bluuebunny/crossref_metadata_2025 huggingface dataset:
Alternatives for purposeful stewardship and wealth planning in Canada
Authors: Cross Pamela
Published: September 2023

There has been a global shift in client demands from tax-focused transactional planning to planning which accommodates using family wealth to address social and community purposes. These purposes may not be limited to charitable purposes or restricted to a geographic region. Stewardship structures are being used in new ways, and new structures are being introduced to accommodate these client needs. The author discusses the Canadian landscape and how Canadian laws may accommodate (or not) such stewardship models.1
Budget impact analysis for implementation decision making, planning, and financing
Authors: Smith Natalie Riva , Levy Douglas E
Published: September 2023

Shelley et al. (in Accelerating integration of tobacco use treatment in the context of lung cancer screening: relevance and application of implementation science to achieving policy and practice. Transl Behav Med 2022;12:1076–1083) laid out how implementation science frameworks and methods can advance the delivery of tobacco use treatment services during lung cancer screening services, which until recently was mandated by the Centers for Medicare and Medicaid Services. Their discussion provides an important overview of the full process of implementation and highlights the vast number of decisions that must be made when planning for implementation of an evidence-based practice such as tobacco use treatment: what specific tobacco use treatment services to deliver, when to deliver those services within the lung cancer screening process, and what implementation strategies to use. The costs of implementation play a major role in decision making and are a key implementation determinant discussed in major implementation frameworks. When making decisions about what and how to implement, budget impact analyses (BIAs) can play an important role in informing decision making by helping practitioners understand the overall affordability of a given implementation effort. BIAs can also inform the development of financing strategies to support the ongoing sustainment of tobacco use treatment service provision. More attention is needed by the research community to produce high-quality, user-friendly, and flexible BIAs to inform implementation decision making in health system and community settings. The application of BIA can help ensure that the considerable time and effort spent to develop and evaluate evidence-based programs has the best chance to inform implementation practice.
A Tomato-Free Period Delays and Reduces Begomovirus Disease in Processing Tomato Fields in a Complex Agroecosystem in Central Brazil
Authors: de Macedo Mônica Alves , Gilbertson Robert L. , Rojas Maria R. , Filho Armando Bergamin , Pereira José Luiz , Costa Thiago Marques , Inoue-Nagata Alice Kazuko
Published: September 2023

A mandatory tomato-free period (TFP) was implemented in the state of Goiás, Brazil, in 2007 to help manage diseases caused by whitefly-transmitted begomoviruses. The impact of the TFP was examined in five locations across three states in Central Brazil from 2013 to 2016. Surveys revealed significant differences in begomovirus disease incidence among locations, i.e., low in Guaíra-TFP and Patos de Minas-TFP; moderate-high in Itaberaí-TFP and Morrinhos-TFP; and high in the non-TFP (NTFP) control, Cristalina-NTFP. PCR tests and DNA sequencing were used to validate the symptoms and showed that all collected symptomatic plant samples were infected with tomato severe rugose virus (ToSRV), a common indigenous bipartite begomovirus. Early season surveys (20 to 40 days after transplants [DAT]) in Itaberaí-TFP and Morrinhos-TFP revealed significantly less begomovirus disease in fields established sooner after the TFP (0 to 2 months) compared with incidences in (i) equivalent early planted fields in the Cristalina-NTFP control and (ii) fields established longer after the end of the TFP (>2 to 5 months). Whitefly infestation of crops was detected year-round in all locations and years, and all tested adults were classified in the Bemisia tabaci MEAM1 cryptic species. Infestation levels were significantly higher during the summer but did not vary significantly among locations. Results of monthly monitoring of adult whiteflies for general begomovirus and ToSRV were positively correlated and were indicators of disease incidence in the field. Notably, ToSRV was not detected in whiteflies collected from nontomato plants during the TFP, and there was a longer lag period before detection in whiteflies collected from processing tomatoes for Itaberaí-TFP and Morrinhos-TFP compared with Cristalina-NTFP. Taken together with the low levels of ToSRV infection detected in potential nontomato reservoir hosts at all locations, our results revealed low levels of primary inoculum during the TFP. Thus, even in a complex agroecosystem with year-round whitefly infestation of crops, the TFP was beneficial due to delayed and reduced begomovirus disease pressure during a critical stage of plant development (first month) and for favoring low levels of primary inoculum. Thus, we concluded that the TFP should be part of a regional integrated pest management (IPM) program targeting ToSRV in Brazil.
Aminoacyl‐tRNA synthetase – a molecular multitasker
Authors: Gupta Swadha , Jani Jaykumar , Vijayasurya  , Mochi Jigneshkumar , Tabasum Saba , Sabarwal Akash , Pappachan Anju
Published: September 2023

