bluuebunny/crossref_metadata_2025 huggingface dataset:
PROGNOSTIC VALUE OF LOW-DOSE ADRENOCORTICOTROPIC HORMONE TEST IN CRITICALLY ILL PATIENTS
Authors: Abdelrehim Ahmad B. , Mohsen Fatma M. , Haredi Mostafa A. , Hameed Zeinab Abdel , Ibrahim Walaa H.
Published: April 2023

Background: Previous trials evaluated the incidence of critical illness–related corticosteroid insufficiency (CIRCI) using 250 μg adrenocorticotropic hormone (ACTH). However, this supraphysiological dose could result in false-positive levels. We aimed to determine the incidence of CIRCI in septic patients using a 1 μg ACTH stress test. Methods: We conducted a prospective cohort study on 39 patients with septic shock. Critical illness–related corticosteroid insufficiency was defined as a Δ max cortisol <9 μg/dL after 1 μg ACTH stress test. The primary outcome of the study was death. Secondary outcomes included days of vasopressors, days of mechanical ventilation (MV), amount of fluid per day, the incidence of acute kidney injury (AKI), and days of intensive care unit (ICU) stay. Results: The incidence of CIRCI in our cohort was 43.6% using 1 μg ACTH. There were no significant differences between groups in terms of ICU scores, laboratory investigations, vasopressors, MV days, amount of fluid per day, and the ICU stay (P = > 0.05). The CIRCI group had lower median survival and survival probability rates (5 days and 48.4%, respectively) compared with the non-CIRCI group (7 days and 49.5%, respectively). In addition, the CIRCI group had a shorter time to develop AKI and a higher probability of developing AKI (4 days and 44.6%, respectively) in comparison with the non-CIRCI group (6 days and 45.57%, respectively). Conclusion: We concluded that the CIRCI group had a lower mean survival rate and a higher incidence of AKI. We recommend the use of 1 μg ACTH test in septic shock patients to identify this subgroup of patients.
Increasing Systemic Immune-inflammation Index During Treatment in Patients With Advanced Pancreatic Cancer is Associated With Poor Survival
Authors: van ‘t Land Freek R. , Aziz Mohammad H. , Michiels Nynke , Mieog J. Sven D. , Bonsing Bert A. , Luelmo Saskia A.C. , Homs Marjolein Y.V. , Groot Koerkamp Bas , Papageorgiou Grigorios , van Eijck Casper H.J.
Published: April 2023

Background and Objectives:

A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer.

Methods:

Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data.

Results:

Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6–31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0–15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by −0.588 (95% CI: −0.0978, −0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068–2.409; P = 0.023).

Conclusions:

In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.
A Noninvasive Technology Using Artificial Intelligence to Measure the Diameter of Esophageal Varices Under Endoscopy
Authors: Jin Jing , Dong Bill , Ye Chao , Zhang Qianqian , Wu Aijiu , Dong Lanfang , Kong Derun
Published: April 2023

Background:

The diameter of esophageal varices (EVs) can not only predict variceal bleeding episodes but is also considered to be a significant factor in determining the endoscopic treatment of EVs. At present, visual observation is the most common method for estimating the diameter of EVs, the results of which may vary greatly between endoscopists.

Materials and Methods:

Herein, a noninvasive measurement technology, a virtual ruler (VR), was designed using artificial intelligence. The diameter and pressure of EVs in 7 patients were measured using VR and an esophageal varix manometer (EVM). Statistical methods, including the Bland-Altman Plot and Pearson correlation coefficient analysis, were used to compare the aforementioned 2 methods.

Results:

The results showed that the diameter of EVs measured using the aforementioned 2 methods did not differ. In addition, the time taken to measure the diameter of EVs using VR was 31 seconds (range, 25 to 44 s), significantly shorter compared with 159 seconds (range, 95 to 201 s) taken using an EVM (P< 0.01). Furthermore, the diameter of EVs measured using an EVM exhibited a high linear correlation with pressure.

Conclusions:

The current study demonstrated that VR was more accurate in measuring the diameter of EVs compared with EVMs while reducing unnecessary early intervention and the risk of complications. In terms of clinical risk and economic cost, this technology is hardly a burden. Overall, VR could be a useful software for the endoscopic detection and treatment of EVs in patients with liver cirrhosis.
Extraintestinal pathogenic lineages of extended-spectrum β-lactamase (ESBL)-producing E. coli are associated with prolonged ESBL gene carriage
Authors: van der Putten Boas C.L. , van Hattem Jarne M. , Penders John , Mende Daniel R. , Schultsz Constance
Published: April 2023

