bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive Ventilation for Acute Respiratory Failure in Pediatric Patients: A Systematic Review and Meta-Analysis
Authors: Boghi Daniele , Kim Kyung Woo , Kim Jun Hyun , Lee Sang-Il , Kim Ji Yeon , Kim Kyung-Tae , Ambrosoli Andrea , Guarneri Giovanni , Landoni Giovanni , Cabrini Luca
Published: December 2022

OBJECTIVE:

To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) on the use of noninvasive ventilation (NIV) for acute respiratory failure (ARF) in pediatric patients.

DATA SOURCES:

We searched PubMed, EMBASE, the Cochrane Central Register of Clinical Trials, and Clinicaltrials.gov with a last update on July 31, 2022.

STUDY SELECTION:

We included RCTs comparing NIV with any comparator (standard oxygen therapy and high-flow nasal cannula [HFNC]) in pediatric patients with ARF. We excluded studies performed on neonates and on chronic respiratory failure patients.

DATA EXTRACTION:

Baseline characteristics, intubation rate, mortality, and hospital and ICU length of stays were extracted by trained investigators.

DATA SYNTHESIS:

We identified 15 RCTs (2,679 patients) for the final analyses. The intubation rate was 109 of 945 (11.5%) in the NIV group, and 158 of 1,086 (14.5%) in the control group (risk ratio, 0.791; 95% CI, 0.629–0.996; p = 0.046; I
2 = 0%; number needed to treat = 31). Findings were strengthened after removing studies with intervention duration shorter than an hour and after excluding studies with cross-over as rescue treatment. There was no difference in mortality, and ICU and hospital length of stays.

CONCLUSIONS:

In pediatric patients, NIV applied for ARF might reduce the intubation rate compared with standard oxygen therapy or HFNC. No difference in mortality was observed.
GERD after Peroral Endoscopic Myotomy: Assessment of Incidence and Predisposing Factors
Authors: Rassoul Abu-Nuwar Mohamad , Eriksson Sven E , Sarici Inanc S , Zheng Ping , Hoppo Toshitaka , Jobe Blair A , Ayazi Shahin
Published: December 2022

BACKGROUND:

Peroral endoscopic myotomy (POEM) is an effective intervention for achalasia, but GERD is a major postoperative adverse event. This study aimed to characterize post-POEM GERD and identify preoperative or technical factors impacting development or severity of GERD.

STUDY DESIGN:

This is a retrospective review of patients who underwent POEM at our institution. Favorable outcome was defined as postoperative Eckardt score of 3 or less. Subjective GERD was defined as symptoms consistent with reflux. Objective GERD was based on a DeMeester score greater than 14.7 or Los Angeles grade C or D esophagitis. Severe GERD was defined as a DeMeester score greater than 50.0 or Los Angeles grade D esophagitis Preoperative clinical and objective data and technical surgical elements were compared between those with and without GERD. Multivariate logistic analysis was performed to identify factors associated with each GERD definition.

RESULTS:

A total of 183 patients underwent POEM. At a mean ± SD follow-up of 21.7 ± 20.7 months, 93.4% achieved favorable outcome. Subjective, objective, and severe objective GERD were found in 38.8%, 50.5%, and 19.2% of patients, respectively. Of those with objective GERD, 24.0% had no reflux symptoms. Women were more likely to report GERD symptoms (p = 0.007), but objective GERD rates were similar between sexes (p = 0.606). The independent predictors for objective GERD were normal preoperative diameter of esophagus (odds ratio [OR] 3.4; p = 0.008) and lower esophageal sphincter (LES) pressure less than 45 mmHg (OR 1.86; p = 0.027). The independent predictors for severe objective GERD were LES pressure less than 45 mmHg (OR 6.57; p = 0.007) and obesity (OR 5.03; p = 0.005). The length of esophageal or gastric myotomy or indication of procedure had no impact on the incidence or severity of GERD.

CONCLUSION:

The rate of pathologic GERD after POEM is higher than symptomatic GERD. A nonhypertensive preoperative LES is a predictor for post-POEM GERD. No modifiable factors impact GERD after POEM.
Succinivibrio faecicola sp. nov., isolated from cow faeces
Authors: Choi Ji Young , Park Jam-Eon , Choi Seung-Hyeon , Kim Ji-Sun , Lee Jung-Sook , Lee Ju Huck , Kim Hyeun Bum , Lee Ju-Hoon , Kim Jae-Kyung , Kang Se Won , Park Seung-Hwan
Published: December 2022

A Gram-stain-negative, obligately anaerobic, non-motile, non-spore-forming, helical rod-shaped bacterium, designated AGMB01872T, was isolated from faeces of a cow deposited in the National Institute of Animal Science (Wanju, Republic of Korea). Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain AGMB01872T was most closely related to

Succinivibrio dextrinosolvens

DSM 3072T (= KCTC 25222T, 96.6 %) which belonged to the family

Succinivibrionaceae

. Growth was occurred at 30–40 °C (optimum, 37 °C), pH 6–7 (optimum, pH 7) and in the presence of 0.5–1.0 % (w/v) NaCl. The genomic DNA G+C content of strain AGMB01872T was 35.9 mol%. The average nucleotide identity value between strain AGMB01872T and