Aminoacyl‐tRNA synthetases (AaRSs) are valuable “housekeeping” enzymes that ensure the accurate transmission of genetic information in living cells, where they aminoacylated tRNA molecules with their cognate amino acid and provide substrates for protein biosynthesis. In addition to their translational or canonical function, they contribute to nontranslational/moonlighting functions, which are mediated by the presence of other domains on the proteins. This was supported by several reports which claim that AaRS has a significant role in gene transcription, apoptosis, translation, and RNA splicing regulation. Noncanonical/ nontranslational functions of AaRSs also include their roles in regulating angiogenesis, inflammation, cancer, and other major physio‐pathological processes. Multiple AaRSs are also associated with a broad range of physiological and pathological processes; a few even serve as cytokines. Therefore, the multifunctional nature of AaRSs suggests their potential as viable therapeutic targets as well. Here, our discussion will encompass a range of noncanonical functions attributed to Aminoacyl‐tRNA Synthetases (AaRSs), highlighting their links with a diverse array of human diseases.
Wastewater-based epidemiology for comprehensive communitywide exposome surveillance: A gradient of metals exposure
Authors: Cai Lu , Holm Rochelle H. , Biddle Donald J. , Zhang Charlie H. , Talley Daymond , Smith Ted , States J. Christopher
Published: September 2023

Community wastewater surveillance is an established means to measure health threats. Exposure to toxic metals as one of the key environmental contaminants has been attracting public health attention as exposure can be related to contamination across air, water, and soil as well as associated with individual factors. This research uses Jefferson County, Kentucky, as an urban exposome case study to analyze sub-county metal concentrations in wastewater as a possible indicator of community toxicant exposure risk, and to test the feasibility of using wastewater to identify potential community areas of elevated metals exposure. Variability in wastewater metal concentrations were observed across the county; 19 of the 26 sites had one or more metal results greater than one standard deviation above the mean and were designated areas of concern. Additionally, thirteen of the nineteen sites were of increased concern with levels greater than two standard deviations above the mean. This foundational research found variability in several instances between smaller nested upstream contributing neighborhood sewersheds when measured in the associated downstream treatment plant. Wastewater provides an opportunity to look at integrated toxicology to complement other toxicology data, looking at where people live and what toxicants need to be focused on to protect the health of people in that area.
Exploring the role of the private sector in tuberculosis detection and management in Lima, Peru: a mixed-methods patient pathway analysis
Authors: Wippel Christoph , Farroñay Sheyla , Gilbert Hannah N. , Millones Ana Karina , Acosta Diana , Torres Isabel , Jimenez Judith , Lecca Leonid , Yuen Courtney M.
Published: September 2023

In Latin America, little is known about the involvement of private healthcare providers in TB detection and management. We sought to gain a better understanding of current and potential roles of the private sector in delivering TB services in Peru. We conducted a mixed-methods study in Lima, Peru. The quantitative component comprised a patient pathway analysis assessing the alignment of TB services with patient care-seeking behavior. The qualitative component comprised in-depth interviews with 18 private healthcare providers and 5 key informants. We estimated that 77% of patients initially sought care at a facility with TB diagnostic capacity and 59% at a facility with TB treatment capacity. The lack of TB services at initial care-seeking location was driven by the 41% of patients estimated to seek care first at a private facility. Among private facilities, 43% offered smear microscopy, 13% offered radiography, and none provided TB treatment. Among public sector facilities, 100% offered smear microscopy, 26% offered radiography, and 99% provided TB treatment. Interviews revealed that private providers believed that they offered shorter wait times and a quicker diagnosis, but they struggled with a lack of follow-up systems and communication barriers with the public sector. While expressing willingness to collaborate with public sector programs for diagnosis and referral, private providers had limited interest in treating TB. This study highlights the role of private providers in Peru as an entry point for TB care. Public-private collaboration is necessary to harness the potential of the private sector as an ally for early diagnosis.
Longitudinal and multimodal auditing of tumor adaptation to CDK4/6 inhibitors in HR+ metastatic breast cancers
Authors: Creason Allison L. , Egger Jay , Watson Cameron , Sivagnanam Shamilene , Chin Koei , MacPherson Kevin , Lin Jia-Ren , Chen Yu-An , Johnson Brett E. , Feiler Heidi S. , Galipeau Danielle , Navin Nicholas E. , Demir Emek , Chang Young Hwan , Corless Christopher L. , Mitri Zahi I. , Sorger Peter K. , Thomas George V. , Coussens Lisa M. , Adey Andrew C. , Gray Joe W. , Mills Gordon B. , Goecks Jeremy
Published: September 2023

