bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxia in tomato (Solanum lycopersicum) fruit during ripening: Biophysical elucidation by a 3D reaction–diffusion model
Authors: Xiao Hui , Verboven Pieter , Tong Shuai , Pedersen Ole , Nicolaï Bart
Published: March 2024

Respiration provides energy, substrates, and precursors to support physiological changes of the fruit during climacteric ripening. A key substrate of respiration is oxygen that needs to be supplied to the fruit in a passive way by gas transfer from the environment. Oxygen gradients may develop within the fruit due to its bulky size and the dense fruit tissues, potentially creating hypoxia that may have a role in the spatial development of ripening. This study presents a 3D reaction–diffusion model using tomato (Solanum lycopersicum) fruit as a test subject, combining the multiscale fruit geometry generated from magnetic resonance imaging and microcomputed tomography with varying respiration kinetics and contrasting boundary resistances obtained through independent experiments. The model predicted low oxygen levels in locular tissue under atmospheric conditions, and the oxygen level was markedly lower upon scar occlusion, aligning with microsensor profiling results. The locular region was in a hypoxic state, leading to its low aerobic respiration with high CO2 accumulation by fermentative respiration, while the rest of the tissues remained well oxygenated. The model further revealed that the hypoxia is caused by a combination of diffusion resistances and respiration rates of the tissue. Collectively, this study reveals the existence of the respiratory gas gradients and its biophysical causes during tomato fruit ripening, providing richer information for future studies on localized endogenous ethylene biosynthesis and fruit ripening.
ALKBH8 contributes to neurological function through oxidative stress regulation
Authors: Honda Kohei , Hase Hiroaki , Tanikawa Sayaka , Okawa Katsuya , Chen Lu , Yamaguchi Takumi , Nakai Manami , Kitae Kaori , Ago Yukio , Nakagawa Shinsaku , Tsujikawa Kazutake
Published: March 2024

Transfer RNA (tRNA) modification is essential for proper protein translation, as these modifications play important roles in several biological functions and disease pathophysiologies. AlkB homolog 8 (ALKBH8) is one of the nine mammalian ALKBH family molecules known to regulate selenoprotein translation through the modification of the wobble uridine (U34) in tRNA; however, its specific biological roles remain unclear. In this study, we investigated the role of ALKBH8 using Alkbh8-knockout (Albkh8−/−) mice, which were observed to have reduced 5-methoxycarbonylmethyluridine (mcm5U) and (S)-5-methoxycarbonylhydroxymethyluridine levels; notably, the mcm5U level was partially compensated only in the brain. The results of the novel object recognition test showed reduction in time to explore a novel object in Albkh8−/− mice; increased latency to fall in the rotarod performance test and latency to the immobility period in the forced swim test were also observed. These abnormal behaviors indicate dysfunction of the central nervous system. Furthermore, we observed reduced brain weight and ischemic pathological changes in the cerebral cortex and hippocampus in the form of weak eosin staining in the fiber tracts adjacent to the hippocampal cornu ammonis 1 region and an increase in pyramidal cells in the temporal lobe. Concordantly, we identified the differential expression of oxidative stress-related proteins and metabolites in the cerebral cortex and hippocampus using omics analyses. Finally, neurons and glial cells derived from Albkh8−/− mice show reduced mitochondrial membrane potential. Collectively, these findings indicate that ALKBH8 maintains neural function through an oxidative stress-regulatory mechanism.
Using Machine Translation and Post-Editing in the TRAPD Approach: Effects on the Quality of Translated Survey Texts
Authors: Zavala-Rojas Diana , Behr Dorothée , Dorer Brita , Sorato Danielly , Keck Veronika
Published: March 2024

