bluuebunny/crossref_metadata_2025 huggingface dataset:
Value-Based Integrated Case Management at Payor Level
Authors: Martin Matthew , Suri Yash , Doebbeling Bradley , Andrew Rachel , Kathol Roger
Published: November 2022

Purpose of Study:

Case management is an ideal service for patients with health complexity. However, most case management models do not integrate medical and behavioral health training and interventions, and there are little data evaluating these models in privately insured populations. The purpose of this study was to evaluate impact of an integrated case management (ICM) service at the payor level.

Primary Practice Setting:

Health care insurance company.

Methodology and Sample:

A multimethod observational study was conducted at a health care insurance company in the Pacific Northwest of the United States. We conducted focus groups of case managers, leaders, and administrators and statistical analyses of outcomes data. Measures included care quality data (discharge follow-up appointment, cost per case, depression and anxiety measures, customer experience and satisfaction, and audit scores) of members receiving ICM services and employee focus group data (acceptability, adoption, feasibility, appropriateness, fidelity, and sustainability) related to the practice of ICM.

Results:

Care quality data suggest ICM reduces mental health symptoms and increases discharge follow-up appointments for members. Implementation challenges include new employee orientation to ICM model, traditional views of case management, performance evaluation, documentation, and information technology. Facilitators of implementation include training, autonomy, and leadership support.

Implications for Case Management Practice:

Organizations should be aware both of the benefits and challenges related to implementing ICM. Open communication between case managers and leadership and an improvement-focused culture appear to be important elements of implementation success. Future research should examine the perspective of members receiving ICM services and the implementation of ICM into health care delivery systems.
Imaging of Malignant Pleural, Pericardial, and Peritoneal Mesothelioma
Authors: Strange Chad D. , Marom Edith M. , Ahuja Jitesh , Shroff Girish S. , Gladish Gregory W. , Carter Brett W. , Truong Mylene T.
Published: November 2022

Malignant mesothelioma is a rare tumor arising from the mesothelial cells that line the pleura, pericardium, peritoneum, and tunica vaginalis. Imaging plays a primary role in the diagnosis, staging, and management of malignant mesothelioma. Multimodality imaging, including radiography, computed tomography (CT), magnetic resonance imaging (MRI), and F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), is used in a variety of scenarios, including diagnosis, guidance for tissue sampling, staging, and reassessment of disease after therapy. CT is the primary imaging modality used in staging. MRI has superior contrast resolution compared with CT and can add value in terms of determining surgical resectability in equivocal cases. MRI can further assess the degree of local invasion, particularly into the mediastinum, chest wall, and diaphragm, for malignant pleural and pericardial mesotheliomas. FDG PET/CT plays a role in the diagnosis and staging of malignant pleural mesothelioma (MPM) and has been shown to be more accurate than CT, MRI, and PET alone in the staging of malignant pleural mesothelioma. PET/CT can also be used to target lesions for biopsy and to assess prognosis, treatment response, and tumor recurrence.
Preprocedure care for outpatients in the cardiac catheterization lab in an acute care hospital in central Mississippi: a best practice implementation project
Authors: McGregor Christy , Palokas Michelle J.
Published: November 2022

Objectives:

The objective of this implementation project was to improve the cardiac catheterization lab multidisciplinary team's compliance with best practices regarding preprocedural care.

Introduction:

The cardiac catheterization lab performs numerous diagnostic and interventional outpatient procedures. Preprocedural care is a crucial step in preparing patients and clinical staff.

Methods:

The JBI Evidence Implementation framework was used for this project. The baseline audit for the project included a review of 30 electronic health records for best practice adherence. The Getting Research into Practice tool guided leadership to increase awareness and compliance to evidence-based practice. A follow-up audit of 30 electronic health records followed implementation of strategies.

Results:

Baseline audit data suggested all best practices combined were only followed at 79%, and revealed the need for improvement in preprocedural phone calls to patients and documentation related to patient education regarding the procedure and expectations for procedure recovery. Four barriers were identified and multiple strategies were implemented in an attempt to improve compliance with evidence-based practices. Follow-up audits showed an overall improvement to 81% after project implementation.

