bluuebunny/crossref_metadata_2025 huggingface dataset:
Personalizing the Pressure Reactivity Index for Neurocritical Care Decision Support
Authors: Briggs Jennifer K. , Stroh J.N. , Foreman Brandon , Park Soojin ,   the TRACK-TBI Study Investigators, Bennetty Tellen D. , Albersy David J.
Published: May 2023

Neurocritical care patients may benefit from personalized treatment based on their cerebral autoregulatory function. The pressure reactivity index is an important, prevalent metric used to estimate the state of a patient’s cerebral autoregulation and guide clinical decision-making. However, the pressure reactivity index is highly sensitive to hyperparameter choices and intrapatient variability. In this manuscript, we develop a new personalized pressure reactivity index methodology (pPRx) that increases robustness and reduces the noise of the pressure reactivity index calculation. Using data from traumatic brain injury patients and simulated data, we first show that pressure reactivity index sensitivity to hyperparameters and interpatient variability is large enough to influence clinical interpretation of cerebral autoregulatory function. We identify that patient heart rate is closely related to errors in the pressure reactivity index, which has vital implications for extending the use of PRx to patients with different regular heart rates, such as pediatric populations. We then remove this heart rate-specific sensitivity in the pPRx methodology by adjusting for patient heart rate at resolutions of single heartbeats. Implementing the pPRx methodology decreases error, noise, and sensitivity, and allows the pressure reactivity index to be more robust to variability across patient populations. We also leverage our data and analysis to identify ideal averaging windows in the standard method.
Functional Personalized Treatment of Metastatic Porocarcinoma
Authors: Chan Sharon Pei Yi , Low Chen Ee , Yau Chun En , Lin Tzu Ping , Wang Weining , Xiu Sam Xin , Tang Po Yin , Luo Baiwen , Noor Nur Fazlin Bte Mohamed , Lee Kristen Alexa , Chiang Jianbang , Toh Tan Boon , Chow Edward Kai-Hua , Yang Valerie Shiwen
Published: May 2023

Metastatic porocarcinomas (PC) have high mortality rates of 70%. PC is extremely rare, accounting for 0.01% of malignant cutaneous neoplasms, precluding the possibility of conducting clinical trials to evaluate treatment. Pathogenesis and clinical management of PC remain largely unknown Surgical resection of localized PC remains the mainstay of treatment. There are no effective agents for unresectable PC. Comprehensive genomic profiling did not yield any actionable genomic aberrations in our patient with metastatic PC.Ex vivodrug testing predicted pazopanib efficacy and treatment elicited remarkable clinicoradiological response. A functional precision medicine approach may be effective for the treatment of rare cancers.
Functional filter for whole genome sequence data identifies stress impact, non-coding alternate polyadenylation site variants >5kb from coding DNA
Authors: Xiao Sihao , Kai Zhentian , Murphy Daniel , Li Dongyang , Patel Dilip , Bielowka Adrianna , Bernabeu-Herrero Maria E. , Abdulmogith Awatif , Mumford Andrew D , Westbury Sarah , Aldred Micheala A , Vargesson Neil , Caulfield Mark J ,   Genomics England Research Consortium, Shovlin Claire L
Published: May 2023

Despite whole genome sequencing (WGS), why do many single gene disorder cases remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection? Early WGS data analytic steps prioritize protein-coding sequences. To simultaneously prioritise variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool which integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants per DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3’ untranslated region (UTR) of the proto-oncogeneSMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis. Sited >5.4kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16 nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. MonocyteSMAD4RNA expression differed between patients and controls in resting and cycloheximide-stressed states. Patterns predicted the mutational site for an unrelated case, where a complex insertion was subsequently identified. In conclusion, a new type of functional rare variant is described, exposing novel regulatory systems based on polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.
Closing the Pneumococcal Conjugate Vaccine (PCV) Introduction Gap: An Archetype Analysis of ‘last-mile’ countries
Authors: Banerjee Preetika , Huber Jasmine , Denti Veronica , Sauer Molly , Weeks Rose , Dhaliwal Baldeep K. , Shet Anita
Published: May 2023

Pneumonia remains the leading infectious cause of global childhood deaths, despite the availability of World Health Organization (WHO)-prequalified pneumococcal conjugate vaccine (PCV) products and the evidence of their safety and efficacy for over two decades, along with financial and technical support from Gavi The Vaccine Alliance (Gavi). There are 39 remaining “last-mile” countries (33 low- and middle-income countries [LMICs] and six high-income countries) that haven’t fully included PCV in their National Immunization Programs. To address this inequitable distribution of PCV, we conducted a rapid assessment and landscaping exercise of country indicators related to barriers and facilitators for PCV decision-making, aiming to categorize countries into archetypes that could benefit from shared advocacy approaches. The archetype analysis first created a country matrix focused on three domains - health characteristics, immunization factors, and policy framework - and identified ten related indicators. Countries were scored based on indicator performance and subsequently ranked and grouped into three overarching archetypes of low-, moderate-, and high-barrier to PCV introduction.