A highly controlled experimental setting using a sample of questions from the European Social Survey (ESS) and European Values Study (EVS) was used to test the effects of integrating machine translation and post-editing into the Translation, Review, Adjudication, Pretesting, and Documentation (TRAPD) approach in survey translation. Four experiments were conducted in total, two concerning the language pair English-German and two in the language pair English-Russian. The overall results of this study are positive for integrating machine translation and post-editing into the TRAPD process, when translating survey questionnaires. The experiments show evidence that in German and Russian languages and for a sample of ESS and EVS survey questions, the effect of integrating machine translation and post-editing on the quality of the review outputs—with quality understood as texts output with the fewest errors possible—can hardly be distinguished from the quality that derives from the setting with human translations only.
Sarcopenia assessed by DXA and hand-grip dynamometer: a potential marker of damage, disability and myokines imbalance in inflammatory myopathies
Authors: Giannini Margherita , Charles Anne-Laure , Evrard Charles , Blaess Julien , Bouchard-Marmen Maude , Debrut Léa , Perniola Simone , Laverny Gilles , Javier Rose-Marie , Charloux Anne , Geny Bernard , Meyer Alain
Published: March 2024

Objectives

To assess the ability of dual-energy X-ray absorptiometry (DXA) and hand-grip dynamometer to measure damage in inflammatory myopathies (IM).

Methods

Forty adult IM patients with a disease duration ≥12 months, low or no disease activity for ≥6 months, were prospectively enrolled. Thirty healthy age and sex-matched volunteers were enrolled as controls. Whole-body DXA and hand-grip dynamometer were used to measure muscle mass, grip strength and diagnose sarcopenia (EWGSOP2 criteria). Relationships between the results of strength in 12 muscles, functional tests, patient-reported disability, IMACS damage score, and history of the disease were assessed. The serum levels of potential molecular actors in the damage were measured.

Results

DXA and grip strength measurements took ≤20 min. Both muscle mass and grip strength were decreased in IM patients vs volunteers (−10% and −30%, respectively) with a dispersion that varied widely (interquartile range −24.3% to +7.8% and −51.3% to −18.9%, respectively). Muscle mass and grip strength were non-redundantly correlated (r up to 0.6, P = 0.0001) with strength in 14 muscles (manual muscle test and hand-held dynamometer), functions (of limbs, respiratory and deglutition muscles), patient-reported disability, damage (extension and severity in muscular and extra-muscular domains) and blood levels of several myokines. Seven IM patients (17.5%) were sarcopenic. They had the worst damage, impaired functions, disability and history of severe myopathy. Decreased irisin and osteonectin levels were associated with sarcopenia (area under the curve 0.71 and 0.80, respectively).

Conclusion

DXA and hand-grip dynamometer are useful tools to assess damage in IM. Irisin and osteonectin may play a role in IM damage pathogenesis.
Role of biologics in severe food allergy
Authors: Dinardo Giulio , Cafarotti Arianna , Fierro Vincenzo , Artesani Maria Cristina , Indolfi Cristiana , Miraglia del Giudice Michele , Fiocchi Alessandro
Published: March 2024

Purpose of review

This review examine the dynamic landscape of food allergy treatment within the context of emerging biologics. Our purpose is to comprehensively evaluate the potential benefits, challenges, and transformative impact associated with the utilization of biologics in comparison to conventional therapeutic modalities.

Recent findings

This document synthesizes recent scientific investigations to various biologics, such as omalizumab, ligelizumab, dupilumab, and tezepelumab, providing a nuanced understanding of their roles in oral immunotherapy, rapid desensitization, and overall food allergy management. Recent studies and clinical trials highlight the impact of anti-IgE treatment on food allergies, revealing critical findings such as dose-related efficacy, facilitation of rapid desensitization in peanut allergies, and the sustained positive outcomes observed in individuals with multifood allergies.

The use of biologics presents a groundbreaking approach in the treatment of food allergies. The multifaceted action of these agents, along with their potential to overcome the challenges associated with traditional therapies, marks a significant advancement. Despite the persisting challenges of economic constraints and the need for further safety studies, biologics offer a promising avenue for improving the quality of life for individuals with food allergies. Ongoing research and collaborative efforts are imperative to fully realize the transformative potential inherent in these emerging therapeutic frontiers.
Active Compared With Passive Voiding Trials After Midurethral Sling Surgery
Authors: Drangsholt Siri , Lleras Cassidy , Kindler Rebecca , Babajanian Maytal , Pollack Bracha , Harutyunyan Aleksandr , Grunfeld Matan , Gejerman Yehuda , Kilkenny Katherine , Bulmash Moshe , Hirani Rahim , Alerasool Parissa , McNeil Christopher , Popiel Patrick , Drugge Elizabeth D. , Grimes Cara
Published: March 2024

OBJECTIVE:

To compare active with passive voiding trials on the rate of passing a trial of void and discharge rates with catheter in women who have undergone midurethral sling for treatment of stress urinary incontinence (SUI).