Objectives Extended-spectrum β-lactamase-producing Escherichia coli (ESBL-Ec) are frequently acquired during international travel, contributing to the global spread of antimicrobial resistance. Human-adapted ESBL-Ec are predicted to exhibit increased intestinal carriage duration, resulting in a higher likelihood of onward human-to-human transmission. Yet, bacterial determinants of increased carriage duration are unknown. Previous studies analysed small traveler cohorts, with short follow-up times, or did not employ high-resolution molecular typing, and were thus unable to identify bacterial traits associated with long-term carriage after recent acquisition. We aimed to identify which ESBL-Ec lineages are associated with increased carriage duration after return from international travel.
Methods In a prospective cohort study of 2001 international travelers, we analysed 160 faecal ESBL-Ec isolates from all 38 travelers who acquired ESBL-Ec during travel and subsequently carried ESBL-Ec for at least 12 months after return, by whole-genome sequencing. For 17 travelers, we confirmed the long-term carriage of ESBL-Ec strains through single nucleotide variant typing. To identify determinants of increased carriage duration, we compared the 17 long-term carriers (≥12 months carriage) with 33 age-, sex- and destination-matched short-term carriers (<1 month carriage). Long read sequencing was employed to investigate long-term ESBL plasmid carriage.
Results We show that in healthy travelers with very low antibiotic usage, extraintestinal pathogenic lineages of E. coli (ExPEC) are significantly more likely to persist than other E. coli lineages. The long-term carriage of E. coli from ExPEC lineages is mainly driven by sequence type 131 and phylogroup D E. coli.
Conclusions Although ExPEC lineages frequently cause extra-intestinal infections such as bloodstream infections, our results indicate that ExPEC lineages are also efficient intestinal colonisers, which potentially contributes to their onward transmission.
Relationship between Blood Group (ABO) and Risk of COVID-19 Infection
Authors: Fathollahi Asal , bashizadeh fakhar haniyeh , Shaghaghi Babak
Published: April 2023

Background and purpose: Coronavirus (COVID-19) is a contagious disease causing severe acute respiratory syndrome which had a catastrophic effect on the world population and resulted in more than 2.9 million deaths worldwide. Epidemiological investigations have recently announced blood type has an association with the incidence of COVID-19 infection. Consequently, research in this regard can be effective in determining a person's susceptibility to a viral infection. Therefore, we investigated the relationship between blood types and the risk of COVID-19 in patients admitted to Khorshid laboratory, Tehran, Iran.
Materials and methods: From January to March 2020, around 50 nasal and throat swap samples of patients’ secretions were obtained from patients who were admitted to Khorshid laboratory. They were confirmed to have COVID-19 virus RNA and real-time polymerase chain reaction (PCR)-ABI, and their blood type was determined simultaneously. After collecting data to determine the relationship between COVID-19 infection and blood type, a confidence interval of 12% was considered using SPSS 16.
Results: The mean age of the patients was measured at 38.4±6.3 years. According to PCR results, 100% of the subjects with COVID-19 showed blood type A. In addition, the ratio of blood type A to the percentage of reference type O was higher (P:0.009).
Conclusion: There was a significant relationship between ABO blood type and susceptibility to COVID-19. As the current study suggests, those with blood type A are at a higher COVID-19 infection risk than those with blood type O.
Aquitalea palustris sp. nov., isolated from a wild cranberry bog in the Cape Cod National Seashore
Authors: Schreiber Melinda , Harrison Alisha , Soby Scott
Published: April 2023

A novel species in the genus

Aquitalea

was isolated from soil and plant surfaces in wild cranberry bogs of the Cape Cod National Seashore.

Aquitalea

is a little-known genus in the family

Chromobacteriaceae

(betaproteobacteria) that is associated with freshwater habitats. As part of a culture-dependent comparative survey of bacteria in wild and cultivated cranberry bogs in Massachusetts, strains MWU14-2217T and MWU14-2470 were characterized for taxonomic placement by phenotypic and genotypic testing, and confirmed by genome comparison with a third isolate, MWU14-2238. Genome analysis methods placed the isolates in the genus

Aquitalea

with >98.54 % 16S rRNA gene sequence similarity each to the four recognized

Aquitalea

species, but with a DNA–DNA relatedness of 46 % by digital DNA–DNA hybridization (formula d4) and 91.92 % by orthologous average nucleotide identity with usearch with its closest relative. DNA G+C content of the three isolates ranged from 60.11 to 60.28 mol%. The strains are facultatively anaerobic, motile and reduce NO3. They are non-pigmented, non-haemolytic on sheep blood agar, grow on mannitol but not on citrate, and do not produce urease or HCN. The predominant fatty acids of both isolates were C16 : 0 and summed C16 : 1ω7c/C16  : 1ω6c. Using a combination of phylogenetic, physiological and phenotypic characterization, isolates MWU14-2217T, MWU14-2470 and MWU14-2238 represent a novel species within the genus

Aquitalea

, for which the name Aquitalea palustris sp. nov. is proposed. The type strain is MWU14-2217T (=CCOS 1980T=ATCC TSD-261T).
Flavobacterium pygoscelis sp. nov., isolated from a chinstrap penguin chick (Pygoscelis antarcticus)
Authors: Irgang Rute , Poblete-Morales Matías , Avendaño-Herrera Ruben
Published: April 2023