15 countries were classified as “low-barrier,” indicating that they have more factors favorable for PCV introduction, such as high immunization coverage of common childhood vaccines, recent “new” vaccine introductions, and supportive governments, as well as substantial disease burden and eligibility for Gavi support. Most of the countries classified in the “moderate-barrier” (12 countries) and “high-barrier” (6 countries) archetypes have strong immunization systems, but competing country priorities and cost barriers impede policy decision-making on PCV introduction. Other countries require strengthening of their health systems despite political will.

The barrier-based categorization can provide an actionable framework to design tailored PCV advocacy that addresses obstacles to new vaccine introductions within these “last-mile” countries. Implementation approaches that emerge from this framework can lead to strengthened decision-making on vaccine introduction and mobilization of investments in vaccine access that can enhance child survival worldwide.
Valve Sparing Aortic Root Replacement: long term predictors of outcomes and mortality
Authors: Sharma Varun J. , Kangarajah Abbie , Yang Amy , Kim Michelle , Seevayanagam Siven , Matalanis George
Published: May 2023

Introduction

In aortic root surgery, Valve Sparing Aortic Root Replacement (VSARR) is an attractive alternative by mitigating the risks inherent to prosthetic valves, however little is known about the variables that impact its performance and durability. We have reviewed our mid to long-term outcomes following VSARR and describe factors that impact patient survival and aortic valve reintervention and insufficiency.

Methods

A retrospective review of 284 consecutive patients undergoing VSARR between November 1999 and January 2022 at Austin Health, Melbourne, Australia, was undertaken, with median follow up of 6.43 ± 4.83 years, but up to 22.0 years.

Results

The median age at intervention was 60.0 years (IQR 48.0-67.0), of which 68 (23.9%) had bicuspid aortic valve (BAV) disease, 27 (9.5%) Marfan’s disease, 119 (41.9%) severe aortic root dilation (>50mm), and 155 (54.6%) severe aortic insufficiency at the time of intervention. The 30-day mortality was 1.8%, with freedom from mortality of 96.0% (95% CI 92.6-97.8%) at 5 years, 88.2% (95% CI 81.4-92.6%) at 10 years and 78.6% (66.2-86.9%) at 15 years. Freedom from aortic re-intervention was 92.2% (95% CI 87.7-95.2%) at 5 years, 79.8% (95% CI 71.8-85.8%) at 10 years, and 74.1% (63.5-82.0%) at 15 years. Predictors of re-intervention were concomitant leaflet repair (HR 8.13, 95%CI 1.07-61.7) and bicuspid valvulopathy (HR 2.23, 95% CI 1.07-4.68). The freedom from aortic insufficiency was 89.1% (95% CI 83.5-92.9%), 84.9% (95% CI 77.8-89.9%) and 80.7% (71.0-87.4%) at 5-, 10- and 15-years respectively.

Conclusion

VSARR has excellent long-term outcomes, with low mortality and re-intervention rates. Concomitant Leaflet repair and Bicuspid Aortopathy are the only long-term predictors of re-intervention.
Application of AMR in evaluating microvascular dysfunction after ST-segment elevation myocardial infarction
Authors: Wang Hao , Wu Qi , Yang Lang , Chen Long , Liu Wen-Zhong , Xu Jing-Song
Published: May 2023

BACKGROUND

Quantitative flow ratio (QFR) is a new method to estimate fractional flow reserve based on three-dimensional quantitative coronary angiography, from which angiography-derived microcirculatory resistance (AMR) without guidewires and adenosine is derived as an indicator of microvascular dysfunction. This study aimed to assess coronary microvascular dysfunction (CMD) in patients with ST-segment elevation myocardial infarction (STEMI) by AMR.

METHODS

A retrospective collection of 506 STEMI patients who successfully underwent percutaneous coronary intervention (PCI) from June 1, 2020, to September 28, 2021, was divided into the CMD group and the non-CMD group based on the value of AMR, while we used propensity score matching (PSM) to adjust for baseline characteristics. The primary endpoint was the 1-year rate of major adverse cardiac events (MACE), a composite of death from any cause, myocardial infarction, readmission for heart failure, or ischemia-driven revascularization.