S. dextrinosolvens

DSM 3072T was 72.1 %. Cells of strain AGMB01872T utilized d-glucose, maltose, d-xylose and l-arabinose. The major fatty acids (>10 %) were C14 : 0 (23.9 %), C16 : 0 (29.4 %), summed feature 5 (10.8 %) and summed feature 10 (30.3 %). The major end-product of glucose fermentation was succinate. Based on the phenotypic, phylogenetic, biochemical, genotypic and chemotaxonomic data, AGMB01872T represents a novel species within the genus

Succinivibrio

, for which the name Succinivibrio feacicola sp. nov. is proposed. The type strain is AGMB01872T (= KCTC 25201T=NBRC 115007T=GDMCC 1.2573T).
JMM Profile: Japanese encephalitis virus: an emerging threat
Authors: Sewgobind Sanam , Johnson Nicholas , Mansfield Karen Louise
Published: December 2022

Japanese encephalitis (JE) is an infection that occurs predominantly in Asia and the Pacific Islands. It is transmitted by mosquito bites, with the main vector being Culex tritaeniorhynchus, and is maintained in enzootic cycles involving pigs, wild birds and mosquitoes. JE is caused by infection with Japanese encephalitis virus (JEV), a zoonotic pathogen that also causes disease in mammals such as pigs and horses. In humans, most symptoms are mild or flu-like but can progress to encephalitis. Pigs are considered amplification hosts, and sows may have gestational complications. Horses may exhibit neurological signs. Detection of the virus can be confirmed by serological or molecular laboratory tests. Vaccination offers protection against JEV infection in humans, pigs and horses. Whilst there is no effective treatment of JE, human cases may require hospitalization for supportive therapy, which may include administration of fluids, oxygen and medication to treat symptoms.
Aminoacyl-tRNA synthetase evolution within the dynamic tripartite translation system of plant cells
Authors: Sloan Daniel B. , DeTar Rachael A. , Warren Jessica M.
Published: December 2022

Eukaryotes maintain separate protein translation systems for nuclear and organellar genes, including distinct sets of tRNAs and aminoacyl-tRNA synthetases (aaRSs). In animals, mitochondrial-targeted aaRSs are expressed at lower levels and are less conserved in sequence than cytosolic aaRSs involved in translation of nuclear mRNAs, likely reflecting lower translational demands in mitochondria. In plants, translation is further complicated by the presence of plastids, which share most aaRSs with mitochondria. In addition, plant mitochondrial tRNA pools have a dynamic history of gene loss and functional replacement by tRNAs from other compartments. To investigate the consequences of these distinctive features of translation in plants, we analyzed sequence evolution in angiosperm aaRSs. In contrast to previously studied eukaryotic systems, we found that plant organellar and cytosolic aaRSs exhibit only a small difference in expression levels, and organellar aaRSs are slightlymoreconserved than cytosolic aaRSs. We hypothesize that these patterns result from high translational demands associated with photosynthesis in mature chloroplasts. We also investigated aaRS evolution inSileneae, an angiosperm lineage with extensive mitochondrial tRNA replacement and aaRS retargeting. We predicted positive selection for changes in aaRS sequence resulting from these recent changes in subcellular localization and tRNA substrates but found little evidence for accelerated sequence divergence. Overall, the complex tripartite translation system in plant cells appears to have imposed more constraints on the long-term evolutionary rates of organellar aaRSs compared to other eukaryotic lineages, and plant aaRS protein sequences appear largely robust to more recent perturbations in subcellular localization and tRNA interactions.
Impaired Barrier Integrity of the Skeletal Muscle Vascular Endothelium Drives Progression of Cancer Cachexia
Authors: Kim Young-Mee , Sanborn Mark A. , Wang Xinge , Mancinelli Georgina , Chakraborty Sreeparna , Vijeth Shaluah , Gajwani Priyanka , Grippo Paul , Lee Steve Seung-Young , Valyi-Nagy Tibor , Toth Peter T. , Valyi-Nagy Klara , Rehman Jalees
Published: December 2022

Cancer patients experience cachexia, which is characterized by extensive skeletal muscle wasting that worsens the quality of life and increases mortality. Currently, there are no approved treatments that can effectively counteract cancer cachexia. Vascular endothelial cells (ECs) are essential for maintaining tissue perfusion, nutrient supply, and preventing inappropriate transmigration of immune cells into the tissue. However, little is known about the role of the muscle vasculature in cancer cachexia. We hypothesized that endothelial dysfunction in the skeletal muscle mediates cancer cachexia. Using transgenic pancreatic ductal adenocarcinoma (PDAC) mice and a tissue clearing and high-resolution 3D-tissue imaging approach, we found that the loss of skeletal muscle vascular density precedes the loss of muscle mass. Importantly, we show that cancer cachexia patients exhibit significantly decreased muscle vascular density and severe muscle atrophy when compared to non-cancer patients. Unbiased single cell transcriptomic analyses of the muscle endothelium unveiled a unique EC population present in cachexia muscles. Increased circulating Activin-A suppresses the expression of the transcriptional co-activator PGC1α in the muscle endothelium, thus disrupting junctional integrity in the vasculature and increasing vascular leakage. Conversely, restoration of endothelial-specific PGC1α prevented the decreased vascular density and muscle loss observed in tumor-bearing mice. Our study suggests that EC-PGC1α is essential for maintaining the integrity of the skeletal muscle vascular barrier and that restoring muscle endothelial function could be a valuable therapeutic approach to prevent or reverse cancer cachexia.
Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk
Authors: Chapman S. P. , Duprez E. , Remy E.
Published: December 2022