Conclusions:

The project showed improvements with best practices for preprocedural care in the outpatient setting. However, more work remains to obtain sustainability of best practices, including preprocedural assessment undertaken prior to the cardiac catheterization procedure, information provided to the patient prior to the cardiac catheterization procedure explaining the test and expected recovery, and patients receiving a phone call prior to the procedure for reminders of procedural details.
Effects of rising temperature and prescribed fire on Amblyomma Americanum with ehrlichiosis
Authors: Fulk Alexander , Agusto Folashade
Published: November 2022

Ehrlichiosis is a nationally notifiable disease in the United States and the prevalence of this disease, as with other tick-borne diseases, has been increasing since at least the year 2000. One aspect that has likely contributed to the increase in the prevalence of this disease is rising temperatures due to climate change. A promising method for control of tick populations is prescribed burning. In this study we develop a detailed mathematical model of ordinary differential equations to investigate the effect of rising temperatures on Amblyomma americanum populations in endemic and invasion scenarios. We used an impulsive system of ordinary differential equations to investigate the effects of prescribed burning on infectious ticks to determine if prescribed fire remains effective as temperatures increase under endemic and invasion scenarios. We found the following in the absence of prescribed burning: (1) as temperature increases, there are significant increases in the number of infectious questing nymphs and adults. (2) Ehrlichiosis becomes established in the questing nymph and adult tick populations quicker in an invasion scenario as temperature increases. In the presence of prescribed burning, we observed a reduction in the prevalence of infectious questing nymphs and adults. These results with prescribed burning hold regardless of increases in temperature, indicating that that prescribed burning remains an effective control method for Amblyomma americanum even in the case of a significant increase in temperature such as 2 0C and 4 0C.
VACtrac: Enhancing access immunization registry data for population outreach using Bulk Fast Interoperable Healthcare Resource (FHIR) protocol
Authors: Lenert Leslie , Jacobs Jeff , Agnew James , Ding Wei , Kirchoff Katie , Weatherston Duncan , Deans Kenneth
Published: November 2022

COVID-19 vaccination uptake has been suboptimal, even in high-risk populations. This paper describes work to extend the Bulk Fast Healthcare Interoperability Resource (FHIR) standard for use in querying state Immunization Information Systems (IIS). We also describe a population vaccination outreach tool that uses both Bulk FHIR and automated single queries to access IIS data. Bulk FHIR protocols needed to be extended to support IIS’s responses for care outside an institution resulting in the addition of Group and Master Data Management FHIR profile functionalities to Bulk FHIR queries to support more accurate and easier retrieval of data. While real-world testing of Bulk FHIR queries using the vaccination outreach system was not possible, we tested an automated-single-query tool in a focused effort to reach 1500 high-risk patients. Results confirmed the potential for performance problems during periods of high demand that could be resolved by Bulk FHIR’s asynchronous retrieval methods.
Integrating a tailored recurrent neural network with Bayesian experimental design to optimize microbial community functions
Authors: Thompson Jaron C. , Zavala Victor M. , Venturelli Ophelia S.
Published: November 2022

Microbiomes interact dynamically with their environment to perform exploitable functions such as production of valuable metabolites and degradation of toxic metabolites for a wide range of applications in human health, agriculture, and environmental cleanup. Developing computational models to predict the key bacterial species and environmental factors to build and optimize such functions are crucial to accelerate microbial community engineering. However, there is an unknown web of interactions that determine the highly complex and dynamic behaviors of these systems, which precludes the development of models based on known mechanisms. By contrast, entirely data-driven machine learning models can produce physically unrealistic predictions and often require significant amounts of experimental data to learn system behavior. We develop a physically constrained recurrent neural network that preserves model flexibility but is constrained to produce physically consistent predictions and show that it outperforms existing machine learning methods in the prediction of experimentally measured species abundance and metabolite concentrations. Further, we present an experimental design algorithm to select a set of experimental conditions that simultaneously maximize the expected gain in information and target microbial community functions. Using a bioreactor case study, we demonstrate how the proposed framework can be used to efficiently navigate a large design space to identify optimal operating conditions. The proposed methodology offers a flexible machine learning approach specifically tailored to optimize microbiome target functions through the sequential design of informative experiments that seek to explore and exploit community functions.

1

Author summary

The functions performed by microbiomes hold tremendous promise to address grand challenges facing society ranging from improving human health to promoting plant growth. To design their properties, flexible computational models that can predict the temporally changing behaviors of microbiomes in response to key environmental parameters are needed. When considering bottom-up design of microbiomes, the number of possible communities grows exponentially with the number of organisms and environmental factors, which makes it challenging to navigate the microbiome function landscape. To overcome these challenges, we present a physically constrained machine learning model for microbiomes and a Bayesian experimental design framework to efficiently navigate the space of possible communities and environmental factors.
Isolation and Molecular Identification of Endophytic Bacteria fromTylosema esculentum
Authors: Sinyinza Elisha , Chimwamurombe Percy M
Published: November 2022