RESULTS

The 1-year rate of MACE in CMD group was higher than that in the non-CMD group (post-match HR 1.954, 95% CI:1.025 to 3.726; 14.1% vs. 7.3%, P=0.042); Subgroup analysis showed that the readmission rate of heart failure (HF) was higher in the CMD group than in the non-CMD group (post-match HR 5.082, 95% CI:1.471 to 17.554; 7.9% vs. 1.6%. P=0.010). The results of survival analysis suggested that AMR ≥250mmHg*s/m was an independent predictor of the primary endpoint in STEMI patients (post-match adjusted HR 2.265, 95% CI: 1.136 to 4.515, P = 0.020). CONCLUSION: As an indicator of microvascular dysfunction, AMR can be a viable alternative to invasive wire-based IMR in STEMI patients.
Cactus: a user-friendly and reproducible ATAC-Seq and mRNA-Seq analysis pipeline for data preprocessing, differential analysis, and enrichment analysis
Authors: Salignon Jerome , Millan-Arino Lluis , Garcia Maxime , Riedel Christian G.
Published: May 2023

The ever decreasing cost of Next-Generation Sequencing coupled with the emergence of efficient and reproducible analysis pipelines has rendered genomic methods more accessible. However, downstream analyses are basic or missing in most workflows, creating a significant barrier for non-bioinformaticians. To help close this gap, we developed Cactus, an end-to-end pipeline for analyzing ATAC-Seq and mRNA-Seq data, either separately or jointly. Its Nextflow-, container-, and virtual environment-based architecture ensures efficient and reproducible analyses. Cactus preprocesses raw reads, conducts differential analyses between conditions, and performs enrichment analyses in various databases, including DNA-binding motifs, ChIP-Seq binding sites, chromatin states, and ontologies. We demonstrate the utility of Cactus in a multi-modal and multi-species case study as well as by showcasing its unique capabilities as compared to other ATAC-Seq pipelines. In conclusion, Cactus can assist researchers in gaining comprehensive insights from chromatin accessibility and gene expression data in a quick, user-friendly, and reproducible manner.
Serialized On-grid Lift-In Sectioning for Tomography (SOLIST)
Authors: Dung Nguyen Ho Thuy , Perone Gaia , Vazzana Roberta , Don Flaminia Kaluthantrige , Silva Malan , Sorrentino Simona , Swuec Paolo , Leroux Frederic , Kalebic Nereo , Coscia Francesca , Erdmann Philipp S.
Published: May 2023

Cryo-focused ion beam milling has enabled groundbreaking structural discoveries in native cells. Progress toward medically relevant applications, however, has been slow. We here present an adaptation of the cryo-lift out procedure for Serialized On-grid Lift-In Sectioning for Tomography (SOLIST), which increases throughput, reduces ice contamination, and enhances sample stability. With these improvements, new specimens, ranging from high-pressure frozen reconstituted LLPS droplets to human forebrain organoids, are accessible to cryo-electron tomography.
Forest characteristics predict tri-colored bat activity within novel Colorado habitats
Authors: Bevan Zientek Amanda J. , Colpitts Alexandria B. , Adams Rick. A.
Published: May 2023

Climate change and other anthropogenic pressures are altering species distributions. Several studies have indicated that tri-colored bats (Perimyotis subflavus) are extending their distributional range westward in the United States. Montane and subalpine habitats consist of a mosaic of forest types including lodgepole pine woodlands and montane meadows, which provide an opportunity to study how a newly arriving species, typically associated with lowland riparian systems, is adapting to novel environmental conditions. The objective of this study is to document tri-colored bat activity in these novel habitats using acoustic surveys and to quantify what factors are influencing activity patterns in habitats and at elevations not previously documented. We selected sites at 2700m elevation that differed in stand structure, driven primarily by beetle kill outbreaks, and were in various stages of secondary succession. We used acoustic monitoring to model habitat activity patterns using nonparametric multiplicative regression. Results showed that tri-colored bats used meadows and lodgepole pine stands undergoing secondary succession following bark beetle outbreaks. Activity was highest in meadows and early time-since-kill (TSK) forests in the beginning of the survey period, and tri-colored bats had increased activity in late TSK forest habitats at the end of the survey period in early August. Temporally, activity was lowest during the middle of the survey period (mid-July) indicating that tri-colored bats moved away from our study area. However, activity significantly returned by the end of the survey. Our study demonstrates that tri-colored bats are not restricting their activity to lower elevation riparian areas in the Colorado foothills, but instead appear to be using high elevation habitat types in areas dominated by lodgepole pine and subalpine meadows. We hope this study will support conservation efforts for this species following the proposed U.S. Fish and Wildlife Service listing.
Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhihepatic macrophages
Authors: Sato Ryota , Liu Kaiwen , Shibata Takuma , Hoshino Katsuaki , Yamaguchi Kiyoshi , Miyazaki Toru , Hiranuma Ryosuke , Fukui Ryutaro , Motoi Yuji , Fukuda-Ohta Yuri , Zhang Yun , Reuter Tatjana , Ishida Yuko , Kondo Toshikazu , Chiba Tomoki , Asahara Hiroshi , Taoka Masato , Yamauchi Yoshio , Isobe Toshiaki , Kaisho Tsuneyasu , Furukawa Yoichi , Latz Eicke , Miyake Kensuke
Published: May 2023

Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhihepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clomacrophages activated the transcription factors LXRα and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently,Rnaset2−/−mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses inRnaset2−/−mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages inRnaset2−/−mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages.

Graphical Abstract

In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine.
Foldy: a web application for interactive protein structure analysis
Authors: Roberts Jacob B. , Nava Alberto A. , Pearson Allison N. , Incha Matthew R. , Valencia Luis E. , Ma Melody , Rao Abhay , Keasling Jay D.
Published: May 2023

Foldy is a cloud-based application that allows non-expert scientists to easily access and utilize advanced AI-based structural biology tools, including AlphaFold and DiffDock. Built on Kubernetes, it can be deployed by universities, departments, and labs without requiring hardware resources, but can also be configured to utilize available computers. Foldy enables scientists to predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock.

Our manuscript describes the user interface and deployment considerations of Foldy, as well as some of our applications. By democratizing access to sophisticated AI-based tools, Foldy can facilitate life science research and promote the wider adoption of structural bioinformatics tools. Our work demonstrates that even the most advanced tools can be made accessible to a broad audience through user-friendly platforms like Foldy, and we believe it will be a valuable resource for researchers across scientific disciplines. The public structures available on the Lawrence Berkeley Labs Foldy deployment can be viewed athttps://foldy.lbl.gov.

Author Summary

Foldy is a cloud-based application that enables scientists to use AI-based structural biology tools such as AlphaFold and DiffDock without software expertise. Built on Kubernetes, it can be set up by universities, departments, and labs with no need for hardware resources. Foldy can predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock. Our public structures can be viewed athttps://foldy.lbl.gov.

Our manuscript highlights the user interface, deployment considerations, and product applications of Foldy. It’s an accessible solution for researchers who are not software experts and can handle the traffic of thousands of users and hundreds of thousands of protein structures and docked ligands. This makes advanced AI-based tools more widely available, paving the way for accelerating life science research.

By developing an easy-to-use platform, our work demonstrates that even the most sophisticated AI-based tools can be made accessible to a wide audience. Foldy enables more scientists to draw from the rapidly growing field of structural biology, making it a valuable tool for researchers across scientific disciplines. We look forward to its adoption by the scientific community.
Hybrid computational modeling highlights reverse Warburg effect in breast cancer-associated fibroblasts
Authors: Aghakhani Sahar , Silva-Saffar Sacha E , Soliman Sylvain , Niarakis Anna
Published: May 2023

Cancer-associated fibroblasts (CAFs) are key players of the tumor microenvironment (TME) involved in cancer initiation, progression, and resistance to therapy. These cells exhibit aggressive phenotypes affecting, among others, extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining an asynchronous cell- and disease-specific regulatory Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, considering our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.

All analyses are compiled and thoroughly annotated in Jupyter notebooks and R scripts available on a GitLab repository (https://gitlab.com/genhotel/breast-cafs-reverse-warburg-effect) and a Zenodo permanent archive [1].
The early macrophage response to pathogens requires dynamic regulation of the nuclear paraspeckle
Authors: Azam Sikandar , Armijo Kaitlyn S. , Weindel Chi G. , Devigne Alice , Nakagawa Shinichi , Hirose Tetsuro , Carpenter Susan , Watson Robert O. , Patrick Kristin L.
Published: May 2023

To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages needs to be exquisitely well-controlled. There is a growing appreciation for stress-responsive membraneless organelles (MLOs) regulating various steps of eukaryotic gene expression in response to extrinsic cues. Here, we implicate the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on theNeat1lncRNA, in tuning innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophage paraspeckles rapidly aggregate (0.5 h post-stimulation) and disaggregate (2h post-stimulation). Paraspeckle maintenance and aggregation require active transcription and MAPK signaling whereas paraspeckle disaggregation requires degradation ofNeat1via the nuclear RNA exosome. Expression of a large cohort of cytokines, chemokines, and antimicrobial mediators is compromised in lipopolysaccharide-treated macrophages lackingNeat1, resulting in a failure to express a cohort of pro-inflammatory cytokines, chemokines, and antimicrobial mediators. Consequently,Neat1KO macrophages cannot control replication ofSalmonella entericaserovar Typhimurium or vesicular stomatitis virus. These findings highlight a prominent role for MLOs in orchestrating the macrophage response to pathogens and support a model whereby dynamic assembly and disassembly of paraspeckles reprograms the nuclear RNA binding protein landscape to enable inflammatory gene expression following innate stimuli.