Primary myelofibrosis is an untreatable age-related disorder of haematopoiesis in which a break in the crosstalk between progenitor Haematopoietic Stem Cells (HSCs) and neighbouring mesenchymal stem cells causes HSCs to rapidly proliferate and migrate out of the bone marrow. 90% of patients harbour mutations in driver genes that all converge to overactivate hematopoietic JAK-STAT signalling, which is thought to be critical for disease progression, as well as microenvironment modification induced by chronic inflammation. The trigger to the initial event is unknown but dysregulated thrombopoietin (TPO) and Toll-Like Receptor (TLR) signalling are hypothesised to initiate chronic inflammation which then disrupts stem cell crosstalk. Using a systems biology approach, we have constructed an inter and intracellular logical model that captures JAK-STAT signalling and key crosstalk channels between haematopoietic and mesenchymal stem cells. The aim of the model is to decipher how TPO and TLR stimulation can perturb the bone marrow microenvironment and dysregulate stem cell crosstalk. The model predicted conditions in which the disease was averted and established for both wildtype and ectopically JAK mutated simulations. The presence of TPO and TLR are both required to disturb stem cell crosstalk and result in the disease for wildtype. TLR signalling alone was sufficient to perturb the crosstalk and drive disease progression for JAK mutated simulations. Furthermore, the model predicts the probability of disease onset for wildtype simulations that matches clinical data. These predictions might explain why patients who test negative for the JAK mutation can still be diagnosed with PMF, in which continual exposure to TPO and TLR receptor activation may trigger the initial inflammatory event that perturbs the bone marrow microenvironment and induce disease onset.
Quantifying B-cell Clonal Diversity In Repertoire Data
Authors: Pelissier Aurelien , Luo Siyuan , Stratigopoulou Maria , Guikema Jeroen EJ , Martinez Maria Rodriguez
Published: December 2022

The adaptive immune system has the extraordinary ability to produce a broad range of immunoglobulins that can bind a wide variety of antigens. During adaptive immune responses, activated B cells duplicate and undergo somatic hypermutation in their B-cell receptor (BCR) genes, resulting in clonal families of diversified B-cells that can be related back to a common ancestor. Advances in high-throughput sequencing technologies have enabled the high-throughput characterization of B-cell repertoires, however, the accurate identification of clonally related BCR sequences remains a major challenge. In this study, we compare three different clone identification methods on both simulated and experimental data, and investigate their impact on the characterization of B-cell diversity. We find that different methods may lead to different clonal definitions, which in turn can affect the quantification of clonal diversity in repertoire data. Interestingly, we find the Shannon entropy to be overall the most robust diversity index in regard to different clonal identification. Our analysis also suggests that the traditional germline gene alignment-based method for clonal identification remains the most accurate when the complete information about the sequence is known, but that alignment-free methods may be preferred for shorter read length. We make our implementation freely available as a Python librarycdiversity.
Leveraging a machine learning derived surrogate phenotype to improve power for genome-wide association studies of partially missing phenotypes in population biobanks
Authors: McCaw Zachary R. , Gao Jianhui , Lin Xihong , Gronsbell Jessica
Published: December 2022

Within population biobanks, genetic discovery for specialized phenotypes is often limited by incomplete ascertainment. Machine learning (ML) is increasingly used to impute missing phenotypes from surrogate information. However, imputing missing phenotypes can invalidate statistical inference when the imputation model is misspecified, and proxy analysis of the ML-phenotype can introduce spurious associations. To overcome these limitations, we introduce SynSurr, an approach that jointly analyzes a partially missing target phenotype with a “synthetic surrogate”, its predicted value from an ML-model. SynSurr estimates the same genetic effect as standard genome-wide association studies (GWAS) of the target phenotype, but improves power provided the synthetic surrogate is correlated with the target. Unlike imputation or proxy analysis, SynSurr does not require that the synthetic surrogate is obtained from a correctly specified generative model. We perform extensive simulations and an ablation analysis to compare SynSurr with existing methods. We also apply SynSurr to empower GWAS of dual-energy x-ray absorptiometry traits within the UK Biobank, leveraging a synthetic surrogate composed of bioelectrical impedance and anthropometric traits.
Art therapy is associated with a reduced rate of restrictive practices on an inpatient child and adolescent mental health unit
Authors: Versitano Sarah , Shvetcov Artur , Paton Joy , Perkes Iain
Published: December 2022

Background

The elimination of seclusion and restraint, that is, restrictive practices, is a major aim of mental health services globally. The role of art therapy, a predominantly non-verbal mode of creative expression, is under-explored in this context.

Aims

To determine whether art therapy service provision was associated with a reduction in restrictive practices on an acute inpatient child and adolescent mental health services (CAMHS) unit.

