genotypes and metabolic syndrome (MetS) in an older urban population in South India, as part of the Tata Longitudinal Study on Aging.

Methods

A total of 618 participants aged 45 and above were analyzed cross-sectionally for the association between APOE carrier status and MetS (based on both NCEP ATP III and Consensus criteria).

Results

Despite the high prevalence of MetS observed in this cohort (51.62% by NCEP-ATP III and 61.33% by Consensus criteria), multivariable logistic regression revealed no significant association between APOE genotypes and MetS under both criteria. However, specific associations were noted in age and sex-stratified analyses; notably, E2 carriers under 60 showed 0.42-fold decreased odds (95%CI:0.20,0.89, p-value-0.023) for an increased waist circumference, and E4 carriers above 60 were at 1.85 times increased odds (95% CI:1.04,3.28, p-value<0.05) for decreased HDL.

Conclusion

These findings suggest that while APOE genotypes influence certain metabolic parameters, their impact on MetS may be limited in this urban setting, possibly overshadowed by environmental factors and lifestyle influences which was highlighted by the differences seen in its sister rural cohort.
Health impacts of takeaway management zones around schools in six different local authorities across England: a public health modelling study using PRIMEtime
Authors: Rogers Nina Trivedy , Amies-Cull Ben , Adams Jean , Chang Michael , Cummins Steven , Derbyshire Daniel , Hassan Suzan , Keeble Matthew , Liu Bochu , Medina-Lara Antonieta , Savory Bea , Rahilly John , Smith Richard , Thompson Clare , White Martin , Mytton Oliver , Burgoine Thomas
Published: June 2024

Background

In England, the number of takeaway food outlets (‘takeaways’) has been increasing for over two decades. Takeaway management zones around schools are an effective way to restrict the growth of new takeaways but their impacts on population health have not been estimated.

Methods

To model the impact of takeaway management zones on health, we used estimates of change in and exposure to takeaway outlets (across home, work, and commuting buffers) based on a previous evaluation suggesting that 50% of new outlets were prevented from opening because of management zones. Based on previous cross-sectional findings, we used changes in takeaway exposure to estimate changes in BMI, from 2018 to 2040. Finally, we used PRIMEtime, a proportional multistate lifetable model, and BMI change to estimate the impact of the intervention, in a closed-cohort of adults (25-64 years), in terms of incidence of 12 non-communicable diseases, obesity prevalence, quality-adjusted life years (QALYs) and healthcare costs saved by 2040 in six selected local authorities across the rural-urban spectrum in England (Wandsworth, Manchester, Blackburn with Darwen, Sheffield, North Somerset, and Fenland).

Results

By 2031, compared to no intervention, reductions in outlet exposure ranged from 3 outlets/person in Fenland to 28 outlets/person in Manchester. This corresponded to per person reductions in BMI of 0.68 and 0.08 kg/m2, respectively. Relative to no intervention, obesity prevalence was estimated to be reduced in both sexes in all LAs, including by 2.3 percentage points (PP) (95% uncertainty interval:2.9PP, 1.7PP) to 1.5PP (95%UI:1.9PP, 1.1PP) in males living in Manchester and Wandsworth by 2040, respectively. Model estimates showed reductions in incidence of disease, including type II diabetes (eg: 964 (95%UI:1565, 870) fewer cases /100,000 population for males in Manchester)), cardiovascular diseases, asthma, certain cancers and low back pain. Savings in healthcare costs (millions(£)) ranged from £0.90 (95%UI: £1,23, £0.54) in Fenland to £5.44 (95%UI:£3.87, £7.45) in Manchester. Gains in QALYs/100,000 person were broadly similar across local authorities.

Conclusions

Takeaway management zones in England have the potential to meaningfully contribute towards reducing obesity prevalence and associated healthcare burden in the adult population, both at the local level and across the rural-urban spectrum.
Universal statistics of hippocampal place fields across species and dimensionalities
Authors: Mainali Nischal , da Silveira Rava Azeredo , Burak Yoram
Published: June 2024

Hippocampal place cells form a spatial map by selectively firing at specific locations in an animal’s environment1. Until recently the hippocampus appeared to implement a simple coding scheme for position, in which each neuron is assigned to a single region of space in which it is active1. Recently, new experiments revealed that the tuning of hippocampal neurons to space is much less stereotyped than previously thought: in large environments, place cells are active in multiple locations and their fields vary in shape and size across locations, with distributions that differ substantially in different experiments2–7. It is unknown whether these seemingly diverse observations can be explained in a unified manner, and whether the heterogeneous statistics can reveal the mechanisms that determine the tuning of neural activity to position. Here we show that a surprisingly simple mathematical model, in which firing fields are generated by thresholding a realization of a random Gaussian process, explains the statistical properties of neural activity in quantitative detail, in bats and rodents, and in one-, two-, and three-dimensional environments of varying sizes. The model captures the statistics of field arrangements, and further yields quantitative predictions on the statistics of field shapes and topologies, which we verify. Thus, the seemingly diverse statistics arise from mathematical principles that are common to different species and behavioral conditions. The underlying Gaussian statistics are compatible with a picture in which the synaptic connections between place cells and their inputs are random and highly unstructured.
The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD
Authors: Angendohr Carolin , Koppe Christiane , Schneider Anne T , Keysberg Leonie , Singer Michael T , Dille Matthias A , Bode Johannes G , Conrad Marcus , Vucur Mihael , Luedde Tom
Published: June 2024

Metabolic dysfunction-associated steatotic liver disease is an increasingly prevalent condition, representing a major risk factor for the development of progressive chronic liver damage. This can potentially give rise to the development of steatohepatitis and hepatocellular carcinoma (HCC). It is already known, that patients with metabolic dysfunction-associated steatotic liver disease (MASLD) show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting involvement of ferroptotic cell death in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD.

The aim of this study was to determine whether a liver parenchymal cell specific conditional deletion of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) can ameliorate the onset and progression of MASLD in mice. To this end, ACSL4LPC-KOand floxed wild-type littermates were fed a choline-deficient high-fat diet over the course of 20 and 40 weeks to monitor the progression of metabolic liver injury as well as the development of metabolic syndrome.

In contrast to the recently published studies by Duan et al. [1], our results show no significant differences between ACSL4LPC-KOand WT mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (i.e. weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response. Our analyses therefore suggest that loss of ACSL4 has no effect on the progression of MASLD induced by choline-deficient high fat diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with liver parenchymal cell specific ACSL4 null mice should be taken with caution.