SIGNIFICANCE STATEMENT

To mount appropriate immune responses and fight infection, macrophages need to sense and respond to pathogen-associated signals with incredible precision. Membraneless organelles (MLOs) are complexes of RNAs and proteins that change in size, shape, and abundance in response to extracellular signals. We hypothesized that an MLO called the nuclear paraspeckle helps macrophages initiate and calibrate innate immune gene expression during infection. We found that paraspeckles rapidly aggregate and then dissolve in macrophages following pathogen sensing. Macrophages lacking paraspeckles cannot properly induce inflammatory genes, resulting in a failure to control replication of intracellular bacterial and viral pathogens. These data suggest that altered paraspeckle dynamics may dysregulate inflammatory gene expression in a variety of human diseases.
Baldur: Bayesian hierarchical modeling for label-free proteomics exploiting gamma dependent mean-variance trends
Authors: Berg Philip , Popescu George
Published: May 2023

Due to its simplicity in sample preparation, label-free quantification has become de facto in proteomics research at the expense of precision. We propose a Bayesian hierarchical decision model to test for differences in means between conditions for proteins, peptides, and post-translation modifications. We introduce a novel Bayesian regression model to characterize local mean-variance trends in the data to describe measurement uncertainty and to estimate the decision model hyperparameters. Our model vastly improves over state-of-the-art methods (Limma-Trend and t-test) in several spike-in datasets by having competitive performance in detecting true positives while showing superiority by greatly reducing false positives.
Engineering Ca2+-dependent DNA polymerase activity
Authors: Biggs Bradley W. , de Paz Alexandra M. , Bhan Namita J. , Cybulski Thaddeus R. , Church George M. , Tyo Keith E. J.
Published: May 2023

Advancements in synthetic biology have provided new opportunities in biosensing with applications ranging from genetic programming to diagnostics. Next generation biosensors aim to expand the number of accessible environments for measurement, increase the number of measurable phenomena, and improve the quality of the measurement. To this end, an emerging area in the field has been the integration of DNA as an information storage medium within biosensor outputs, leveraging nucleic acids to record biosensor state over time. However, slow signal transduction steps, due to the timescales of transcription and translation, bottleneck many sensing-DNA recording approaches. DNA polymerases (DNAPs) have been proposed as a solution to the signal transduction problem by operating as both the sensor and responder, but there is presently a lack of DNAPs with functional sensitivity to many desirable target ligands. Here, we engineer components of the Pol δ replicative polymerase complex ofSaccharomyces cerevisiaeto sense and respond to Ca2+, a metal cofactor relevant to numerous biological phenomena. Through domain insertion and binding site grafting to Pol δ subunits, we demonstrate functional allosteric sensitivity to Ca2+. Together, this work provides an important foundation for future efforts in developing DNAP-based biosensors.
A common flanking variant is associated with enhanced meiotic stability of theFGF14-SCA27B locus
Authors: Pellerin David , Gobbo Giulia Del , Couse Madeline , Dolzhenko Egor , Dicaire Marie-Josée , Rebelo Adriana , Roth Virginie , Wandzel Marion , Bonnet Céline , Ashton Catherine , Lamont Phillipa J. , Laing Nigel G. , Renaud Mathilde , Ravenscroft Gianina , Houlden Henry , Synofzik Matthis , Eberle Michael A. , Boycott Kym M. , Pastinen Tomi ,   All of Us Long Reads Working Group, Brais Bernard , Zuchner Stephan , Danzi Matt C.
Published: May 2023

The factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed theFGF14-SCA27B (GAA)•(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5’-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present nearly exclusively on alleles with fewer than 30 GAA-pure repeats and was associated with enhanced meiotic stability of the repeat locus.
Cost-effectiveness of a telemonitoring program in patients with cardiovascular diseases compared to standard of care
Authors: Ziegler Andreas , Öner Alper , Quadflieg Gisela , Betschart Raphael O , Thiéry Alexandre , Babel Hugo , Mwambi Henry G , Neumeyer Henriette , Mackschin Steffen , Hintz Sissy , Mann Miriam , Dittrich Hermann , Schmidt Christian
Published: May 2023

Objectives

The main aim of this work was to analyze the cost-effectiveness of an integrated care concept (NICC) that combines telemonitoring with the support of a care center in addition to guideline therapy for patients. Secondary aims were to compare health utility and health-related quality of life (QoL) between NICC and standard of care (SoC).