Strain I-SCBP12nT, a novel Gram-stain-negative, aerobic, non-spore-forming, motile-by-gliding and rod-shaped bacterium, was isolated from a chinstrap penguin chick (Pygoscelis antarcticus) during a 2015 expedition to the Chilean Antarctic territory. Phylogenetic analysis based on 16S rRNA gene sequencing confirmed that strain I-SCBP12nT belonged to the genus

Flavobacterium

, being closely related to strains

Flavobacterium chryseum

P3160T (98.52 %),

Flavobacterium hercynium

WB 4.2-33T (98.47 %) and

Flavobacterium chilense

LM-19-FpT (98.47 %). The genome size of strain I-SCBP12nT was 3.69 Mb with DNA G+C content 31.95 mol%. Genomic comparisons of strain I-SCBP12nT with type species in the genus

Flavobacterium

were performed, with obtained average values near 75.17 and 84.33 % for the blast and MUMer analyses of average nucleotide identity, respectively, and 0.86 for the tetranucleotides frequency analysis. These values are far from the accepted species cut-off values. Strain I-SCBP12nT contained MK-6 as the predominant menaquinone and the major polar lipids were aminophospholipid, an unidentified aminolipid and unidentified lipids. The predominant fatty acids (> 5 %) were iso-C14 : 0, iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0, iso-C16 : 1, iso-C16 : 0 3-OH, C15 : 1 ω6c and summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c). Phenotypic, chemotaxonomic and genomic data supported the assignment of strain I-SCBP12nT (=CECT 30404T=RGM 3223T) to a novel species of

Flavobacterium

, for which the name Flavobacterium pygoscelis sp. nov.is proposed.
Alternative Substrates in the Critically Ill Subject (ASICS): Safety, Feasibility, Tolerability and Metabolic Profiling of a Novel Ketogenic Feed
Authors: McNelly Angela , Langan Anne , Bear Danielle E. , Page Alexandria , Martin Tim , Seidu Fatima , Santos Filipa , Rooney Kieron , Liang Kaifeng , Baldwin Tomas , Heales Simon J , Alldritt Isabelle , Crossland Hannah , Atherton Philip J. , Wilkinson Daniel , Montgomery Hugh , Prowle John , Pearse Rupert , Eaton Simon , Puthucheary Zudin A.
Published: April 2023

Bioenergetic failure caused by impaired utilisation of glucose and fatty acids contributes to organ dysfunction across multiple tissues in critical illness. Ketone bodies may form an alternative substrate source, but the feasibility and safety of inducing a ketogenic state in physiologically unstable patients is not known.

Twenty-nine mechanically ventilated adults with multi-organ failure were randomised into a two-centre safety and feasibility trial of ketogenic versus standard enteral feeding. Ketogenic feeding was feasible, safe, well tolerated and resulted in ketosis. Patients receiving ketogenic feeding had fewer hypoglycaemic events (0% vs. 1.58%), required less exogenous insulin (0.0 IU (IQR 0-16) vs.78 IU (IQR 0-412) but had slightly more daily episodes of diarrhoea (53.5% vs. 42.9%) over the trial period. Untargeted metabophenotyping revealed altered Cahill cycle flux and bioenergetic states, suggesting an advantageous metabolic profile. Ketogenic feeding is feasible and may be a novel intervention for addressing bioenergetic failure in critically ill patients.

Clinical Trials.govregistration:NCT04101071; 19.09.2019.

Take-home Message

Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. This contributes to organ dysfunction across multiple tissues. Ketones may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.

Tweet

Ketogenic enteral feeding in early critical illness is feasible, safe and may decrease insulin requirements.
A Graph Embedding Approach for Deciphering the Longitudinal Associations of Global Mobility and COVID-19 Cases
Authors: Awasthi Raghav , Modi Meet , Dudeja Hardik , Bajaj Tanav , Rastogi Shruti , Sethi Tavpritesh
Published: April 2023

The COVID-19 pandemic has highlighted the importance of monitoring mobility patterns and their impact on disease spread. This paper presents a methodology for developing effective pandemic surveillance systems by extracting scalable graph features from mobility networks. We utilized Meta’s “Travel Patterns” dataset to capture the daily number of individuals traveling between countries from March 2020 to April 2022. We have used an optimized node2vec algorithm to extract scalable features from the mobility networks. Our analysis revealed that movement embeddings accurately represented the movement patterns of countries, with geographically proximate countries exhibiting similar movement patterns. The temporal association dynamics between Global mobility and COVID-19 cases highlighted the significance of high-page rank centrality countries in mobility networks as a key intervention target in controlling infection spread. Our proposed methodology provides a useful approach for tracking the trajectory of infectious diseases and developing evidence-based interventions.
The patterns of codon usage between chordates and arthropods are different but co-evolving with mutational biases
Authors: Kotari Ioanna , Kosiol Carolin , Borges Rui
Published: April 2023