Tylosema esculentumis a perennial legume that is predominant in Namibia, Botswana, and South Africa. It is rich in nutrients, drought-tolerant, and a climate change contender for future agriculture. The objectives of this study were to isolate and identify culturable bacterial endophytes. Our study assessed the mean CFUs/mL among the tuberous roots, stems, and leaves to determine the density and diversity using ANOVA. It was a quantitatively controlled experiment in which seeds were grown in a greenhouse. The bacteria number varied from 1.29 × 108to 3.5 × 108CFU/ml of broth, with the highest in the tuberous roots and the lowest in the leaves. At a 5% significant level, we revealed that there is a difference among the bacterial densities of the plant parts. Shannon-Weiner diversity showed that there is a higher diversity of bacteria in the tuberous roots. Of the isolates that were obtained, 53.8% belonged toEnterobacter, 15.4% toBacillus, 15.4% toPantoea, and 7.67% toBurkholderia. These discoveries have made us more aware of the endophytic bacteria we now have. These strains might thus be used in food crops to boost productivity, enabling food security, especially in Africa. The significance of the isolates in biological control, agriculture, and biotechnology for growth promotion will be determined by further research.
Interactional roles in research meetings: a combined conversation analytic and quantitative network approach
Authors: Bet Marloes D. A. , Antvelink Aniek R. , van der Burgt Stéphanie M. E. , Peerdeman Saskia M. , Geurts Jeroen J. G. , Lamerichs Joyce , Douw Linda
Published: November 2022

Translational processes that facilitate effective interdisciplinary communication remain a ‘black box’. Here, we aimed to operationalize translational practices by combining conversation analysis and network science to analyze interdisciplinary research meetings. We applied conversation analysis to transcribed meetings, and identified chair, clarifying, skeptical, expert, connecting, and practical actions. For each meeting, we constructed a network (‘meetome’) with team members as nodes, and the number of consecutive speaking turns between members as links. We found that the relative occurrence of role-specific actions correlated with network measures. We discuss how awareness of interactional roles within meetings may help to implement a translational approach in interdisciplinary research teams.
Multiomics characterization of the of the zoo-housed gorilla gut microbiome reveals bacterial community compositions shifts, fungal cellulose-degrading, and archaeal methanogenic activity
Authors: Houtkamp Isabel Mathilde , van Zijll Langhout Martine , Bessem Mark , Pirovano Walter , Kort Remco
Published: November 2022

We carried out a comparative analysis between the bacterial microbiota composition of zoo-housed western lowland gorillas and their wild counterparts through 16S rRNA gene amplicon sequencing. In addition, we characterized the carbohydrate-active and methanogenic potential of the zoo-housed gorilla microbiome through shotgun metagenomics and RNA sequencing. The zoo-housed gorilla microbiota showed increased alpha diversity in terms of bacterial species richness and a distinct composition from that of the wild gorilla microbiota, including a loss of abundant fiber-degrading and hydrogenic Chloroflexi. Metagenomic analysis of the CAZyome indicated predominant oligosaccharide-degrading activity, while RNA sequencing revealed diverse cellulase and hemi-cellulase activities in the zoo-housed gorilla gut, contributing to a total of 268 identified carbohydrate-active enzymes. Metatranscriptome analysis revealed a substantial contribution of 38% of the transcripts from anaerobic fungi and archaea to the gorilla microbiome. This activity originates from cellulose-degrading and hydrogenic fungal species belonging to the class Neocallimastigomycetes, as well as from methylotrophic and hydrogenotrophic methanogenic archaea belonging to the classes Thermoplasmata and Methanobacteria, respectively. Our study shows the added value of RNA sequencing in a multiomics approach and highlights the contribution of eukaryotic and archaeal activities to the gut microbiome of gorillas.
Relationship between thyroid hormones, their associated metabolites, and gene expression bioindicators in the serum ofRana [Lithobates] catesbeianatadpoles and frogs during metamorphosis
Authors: Poulsen Rikke , Jackman Shireen H. , Hansen Martin , Helbing Caren C.
Published: November 2022

Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum ofRana [Lithobates] catesbeiana(n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra,thrb, andthibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3’,5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28±10 and 2.3±0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. Whilethratranscript levels remained constant and then decreased at the end of metamorphic climax,thrbandthibzwere induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.
Fibronectin improves the impaired calcium signaling and myofilament activation in diabetic cardiomyocytes
Authors: Wu Xin , Trzeciakowski Jerome P , Meininger Gerald A , Muthuchamy Mariappan
Published: November 2022