Methods

The rate (events per 1,000 occupied bed days), frequency (percent of admitted care episodes with incident), duration, and total number of incidents of restrictive practices occurring between July 2015 – December 2021 were analysed in an ABAB design. The rate, frequency and number of incidents of intramuscular injected (IM) sedation, oral PRN (as-needed medication) use, and absconding incidents occurring in conjunction with an episode of seclusion or restraint were also analysed.

Results

The rate, frequency, duration, and total number of incidents of seclusion, the frequency and total number of incidents of physical restraint, and the rate, frequency and total number of incidents of IM sedation showed a statistically significant decrease during phases of art therapy service provision.

Conclusions

Art therapy service provision is associated with reduced use of restrictive practices in inpatient CAMHS.
Early human lung immune cell development and its role in epithelial cell fate
Authors: Barnes Josephine L. , He Peng , Yoshida Masahiro , Worlock Kaylee B. , Lindeboom Rik G.H. , Suo Chenqu , Pett J. Patrick , Wilbrey-Clark Anna , Dann Emma , Mamanova Lira , Richardson Laura , Oliver Amanda J. , Pennycuick Adam , Allen-Hyttinen Jessica , Herczeg Iván T. , Hynds Robert E. , Teixeira Vitor H. , Haniffa Muzlifah , Lim Kyungtae , Sun Dawei , Rawlins Emma L. , Polanski Krzysztof , Lyons Paul A. , Marioni John C. , Tuong Zewen Kelvin , Clatworthy Menna R. , Reading James L. , Janes Sam M. , Teichmann Sarah A. , Meyer Kerstin B. , Nikolić Marko Z.
Published: December 2022

During human development, lungs develop their roles of gas exchange and barrier function. Recent single cell studies have focused on epithelial and mesenchymal cell types, but much less is known about the developing lung immune cells, although the airways are a major site of mucosal immunity after birth. An open question is whether tissue-resident immune cells play a role in shaping the tissue as it developsin utero. In order to address this, we profiled lung immune cells using scRNAseq, smFISH and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including ILCs, NK, myeloid cells and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes high in cytotoxicity genes, and mature B lymphocytes, including B1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the abundance of immune cells, we investigated their possible effect on epithelial maturation and found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cellsin vitro.In vivo, IL-1β-producing myeloid cells were found adjacent to epithelial tips, suggesting that immune cells may direct the developing lung epithelium.
Strategies and experimental tips for optimized quantitative single-molecule studies of membrane and membrane-associated proteins
Authors: Magrassi Raffaella , Picollo Alessandra , Diaspro Alberto , Zanacchi Francesca Cella
Published: December 2022

The study of stoichiometry and supra-molecular organization of membrane (and membrane-associated) proteins plays a key role in understanding membrane structure and function. Single-molecule localization techniques (SML), besides providing imaging at unprecedented resolution, also offer quantitative tools such as stepwise photobleaching (SP) experiments and quantitative single-molecule localization (qSMLM). SML is becoming widely present in imaging core facilities but addressing biological problems by molecular counting experiments still remains not straightforward since experimental approaches for sample preparation require particular attention.

We will focus on the experimental aspects that may prevent successful quantitative SML experiments of membrane-associated proteins.

Depending on the specific experiment, to avoid artifacts and to miscount, fine-tuning of the expression levels and proper staining procedures are required, as well as optimized protocols and controls for counting.

The work aims to highlight the crucial aspects that must be faced when quantitative single-molecule experiments are performed, helping to match the gap between sample preparation and the application of quantitative fluorescence microscopy techniques.
A theory of physiological similarity in muscle-driven motion
Authors: Labonte David
Published: December 2022

Muscle contraction is the primary source of all animal movement. I show that the maximum mechanical output of such contractions is determined by a characteristic dimensionless number, the “effective inertia”, Γ, defined by a small set of mechanical, physiological and anatomical properties of the interrogated musculoskeletal complex. Different musculoskeletal systems with equal Γ may be consideredphysiologically similar, in the sense that maximum performance involves equal fractions of the muscle’s maximum strain rate, strain capacity, work and power density. I demonstrate that there exists a unique, “optimal” musculoskeletal anatomy which enables a unit volume of muscle to deliver maxi-mum work and power simultaneously, corresponding to Γ close to unity. External forces truncate the mechanical performance space accessible to muscle by introducing parasitic losses, and subtly alter how musculoskeletal anatomy modulates muscle performance, challenging canonical notions of skeletal force-velocity trade-offs. Γ varies systematically under isogeometric transformations of musculoskeletal systems, a result which yields new fundamental insights into the key determinants of animal locomotor performance across scales.
Systematic engineering of plant cytochrome P450 system identifies a comprehensive strategy for expression of highly functional P450 enzymes inEscherichia coli
Authors: Poborsky Michal , Crocoll Christoph , Motawie Mohammed Saddik , Halkier Barbara Ann
Published: December 2022