CDK4/6 inhibitors (CDK4/6i) have transformed the treatment of hormone receptor-positive (HR+), HER2-negative (HR+) breast cancers as they are effective across all clinicopathological, age, and ethnicity subgroups for metastatic HR+ breast cancer. In metastatic ER+ breast cancer, CDK4/6i lead to strong and consistent improvement in survival across different lines of therapy. To improve understanding of how metastatic HR+ breast cancers become refractory to CDK4/6i, we have created a multimodal and longitudinal tumor atlas to investigate therapeutic adaptations in malignant cells and in the tumor immune microenvironment. This atlas is part of the NCI Cancer Moonshot Human Tumor Atlas Network and includes seven pairs of pre- and on-progression biopsies from five metastatic HR+ breast cancer patients treated with CDK4/6i. Biopsies were profiled with bulk genomics, transcriptomics, and proteomics as well as single-cell ATAC-seq and multiplex tissue imaging for spatial, single-cell resolution. These molecular datasets were then linked with detailed clinical metadata to create an atlas for understanding tumor adaptations during therapy. Analysis of our atlas datasets suggests a diverse set of tumor adaptations to CDK4/6i therapy. Malignant cells may adapt to therapy via mTORC1 activation, cell cycle bypass, and increased replication stress. The tumor immune microenvironment displayed evidence of both immune activation and immune suppression during therapy. Together, our metastatic ER+ breast cancer atlas represents a rich multimodal resource to better understand HR+ breast cancer tumor therapeutic adaptations to CDK4/6i therapy.
Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis
Authors: Ersoy Ufuk , Alameddine Moussira , Kanakis Ioannis , Peffers Mandy Jayne , Jackson Malcolm J. , Goljanek-Whysall Katarzyna , Vasilaki Aphrodite , Ozanne Susan E , Vazquez Gibran Pedraza
Published: September 2023

The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.
A Mechanistically Integrated Model of Exploitative and Interference Competition over a Single Resource Produces Widespread Coexistence
Authors: Smith Daniel J.B. , Masel Joanna
Published: September 2023

Many ecological models treat exploitative competition in isolation from interference competition. Corresponding theory centers around theR*rule, according to which consumers who share a single limiting resource cannot coexist. Here we model motile consumers that directly interfere while handling resources, mechanistically capturing both exploitative and interference competition. Our analytical coexistence conditions show that interference competition readily promotes coexistence. In contrast to previous theory, coexistence does not require intra-specific interference propensities to exceed inter-specific interference propensities, nor for interference behaviors to carry a direct (rather than merely an opportunity) cost. The underlying mechanism of coexistence can resemble the hawk-dove game, the dominance-discovery trade-off (akin to the competition-colonization trade-off), or a novel trade-off we call the “dove-discovery trade-off”, depending on parameter values. Competitive exclusion via theR*rule occurs only when differences in exploitative abilities swamp other differences between species, and more easily when differences inR*reflect different search speeds than when they reflect different handling times. Our model provides a mathematically tractable framework that integrates exploitative and interference competition, and synthesizes previous disparate models.
Deepurify: a multi-modal deep language model to remove contamination from metagenome-assembled genomes
Authors: Zou Bohao , Wang Jingjing , Ding Yi , Zhang Zhenmiao , Huang Yufen , Fang Xiaodong , Cheung Ka Chun , See Simon , Zhang Lu
Published: September 2023

Metagenome-assembled genomes (MAGs) offer valuable insights into the exploration of microbial dark matter using metagenomic sequencing data. However, there is a growing concern that contamination in MAGs may significantly impact the downstream analysis results. Existing MAG decontamination methods heavily rely on marker genes but do not fully leverage genomic sequences. To address the limitations, we have introduced a novel decontamination approach named Deepurify, which utilizes a multi-modal deep language model employing contrastive learning to learn taxonomic similarities of genomic sequences. Deepurify utilizes inferred taxonomic lineages to guide the allocation of contigs into a MAG-separated tree and employs a tree traversal strategy for maximizing the total number of medium- and high-quality MAGs. Extensive experiments were conducted on two simulated datasets, CAMI I, and human gut metagenomic sequencing data. These results demonstrate that Deepurify significantly outperforms other decontamination methods.
FetoML: Interpretable predictions of the fetotoxicity of drugs based on machine learning approaches
Authors: Jeong Myeonghyeon , Yoo Sunyong
Published: September 2023

Pregnant females may use medications to manage health problems that develop during pregnancy or that they had prior to pregnancy. However, using medications during pregnancy has a potential risk to the fetus. Assessing the fetotoxicity of drugs is essential to ensure safe treatments, but the current process is challenged by ethical issues, time, and cost. Therefore, the need forin silicomodels to efficiently assess the fetotoxicity of drugs has recently emerged. Previous studies have proposed successful machine learning models for fetotoxicity prediction and even suggest molecular substructures that are possibly associated with fetotoxicity risks or protective effects. However, the interpretation of the decisions of the models on fetotoxicity prediction for each drug is still insufficient. This study constructed machine learning-based models that can predict the fetotoxicity of drugs while providing explanations for the decisions. For this, permutation feature importance was used to identify the general features that the model made significant in predicting the fetotoxicity of drugs. In addition, features associated with fetotoxicity for each drug were analyzed using the attention mechanism. The predictive performance of all the constructed models was significantly high (AUROC: 0.854–0.974, AUPR: 0.890–0.975). Furthermore, we conducted literature reviews on the predicted important features and found that they were highly associated with fetotoxicity. We expect that our model will benefit fetotoxicity research by providing an evaluation of fetotoxicity risk for drugs or drug candidates, along with an interpretation of that prediction.