Ventricular remodeling is one of the primary adaptive mechanisms in response to long-term mechanical overload in diabetes. In addition to cardiomyocyte hypertrophy, alterations in noncardiomyocyte compartments [e.g. extracellular matrix (ECM)] are an essential process in the remodeling of ventricle during diabetes. Integrins that link the ECM and intracellular cytoskeleton function as mechanotransducers to translate the mechanical force to intracellular signals. We hypothesize that mechanotransduction mechanisms are altered in diabetic cardiomyopathy mouse hearts. To test this hypothesis, force and intracellular calcium ([Ca2+]i) measurements on papillary muscle fibers were investigated in adult mouse cardiomyocytes from normal (non-db) and type 2 diabetic (db/db) mice. In addition, atomic force microscopy (AFM) was used to measure adhesion force between integrin receptors and ECM protein fibronectin (FN) by quantifying the unbinding force required to break FN-cardiomyocytes (integrin) bonds. In db/db mice, the peak active force decreased at 71% or 73% while the peak of [Ca2+]i decreased at 64% and 68% at 1 Hz or 2 Hz. In the presence of the FN (35 nM), active force was increased significantly by 40-50% in db/db mice. Furthermore, increased active force in the presence of FN was associated with 26-42% increase in [Ca2+]iat all giving stimulations of 1 Hz and 2 Hz in db/db mice, respectively. The increased effects on force and [Ca2+]icaused by FN were greater in ventricular muscles from db/db mice than from non-db mice. The unbinding force between FN (2.7 μM) coated AFM probes and cardiomyocyte in db/db was 52% higher than non-db (58.3 ± 0.3 pNvs38.6 ± 0.9 pN. p < 0.05). The binding probability of FN-cardiomyocytes, calculated as number of force curves with adhesion / number of total force curves sampled, was significantly reduced by 30% in db/db cardiomyocytes when compared to normal. In addition, the cell stiffness, representing changes in Ca2+ signaling and cytoskeletal reorganization, was 19% increase in db/db cardiomyocytes. The presented data indicate that dynamic changes of the mechanical properties of integrin-ECM interactions may contribute to impaired intracellular Ca2+ signaling and myofilament activation in the diabetic cardiomyopathy.
The prevalence of probable mental health disorders among hospital healthcare workers during COVID-19: A systematic review and meta-analysis
Authors: Lee Brian En Chyi , Ling Mathew , Boyd Leanne , Olsson Craig , Sheen Jade
Published: November 2022

Objectives

The mental health impacts of the COVID-19 pandemic continue to be documented worldwide with systematic reviews playing a pivotal role. Here we present updated findings from our systematic review and meta-analysis on the mental health impacts among hospital healthcare workers during COVID-19.

Methods

We searched MEDLINE, CINAHL, PsycINFO, Embase and Web Of Science Core Collection between 1st January 2000 to 17thFebruary 2022 for studies using validated methods and reporting on the prevalence of diagnosed or probable mental health disorders in hospital healthcare workers during the COVID-19 pandemic. A meta-analysis of proportions and odds ratio was performed using a random effects model. Heterogeneity was investigated using test of subgroup differences and 95% prediction intervals.

Results

The meta-analysis included 401 studies, representing 458 754 participants across 58 countries. Pooled prevalence of depression was 28.5% (95%CI: 26.3-30.7), anxiety was 28.7% (95%CI: 26.5-31.0), PTSD was 25.5% (95%CI: 22.5-28.5), alcohol and substance use disorder was 25.3% (95%CI: 13.3-39.6) and insomnia was 24.4% (95%CI: 19.4-29.9). Prevalence rates were stratified by physicians, nurses, allied health, support staff and healthcare students, which varied considerably. There were significantly higher odds of probable mental health disorders in women, those working in high-risk units and those providing direct care.

Limitations

Majority of studies used self-report measures which reflected probable mental health disorders rather than actual diagnosis.

Conclusions

These updated findings have enhanced our understanding of at-risk groups working in hospitals. Targeted support and research towards these differences in mental health risks are recommended to mitigate any long-term consequences.
Whole genome sequencing of 2,023 colorectal cancers reveals mutational landscapes, new driver genes and immune interactions
Authors: Cornish Alex J. , Gruber Andreas J. , Kinnersley Ben , Chubb Daniel , Frangou Anna , Caravagna Giulio , Noyvert Boris , Lakatos Eszter , Wood Henry M. , Arnedo-Pac Claudia , Culliford Richard , Househam Jacob , Cross William , Sud Amit , Law Philip , Ni Leathlobhair Maire , Hawari Aliah , Thorn Steve , Sherwood Kitty , Gül Güler , Fernandez-Tajes Juan , Zapata Luis , Alexandrov Ludmil B. , Murugaesu Nirupa , Sosinsky Alona , Mitchell Jonathan ,   Genomics England Research Consortium, Lopez-Bigas Nuria , Quirke Philip , Church David N , Tomlinson Ian P.M. , Sottoriva Andrea , Graham Trevor A. , Wedge David C. , Houlston Richard S.
Published: November 2022