Different frequencies amongst codons that encode the same amino acid (i.e. synonymous codons) have been observed in multiple species. Studies focused on uncovering the forces that drive such codon usage showed that a combined effect of mutational biases and translational selection works to produce different frequencies of synonymous codons. However, only few have been able to measure and distinguish between these forces that may leave similar traces on the coding regions. Here, we have developed a codon model that allows the disentangling of mutation, selection on amino acids and synonymous codons, and GC-biased gene conversion (gBGC) which we employed on an extensive dataset of 415 chordates and 191 arthropods. We found that chordates need 15 more synonymous codon categories than arthropods to explain the empirical codon frequencies, which suggests that the extent of codon usage can vary greatly between animal phyla. Moreover, methylation at CpG sites seems to partially explain these patterns of codon usage in chordates but not in arthropods. Despite the differences between the two phyla, our findings demonstrate that in both, GC-rich codons are disfavoured when mutations are GC-biased, and the opposite is true when mutations are AT-biased. This indicates that selection on the genomic coding regions might act primarily to stabilise its GC/AT content on a genome-wide level. Our study shows that the degree of synonymous codon usage varies considerably among animals, but is likely governed by a common underlying dynamic.
CORE CONSERVED TRANSCRIPTIONAL REGULATORY NETWORKS DEFINE THE INVASIVE TROPHOBLAST CELL LINEAGE
Authors: Vu Ha T.H. , Scott Regan L. , Iqbal Khursheed , Soares Michael J. , Tuteja Geetu
Published: April 2023

The invasive trophoblast cell lineage in rat and human share crucial responsibilities in establishing the uterine-placental interface of the hemochorial placenta. These observations have led to the rat becoming an especially useful animal model to study hemochorial placentation. However, our understanding of similarities or differences between regulatory mechanisms governing rat and human invasive trophoblast cell populations is limited. In this study, we generated single-nucleus (sn) ATAC-seq data from gestation day (gd) 15.5 and 19.5 rat uterine-placental interface tissues and integrated the data with single-cell RNA-seq data generated at the same stages. We determined the chromatin accessibility profiles of invasive trophoblast, natural killer, macrophage, endothelial, and smooth muscle cells, and compared invasive trophoblast chromatin accessibility to extravillous trophoblast (EVT) cell accessibility. In comparing chromatin accessibility profiles between species, we found similarities in patterns of gene regulation and groups of motifs enriched in accessible regions. Finally, we identified a conserved gene regulatory network in invasive trophoblast cells. Our data, findings and analysis will facilitate future studies investigating regulatory mechanisms essential for the invasive trophoblast cell lineage.
Ongoing introgression of a secondary sexual plumage trait in a stable avian hybrid zone
Authors: Long Kira M. , Rivera-Colón Angel G. , Bennett Kevin F. P. , Catchen Julian M. , Braun Michael J. , Brawn Jeffrey D.
Published: April 2023

Abstract

Hybrid zones are dynamic systems where natural selection, sexual selection, and other evolutionary forces can act on reshuffled combinations of distinct genomes. The movement of hybrid zones, individual traits, or both are of particular interest for understanding the interplay between selective processes. In a hybrid zone involving two lek-breeding birds, secondary sexual plumage traits ofManacus vitellinus, including bright yellow collar and olive belly color, have introgressed asymmetrically ∼50 km across the genomic center of the zone into populations more genetically similar toManacus candei. Males with yellow collars are preferred by females and are more aggressive than parentalM. candei, suggesting that sexual selection was responsible for the introgression of male traits. We assessed the spatial and temporal dynamics of this hybrid zone using historical (1989 - 1994) and contemporary (2017 - 2020) transect samples to survey both morphological and genetic variation. Genome-wide SNP data and several male phenotypic traits show that the genomic center of the zone has remained spatially stable, whereas the olive belly color of maleM. vitellinushas continued to introgress over this time period. Our data suggest that sexual selection can continue to shape phenotypes dynamically, independent of a stable genomic transition between species.
Improved detection of aberrant splicing using the Intron Jaccard Index
Authors: Scheller Ines F. , Lutz Karoline , Mertes Christian , Yépez Vicente A. , Gagneur Julien
Published: April 2023

Detection of aberrantly spliced genes is an important step in RNA-seq-based rare disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method for aberrant splicing detection that outperformed alternative approaches. However, as FRASER’s three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron excision metric, the Intron Jaccard Index, that combines alternative donor, alternative acceptor, and intron retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs using candidate rare splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare splice-disrupting variants by 10 fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. Application on 303 rare disease samples confirmed the reduction fold-change of the number of outlier calls for a slight loss of sensitivity (only 2 out of 22 previously identified pathogenic splicing cases not recovered). Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by a drastic reduction of the amount of splicing outlier calls per sample at minimal loss of sensitivity.
Pharmaceutical and Non-Pharmaceutical Interventions for Controlling the COVID-19 Pandemic
Authors: Molla Jeta , Farhang-Sardroodi Suzan , Moyles Iain R , Heffernan Jane M
Published: April 2023