DATA SOURCES:

MEDLINE, EMBASE, and ClinicalTrials.gov were searched through February 24, 2023.

METHODS OF STUDY SELECTION:

Our population included women undergoing midurethral sling, with or without anterior or posterior repair, for treatment of SUI. Our two primary outcomes were rate of passing voiding trial and rate of discharge with a catheter. Our secondary outcome was the rate of delayed postoperative urinary retention, when a patient initially passes a trial of void but then subsequently presents in retention.

TABULATION, INTEGRATION, AND RESULTS:

Abstracts were doubly screened; full-text articles were doubly screened; and accepted articles were doubly extracted. In single-arm studies evaluating either passive or active voiding trial, random-effects meta-analyses of pooled proportions were used to assess outcomes. Of 3,033 abstracts screened, 238 full-text articles were assessed, and 26 met inclusion criteria. Ten studies including 1,370 patients reported active trial of void. Sixteen studies including 3,643 patients reported passive trial of void. We included five randomized controlled trials, five comparative retrospective studies, five prospective single group studies, and 11 retrospective single group studies. Five of the studies included patients with a concomitant anterior or posterior colporrhaphy. On proportional meta-analysis, the active trial of void group was less likely to pass the voiding trial (81.0%, 95% CI, 0.76–0.87% vs 89.0%, 95% CI, 0.84–0.9%3,P=.029) with high heterogeneity (I2=93.0%). Furthermore, there were more discharges with catheter in active trial of void compared with passive trial of void (19.0%, 95% CI, 0.14–0.24% vs 7.0%, 95% CI, 0.05–0.10%,P<.01). The rates of delayed postoperative urinary retention were low and not different between groups (0.6%, 95% CI, 0.00–0.02% vs 0.2%, 95% CI, 0.00–0.01%,P=.366) with low heterogeneity (I2=0%). Sling revisions were statistically lower in the active trial of void group (0.5%, 95% CI, 0.00–0.01% vs 1.5%, 95% CI, 0.01–0.02%,P=.035) with low heterogeneity (I2=10.4%).

CONCLUSION:

Passive trial of void had higher passing rates and lower discharge with catheter than active trial of void. Rates of most complications were low and similar between both groups, although passive trial of void had higher sling revisions.

SYSTEMATIC REVIEW REGISTRATION:

PROSPERO, CRD42022341318.
The sounds of silencing: dynamic epigenetic control of HIV latency
Authors: Nguyen Kien , Karn Jonathan
Published: March 2024

Purpose of review

This review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T-cells and microglial cells and describes the potential of current therapeutic approaches targeting the epigenetic machinery to eliminate or block the HIV-1 latent reservoir.

Recent findings

Large-scale unbiased CRISPR-Cas9 library-based screenings, coupled with biochemical studies, have comprehensively identified the epigenetic factors pivotal in regulating HIV-1 latency, paving the way for potential novel targets in therapeutic development. These studies also highlight how the bivalency observed at the HIV-1 5’LTR primes latent proviruses for rapid reactivation.

The HIV-1 latent is established very early during infection, and its persistence is the major obstacle to achieving an HIV-1 cure. Here, we present a succinct summary of the latest research findings, shedding light on the pivotal roles played by host epigenetic machinery in the control of HIV-1 latency. Newly uncovered mechanisms permitting rapid reversal of epigenetic restrictions upon viral reactivation highlight the formidable challenges of achieving enduring and irreversible epigenetic silencing of HIV-1.
Humanized mice for studying HIV latency and potentially its eradication
Authors: Hasler Moa F. , Speck Roberto F. , Kadzioch Nicole P.
Published: March 2024

Purpose of the review

The quest for an HIV cure faces a formidable challenge: the persistent presence of latent viral infections within the cells and tissues of infected individuals. This review provides a thorough examination of discussions surrounding HIV latency, the use of humanized mouse models, and strategies aimed at eliminating the latent HIV reservoir. It explores the hurdles and advancements in understanding HIV pathogenesis, mainly focusing on establishing latent reservoirs in CD4+ T cells and macrophages. Introducing the concepts of functional and sterile cures, the review underscores the indispensable role of humanized mouse models in HIV research, offering crucial insights into the efficacy of cART and the ongoing pursuit of an HIV cure.