To characterise the somatic alterations in colorectal cancer (CRC), we conducted whole-genome sequencing analysis of 2,023 tumours. We provide the most detailed high-resolution map to date of somatic mutations in CRC, and demonstrate associations with clinicopathological features, in particular location in the large bowel. We refined the mutational processes and signatures acting in colorectal tumorigenesis. In analyses across the sample set or restricted to molecular subtypes, we identified 185 CRC driver genes, of which 117 were previously unreported. New drivers acted in various molecular pathways, including Wnt (CTNND1, AXIN1, TCF3), TGF-β/BMP (TGFBR1) and MAP kinase (RASGRF1, RASA1, RAF1, and several MAP2K and MAP3K loci). Non-coding drivers included intronic neo-splice site alterations inAPCandSMAD4. Whilst there was evidence of an excess of mutations in functionally active regions of the non-coding genome, no specific drivers were called with high confidence. Novel recurrent copy number changes included deletions ofPIK3R1andPWRN1, as well as amplification ofCCND3andNEDD9. Putative driver structural variants includedBRD4andSOX9regulatory elements, andACVR2AandANKRD11hotspot deletions. The frequencies of many driver mutations, including somatic Wnt and Ras pathway variants, showed a gradient along the colorectum. The Pks-pathogenicE. colisignature andTP53mutations were primarily associated with rectal cancer. A set of unreported immune escape driver genes was found, primarily in hypermutated CRCs, most of which showed evidence of genetic evasion of the anti-cancer immune response. About 25% of cancers had a potentially actionable mutation for a known therapy. Thirty-three of the new driver genes were predicted to be essential, 17 possessed a druggable structure, and nine had a bioactive compound available. Our findings provide further insight into the genetics and biology of CRC, especially tumour subtypes defined by genomic instability or clinicopathological features.
How to determine microbial lag phase duration?
Authors: Opalek Monika , Smug Bogna J. , Wloch-Salamon Dominika
Published: November 2022

The lag phase is a temporary non-replicative period observed when a microbial population is introduced to a new nutrient-rich environment. Its duration can have a pronounced effect on population fitness, and it is often measured in laboratory conditions. However, calculating the lag phase length may be challenging and method and parameters dependent. Moreover, the details of these methods and parameters used throughout experimental studies are often under-reported. Here we discuss the most frequently used methods in experimental and theoretical studies, and we point out some inconsistencies between them. Using experimental and simulated data we study the performance of these methods depending on the frequency of population size measurements, and parameters determining the growth curve shape, such as growth rate. It turns out that the sensitivity to each of these parameters depends on the lag calculation methods. For example, lag duration calculation by parameter fitting to a logistic model is very robust to low frequency of measurements, but it may be highly biased for growth curves with low growth rate. On the contrary, the method based on finding the point where growth acceleration is the highest, is robust to low growth rate, but highly sensitive to low frequency of measurements and the level of noise in the data. Based on our results, we propose a decision tree to choose a method most suited to one’s data. Finally, we developed a web tool where the lag duration can be calculated based on the user-specified growth curve data, and for various explicitly specified methods, parameters, and data pre-processing techniques.

GRAPHICAL ABSTRACT
Inferring a cell’s capabilities from omics data with ImmCellFie
Authors: Masson Helen O. , Borland David , Reilly Jason , Telleria Adrian , Shrivastava Shalki , Watson Matt , Bustillo Luthfi , Li Zerong , Capps Laura , Kellman Benjamin P. , King Zachary A. , Richelle Anne , Lewis Nathan E. , Robasky Kimberly
Published: November 2022

ImmCellFie is a user-friendly, web-based platform for comprehensive analysis of metabolic functions inferred from transcriptomic or proteomic data. It enables researchers to leverage the powerful mechanistic insight provided by complex genome-scale metabolic models with little to no bioinformatics training required. The platform has been integrated with a series of useful tools and richly annotated scientific visualizations for interactive exploration by the user. ImmCellFie pushes beyond simple statistical enrichment and incorporates complex biological mechanisms to quantify cell activity.

Graphical abstract
Functional gradients reveal altered functional segregation in patients with amnestic mild cognitive impairment and Alzheimer’s disease
Authors: He Yirong , Li Qiongling , Fu Zhenrong , Zeng Debin , Han Ying , Li Shuyu
Published: November 2022

Background

Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) are associated with disrupted functional organization in brain networks, yet the finer changes in the topological organization in aMCI and AD remain to be investigated. Connectome gradients are a new tool representing brain functional topological organization in a low-dimensional space to smoothly capture the human macroscale hierarchy.

Methods

Here, we examined altered topological organization in aMCI and AD by connectome gradient mapping. We further quantified functional segregation by gradient dispersion. Then, we systematically compared the alterations observed in aMCI and AD patients with those in normal controls (NCs) in a two-dimensional functional gradient space from both the whole-brain level and module level.

Results

Compared with NCs, the first gradient, which described the neocortical hierarchy from unimodal to transmodal regions, showed a distributed and significant suppression in AD patients, while abnormalities were only limited to local regions in aMCI patients. The second gradient showed a decreased pattern in the somatomotor module in both aMCI and AD patients. Furthermore, gradient dispersion showed significant decreases in AD patients at both the global level and module level, whereas this alteration was limited only to limbic areas in aMCI. Notably, we demonstrated that suppressed gradient dispersion in aMCI and AD patients was associated with cognitive scores.