Disease spread can be affected by pharmaceutical (such as vaccination) and non-pharmaceutical interventions (such as physical distancing, mask-wearing, and contact tracing). Understanding the relationship between disease dynamics and human behavior is a significant factor to controlling infections. In this work, we propose a compartmental epidemiological model for studying how the infection dynamics of COVID-19 evolves for people with different levels of social distancing, natural immunity, and vaccine-induced immunity. Our model recreates the transmission dynamics of COVID-19 in Ontario up to December 2021. Our results indicate that people change their behaviour based on the disease dynamics and mitigation measures. Specifically, they adapt more protective behaviour when the number of infections is high and social distancing measures are in effect, and they recommence their activities when vaccination coverage is high and relaxation measures are introduced. We demonstrate that waning of infection and vaccine-induced immunity are important for reproducing disease transmission in Fall 2021.
Clinical Phenotype Prediction From Single-cell RNA-seq Data using Attention-Based Neural Networks
Authors: Mao Yuzhen , Lin Yen-Yi , Wong Nelson K.Y. , Volik Stanislav , Sar Funda , Collins Colin , Ester Martin
Published: April 2023

Motivation

A patient’s disease phenotype can be driven and determined by specific groups of cells whose marker genes are either unknown, or can only be detected at late-stage using conventional bulk assays such as RNA-Seq technology. Recent advances in single-cell RNA sequencing (scRNA-seq) enable gene expression profiling in cell-level resolution, and therefore have the potential to identify those cells driving the disease phenotype even while the number of these cells is small. However, most existing methods rely heavily on accurate cell type detection, and the number of available annotated samples is usually too small for training deep learning predictive models.

Results

Here we propose the method ScRAT for clinical phenotype prediction using scRNA-seq data. To train ScRAT with a limited number of samples of different phenotypes, such as COVID and non-COVID, ScRAT first applies a mixup module to increase the number of training samples. A multi-head attention mechanism is employed to learn the most informative cells for each phenotype without relying on a given cell type annotation. Using three public COVID datasets, we show that ScRAT outperforms other phenotype prediction methods. The performance edge of ScRAT over its competitors increases as the number of training samples decreases, indicating the efficacy of our sample mixup. Critical cell types detected based on high-attention cells also support novel findings in the original papers and the recent literature. This suggests that ScRAT overcomes the challenge of missing marker genes and limited sample number with great potential revealing novel molecular mechanisms and/or therapies.
When cheating turns into a stabilizing mechanism of mutualistic networks
Authors: Duchenne François , Aubert Stéphane , Barreto Elisa , Brenes Emanuel , Maglianesi María A. , Santander Tatiana , Guevara Esteban A. , Graham Catherine H.
Published: April 2023

Mutualistic interactions, such as plant-mycorrhizal or plant-pollinator interactions, are widespread in ecological communities and frequently exploited by cheaters, species that profit from interactions without providing benefits in return. Cheating usually negatively affects the fitness of the individuals that are cheated on, but the effects of cheating at the community level remains poorly understood. Here we describe two different kinds of cheating in mutualistic networks and use a generalized Lotka-Volterra model to show that they have very different consequences for the persistence of the community. Conservative cheating, where a species cheats on its mutualistic partners to escape the cost of mutualistic interactions, negatively affects community persistence. In contrast, innovative cheating occurs with species with whom legitimate interactions are not possible, because of a physiological or morphological barrier. Innovative cheating can enhance community persistence under some conditions: when cheaters have few mutualistic partners, cheat at low or intermediate frequency and the cost associated with mutualism is not too high. In this case, the negative effects of cheating on partner persistence are over-compensated at the community level by the positive feedback loops that arise in mutualistic networks. Using an empirical dataset of plant-bird interactions, we found that observed cheating patterns are highly consistent with theoretical cheating patterns found to increase community persistence. This result suggests that the cheating patterns observed in nature could contribute to promote species coexistence in mutualistic communities, instead of necessarily destabilizing them.
ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7
Authors: van Veen Sarah , Kourti Antria , Ausloos Elke , Van Asselberghs Joris , Van den Haute Chris , Baekelandt Veerle , Eggermont Jan , Vangheluwe Peter
Published: April 2023

Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). So far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether upregulation of candidate polyamine transporters of the P5B- transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells present elevated expression of a previously uncharacterized P5B-ATPase ATP13A4, which is responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells are more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, overexpression of ATP13A4 WT in MCF10A cells induces a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labelled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we establish ATP13A4 as a new polyamine transporter in the human PTS and show that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.
Single-cell phenomics reveals behavioural and mechanical heterogeneities underpinning collective migration during mouse anterior patterning
Authors: Stower Matthew , Zhou Felix , Hathrell Holly , Yeung Jason , Thowfeequ Shifaan , Godwin Jonathan , Schneider Falk , Lagerholm Christoffer , Fritzsche Marco , Thiyagalingam Jeyan , Lu Xin , Rittscher Jens , Srinivas Shankar
Published: April 2023