Recent findings

Here, we highlight studies investigating molecular mechanisms and pathogenesis related to HIV latency in humanized mice and discuss novel strategies for eradicating latent HIV. Emphasizing the importance of analytical cART interruption in humanized mouse studies to gauge its impact on the latent reservoir accurately, the review underlines the ongoing progress and challenges in harnessing humanized mouse models for HIV research.

This review suggests that humanized mice models provide valuable insights into HIV latency and potential eradication strategies, contributing significantly to the quest for an HIV cure.
Circulating factors in cancer cachexia: recent opportunities for translational research
Authors: Coêlho Marina de Castro , de Aquino Giovana Parreira , Santos Amanda Soares , Seelaender Marilia
Published: March 2024

Purpose of review

To discuss the recent discoveries and limitations of the available literature on emerging circulating biomarkers of cancer cachexia.

Recent findings

Studies on circulating factors in cancer cachexia show promising alternatives for diagnosing the syndrome in a minimally invasive manner in the clinic setting, as well as potential targets for cancer cachexia treatment. Factors secreted by the tumor and the adipose tissue, such as extracellular vesicles and soluble proteins, respectively, have been shown to either directly induce wasting in vitro and in vivo or to be altered in the cachectic phenotype. The detection and characterization of circulating cells allows detection of the precachectic stage and the levels of the soluble immune checkpoint protein programmed death ligand-1 (PD-L1) are correlated with the presence of the hallmarks of cancer cachexia.

Structural, molecular, and metabolic alterations have been observed in various tissues, revealing the occurrence of sustained inter-compartment crosstalk in cachectic patients. Early diagnosis of cancer cachexia becomes crucial to avoid the establishment of refractory cachexia through the implementation of interventions that may attenuate systemic inflammation and muscle loss. More studies on human cancer cachexia are required in order to address the recently discovered cachexia-associated circulating factors’ value as biomarkers of the syndrome.
Expert Consensus on Classification and Performance in Paralympic Powerlifting
Authors: Rum Lorenzo , Romagnoli Ruggero , Lazich Aldo , Sciarra Tommaso , Balletti Nicoletta , Piacentini Maria Francesca , Boraschi Alessandro , Bergamini Elena
Published: March 2024

Background

In Paralympic sports, classification ensures fair competition by grouping athletes based on their impairments. The International Paralympic Committee has provided scientific principles to guide evidence-based classification procedures. In Paralympic Powerlifting, athletes compete in one class, divided by sex and bodyweight categories, overlooking impairment impact on performance.

Objective

This study aimed to establish a consensus among international Paralympic powerlifting experts regarding classification and performance issues to guide future research.

Methods

A two-round Delphi study was conducted involving 26 experts. The study sought to identify the adequacy of the current classification and competition systems, explore the impact of various impairments, and lay the initial groundwork for a performance determinants model.

Results

Experts agreed that existing classification and competition systems in Paralympic powerlifting do not align with Paralympic standards. Impairments from neurological conditions and those causing anthropometric changes were suggested to have opposing performance impacts. Initial directions for a performance determinants model were outlined, focusing on arm and bar kinematics, anthropometry, and body composition.