Conclusions

Changes in functional gradients could reflect different degrees of altered brain network segregation in aMCI and AD. These findings provide new evidence for altered brain hierarchy in aMCI and AD, which strengthens our understanding of the progressive mechanism of cognitive decline.
Subspace partitioning in human prefrontal cortex resolves cognitive interference
Authors: Weber Jan , Iwama Gabriela , Solbakk Anne-Kristin , Blenkmann Alejandro O. , Larsson Pal G. , Ivanovic Jugoslav , Knight Robert T. , Endestad Tor , Helfrich Randolph
Published: November 2022

Human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task-features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task-relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between co-existing representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.
Efficient reliability analysis of spatially resolved transcriptomics at varying resolutions using SpaSEG
Authors: Bai Yong , Guo Xiangyu , Liu Keyin , Zheng Bingjie , Wang Yingyue , Luo Qiuhong , Yin Jianhua , Wu Liang , Li Yuxiang , Zhang Yong , Chen Ao , Xu Xun , Jin Xin
Published: November 2022

Spatially resolved transcriptomics (SRT) for characterizing cellular heterogeneities and activities requires systematic analysis approaches to decipher gene expression variations in physiological contexts. Here we develop SpaSEG, an unsupervised convolutional neural network-based model for multiple SRT analysis tasks by jointly learning the transcriptional similarity of spots and their spatial dependence. SpaSEG adopts an edge strength constraint to encourage spatial domain coherence and allows integrative analysis by automatically aligning the spatial domains across multiple adjacent sections. It also enables the detection of domain-specific gene expression patterns and the inference of intercellular interactions and colocalizations within a tissue. In an invasive ductal carcinoma sample analysis, SpaSEG facilitates the unraveling of intratumor heterogeneity and the understanding of immunoregulatory mechanisms. Through comprehensive evaluation over a collection of SRT datasets generated by different platforms at various resolutions, SpaSEG shows superior reliability and computational efficiency over existing methods, endowing it with a great potential for the exploration of tissue architectures and pathological biology.
A stable reference human transcriptome and proteome as a standard for reproducible omics experiments
Authors: Lu Shaohua , Lu Hong , Zheng Tingkai , Yuan Huiming , Du Hongli , Gao Youhe , Liu Yongtao , Pan Xuanzhen , Zhang Wenlu , Fu Shuying , Sun Zhenghua , Jin Jingjie , He Qing-Yu , Chen Yang , Zhang Gong
Published: November 2022

In recent years, the development of high-throughput omics technology has greatly promoted the development of biomedicine. However, the poor reproducibility of omics techniques limits its application. It is necessary to use standard reference materials of complex RNAs or proteins to test and calibrate the accuracy and reproducibility of omics workflows. However, the transcriptome and proteome of most cell lines shift during culturing, which limits their applicability to serve as standard samples. In this study, we demonstrated that the human hepatocellular cell line MHCC97H has a very stable transcriptome (R2=0.966-0.995) and proteome (R2=0.934-0.976 for DDA, R2=0.942-0.986 for DIA) after 9 subculturing generations, which allows this stable standard sample to be stably produced on an industrial scale for several decades. Moreover, this stability was maintained across labs and platforms. In sum, our results justified a omics standard reference material and reference datasets for transcriptomic and proteomics research. This helps to further standardize the workflow and data quality of omics techniques and thus promotes the application of omics technology in precision medicine.
Pioneer factor Pax7 initiates two-step cell-cycle dependent chromatin opening
Authors: Gouhier Arthur , Dumoulin-Gagnon Justine , Lapointe-Roberge Vincent , Harris Juliette , Balsalobre Aurelio , Drouin Jacques
Published: November 2022

Pioneer transcription factors direct cell differentiation by deploying new enhancer repertoires through their unique ability to target and initiate remodelling of closed chromatin. The initial steps of their action remain undefined although pioneers were shown to interact with nucleosomal target DNA and with some chromatin remodelling complexes. We now define the sequence of events that enable the pioneer Pax7 with its unique abilities. Chromatin condensation exerted by linker histone H1 is the first constraint on Pax7 recruitment, and this establishes the initial speed of chromatin remodelling. The first step of pioneer action involves recruitment of the KDM1A (LSD1) H3K9me2 demethylase for removal of this repressive mark, as well as recruitment of the MLL complex for deposition of the activating H3K4me1 mark. Further progression of pioneer action requires passage through cell division, and this involves dissociation of pioneer targets from perinuclear lamin B. Only then, the SWI/SNF remodeling complex and the coactivator p300 are recruited, leading to nucleosome displacement and enhancer activation. Thus, the unique features of pioneer actions are those occurring in the lamin-associated compartment of the nucleus. This model is consistent with prior work that showed a dependence on cell division for establishment of new cell fates.
Synergy of HLA class I and II shapes the timing of antitumor immune response
Authors: Papp Benjamin Tamás , Fülöp Anna Tácia , Balogh Gergő Mihály , Koncz Balázs , Spekhardt Dóra , Manczinger Máté
Published: November 2022