Methods

The randomized controlled CardioCare MV trial compared NICC and SoC in patients from Mecklenburg-West Pomerania (Germany) with atrial fibrillation, heart failure, or treatment-resistant hypertension. QoL was measured using the EQ-5D-5L at baseline, 6 months, and 1 year follow-up. Quality-adjusted life-years (QALY), EQ5D utility scores, visual analogue scale (VAS) scores, and VAS adjusted life-years (VAS-AL) were calculated. Cost data were obtained from health insurance companies, and the payer perspective was taken in health economic analyses. Quantile regression was used with adjustments for stratification variables.

Results

The net benefit of NICC (QALY) was 0.031 (95%CI: 0.012–0.050; p=0.001) in this trial involving 957 patients. EQ5D index values, VAS-ALs and VAS were larger for NICC compared to SoC at 1 year follow-up (all p≤0.004). Direct cost per patient and year were €323 (CI: €157–489) lower in the NICC group. When 2000 patients are served by the care center, NICC is cost-effective if one is willing to pay 10,652€ per QALY per year.

Conclusion

NICC was associated with higher QoL and health utility. The program is cost-effective if one is willing to pay approximately 11,000€ per QALY per year.

WHAT IS ALREADY KNOWN ON THIS TOPIC

Integrated care concepts, i.e., the combination of telemedicine and the reinforcement of patient self-care in a multidisciplinary team together with telephone support, reduce mortality, morbidity, and levels of depression in patients with cardiovascular diseases.

WHAT THIS STUDY ADDS

The integrated care concept investigated in the CardioCare MV trial was also associated with higher quality of life, higher health utility, and it is cost-effective if one is willing to pay approximately 11,000 € per quality-adjusted life-year (QALY).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

With the demonstrated cost effectiveness of the integrated care concept, policy makers and health insurance companies are enabled to decide on the introduction of these concepts as standard of care.
Integrative single-nucleus multi-omics analysis prioritizes candidatecisandtransregulatory networks and their target genes in Alzheimer’s disease brains
Authors: Gamache Julia , Gingerich Daniel , Shwab E. Keats , Barrera Julio , Garrett Melanie E. , Hume Cordelia , Crawford Gregory E. , Ashley-Koch Allison E. , Chiba-Falek Ornit
Published: May 2023

Background

The genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.

Methods

Here, we present the largestparallelsingle-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) andcisco-accessibility networks (CCANs).

Results

Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype specific candidatecisregulatory elements (cCREs), their candidate target genes, andtrans-interacting transcription factors (TFs), some of which were LOAD-DEG, for example,ELK1in excitatory neurons (Exc1) andKLF13andJUN, found in multiple cell subtypes. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs including,APOEandMYO1Ein a specific subtype of microglia andBIN1in a subpopulation of oligodendrocytes.

Conclusions

To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings revealed crosstalk between epigenetic, genomic, and transcriptomic determinates of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specificcis-transinteractions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.
Highly pathogenic avian influenza causes mass mortality in Sandwich tern (Thalasseus sandvicensis) breeding colonies across northwestern Europe
Authors: Knief Ulrich , Bregnballe Thomas , Alfarwi Ibrahim , Ballmann Mónika , Brenninkmeijer Allix , Bzoma Szymon , Chabrolle Antoine , Dimmlich Jannis , Engel Elias , Fijn Ruben , Fischer Kim , Hälterlein Bernd , Haupt Matthias , Hennig Veit , Herrmann Christof , in ‘t Veld Ronald , Kirchhoff Elisabeth , Kristersson Mikael , Kühn Susanne , Larsson Kjell , Larsson Rolf , Lawton Neil , Leopold Mardik , Lilipaly Sander , Lock Leigh , Marty Régis , Matheve Hans , Meissner Włodzimierz , Morisson Paul , Newton Stephen , Olofsson Patrik , Packmor Florian , Pedersen Kjeld T. , Redfern Chris , Scarton Francesco , Schenk Fred , Scher Olivier , Serra Lorenzo , Smith Julian , Smith Wez , Sterup Jacob , Stienen Eric , Strassner Viola , Valle Roberto G. , van Bemmelen Rob S. A. , Veen Jan , Vervaeke Muriel , Weston Ewan , Wojcieszek Monika , Courtens Wouter
Published: May 2023