Cytochrome P450s catalyse diverse and unique chemical reactions, which makes them invaluable enzymes in nature and industry. Metabolic engineers leverage these unique catalytic properties when refactoring plant biosynthetic pathways into microbial cell factories. However, due to their hydrophobic anchor, microbial expression of membrane-bound cytochrome P450s is challenging. An arsenal of protein engineering strategies was developed to improve their expression inEscherichia coli, but extensive screening is often necessary to tailor the engineering approach to an individual enzyme. Here, we propose a universal strategy that allows the expression of highly active cytochrome P450s inE. coliby systematically evaluating six common N-terminal modifications and their effect onin vivoactivity of enzymes from the CYP79 and CYP83 families. We identified transmembrane domain truncation as the only strategy that had a significantly positive effect on all seven tested enzymes, increasing product titres between 2- to 170-fold. When comparing the changes in protein titre and product generation, we show that higher expression does not always translate to higherin vivoactivity, thus making protein titre an unreliable screening target. Our results demonstrate that transmembrane domain truncation improvesin vivoactivity across a broad range of cytochrome P450s with diverse N-terminal sequences and could be applied as the modification-of-choice to avoid the time-consuming screening process and accelerate the future design ofE. colicell factories.
Evaluation of a scalable approach to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells
Authors: Dillard Luke J , Rosenow Will T , Calabrese Gina M , Mesner Larry D , Al-Barghouthi Basel M , Abood Abdullah , Farber Emily A , Onengut-Gumuscu Suna , Tommasini Steven M , Horowitz Mark A , Rosen Clifford J , Yao Lutian , Qin Ling , Farber Charles R
Published: December 2022

Genome-wide association studies (GWASs) have revolutionized our understanding of the genetics of complex diseases, such as osteoporosis; however, the challenge has been converting associations to causal genes. Studies have demonstrated the utility of transcriptomics data in linking disease-associated variants to genes; though for osteoporosis, few population transcriptomics datasets have been generated on bone or bone cells, and an even smaller number have profiled individual cell-types. To begin to evaluate approaches to address this challenge, we profiled the transcriptomes of bone marrow-derived stromal cells (BMSCs) cultured under osteogenic conditions, a popular model of osteoblast differentiation and activity, from five Diversity Outbred (DO) mice using single-cell RNA-seq (scRNA-seq). The goal of the study was to determine if BMSCs could serve as a model for the generation of cell-type specific transcriptomic profiles of mesenchymal lineage cells derived from large populations of mice to inform genetic studies. We demonstrate that dissociation of BMSCs from a heavily mineralized matrix had little effect on viability or their transcriptomic signatures. Furthermore, we show that BMSCs cultured under osteogenic conditions are diverse and consist of cells with characteristics of mesenchymal progenitors, marrow adipogenic lineage precursors (MALPs), osteoblasts, osteocyte-like cells, and immune cells. Importantly, all cells were nearly identical from a transcriptomic perspective to cells isolated directly from bone. We also demonstrated the ability to multiplex single cells and subsequently assign cells to their “mouse-of-origin” using demultiplexing approaches based on genotypes inferred from coding SNPs. We employed scRNA-seq analytical tools to confirm the biological identity of profiled cell-types. SCENIC was used to reconstruct gene regulatory networks (GRNs) and we showed that identified cell-types show GRNs expected of osteogenic and pre-adipogenic lineage cells. Further, CELLECT analysis showed that osteoblasts, osteocyte-like cells, and MALPs captured a significant component of BMD heritability. Together, these data suggest that BMSCs cultured under osteogenic conditions coupled with scRNA-seq can be used as a scalable and biologically informative model to generate cell-type specific transcriptomic profiles of mesenchymal lineage cells in large mouse, and potentially human, populations.
Armed to the teeth: the underestimated diversity in tooth shape in snakes and its relationship to feeding constraints
Authors: Segall Marion , Houssin Céline , Delapré Arnaud , Cornette Raphaël , Milgram Joshua , Shahar Ron , Herrel Anthony , Dumont Maïtena
Published: December 2022

Teeth are one of the most studied hard tissues in vertebrates. Their structure, composition and shape are related to dietary specialization in many species. At first glance, snake teeth all look similar; conical, sharp, curved. Yet, snakes, like other vertebrates, have very diverse diets that may have affected their shape. We compared the morphology of the teeth of 63 species that cover both the phylogenetic and dietary diversity of snakes. We predicted that prey properties play a role in shaping snakes teeth along with their feeding behavior. Limblessness combined to the peculiar feeding behavior of snakes impose strong functional constraints on their teeth, especially during arboreal or aquatic feeding. Our results show that prey hardness, foraging substrate and the main feeding constraint are drivers of tooth shape, size, and curvature. We highlight two main morphotypes: long, slender, curved with a thin layer of hard tissue for snakes that need a good grip on their prey and short, stout, less curved teeth in snakes that eat hard or long prey. Our study demonstrates the diversity of tooth morphology in snakes and the need to investigate the underlying functional implications to better understand the evolution of teeth in vertebrates.
Turtle body size evolution is determined by lineage-specific specializations rather than global trends
Authors: Farina Bruna M. , Godoy Pedro L. , Benson Roger B.J. , Langer Max C. , Ferreira Gabriel S.
Published: December 2022