The presentation of mutated cancer peptides to T cells by human leukocyte antigen (HLA) class I and II molecules is necessary for antitumor immune response. Both classes are diverse and the variants have distinct peptide-binding specificities. HLA class I diversity was suggested to influence antitumor immunity, however, the findings are controversial. We examined the joint effect of the two HLA classes in melanoma patients. Numerous combinations were associated with better or worse survival in metastatic melanoma patients receiving immune checkpoint blockade (ICB) immunotherapy and they also predicted the survival of ICB-naive patients. Carrying detrimental and beneficial combinations had markedly different effects in primary and metastatic samples. Detrimental combinations were associated with cytotoxic immune response in primary tumors, while metastases showed signs of immune evasion and ineffective antitumor immunity. On the contrary, beneficial combinations were associated with an active cytotoxic immune response only in metastatic samples. HLA class I and II variants in both detrimental and beneficial combinations presented melanoma-associated mutations effectively. However, detrimental combinations were more likely to present immunogenic ones. Our results provide evidence of the joint effect of HLA class I and II variants on antitumor immunity. They potentially influence the strength and timing of antitumor immune response with implications on response to therapy and patient survival.
Amplicon sequencing reveals complex infection in infants congenitally infected withTrypanosoma cruziand informs the dynamics of parasite transmission
Authors: Hakim Jill , Waltmann Andreea , Tinajeros Freddy , Kharabora Oksana , Machaca Edith Málaga , Calderon Maritza , Menduiña María del Carmen , Wang Jeremy , Rueda Daniel , Zimic Mirko , Verástegui Manuela , Juliano Jonathan J , Gilman Robert H , Mugnier Monica R. , Bowman Natalie M ,   Chagas working group
Published: November 2022

Congenital transmission ofTrypanosoma cruzi, the causative agent of Chagas disease, is an important source of new infections worldwide. The mechanisms of congenital transmission remain poorly understood, but there is evidence that parasite factors could play a role.

Investigating changes in parasite strain diversity during transmission could provide insight into the parasite factors that influence the process. Here we use deep amplicon sequencing of a single copy gene in theT. cruzigenome to evaluate the diversity of infection in a collection of clinical blood samples from Chagas positive mothers and their infected infants. We found several infants and mothers infected with more than two parasite haplotypes, indicating infection with multiple parasite strains. Two haplotypes were detected exclusively in infant samples, while one haplotype was never found in infants, suggesting a relationship between the probability of transmission and parasite genotype. Finally, we found an increase in parasite population diversity in children after birth compared to their mothers, suggesting that there is no transmission bottleneck during congenital infection and that multiple parasites breach the placenta in the course of congenital transmission.
Germline determinants of the prostate tumor genome
Authors: Houlahan Kathleen E. , Yuan Jiapei , Schwarz Tommer , Livingstone Julie , Fox Natalie S. , Jaratlerdsiri Weerachai , van Riet Job , Taraszka Kodi , Kurganovs Natalie , Zhu Helen , Sietsma Penington Jocelyn , Jung Chol-Hee , Yamaguchi Takafumi N , Jiang Jue , Heisler Lawrence E , Jovelin Richard , Ramanand Susmita G , Bell Connor , O’Connor Edward , Mutambirwa Shingai B.A. , Seo Ji-Heui , Costello Anthony J. , Pomerantz Mark M. , Pope Bernard J. , Zaitlen Noah , Kishan Amar U. , Corcoran Niall M. , Bristow Robert G. , Waszak Sebastian M. , Bornman Riana M.S. , Gusev Alexander , Lolkema Martijn P. , Weischenfeldt Joachim , Hung Rayjean J. , He Housheng H. , Hayes Vanessa M. , Pasaniuc Bogdan , Freedman Matthew L. , Hovens Christopher M. , Mani Ram S. , Boutros Paul C.
Published: November 2022

A person’s germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of individual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates ofTMPRSS2-ERGgene fusions and 67.3% of ancestry-biases in rates ofFOXA1point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.
New insights into CFTR modulation in reproduction: testicular microenvironment imbalance leads to over-activated caspase signalling in spermatogenesis and adversely affects fertility
Authors: Chen Guan-Ru , Chiang Han-Sun , Chung Shiu-Dong , Tseng Xiao-Wen , Rajneesh Chellappan Praveen , Chen Kuo-Chiang , Wang Kuan-Lin , Wu Yi-No
Published: November 2022