Author summary

Drugs are often necessary for the treatment of diseases in pregnant females. However, some drugs can potentially cause fetotoxicities, such as teratogenicity and abortion. Therefore, it is essential to study fetotoxicity, but traditional toxicity testing demands time, money, and labor. To modernize these testing methods,in silicoapproaches for predicting the fetotoxicity of drugs are emerging. The proposed models so far have successfully predicted the fetotoxicity of drugs and proposed some fetotoxicity-related substructures, but the interpretation of the model’s determination is still insufficient. In this study, we proposed FetoML to predict the fetotoxicity of drugs based on machine learning and provide the substructures that the model focused on in predicting fetotoxicity for each drug. We confirmed the significant predictive performance and interpretability of the model through a quantitative performance evaluation and literature review. We expect FetoML to benefit fetotoxicity studies of drugs by modernizing the paradigm of fetotoxicity testing and providing insights to researchers.
Timing specific parental effects of ocean warming in a coral reef fish
Authors: Bonzi L.C. , Spinks R.K. , Donelson J.M. , Munday P.L. , Ravasi T. , Schunter C.
Published: September 2023

Population and species persistence in a rapidly warming world will be determined by an organisms’ ability to acclimate to warmer conditions, especially across generations. There is potential for transgenerational acclimation, but the importance of ontogenetic timing in the transmission of environmentally induced parental effects remains mostly unknown. We aimed to disentangle the contributions of two critical ontogenetic stages (juvenile development and adult reproduction) to transgenerational plasticity, by exposing the coral reef fishAcanthochromis polyacanthusto simulated ocean warming with natural diel thermal fluctuations across two generations. By using hepatic transcriptomics, we discovered that the developmental environment of the offspring themselves had little effect on their acclimation potential at 2.5 months of life. Instead, the developmental experience of parents increased regulatory RNA production and protein synthesis, which could improve the offspring’s response to warming. Conversely, reproduction in warmer water elicited stress response mechanisms, with suppression of translation and mitochondrial respiration. Mismatches between temperatures in the parental ontogenetic thermal experience deeply affected offspring gene expression profiles, and detrimental effects were also evident when warming occurred both during parents’ development and reproduction. This study reveals that the previous generation’s developmental temperature contributes substantially to thermal acclimation potential during early life, however prolonged heat stress will likely have adverse effects on the species’ persistence.
Visuomotor memory is not bound to visual motion
Authors: Warburton Matthew , Campagnoli Carlo , Mon-Williams Mark , Mushtaq Faisal , Morehead J. Ryan
Published: September 2023

Sensory feedback plays a critical role in motor control and motor learning, with both processes adjusting outgoing motor commands relative to the error between actual sensory feedback and the predictions of a forward model. However, models of motor control rarely specify the exact nature of these predictions. We hypothesized that large differences in low-level perceptual feedback would delineate contextual boundaries for motor memory, as sufficiently different feedback would require a distinct mapping between motor commands and sensory states. We tested this hypothesis by measuring transfer of visuomotor adaptation across contexts where hand movements caused visual motion in opposite directions. Instead of observing that visual feedback is bound to distinct internal models, we found nearly complete transfer of learning across the contexts, with evidence that the motor memory was bound to the planned displacement of the hand, rather than visual features of the task space.
ecDNA amplification ofMYCdrives intratumor copy-number heterogeneity and adaptation to stress in PDAC
Authors: Malinova Antonia , Schreyer Daniel , Fiorini Elena , Pasini Davide , Bevere Michele , D’Agosto Sabrina , Andreani Silvia , Lupo Francesca , Veghini Lisa , Grimaldi Sonia , Pedron Serena , Nourse Craig , Salvia Roberto , Malleo Giuseppe , Ruzzenente Andrea , Guglielmi Alfredo , Milella Michele , Lawlor Rita T. , Luchini Claudio , Pilarsky Christian , Scarpa Aldo , Tuveson David A. , Bailey Peter , Corbo Vincenzo
Published: September 2023

Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor ofMYCheterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNA can drive exceptionally high dosage ofMYCand afford cancer cells rapid adaptation to microenvironmental changes. The continued maintenance of extrachromosomalMYCis uniquely ensured by the presence of the selective pressure. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors, with the highest MYC levels correlating with squamous-like phenotypes. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism drivingMYCheterogeneity in PDAC.
Finding Antibodies in Cryo-EM densities with CrAI
Authors: Mallet Vincent , Rapisarda Chiara , Minoux Hervé , Ovsjanikov Maks
Published: September 2023

Therapeutic antibodies have emerged as a prominent class of new drugs due to their high specificity and their ability to bind to several protein targets. Once an initial antibody has been identified, an optimization of this hit compound follows based on the 3D structure, when available. Cryo-EM is currently the most efficient method to obtain such structures, supported by well-established methods that can transform raw data into a potentially noisy 3D map. These maps need to be further interpreted by inferring the number, position and structure of antibodies and other proteins that might be present. Unfortunately, existing automated methods addressing this last step have a limited accuracy and usually require additional inputs, high resolution maps, and exhibit long running times.