Conclusions

This study underscores the need for comprehensive research in Paralympic powerlifting, revealing critical discrepancies between current classification system and Paralympic standards. Insights into the multifaceted relationship between impairments and performance are provided to shape the future of Paralympic powerlifting research.
Diagnostic Neuromuscular Ultrasound to Confirm Clinical Significance of a Genetic Variant for Charcot-Marie-Tooth Type 4C
Authors: Meiling James B. , Baute Penry Vanessa
Published: March 2024

Neuromuscular ultrasound has emerged as a beneficial, complementary tool to electromyography (EMG) in the diagnosis of neuromuscular diseases as it provides high-resolution anatomic imaging of peripheral nerves and muscles. It has been used previously as an adjunct to EMG to diagnose Charcot-Marie-Tooth disease. Here, we present a case of a 64-yr-old man with bilateral sensorineural hearing loss of 14 yrs who presented to an outpatient neuromuscular clinic at a tertiary medical center with very slow progressive paresthesias. This case highlights the application of neuromuscular ultrasound to help confirm the presence of a likely Charcot-Marie-Tooth disease type 4C despite indeterminate genetic testing results and challenging EMG results. He had genetic testing which revealed a normal PMP22 gene; however, he had a variant of uncertain significance in the SH3TC2 gene which has shown associations with autosomal recessive CMT4C. Neuromuscular ultrasound revealed mild median and significant tibial nerve uniform enlargement throughout their course. There may also be utility in performing neuromuscular ultrasound on similarly affected family members if the same variant of uncertain significance returns for SH3TC2, with consideration of both peripheral nerve and nerve root assessment.
The Impact of Surgical Timing in Orbital Fracture Repair: A New Paradigm
Authors: Hassan Bashar , Resnick Eric , Er Seray , Liang Fan , Redett Richard , Yang Robin , Manson Paul , Grant Michael
Published: March 2024

Background:

For decades, there has been an ongoing debate about the ideal timing of orbital fracture repair (OFR) in adults.

Methods:

The authors conducted a retrospective review of patients who underwent OFR at 2 centers (2015 to 2019). Excluded were patients younger than 18 years and those with follow-up less than 2 weeks. The study’s primary outcome was the incidence/persistence of postoperative enophthalmos/diplopia at least 2 weeks following OFR. The association between surgical timing and postoperative ocular complications was assessed in patients with extraocular muscle (EOM) entrapment, enophthalmos and/or diplopia, and different fracture sizes.

Results:

Of 253 patients, 13 (5.1%) had preoperative EOM entrapment. Of these, patients who had OFR within 2 days of injury were less likely to develop postoperative diplopia compared with patients who had OFR within 8 to 14 days (1 of 8 patients [12.5%] versus 3 of 3 patients [100%]; P = 0.018). Patients who had OFR for nearly total defects within 1 week of injury were significantly less likely to have postoperative enophthalmos (0 patients [0.0%]) compared with those who had surgery after 2 weeks (2 patients [33.3%] after 15 to 28 days versus 8 patients [34.8%] after 28 days from injury; P < 0.001). Patients who had delayed OFR for large fractures smaller than nearly total defects, preoperative persistent diplopia, or enophthalmos were not at significantly greater likelihood of postoperative ocular complications compared with those who had early OFR.

Conclusions:

The authors recommend OFR within 2 days of injury for EOM entrapment and 1 week for nearly total defects. Surgical delay up to at least 4 weeks is possible in case of less severe fractures, preoperative persistent diplopia, or enophthalmos.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, IV.
An overview of risk factors, management and prevention of cochlear implant infections
Authors: MacKay Conor I. , Kuthubutheen Jafri , Campbell Anita J.
Published: March 2024

Purpose of review

With cochlear implantation becoming increasingly performed worldwide, an understanding of the risk factors, preventive measures, and management of cochlear implant (CI) infection remains important given the significant morbidity and cost it conveys.

Recent findings

At the turn of the 21st century there was a decrease in rates of CI infection, particularly meningitis, following the discontinuation of positioner use for CI. However, in more recent years rates of CI infection have remained largely static. Recently, studies evaluating preventive measures such as pneumococcal vaccination, S. aureus decolonization and surgical antibiotic prophylaxis have emerged in the literature.