Abstract

In 2022, highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b became enzootic and caused mass mortality in Sandwich terns and other seabird species across northwestern Europe. We present data on characteristics of the spread of the virus between breeding colonies and the number of dead adult Sandwich terns recorded at breeding sites throughout northwestern Europe. Within two months after the first mortalities were reported, in total 20,531 adult Sandwich terns were found dead, which is >17% of the total northwestern European breeding population. Losses are likely higher, as we expect that many victims were not found (mortality rate might be up to 74% of the breeding population). Inside the colonies almost all chicks died. After the peak of the outbreak, in a colony established by late breeders, 25.7% of adults showed immunity against HPAI subtype H5. Removal of carcasses helped in reducing the spread of the disease and consequently total mortality. More research on the sources and modes of transmission, incubation times, effective containment and immunity is urgently needed to combat this major threat for colonial seabirds.
Population genomics of harbour sealPhoca vitulinafrom northern British Columbia through California and comparison to the Atlantic subspecies
Authors: Sutherland Ben J. G. , Rycroft Claire , Duguid Ashtin , Beacham Terry D. , Tucker Strahan
Published: May 2023

The harbour sealPhoca vitulinais a ubiquitous pinniped species found throughout coastal waters of the Northern Hemisphere. Harbour seal impacts on ecosystem dynamics may be significant due to their high abundance and food web position. Two subspecies exist in North America,P. v. richardiiin the Pacific Ocean, andP. v. vitulinain the Atlantic. Strong natal philopatry of harbour seals can result in fine-scale genetic structure and isolation-by-distance. Management of harbour seals is expected to benefit from improved resolution of seal population structure and dynamics. Here we use genotyping-by-sequencing to genotype 146 harbour seals from the eastern Pacific Ocean (i.e., British Columbia (BC), Oregon, and California) and the western Atlantic Ocean (i.e., Québec, Newfoundland, and Labrador). Using 12,742 identified variants, we confirm the recently identified elevated genetic diversity in the eastern Pacific relative to the western Atlantic and greatest differentiation between the subspecies. Further, we demonstrate that this is independent of reference genome bias or other potential technical artefacts. Coast-specific analyses with 8,933 and 3,828 variants in Pacific and Atlantic subspecies, respectively, identify divergence between BC and Oregon-California, and between Québec and Newfoundland-Labrador. Unexpected PCA outlier clusters were observed in two populations due to cryptic relatedness of individuals; subsequently, closely related samples were removed. Admixture analysis indicates an isolation-by-distance signature where Oregon seals contained some of the BC signature, whereas California did not. Additional sampling is needed in the central and north coast of BC to determine whether a discrete separation of populations exists within the region.
MsQuality – an interoperable open-source package for the calculation of standardized quality metrics of mass spectrometry data
Authors: Naake Thomas , Rainer Johannes , Huber Wolfgang
Published: May 2023

Motivation

Multiple factors can impact accuracy and reproducibility of mass spectrometry data. There is a need to integrate quality assessment and control into data analytic workflows.

Results

TheMsQualitypackage calculates 40 low-level quality metrics based on the controlled mzQC vocabulary defined by the HUPO-PSI on a single mass spectrometry-based measurement of a sample. It helps to identify low-quality measurements and track data quality. Its use of community-standard quality metrics facilitates comparability of quality assessment and control (QA/QC) criteria across datasets.

Availability

The R packageMsQualityis available through Bioconductor athttps://bioconductor.org/packages/MsQuality.

Contact

naake@embl.de

Supplementary information

Supplementary data are available online.
How Older Adults Regulate Lateral Stepping on Narrowing Walking Paths
Authors: Kazanski Meghan E. , Cusumano Joseph P. , Dingwell Jonathan B.
Published: May 2023

Walking humans often navigate complex, varying walking paths. To reduce falls, we must first determine how older adults purposefully vary their steps in contexts that challenge balance. Here, 20 young (21.7±2.6 yrs) and 18 older (71.6±6.0 yrs) healthy adults walked on virtual paths that slowly narrowed (from 45 cm to as narrow as 5 cm). Participants could switch onto an “easier” path whenever they chose. We applied our Goal Equivalent Manifold framework to quantify how participants adjusted their lateral stepping variability and step-to-step corrections of step width and lateral position as these paths narrowed. We also extracted these characteristics where participants switched paths. As paths narrowed, all participants reduced their lateral stepping variability, but older adults less so. To stay on the narrowing paths, young adults increasingly corrected step-to-step deviations in lateral position more, by correcting step-to-step deviations in step widthless. Conversely, as older adults also increasingly corrected lateral position deviations, they did sowithoutsacrificing correcting step-to-step deviations in step width, presumably to preserve balance. While older adults left the narrowing paths sooner, several of their lateral stepping characteristics remained similar to those of younger adults. While older adults largely maintained overall walking performanceper se, they did so by changing how they balanced the competing stepping regulation requirements intrinsic to the task: maintaining position vs. step width. Thus, balancing how to achieve multiple concurrent stepping goals while walking provides older adults the flexibility they need to appropriately adapt their stepping on continuously narrowing walking paths.
Demographic effects of aggregation in the presence of a component Allee effect
Authors: Jorge Daniel C.P. , Martinez-Garcia Ricardo
Published: May 2023