We propose the first fully automatic and efficient method dedicated to finding antibodies in cryo-EM densities:CrAI. This machine learning approach leverages the conserved structure of antibodies and exploits a dedicated novel database that we built to solve this problem. Running a prediction takes only a few seconds, instead of hours, and requires nothing but the cryo-EM density, seamlessly integrating in automated analysis pipelines. Our method is able to find the location of both Fabs and VHHs, at resolutions up to 10Å and is significantly more reliable than existing methods. It also provides an accurate estimation of the antibodies’ pose, even in challenging examples such as Fab binding to VHHs and vice-versa. We make our method available as a ChimeraX[44] bundle.1
Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4
Authors: Dao Thuy P. , Rajendran Anitha , Galagedera Sarasi K. K. , Haws William , Castañeda Carlos A.
Published: September 2023

Highly homologous ubiquitin-binding shuttle proteins UBQLN1, UBQLN2 and UBQLN4 differ in both their specific protein quality control functions and their propensities to localize to stress-induced condensates, cellular aggregates and aggresomes. We previously showed that UBQLN2 phase separatesin vitro, and that the phase separation propensities of UBQLN2 deletion constructs correlate with their ability to form condensates in cells. Here, we demonstrated that full-length UBQLN1, UBQLN2 and UBQLN4 exhibit distinct phase behaviorsin vitro. Strikingly, UBQLN4 phase separates at a much lower saturation concentration than UBQLN1. However, neither UBQLN1 nor UBQLN4 phase separates with a strong temperature dependence, unlike UBQLN2. We determined that the temperature-dependent phase behavior of UBQLN2 stems from its unique proline-rich (Pxx) region, which is absent in the other UBQLNs. We found that the short N-terminal disordered regions of UBQLN1, UBQLN2 and UBQLN4 inhibit UBQLN phase separation via electrostatics interactions. Charge variants of the N-terminal regions exhibit altered phase behaviors. Consistent with the sensitivity of UBQLN phase separation to the composition of the N-terminal regions, epitope tags placed on the N-termini of the UBQLNs tune phase separation. Overall, ourin vitroresults have important implications for studies of UBQLNs in cells, including the identification of phase separation as a potential mechanism to distinguish the cellular roles of UBQLNs, and the need to apply caution when using epitope tags to prevent experimental artifacts.

Highlights

1) Full-length UBQLN1, UBQLN2 and UBQLN4 all exhibit LCST phase transitions but to different degrees.

2) The N-terminal region (N-terminal to the UBL) substantially regulates UBQLN phase separation.

3) Removal of the disease-associated proline-rich (Pxx) region in UBQLN2 removes the strong temperature dependence of UBQLN2 phase separation.
Large Scale Comparative Deconvolution Analysis of the Canine and Human Osteosarcoma Tumor Microenvironment Uncovers Conserved Clinically Relevant Subtypes
Authors: Patkar Sushant , Mannheimer Josh , Harmon Stephanie , Mazcko Christina , Choyke Peter , Brown G Tom , Turkbey Baris , LeBlanc Amy , Beck Jessica
Published: September 2023

Osteosarcoma is a relatively rare but aggressive cancer of the bones with a shortage of effective biomarkers. Although less common in humans, Osteosarcomas are fairly common in adult pet dogs and have been shown to share many similarities with their human analogs. In this work, we analyze bulk transcriptomic data of 213 primary and 100 metastatic Osteosarcoma samples from 210 pet dogs enrolled in nation-wide clinical trials to uncover three Tumor Microenvironment (TME)-based subtypes: Immune Enriched (IE), Immune Enriched Dense Extra-Cellular Matrix-like (IE-ECM) and Immune Desert (ID) with distinct cell type compositions, oncogenic pathway activity and chromosomal instability. Furthermore, leveraging bulk transcriptomic data of canine primary tumors and their matched metastases from different sites, we characterize how the Osteosarcoma TME evolves from primary to metastatic disease in a standard of care clinical setting and assess its overall impact on clinical outcomes of canines. Most importantly, we find that TME-based subtypes of canine Osteosarcomas are conserved in humans and predictive of progression free survival outcomes of human patients, independently of known prognostic biomarkers such as presence of metastatic disease at diagnosis and percent necrosis following chemotherapy. In summary, these results demonstrate the power of using canines to model the human Osteosarcoma TME and discover novel biomarkers for clinical translation.
Sympathetic Motor Neuron Dysfunction is a Missing Link in Age-Associated Sympathetic Overactivity
Authors: de la Cruz Lizbeth , Bui Derek , Moreno Claudia M. , Vivas Oscar
Published: September 2023