Distal Visceral Endoderm (DVE) cells show a stereotypic unidirectional migration essential for correct orientation of the anterior-posterior axis. They migrate within a simple epithelium, the Visceral Endoderm (VE). It is unknown how DVE cells negotiate their way amongst the surrounding VE cells, what determines the bounds of DVE migration within the VE, and the relative contributions of different cell behaviours to this migration. To address these questions, we used lightsheet microscopy to generate a multi-embryo, singlecell resolution, longitudinal dataset of cell behaviour and morphology. We developed a machine learning based pipeline to segment cells and a data-informed systematic computational framework to extract and compare select morphological, behavioural and molecular parameters of all VE cells in a unified coordinate space. Unbiased clustering of this single-cell ‘phenomic’ dataset reveals considerable patterned phenotypic heterogeneity within the VE and a previously unknown sub-grouping within the DVE. While migrating, DVE cells retain regular morphology, do not exchange neighbours and are crowded, all hallmarks of the jammed state. In contrast, VE cells immediately ahead of them deform and undergo neighbour exchange. We show that DVE cells are characterised by higher levels of apical F-actin and elevated tension relative to the VE cells immediately ahead of them through which they migrate, but stop migrating upon reaching a region of the VE with matching elevated tension.Lefty1mutants, known to show abnormal over-migration of DVE cells, show disruption to this patterned tension in the VE. Our findings provide novel insights into the control of cell behaviour during the remodelling of curved epithelia, indicating that the collective migration of sub-sets of cells can be circumscribed by modulating the mechanical properties of surrounding cells and that migrating cells in this context remain as a jammed solid flock, with surrounding cells facilitating their movement by becoming unjammed.

Graphical Abstract
Epigenetic mechanisms to propagate histone acetylation by p300/CBP
Authors: Kikuchi Masaki , Morita Satoshi , Wakamori Masatoshi , Sato Shin , Uchikubo-Kamo Tomomi , Shirouzu Mikako , Umehara Takashi
Published: April 2023

Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTacviathe bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor groovesviathe outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
The unreasonable effectiveness of equilibrium gene regulation through the cell cycle
Authors: Vilar Jose M. G. , Saiz Leonor
Published: April 2023

Systems like the prototypicallacoperon can reliably hold the repression of transcription upon DNA replication across cell cycles with just ten repressor molecules per cell and, in addition, behave as if they were at equilibrium. The origin of this type of phenomena is still an unresolved question of major implications. Here, we develop a general theory to analyze strong perturbations in quasi-equilibrium systems and use it to quantify the effects of DNA replication in gene regulation. We find a scaling law that connects actual transcription with its predicted equilibrium values in terms of a single kinetic parameter. We show that even the simplest, exceptionally reliable natural system functions beyond the physical limits of naïve regulation through compensatory mechanisms that suppress nonequilibrium effects. We validate the approach with bothin vivocell-population and single-cell characterization of thelacoperon. Analyses of synthetic systems without adjuvant activators, such as the cAMP receptor protein (CRP), do not show this reliability. Our results provide a rationale for the function of CRP, beyond just being a tunable activator, as a mitigator of cell cycle perturbations.
Reversing myeloid-derived suppressor cells mediated immunosuppression via p38α inhibition enhances immunotherapy efficacy in triple negative breast cancer
Authors: Wang Qianyu , Li Shasha , Dai Yifei , Yu Xiankuo , Wang Yumei , Li Lu , Yang Ming , Lin Kequan , Shao Wei , Wang Haiyan , Wang Huili , Zhang Guanbin , Wang Dong
Published: April 2023

Infiltration of myeloid-derived suppressor cells (MDSCs) leads to Immunosuppressive tumor microenvironment (TME), which is one of the major causes for low objective response rates of immune checkpoint blockade (ICB) therapy. Here, we report that chemical inhibition of p38α reverses this MDSC-induced immunosuppressive TME and improves the immunotherapy efficacy in triple negative breast cancer (TNBC). Firstly, by combining the tumor immunological phenotype (TIP) gene signature and high throughput sequencing based high throughput screening (HTS2), we identified that ponatinib significantly inhibits the expression of “cold” tumor associated chemokines CXCL1 and CXCL2 in cancer cells. This inhibition decreases the infiltration of MDSCs and consequently increased the accumulation of “hot” tumor associated T cells and NK cells and thus reverses the immunosuppressive TME. Then, by multiple preclinical models, we found that ponatinib significantly inhibits tumor growth in a TME-dependent manner and enhances the efficacy of anti-PD-L1 immunotherapy on TNBCin vivo. Notably, ponatinib exhibits no significant inhibition on immune cells in mouse spleens. Mechanistically, ponatinib directly inhibits the kinase activity of p38α, which results in the reduction of the phosphorylation of STAT1 at Ser727, and thus the decreased expression of CXCL1 and CXCL2 in cancer cells. Our study provided the therapeutic potential of combining p38α inhibition with ICB for the treatment of TNBC.
Novel expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice
Authors: Whitaker Emily E. , Mecum Neal E. , Cott Riley C. , Goode Diana J.
Published: April 2023

Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+T cells are activated, and the extent cytokines released by CD4+T cells target DRG neurons are unknown. Here, we found novel expression of functional major histocompatibility complex II (MHCII) protein in DRG neurons, and CD4+T cells in close proximity to DRG neurons, together suggesting CD4+T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male mouse DRG regardless of PTX, while MHCII is induced in small nociceptive neurons in female DRG after PTX. Accordingly, reducing MHCII in small nociceptive neurons increased hypersensitivity to cold only in naïve male mice, but increased severity of PTX-induced cold hypersensitivity in both sexes. Collectively, our results demonstrate expression of MHCII on DRG neurons and a functional role during homeostasis and inflammation.

Graphical abstract

Created withBiorender.com

Novel expression of functional MHCII protein was detected on the surface of DRG neurons, suggesting a potential mechanism for CD4+T cell activation and targeted cytokine release. Reducing MHCII from a subpopulation of neurons known to contribute to CIPN increased the severity of PTX-induced cold hypersensitivity in female and male mice.
A high-throughput approach reveals distinct peptide charging behaviors in electrospray ionization mass spectrometry
Authors: Xu Allyn M. , Tang Lauren C. , Jovanovic Marko , Regev Oded
Published: April 2023

Electrospray ionization is a powerful and prevalent technique used to ionize analytes in mass spectrometry. The distribution of charges that an analyte receives (charge state distribution, CSD) is an important consideration for interpreting mass spectra. However, due to an incomplete understanding of the ionization mechanism, the analyte properties that influence CSDs are not fully understood. Here, we employ a machine learning-based high-throughput approach and analyze CSDs of hundreds of thousands of peptides. Interestingly, half of the peptides exhibit charges that differ from what one would naively expect (number of basic sites). We find that these peptides can be classified into two regimes—undercharging and overcharging—and that these two regimes display markedly different charging characteristics. Strikingly, peptides in the overcharging regime show minimal dependence on basic site count, and more generally, the two regimes exhibit distinct sequence determinants. These findings highlight the rich ionization behavior of peptides and the potential of CSDs for enhancing peptide identification.
Study of the Effect of Intestinal Microbes on Obesity: A Bibliometric Analysis
Authors: Su Zehao , Tian Chenyu , Wang Guan , Guo Jingjing , Yang Xiaoyan
Published: April 2023

Background

Obesity is a serious public health problem. According to statistics, there are millions obese people worldwide. The intestinal microbiota is the microbiota that lives in the gastrointestinal tract of the human body and can interact with the external environment through diet. Probing and summarizing the relationship between intestinal microbes and obesity has important guiding significance for the accurate control of the research direction and expanding the choice of obesity treatment methods. We aimed to use bibliometrics to qualitatively and quantitatively analyze the published literature and to reveal the research hotspots and development trends in the effects of intestinal microbes on obesity research.

Methods

We obtained documents from the core collection of Web of Science (WoSCC) from 2013–2022 on February 2nd, 2023. Microsoft Excel, Biblioshiny R language software packages and CiteSpace were employed to collect publication data, analyze publication trends, and visualize relevant results.

Results

We identified 8888 original research articles on the effects of intestinal microbes on obesity published between 2013 and 2022. China made the highest number of publications on the topic, with 3036 publications (34.16%), and the United States with 87065 citations made the greatest contribution. University of Copenhagen was the most prolific institution (209 publications). Patrice D. Cani published the most related articles (97 publications), whereas Peter J. Turnbaugh was cited the most frequently (3307 citations). Nutrients was the journal with the most studies (399 publications, 4.49%), and Nature was the most commonly co-cited journal (6446 citations). The burst keywords “obese patient” and “serum” recently appeared as research frontiers.

Conclusion

Although China has the largest number of publications, the United States, depending on its largest citations, has become the leader in the effects of intestinal microbes on obesity research. Current research hotspots focus on related mechanisms of the effects of intestinal microbes on obesity and therapeutic methods for obesity with intestinal microbes. Through diet, probiotic preparations and regulation of the intestinal flora, fecal microbe transplantation may have a significant impact on reducing the obesity epidemic. Considering the great potential and application prospects, intestinal microbe applications in obesity therapy will remain a research hotspot in the future.
Transposable Elements are differentially activated in cell lineages during the developing murine submandibular gland
Authors: Valdebenito-Maturana Braulio
Published: April 2023