Organisms display considerable variety of body sizes and shapes, and macroevolutionary investigations help to understand the evolutionary dynamics behind to such variations. Turtles (Testudinata) show great body size disparity, especially when their rich fossil record is accounted for. We explored body size evolution in turtles, testing which factors might influence the observed patterns and evaluating the existence of long-term directional trends. We constructed the most comprehensive body size dataset for the group to date, tested for correlation with paleotemperature, estimated ancestral body sizes, and performed macroevolutionary model-fitting analyses. We found no evidence for directional body size evolution, even when using very flexible models, thereby rejecting the occurrence of Cope’s rule. We also found no significant effect of paleotemperature on overall through-time body size patterns. In contrast, we found a significant influence of habitat preference on turtle body size. Freshwater turtles display a rather homogenous body size distribution through time. In contrast, terrestrial and marine turtles show more pronounced variation, with terrestrial forms being restricted to larger body sizes, up to the origin of testudinids in the Cenozoic, and marine turtles undergoing a reduction in body size disparity after the extinctions of many groups in the mid-Cenozoic. Our results therefore suggest that long-term, generalized patterns are probably explained by factors specific to certain groups and related at least partly to habitat use.
Preclinical development of non-viral gene therapy for patients with advanced pancreatic cancer
Authors: Barbey Odile , Lulka Hubert , Hanoun Naima , Belhadj-Tahar Hafid , Vernejoul Fabienne , Cambois Gilles , Tiraby Michèle , Buscail Louis , Gross Fabian , Cordelier Pierre
Published: December 2022

Pancreatic ductal adenocarcinoma remains one of the greatest challenges in oncology for which therapeutic intervention is urgently needed. We demonstrated that the intratumoral gene transfer of somatostatin receptor 2, to combat tumor aggressiveness, or of deoxycytidine kinase and uridylate monophosphate kinase, to sensitize to gemcitabine chemotherapy, has antitumoral potential. Here, we describe the development of CYL-02 non-viral gene-therapy product, that comprises a DNA-plasmid encoding for the three aforementioned genes complexed with PolyEthylEnimine (22 kDa). In this work, we performed preclinical toxicology, biodistribution and therapeutic activity studies of CYL-02 in experimental models of pancreatic cancer. We demonstrated the safety of CYL-02 and defined the maximal tolerated dose in two animal species. CYL-02 co-administrated with gemcitabine did not increase gemcitabine toxicity. Biodistribution studies revealed that CYL-02 is rapidly cleared from blood following intravenous administration, and sequestered in tumors following intratumoral injection. CYL-02 drives the expression of therapeutic genes in cancer cells and strongly sensitizes tumor cells to gemcitabine, with significant inhibition of tumor cells dissemination. This study was instrumental for the later use of CYL-02 in patients with advanced pancreatic cancer, demonstrating that rigorous and thorough preclinical investigations are informative for the clinical transfer of gene therapy against pancreatic cancer.

GRAPHICAL ABSTRACT
Comparingin silicoandin vitromethods for classification of BCS II and CYP3A4 and MDR-1 substrate specificity
Authors: Fagerholm Urban
Published: December 2022

Background

Previous work has shown considerable laboratory variability of Biopharmaceutics Classification System (BCS) classification, efflux ratio in intestinal cell lines and cytochrome P450 (CYP450)-metabolism pathways. Such variability and inconsistency create uncertainty in predictions of human clinical pharmacokinetics and the pharmacokinetic optimization process and is a problem when developing correspondingin silicomethods.

Objectives and Methodology

One objective of the study was to quantify the degree of laboratory inconsistency for BCS II-classing, MDR-1 and CYP3A4 substrate specificity (substrate/non-substrate). Another objective was to predict BCS II-classing, MDR-1 and CYP3A4 substrate specificity usingin silicomethodology and compare results to laboratory data/classifications.

Results and Discussion

27 BCS II-classified drugs (with non-contradictory BCS-classing in various sources) were found. 17 (63 %) had anin vivofraction absorbed (fa) of ≥90 % and belong toin vivoBCS I. Within silicomethodology, 74 % correct BCS-classing was reached for the same set of compounds. The mean prediction error for fawas 1.2-fold. MDR-1 and CYP3A4 substrate specificities were collected for 346 and 808 compounds, respectively. For MDR-1, 143 of the compounds had reported data in at least two studies, and out of these, 49 (34 %) and 18 (13 %) had contradictory (reported as both substate and non-substrate) and uncertain substrate specificities, respectively. For CYP3A4, 42 (9.8 %) out of 427 compounds showed inconsistency between laboratories. Within silicomethodology, MDR-1 and CYP3A4 classification predictions were incorrect for 13 and 15 % of compounds.

Conclusion

The results show considerable variability/inconsistency for BCS II-classing (63 % inconsistency between BCS II-classing andin vivofa) and MDR-1 (34 % inconsistency between sources) and CYP3A4 (10 % inconsistency between sources) substrate specificities. Corresponding estimates obtained within silicomethodology are 22, 13 and 15 %, respectively, demonstrating the power and applicability of such technology.
Steroid hormone imbalance drives macrophage infiltration andSpp1/osteopontin+foam cell differentiation in the prostate
Authors: Popovics Petra , Skalitzky Kegan O. , Schroeder Elise , Jain Asha , Silver Samara V. , Van Fritz Francesca , Uchtmann Kristen S. , Vezina Chad M. , Ricke William A.
Published: December 2022