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.
Electrical Coupling between Parvalbumin Basket Cells is Reduced after Experimental Status Epilepticus
Authors: Yu Jiandong , Santhakumar Vijayalakshmi
Published: September 2023

Acquired epilepsies, characterized by abnormal increase in hypersynchronous network activity, can be precipitated by various factors including brain injuries which cause neuronal loss and increases in network excitability. Electrical coupling between neurons, mediated by gap junctions, has been shown to enhance synchronous neuronal activity and promote excitotoxic neurodegeneration. Consequently, neuronal gap junctional coupling has been proposed to contribute to development of epilepsy. Parvalbumin expressing interneurons (PV-INs), noted for their roles in powerful perisomatic inhibition and network oscillations, have gap junctions formed exclusively by connexin 36 subunits which show changes in expression following seizures, and in human and experimental epilepsy. However, only a fraction of the connexin hemichannels form functional connections, leaving open the critical question of whether functional gap junctional coupling between neurons is altered during development of epilepsy. Using a pilocarpine induced status epilepticus (SE) model of acquired temporal lobe epilepsy in rat, this study examined changes in electrical coupling between PV-INs in the hippocampal dentate gyrus one week after SE. Contrary to expectations, SE selectively reduced the probability of electrical coupling between PV-INs without altering coupling coefficient. Both coupling frequency and coupling coefficient between non-parvalbumin interneurons remained unchanged after SE. The early and selective decrease in functional electrical coupling between dentate PV-INs after SE may represent a compensatory mechanism to limit excitotoxic damage of fast-spiking interneurons and network synchrony during epileptogenesis.
Multi-omics computational analysis unveils the involvement of AP-1 and CTCF in hysteresis of chromatin states during macrophage polarization
Authors: Zhang Yubo , Yang Wenbo , Kumagai Yutaro , Loza Martin , Park Sung-Joon , Nakai Kenta
Published: September 2023

Macrophages display extreme plasticity, and the mechanisms and applications of polarization and de/repolarization of macrophages have been extensively investigated. However, the regulation of macrophage hysteresis de/repolarization remains unclear. In this study, by using a large-scale computational analysis of macrophage omics data, we report a list of hysteresis genes that maintain their expression patterns after polarization after ulti- and de/repolarization. While the polarization in M1 macrophages leads to a higher level of hysteresis in genes associated with cell cycle progression, cell migration, and enhancement of the immune response, we found weak levels of hysteresis after M2 polarization. During the polarization process from M0 to M1 and back to M0, the factors IRFs/STAT, AP-1, and CTCF regulate hysteresis by altering their binding sites to the chromatin. Overall, our results show that a history of polarization can lead to hysteresis in gene expression and chromatin changes over a given period. This study contributes to the understanding of de-/repolarization memory in macrophages.
AutoMolDesigner for Antibiotic Discovery: An AI-based Open-source Software for Automated Design of Small-molecule Antibiotics
Authors: Shen Tao , Guo Jiale , Han Zunsheng , Zhang Gao , Liu Qingxin , Si Xinxin , Wang Dongmei , Wu Song , Xia Jie
Published: September 2023

Discovery of small-molecule antibiotics with novel chemotypes serves as one of the essential strategies to address antibiotic resistance. Although a considerable number of computational tools committed to molecular design have been reported, there is a deficit in the holistic and efficient tool specifically developed for small-molecule antibiotic discovery. To address this issue, we report AutoMolDesigner, a computational modeling software dedicated to small-molecule antibiotic design. It is a generalized framework comprising two functional modules, i.e., generative deep learning-enabled molecular generation and automated machine learning based-antibacterial activity/property prediction, wherein individually trained models and curated datasets are out-of-the-box for whole cell-based antibiotic screening and design. It is open-source thus allows for the incorporation of new features for flexible use. Unlike most software programs based on Linux and command lines, this application equipped with Qt-based graphical user interface can be run on personal computers with multiple operating systems, making it much easier to use for experimental scientists. The software and related materials are freely available at GitHub (https://github.com/taoshen99/AutoMolDesigner) and Zenodo (https://zenodo.org/record/8366085).
Nucleotide Excision Repair of Aflatoxin-induced DNA Damage within the 3D Human Genome Organization
Authors: Wu Yiran , Adeel Muhammad Muzammal , Sancar Aziz , Li Wentao
Published: September 2023

Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the two primary risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. We have adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts. We have found that transcription-coupled repair plays a major role in the damage removal process and the released excision products have a distinctive length distribution pattern. We further analyzed the impact of 3D genome organization on the repair of AFB1-induced DNA adducts. We have revealed that chromosomes close to the nuclear center and A compartments undergo expedited repair processes. Notably, we observed an accelerated repair around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced liver cancer.