The murine submandibular gland (SMG) is a model organ to study development, because it follows a branching morphogenesis pattern that is similar to that of lung, kidney, and other systems. It has been speculated that through its study, insights into regeneration and cancer could be obtained. Previously, using bulk RNA-Seq data, we reported that Transposable Elements (TEs) become activated during the SMG development. However, an outstanding question was as to whether their activity influenced different cell populations. Here, taking advantage of a single cell RNA-Seq atlas of the developing SMG, I studied TE expression to find out whether their activity can be recapitulated across its development, and if so, how they influenced cell types and cell fate specification. In this work, I found a total of 339 TEs that are markers of different cell populations, and then, through the modeling of the SMG development using Trajectory Inference methods, I found 2 TEs that could be potentially influencing differentiation processes. In sum, this short report reveals that TEs may be involved in the normal development of the SMG, and it highlights the importance of considering them in scRNA-Seq studies.
The Effect of Evaluating Self’s Emotions on Frontal Alpha Asymmetry
Authors: Ito Masato , Takahashi Toru , Kurihara Yuto , Osu Rieko
Published: April 2023

In this research to assess emotions from biometric signals, participants are asked to evaluate the emotions they subjectively experienced in order to confirm whether the assumed emotions were actually elicited. However, the evaluation of emotions is not routinely performed in daily life, and it is possible that this evaluation may alter biological signals. In fMRI studies, evaluation has been shown to activate the amygdala, which is said to be related to emotional expression. However, electroencephalography (EEG) studies do not take into consideration the effects of such evaluations, and it is unclear how these evaluations affect emotion-related brain activity observed in EEG. We hypothesized that emotion evaluations would amplify emotions and c alter Frontal Alpha Asymmetry (FAA), which has been shown to be related to emotional pleasantness and unpleasantness. We suspect this is because in order to evaluate one’s emotions, one must pay attention to one’s internal state, and this self-focused attention has been found to enhance the subjective emotional experience. We measured a 29-channel EEG when presented with unpleasant and highly arousing images from the International Affective Picture System (IAPS) from 40 healthy male and female participants. The results revealed that FAA was significantly lower in the condition in which participants rated their own emotions compared to the condition in which they did not. Similar to fMRI studies, this result indicates that emotion-related brain activity is amplified on an EEG. This paper provides a cautionary note regarding the use of such evaluations in EEG emotion estimation studies.
Defective Schwann cell lipid metabolism alters plasma membrane dynamics in Charcot-Marie-Tooth disease 1A
Authors: Prior Robert , Silva Alessio , Vangansewinkel Tim , Idkowiak Jakub , Tharkeshwar Arun Kumar , Hellings Tom P. , Michailidou Iliana , Vreijling Jeroen , Loos Maarten , Koopmans Bastijn , Vlek Nina , Straat Nina , Agaser Cedrick , Kuipers Tom , Michiels Christine , Rossaert Elisabeth , Verschoren Stijn , Vermeire Wendy , de Laat Vincent , Dehairs Jonas , Eggermont Kristel , van den Biggelaar Diede , Bademosi Adekunle T. , Meunier Frederic A. , vandeVen Martin , Van Damme Philip , Mei Hailiang , Swinnen Johannes V. , Lambrichts Ivo , Baas Frank , Fluiter Kees , Wolfs Esther , Den Bosch Ludo Van
Published: April 2023

Duplication ofPMP22causes Charcot-Marie-Tooth disease type 1A (CMT1A) and is known to disrupt the lipid metabolism in myelinating Schwann cells by unknown mechanisms. By using two CMT1A mouse models overexpressing humanPMP22, we discovered thatPMP22dose-dependently downregulates genes that are involved in lipid and cholesterol metabolism. Lipidomic analysis on CMT1A mouse sciatic nerves confirmed lipid metabolic abnormalities primarily associated with cholesterol and sphingolipids. We observed similar lipidomic profiles and downregulation of genes associated with lipid metabolism in human CMT1A patient induced pluripotent stem cell-derived Schwann cell precursors (iPSC-SCPs). We confirmed these findings by demonstrating altered lipid raft dynamics and plasma membrane fluidity in CMT1A iPSC-SCPs. Additionally, we identified impaired cholesterol incorporation in the plasma membrane due to altered lipid storage homeostasis in CMT1A iPSC-SCPs, which could be modulated by changing the lipid composition of the cell culture medium. These findings suggest that PMP22 plays a role in regulating the lipid composition of the plasma membrane and lipid storage homeostasis. Targeting lipid metabolism may hold promise as a potential treatment for CMT1A patients.

Graphical abstract

Highlights

PMP22copy number causes a dose-dependent suppression of cholesterol and lipid biosynthesis in peripheral nerves of CMT1A mice

Lipid composition is altered in the sciatic nerves of CMT1A mice and in the membranes of patient derived iPSC-SCPs, with a significant reduction in sphingolipids

CMT1A iPSC-SCPs show decreased plasma membrane lipids required for regulating lipid raft dynamics, membrane fluidity, and membrane order

Lipid storage misregulation is key in the pathogenesis of CMT1A