Cystic fibrosis transmembrane conductance regulator (CFTR) is a prominent chloride channel that governs mucous secretion in multiple organs, including the reproductive tract. According to earlier reports, defective CFTR results in infertility due to congenital bilateral absence of the vas deferens (CBAVD). However, obstruction in the vas deferens is not the only reason CFTR deficiency causes male infertility. The mechanism underlying the loss of mature sperm owing to CFTR deficiency remains elusive. This study aimed to assess the role of CFTR in spermatogenesis, for which 6- and 8-week-old male mice withCftr+/+,Cftr+/-, andCftr-/-genotypes were chosen. Furthermore, we assessed the correlation between CFTR deficiency and delayed development of the reproductive system, anomalous apoptosis activation in spermatogenesis, and ionic alterations of the testis lumen. The results demonstrated that the growth ofCftr-/-mice were delayed, with underweight reproductive organs and mild hypospermatogenesis. CFTR depletion destabilizes spermatogenesis by producing abnormal sperm and triggers activation of the Bax/Bcl-2 ratio inCftr-/-andCftr+/-mice, causing caspase-mediated irreversible intrinsic apoptosis. Stage-specific apoptosis in germ cells targeted the sexually mature mice, and the testis microenvironment affirmed that ion concentrations influence sperm capacitation. The blood pH determines apoptosis induction, as CFTR is a bicarbonate transporter. In conclusion,Cftr-/-mice were infertile because CFTR deficiency generated an ionic imbalance in the testis lumen, leading to Bax expression and Bcl-2 blockage, which triggered caspases or further activation of voltage-dependent anion-selective channel 1 (VDAC1). Cumulatively, cytochromeCwas released due to altered mitochondrial membrane potential. Eventually, anomalous up-regulated apoptosis activation affected spermatogenesis, thus rendering the Cftr-/-male mice infertile. The results supplied new insights into CFTR modulation in reproduction: an imbalanced testicular microenvironment due to CFTR deficiency affects spermatogenesis and fertility in mice through the overactivation of spermatocyte caspase signalling, thus driving us to focus on updated treatments for CFTR deficiency-caused infertility.
Dynamics of alpha suppression index both modality specific and general attention processes
Authors: Clements Grace M. , Gyurkovics Mate , Low Kathy A. , Kramer Arthur F. , Beck Diane M. , Fabiani M. , Gratton G.
Published: November 2022

EEG alpha power varies under many circumstances requiring visual attention. However, mounting evidence indicates that alpha may not only serve visual processing, but also the processing of stimuli presented in other sensory modalities, including hearing. We previously showed that alpha dynamics during an auditory task vary as a function of competition from the visual modality (Clements et al., 2022) suggesting that alpha may be engaged in multimodal processing. Here we assessed the impact of allocating attention to the visual or auditory modality on alpha dynamics, during the preparatory period of a bimodal-cued conflict task. In this task, precues indicated the modality (vision, hearing) relevant to a subsequent reaction stimulus. This task afforded us the opportunity to assess alpha during modality-specific preparation and while switching between modalities. Alpha suppression following the precue occurred in all conditions indicating that it may reflect general preparatory mechanisms. However, we observed a switch effect when preparing to attend to the auditory modality, in which greater alpha suppression was elicited when switching to the auditory modality compared to repeating. No switch effect was evident when preparing to attend to visual information (although robust suppression did occur in both conditions). In addition, waning alpha suppression preceded error trials, irrespective of sensory modality. These findings indicate that alpha can be used to monitor the level of preparatory attention to process both visual and auditory information. These results support the emerging view that alpha band activity may index a general attention control mechanism used across modalities, at least vision and hearing.
Novel regulatory logic in the antibiotic resistance response ofEnterococcus faecalisagainst cell envelope targeting antibiotics
Authors: Morris Sali M. , Fritz Georg , Rogers Tim , Gebhard Susanne
Published: November 2022

Enterococcal infections frequently show high levels of antibiotic resistance, including to cell envelope-acting antibiotics like daptomycin (DAP). While we have a good understanding of the resistance mechanisms, less is known about the control of such resistance genes in enterococci. Previous work unveiled a bacitracin resistance network, comprised of the sensory ABC transporter SapAB, the two-component system (TCS) SapRS and the resistance ABC transporter RapAB. Interestingly, components of this system have recently been implicated in DAP resistance, a role usually regulated by the TCS LiaFSR. We here explored the interplay between these two regulatory pathways. Our results show the regulation by SapR of an additional resistance operon,dltXABCD, and show that LiaFSR regulates the expression ofsapRS, placing SapRS target genes under dual control:dltXABCDexpression depends on both antibiotic-induced cellular damage (LiaFSR)andthe presence of a substrate drug for the sensory transporter (SapAB). We further show that this network protectsE. faecalisfrom antimicrobials produced by potential competitor bacteria, providing a potential rationale for the evolution of this regulatory strategy. The network structure described here can explain why clinical DAP resistance often emerges via mutations in regulatory components, which may ultimately lead to the discovery of new therapeutic targets.

Graphical abstract