TEASER

Genome-wide mapping repair of AFB1-caused DNA damage by tXR-seq reveals 3D genome organization’s significant impact on the repair.
Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice
Authors: Guo Zhi-Fu , Tongmuang Nopprarat , Li Chao , Zhang Chen , Hu Louis , Capreri Daniel , Zuo Mei-Xing , Summer Ross , Sun Jianxin
Published: September 2023

Background

Lung endothelium plays a pivotal role in the orchestration of inflammatory and injury responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1), a mammalian homolog of Hippo, is a serine/threonine kinase that is ubiquitously expressed in many tissues and has been shown to play an important role in the regulation of apoptosis, inflammation, stress responses, and organ growth. While Mst1 exhibits high expression in the lung, its involvement in the endothelial response to pulmonary insults remains largely unexplored.

Methods

Mst1 activity was assessed in lung endothelium by western blot. Mst1 endothelial specific knockout mice and a pharmacological inhibitor were employed to assess the effects of Mst1 on homeostatic and lipopolysaccharide (LPS)-induced endothelial responses. Readouts for these studies included various assays, including NF-κB activation and levels of various inflammatory cytokines and adhesion molecules. The role of Mst1 in lung injury was evaluated in a LPS-induced murine model of acute lung injury (ALI).

Results

Mst1 phosphorylation was significantly increased in lung endothelial cells after exposure to tumor necrosis factor (TNF)-alpha (TNF-α) and mouse lung tissues after LPS exposure. Overexpression of full length Mst1 or its kinase domain promoted nuclear factor kappaB (NF-κB) activation through promoting JNK and p38 activation, whereas dominant negative forms of Mst1 (DN-Mst1) attenuated endothelial responses to TNF-α and interleukin-1β. Consistent with this, targeted deletion of Mst1 in lung endothelium reduced lung injury to LPS in mice. Similarly, wild-type mice were protected from LPS-induced lung injury following treatment with a pharmacological inhibitor of Mst1/2.

Conclusions

Our findings identified Mst1 kinase as a key regulator in the control of lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of lung injury to inflammatory insults.
Mechanism of ZNF143 in chromatin looping and 3D genome organization
Authors: Zhang Mo , Huang Haiyan , Li Jingwei , Wu Qiang
Published: September 2023

The transcription factor ZNF143 contains a central domain of seven zinc fingers in a tandem array and is involved in 3D genome construction; however, the mechanism by which ZNF143 functions in chromatin looping remains unclear. Here, we show that ZNF143 directionally recognizes a diverse range of genomic sites within enhancers and promoters and is required for chromatin looping between these sites. In addition, ZNF143 is located between CTCF and cohesin at numerous CTCF sites, and ZNF143 removal narrows the space between CTCF and cohesin. Moreover, genetic deletion of ZNF143, in conjunction with acute CTCF depletion, reveals that ZNF143 and CTCF collaborate to regulate higher-order chromatin organization. Thus, ZNF143 is recruited by CTCF to the CTCF sites to regulate TAD formation, whereas directional recognition of genomic DNA motifs directly by ZNF143 itself regulates promoter activity via chromatin looping.
IMpact of a Point-of care UltraSound Examination on the management of acute respiratory or circulatory failure patients in the emergency department: The IMPULSE before-and-after implementation study
Authors: Bieler Sandra , Tagan Damien , Grosgurin Olivier , Fumeaux Thierry
Published: September 2023

Background

Despite its diagnostic accuracy, the clinical impact of the use of Point-of-care Ultrasound (POCUS) in the emergency department (ED) is not well described, especially when performed by junior in-training residents.

Aim of the study

to assess the effect of a short, structured POCUS training program on the management of ED patients by in-training residents.

Method

IMPULSE is a before-and-after implementation study, evaluating the impact of a structured POCUS training program for ED in-training residents on the management of patients admitted for acute respiratory and/or circulatory failure in a Swiss regional hospital. The training curriculum was organized in three stages and combined an on-line training course, an 8-hour practical hands-on session, and 10 supervised POCUS exams. The ED residents who successfully completed the curriculum participated in the study. Observed outcomes were time to ED diagnosis, rate of correct diagnosis made during the ED stay and time needed to reach it, time to prescribe an appropriate treatment, and hospital mortality. Standard statistical analyses were performed with the use of Chi-square and Mann-Whitney U tests as appropriate, completed by a Bayesian analysis, with a Bayes Factor (BF) > 3 considered as significant.