Prompt recognition of CI infection and appropriate investigation and management are key, however at present treatment is largely informed by cohort and case-control studies and expert opinion. Preventive measures including pneumococcal vaccination, S. aureus decolonization and preoperative antibiotic prophylaxis play a role in reducing rates of CI infection. However, there remains a need for well designed clinical trials to provide higher level evidence to better guide preventive measures for, and management decisions of, CI infections in the future.
Identifying the suite of genes central to swimming in the biocontrol bacterium Pseudomonas protegens Pf-5
Authors: Fabian B.K. , Foster C. , Asher A. , Hassan K.A. , Paulsen I.T. , Tetu S.G.
Published: March 2024

Swimming motility is a key bacterial trait, important to success in many niches. Biocontrol bacteria, such as Pseudomonas protegens Pf-5, are increasingly used in agriculture to control crop diseases, where motility is important for colonization of the plant rhizosphere. Swimming motility typically involves a suite of flagella and chemotaxis genes, but the specific gene set employed for both regulation and biogenesis can differ substantially between organisms. Here we used transposon-directed insertion site sequencing (TraDIS), a genome-wide approach, to identify 249 genes involved in P. protegens Pf-5 swimming motility. In addition to the expected flagella and chemotaxis, we also identified a suite of additional genes important for swimming, including genes related to peptidoglycan turnover, O-antigen biosynthesis, cell division, signal transduction, c-di-GMP turnover and phosphate transport, and 27 conserved hypothetical proteins. Gene knockout mutants and TraDIS data suggest that defects in the Pst phosphate transport system lead to enhanced swimming motility. Overall, this study expands our knowledge of pseudomonad motility and highlights the utility of a TraDIS-based approach for analysing the functions of thousands of genes. This work sets a foundation for understanding how swimming motility may be related to the inconsistency in biocontrol bacteria performance in the field.
Potential multiple disease progression pathways in female patients with Alzheimer's disease inferred from transcriptome and epigenome data of the dorsolateral prefrontal cortex
Authors: Honda Kousei , Awazu Akinori
Published: March 2024

Late-onset Alzheimer's disease (AD) is a typical type of dementia for which therapeutic strategies have not yet been established. The database of the Rush Alzheimer's Disease study by the ENCODE consortium contains transcriptome and various epigenome data. Although the Rush AD database may contain a satisfactory amount of data for women, the amount of data for men remains insufficient. Here, based on an analysis of publicly available data from female patients, this study found that AD pathology appears to be nonuniform; several different typical forms of cognitive deterioration were observed. First, cluster analysis was performed on individuals diagnosed with "No Cognitive Impairment (NCI)," "Mild Cognitive Impairment (MCI)," and "Alzheimer's Disease (AD)" stages in clinical trials using gene expression. NCI was found to contain at least two substages, whereas MCI and AD contained four and six substages, respectively. The epigenome data, in particular genome-wide H3k4me3 distribution data, also supported the existence of multiple AD substages. However, APOE gene polymorphisms of individuals seemed to not correlate with disease stage. An inference of adjacency networks among substages, evaluated via partition-based graph abstraction using the gene expression profiles of individuals, suggested the possibility of multiple typical disease progression pathways from NCI to different AD substages through various MCI substages. These results will aid future research on the pathological features and mechanisms of AD and may induce changes in the strategic bases of conventional AD prevention and treatment.
The shared and disorder-specific resting state functional connectivity associated with emotion regulation between ADHD and bipolar disorder
Authors: Zhuang Qian , Xu Chuxian , Xu Nuo , Wang Tongtong , Lock Matthew , Chen Shuaiyu
Published: March 2024

Background

Emotion regulation deficits have been frequently observed between ADHD (Attention-deficit/hyperactivity disorder, ADHD) and BD (bipolar disorder, BD) adults, however, common and distinguishable alterations in functional connectivity during rest remain poorly understood.

Objectives

The current study was performed to determine the shared and disorder-specific resting state functional connectivity (rsFC) features within the proposed hierarchical emotion regulation model.

Method

The whole-brain seed-to-voxel functional connectivity analyses were performed on the neuroimaging data from the OpenFMRI project included 40 ADHD adults, 49 BD adults, as well as 49 age and gender matched healthy controls.