Benign Prostatic Hyperplasia (BPH) occurs progressively with aging in men and drives deteriorating symptoms collectively known as Lower Urinary Tract Symptoms (LUTS). Age associated changes in circulating steroid hormones, and prostate inflammation have been postulated in the etiology of BPH/LUTS. The link between hormones and inflammation in the development of BPH/LUTS is conflicting because they may occur independently or as sequential steps in disease pathogenesis. This study aimed to decipher the prostatic immune landscape in a mouse model of lower urinary tract dysfunction (LUTD). Steroid hormone imbalance was generated by the surgical implantation of testosterone (T) and estradiol (E2) pellets to male C57BL/6J mice and gene expression analysis was performed on ventral prostates (VP). These experiments identified an increase in the expression of macrophage markers andSpp1/osteopontin (OPN). Localization studies of OPN pinpointed that OPN+ macrophages travel to the prostate lumen and transition into lipid accumulating foam cells. We also observed a significantly increased number of tissue macrophages in the VP which was prevented in OPN knockout (OPN-KO) mice. In contrast, mast cells, but not macrophages, were significantly elevated in the dorsal prostate of T+E2 treated mice which was diminished in OPN-KO mice. Steroid hormone implantation progressively increased urinary frequency, which was ameliorated in OPN-KO mice. Our study underscores the role of age associated steroid hormone imbalances as a mechanism of expanding the prostatic macrophage population, their luminal translocation and foam cell differentiation.
Predicting the prevalence of complex genetic diseases from individual genotype profiles using capsule networks
Authors: Luo Xiao , Kang Xiongbin , Schönhuth Alexander
Published: December 2022

Diseases that have a complex genetic architecture tend to suffer from considerable amounts of genetic variants that, although playing a role in the disease, have not yet been revealed as such. Two major causes for this phenomenon are genetic variants that do not stack up effects, but interact in complex ways; in addition, as recently suggested, the omnigenic model postulates that variants interact in a holistic manner to establish disease phenotypes.

We present DiseaseCapsule, as a capsule network based approach that explicitly addresses to capture the hierarchical structure of the underlying genome data, and has the potential to fully capture the non-linear relationships between variants and disease. DiseaseCapsule is the first such approach to operate in a whole-genome manner when predicting disease occurrence from individual genotype profiles.

In experiments, we evaluated DiseaseCapsule on amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD), with a particular emphasis on ALS because known known to have a complex genetic architecture, so being affected by considerable missing heritability (40%). On ALS, Disease-Capsule achieves 86.9% accuracy on held out test data in predicting disease occurrence, thereby outperforming all other approaches by large margins. Also, DiseaseCapsule required sufficiently less training data for reaching optimal performance. Last but not leaset, the systematic exploitation of the network architecture yielded 922 genes of particular interest, and 644 ”non-additive” genes that are crucial factors in DiseaseCapsule, but have no effect within linear schemes.
ohun: an R package for diagnosing and optimizing automatic sound event detection
Authors: Araya-Salas Marcelo , Smith-Vidaurre Grace , Chaverri Gloriana , Brenes Juan C. , Chirino Fabiola , Elizondo-Calvo Jorge , Rico-Guevara Alejandro
Published: December 2022

Animal acoustic signals are widely used in diverse research areas due to the relative ease with which sounds can be registered across a wide range of taxonomic groups and research settings. However, bioacoustics research can quickly generate large data sets, which might prove challenging to analyze promptly. Although many tools are available for the automated detection of sounds, choosing the right approach can be difficult only a few tools provide a framework for evaluating detection performance. Here we presentohun, an R package intended to facilitate automated sound detection.ohunprovides functions to diagnose and optimize detection routines and compare performance among different detection approaches. The package uses reference annotations containing the time position of target sounds in a training data set to evaluate detection routines performance using common signal detection theory indices. This can be done both with routine outputs imported from other software and detections run within the package. The package also provides functions to organize acoustic data sets in a format amenable to detection analyses. ohun also includes energy-based and template-based detection methods, two commonly used automatic approaches in bioacoustic research. We show how ohun automatically can be used to detect vocal signals with case studies of adult male zebra finch (Taenopygia gutata) songs and Spix’s disc-winged bat (Thyroptera tricolor) ultrasonic social calls. We also include examples of how to evaluate the detection performance of ohun and external software. Finally, we provide some general suggestions to improve detection performance.
Absolute scattering length density profile of liposome bilayers obtained by SAXS combined with GIXOS - a tool to determine model biomembrane structure
Authors: Shen Chen , Woelk Christian , Kikhney Alexey G. , Torres Jaume , Surya Wahyu , Harvey Richard D. , Bello Gianluca
Published: December 2022