Results

Sixty-nine patients were included before the training program implementation and 54 after. After implementation, the median time to ED diagnosis was 25 minutes (IQR 44) vs 30 minutes (IQR 56) before implementation, a difference that was significant (BF 9.6). The rate of correct diagnosis was higher (95 vs 52 %) (p<0.001) and the time to make this correct diagnosis was significantly shorter after implementation (25 minutes, IQR 45, vs 43, IQR 60) (BF 5.0). This had an impact on the median time to prescribe the appropriate therapy, with a trend toward a shorter delay (47 minutes, IQR 76, vs 70, IQR 100) (BF 2.0). Eventually, there was a significant difference in hospital mortality (13 % vs 5.5 %, BF 15.7).

Conclusion

the IMPULSE study shows that the implementation of a short, structured POCUS training program for ED residents to use ultrasound for the initial evaluation of acute respiratory and circulatory failure patients has an impact on diagnostic accuracy, on time to make a correct diagnosis and to prescribe an appropriate therapy, and eventually possibly on hospital mortality. If these results are reproduced in other settings, POCUS use by ED residents after short, structured training curriculum could become the standard of care for these patients.
Evaluating Performance of Near-Term Influenza Forecasters Across Consecutive Seasons
Authors: Nagraj VP , Williams Desiree , Turner Stephen D.
Published: September 2023

Near-term forecasting efforts for seasonal influenza (flu) aim to enable better public health preparedness before, during, and after each season. The FluSight initiative has fostered flu forecasting activities since 2013. In 2021-22, the organizers switched the primary target to incident weekly flu hospitalizations at state, territorial, and national levels in the United States. Here we studied the performance of contributors who submitted forecasts for this target during the 2021-22 and 2022-23 seasons. We found that forecasters generally did not perform consistently across locations within seasons. For the select group of forecasters who submitted to both seasons, the overall performance relative to one another was not always consistent either. However, several forecasters, including the FluSight ensemble, were among the top performers in both seasons.
Endemic means change as SARS-CoV-2 evolves
Authors: Otto Sarah P. , MacPherson Ailene , Colijn Caroline
Published: September 2023

COVID-19 has become endemic, with dynamics that reflect the waning of immunity and re-exposure, by contrast to the epidemic phase driven by exposure in immunologically naïve populations. Endemic does not, however, mean constant. Further evolution of SARS-CoV-2, as well as changes in behaviour and public health policy, continue to play a major role in the endemic load of disease and mortality. In this paper, we analyse evolutionary models to explore the impact that newly arising variants can have on the short-term and longer-term endemic load, characterizing how these impacts depend on the transmission and immunological properties of variants. We describe how evolutionary changes in the virus will increase the endemic load most for persistently immune-escape variants, by an intermediate amount for more transmissible variants, and least for transiently immune-escape variants. Balancing the tendency for evolution to favour variants that increase the endemic load, we explore the impact of vaccination strategies and non-pharmaceutical interventions (NPIs) that can counter these increases in the impact of disease. We end with some open questions about the future of COVID-19 as an endemic disease.
Factors associated with osteoarthritis in elderly people in Shanghai: A cross-sectional study
Authors: Liang Xueyao , Zheng Bo , Cao Xiyou , Xu Shuangfei , Zhang Qiongmei , Fei Qing , Lu Nanqian , Zhang Kai , Liu Qingchun , Han Ying , Hu Xiaoyin , Wang Weibing , Liu Bing , Li Mengfan , Wu Ying , Zhao Yefeng
Published: September 2023

Background

Osteoarthritis (OA) is a degenerative disease of mostly’ middle-aged and elderly people that contributes a high burden of disease in China and worldwide. However, many putative risk factors associated with OA in elderly populations remain substantially unclear.

Methods

In our cross-sectional study, 2177 residents of the Putuo District of Shanghai aged 40 years and above were recruited to complete a questionnaire that queried basic health information and assessed the prevalence of OA. A non-conditional and an ordinal logistic regression model was used to analyze the associations between putative risk factors and the severity of confirmed OA.

Results

Among 2099 eligible participants, the average age was 65.21 years (41.4% were male), and 551 self-reported OA [prevalence = 26.25% (24.13, 28.51)]. The prevalence of knee OA were the most common (23.11%, 21.12 to 25.23). OA was associated with age ≥ 60 years (aOR = 1.56; 1.18, 2.07), overweight BMI (24∼27.9 kg/m2) (1.30; 1.02 to 1.65), female sex (1.66; 1.30 to 2.12), unmarried status (1.41; 1.03 to 1.90), a family history of OA (6.23; 4.17 to 9.38), two or more comorbidities (2.18; 1.52 to 3.11), and prior injury to any joint (12.02; 4.86 to 31.22).

Conclusions

Old age, Female sex,family history and multiple comorbidities were significant contributors to promote the severity of OA. Appropriate prevention and treatment strategies must be developed to reduce the burden of the disease.