Intraspecific interactions are key drivers of population dynamics because they establish relations between individual fitness and population density. The component Allee effect is defined as a positive correlation between any fitness component of a focal organism and population density, and it can lead to positive density dependence in the population per capita growth rate. The spatial population structure is key to determining whether and to which extent a component Allee effect will manifest at the demographic level because it determines how individuals interact with one another. However, existing spatial models to study the Allee effect impose a fixed spatial structure, which limits our understanding of how a component Allee effect and the spatial dynamics jointly determine the existence of demographic Allee effects. To fill this gap, we introduce a spatially-explicit theoretical framework where spatial structure and population dynamics are emergent properties of the individual-level demographic and movement rates. Depending on the intensity of the individual-level processes the population exhibits a variety of spatial patterns, including evenly spaced aggregates of organisms, that determine the demographic-level by-products of an existing individual-level component Allee effect. We find that aggregation increases population abundance and allows populations to survive in harsher environments and at lower global population densities when compared with uniformly distributed organisms. Moreover, aggregation can prevent the component Allee effect from manifesting at the population level or restrict it to the level of each independent group. These results provide a mechanistic understanding of how component Allee effects might operate for different spatial population structures and show at the population level. Because populations subjected to demographic Allee effects exhibit highly nonlinear dynamics, especially at low abundances, our results contribute to better understanding population dynamics in the presence of Allee effects and can potentially inform population management strategies.
The clathrin adaptor AP-1B independently controls proliferation and differentiation in the mammalian intestine
Authors: Duclos Maela , Bourdais Anne , Nicolle Ophélie , Michaux Grégoire , Bidaud-Meynard Aurélien
Published: May 2023

Maintenance of the polarity of the epithelial cells facing the lumen of the small intestine is crucial to ensure the vectorial absorption of nutrients as well as the integrity of the apical brush border and the intestinal barrier. Polarized vesicular trafficking plays a key role in this process, and defective transport due to mutations in apical trafficking-related genes has been shown to affect nutrient absorption. Interestingly, it has been demonstrated that downregulation of the polarized sorting clathrin adaptor AP-1B led to both epithelial polarity and proliferation defects in the mouse intestine. This enlightened a new function of polarized trafficking in the gut epithelium and a novel link between trafficking, polarity, and proliferation. Here, using CRISPR-Cas9-mediated mutation of the AP-1B coding geneAp1m2in mouse intestinal organoids, we uncovered a novel proliferation pathway controlled by AP-1B. We showed that the polarity defects induced byAp1m2mutations led to a defective apical targeting of both Rab11+apical recycling endosomes and of the polarity determinant Cdc42. Moreover, we showed that these polarity defects were accompanied by an induction of YAP and EGFR/mTOR-dependent proliferation pathways. Finally, we showed that AP-1B additionally controlled a proliferation-independent differentiation pathway towards the secretory lineage. Overall, our results highlighted the pleiotropic roles played by AP-1B in the homeostasis of the gut epithelium.
Towards substitution of invasive telemetry: An integrated home cage concept for unobstrusive monitoring of objective physiological parameters in rodents
Authors: Mösch Lucas , Kunczik Janosch , Breuer Lukas , Merhof Dorit , Gass Peter , Potschka Heidrun , Zechner Dietmar , Vollmar Brigitte , Tolba René , Häager Christine , Bleich André , Czaplik Michael , Pereira Carina Barbosa
Published: May 2023

This study presents a novel concept for a smart cage designed to monitor the physiological parameters of mice and rats in animal-based experiments. The system focuses on monitoring key clinical parameters, including heart rate, respiratory rate, body temperature, activity, and circadian rhythm. To create the smart home cage system, an in-depth analysis of the requirements was performed, including camera positioning, imaging system types, resolution, frame rates, external illumination, video acquisition, data storage, and synchronization. Two different camera perspectives were considered, and specific camera models, including two near-infrared and two thermal cameras, were selected to meet the requirements. During the first testing phase, the system demonstrated the potential of extracting vital parameters such as respiratory and heart rate. This technology has the potential to reduce the need for implantable sensors while providing reliable and accurate physiological data, leading to refinement and improvement in laboratory animal care.