Lipid membranes play an essential role in biology, acting as host matrices for biomolecules like proteins and facilitating their functions. Their structures, and structural responses to physiologically relevant interactions, i.e. with membrane proteins, provide key information for understanding biophysical mechanisms. Hence, there is a crucial need of methods to understand the effects of membrane host molecules on the lipid bilayer structure. Here, we present a purely experimental method for obtaining the absolute scattering length density (SLD) profile and the area per lipid of liposomal bilayers, by aiding the analysis of small angle X-ray scattering (SAXS) data with the volume of bare headgroups obtained from fast (20-120s) grazing incidence off-specular scattering (GIXOS) data from monolayers of the same model membrane lipid composition. The GIXOS data experimentally demonstrate that the variation of the bare headgroup volume upon lipid packing density change is small enough to allow its usage as a reference value without knowing the lipid packing stage in a bilayer. This approach also bares the advantage that the reference volume is obtained at the same aqueous environment as used for the model membrane bilayers. We demonstrate the validity of this method using several typical membrane compositions, as well as one example of a phospholipid membrane with an incorporated transmembrane peptide. This methodology allows to obtain absolute scale values rather than relative scale by using solely X-ray-based instrumentation, retaining a similar resolution of SAXS experiments. The presented method has high potential to understand structural effects of membrane proteins on the biomembrane structure.
Recruitment of TRiC chaperonin in rotavirus viroplasms directly associates with virus replication
Authors: Vetter Janine , Papa Guido , Tobler Kurt , Kley Manuel , Myers Michael , Wiesendanger Mahesa , Schraner Elisabeth M. , Burrone Oscar R. , Fraefel Cornel , Eichwald Catherine
Published: December 2022

Rotavirus replication takes place in the viroplasms, cytosolic inclusions that allow the synthesis of virus genome segments and their encapsidation in the core shell followed by the addition of the second layer of the virion. The viroplasms are composed of several viral proteins, including NSP5, which is the main building block. Microtubules, lipid droplets, and miRNA-7 are among the host components recruited in viroplasms. To investigate the relationship between rotavirus proteins and host components of the viroplasms, we performed a pull-down assay of lysates from rotavirus-infected cells expressing NSP5-BiolD2. Subsequent tandem mass spectrometry identified all eight subunits of the TRiC complex, a cellular chaperonin responsible for folding at least 10% of the cytosolic proteins. Our validated results show that TRiC is recruited in viroplasms and specifically surrounds newly formed double-layered particles (DLPs). Chemical inhibition of TRiC and silencing of its subunits drastically reduced virus progeny production. Interestingly, TRiC-inhibited RV-infected cells lacked triple-layered particles (TLPs) but harbored empty DLPs. Through sequence-specific direct RNA nanopore sequencing, we show that TRiC is critical for RV replication by controlling dsRNA genome segment synthesis, particularly (-)ssRNA. Moreover, TRiC associates and regulates the folding of VP2, a cofactor allowing dsRNA synthesis. This study provides in-cell culture evidence of the regulatory mechanism by which dsRNA genome segment replication is controlled and coordinated in the rotavirus viroplasms.

Importance

The replication of rotavirus takes place in cytosolic inclusions termed viroplasms. In these inclusions, the eleven double-stranded RNA genome segments are synthesized and packaged individually into the newly generated virus particles. In this study, we show for the first time that the TRiC complex, a cellular chaperonin responsible for the folding of at least 10% of the cytosolic proteins, is a component of viroplasms and is required for the synthesis of the viral (-)ssRNA. Specifically, TRiC interacts and assists in folding VP2, the cofactor involved in RNA replication. Our study adds a new component to the current model of rotavirus replication, where TRiC is recruited in viroplasm to assist replication.
Acceleration of genome replication uncovered by single-cell nascent DNA sequencing
Authors: van den Berg Jeroen , van Batenburg Vincent , van Oudenaarden Alexander
Published: December 2022

In a human cell thousands of replication forks simultaneously coordinate the duplication of the entire genome. The rate at which this process occurs, might depend on the epigenetic state of the genome and vary between, or even within, cell types. To accurately measure DNA replication speeds, we developed a technology to detect recently replicated DNA using single-cell sequencing. Replication speed is not constant but increases during S-phase of the cell cycle. Using genetic and pharmacological perturbations we are able to alter this acceleration of replication and conclude that DNA damage inflicted by the process of transcription limits the speed of replication during early S-phase. In late S-phase, during which less transcription occurs, replication accelerates and approaches its maximum speed.
Compensatory mechanisms enables intelligibility in prodromal Parkinson’s disease
Authors: Thies Tabea , Mücke Doris , Geerts Nuria , Seger Aline , Fink Gereon R. , Barbe Michael T. , Sommerauer Michael
Published: December 2022

Background

Speech impairment is already present on the acoustic level in speakers with isolated rapid eye movement sleep behavior disorder (iRBD). The aim of this study was to determine whether speech changes are already present on the articulatory level and if how these differ from healthy control speakers and speakers with Parkinson’s disease (PD).

Methods

Kinematic data were collected from 68 age and sex-matched subjects: healthy control speakers (n=23), patients with iRBD (n=22), and patients with PD (n=23). All participants were recorded with electromagnetic articulography (AG 501) to capture articulatory movements of the lower lip, the tongue tip and the tongue body. Movement amplitudes, durations and average speeds were calculated per articulator. In addition, naïve listeners rated the intelligibility of the speech sampled produced by the participants.

Results

The results of the production experiment indicate changes between the control and the iRBD group as well as between the iRBD and the PD group. Movement durations increase from the control group to the iRBD group and further to the PD group. In contrary, movement amplitudes increase in prodromal PD and decreased from PD onwards. This relationship was reflected by preserved articulatory speed in iRBD patients, but articulatory slowdown in PD. Intelligibility is lower in speakers with PD, but does not differ between the control and the iRBD group.

Conclusion

Speakers with iRBD adjust underlying articulatory movement patterns to maintain their intelligibility level.