Results

Our findings showed significantly shared and disorder-specific rsFC circuits mainly linking to the processes of emotion perception and interception during emotion regulation but not response inhibition or executive control. Such as, the results found significantly enhanced functional connectivity strength between inferior occipital gyrus (IOG)-lingual/fusiform gyrus as well as superior parietal lobule (SPL)-insula circuits in ADHD group compared to healthy group (HG) and BD group, which suggests impaired emotional facial perception and interoceptive processing in ADHD than BD adults. In addition, the connectivity between precuneus and fusiform was significantly lower in both of ADHD and BD group compared to HG and no significant difference was found between patient groups. This indicates similar neural patterns underlying the impairment in emotion classification and emotional experience for ADHD and BD adults.

Conclusions

Together these findings can promote the understanding of common and disorder-specific neural mechanism underlying emotion dysregulations and facilitate neuroimaging-based clinical evaluation for ADHD and BD adults.
The iPhylo Suite: An Interactive Platform for Building and Annotating Biological and Chemical Taxonomic Trees
Authors: Li Yueer , Peng Chen , Chi Fei , Huang Zinuo , Yuan Mengyi , Jiang Chao
Published: March 2024

Accurate and rapid taxonomic classifications are essential for systematically exploring organisms and metabolites in diverse environments. Many tools have been developed for biological taxonomic trees, but limitations apply, and a streamlined method for constructing chemical taxonomic trees is lacking. We present the iPhylo suite (https://www.iphylo.net/), a comprehensive, automated, and interactive platform for biological and chemical taxonomic analysis. The iPhylo suite includes the Tree and Visual web-based modules for interactive building and annotating biological and chemical taxonomic trees, and a stand- alone command-line interface (CLI) module for local use and deployment on high-performance computing clusters. Furthermore, the iPhylo visualization module is fully implemented in R, allowing users to save progress locally and modify the underlying R codes. Finally, the iPhylo CLI module extends the analysis to all hierarchical relational databases. In summary, the iPhylo suite provides an integrated interactive framework for in-depth taxonomic analyses of biological and chemical features and beyond.

Highlights

A platform for both biological and chemical classification analysis and visualizations.

A stand-alone Command line interface module for local or HPC deployment.

R-based interactive visualization module with session-saving options.

Supports customized hierarchical databases for analysis beyond taxonomy.
Dynamics of compartment-specific proteomic landscapes of hepatotoxic and cholestatic models of liver fibrosis
Authors: Jirouskova Marketa , Harant Karel , Cejnar Pavel , Ojha Srikant , Korelova Katerina , Sarnova Lenka , Sticova Eva , Mayr Christoph H. , Schiller Herbert B. , Gregor Martin
Published: March 2024

Accumulation of extracellular matrix (ECM) in liver fibrosis is associated with changes in protein abundance and composition depending upon etiology of the underlying liver disease. Current efforts to unravel etiology-specific mechanisms and pharmacological targets rely on several models of experimental fibrosis. Here, we characterize and compare dynamics of hepatic proteome remodeling during fibrosis development and spontaneous healing in experimental models of hepatotoxic (carbon tetrachloride (CCl4) intoxication) and cholestatic (3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding) injury. Using detergent-based tissue extraction and mass spectrometry, we identified compartment-specific changes in the liver proteome with detailed attention to ECM composition and changes in protein solubility. Our analysis revealed distinct time-resolved CCl4and DDC signatures, with identified signaling pathways suggesting limited healing and a potential for carcinogenesis associated with cholestasis. Correlation of protein abundance profiles with fibrous deposits revealed extracellular chaperone clusterin with implicated role in fibrosis resolution. Dynamics of clusterin expression was validated in the context of human liver fibrosis. Atomic force microscopy of fibrotic livers complemented proteomics with profiles of disease-associated changes in local liver tissue mechanics. This study determined compartment-specific proteomic landscapes of liver fibrosis and delineated etiology-specific ECM components, providing thus a foundation for future antifibrotic therapies.
Aurora B inhibition promotes a hyper-polyploid state and continued endomitotic cycles in RB and p53 defective cells
Authors: Vora Shivam , Andrew Ariel , Kumar Ramyashree Prasanna , Nazareth Deborah , Fernando Madushan , Jones Mathew JK , He Yaowu , Hooper John D. , McMillan Nigel AJ , Urosevic Jelena , Saeh Jamal , Travers Jon , Gabrielli Brian
Published: March 2024

Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether this is a source of increased chemotherapy resistance and aggressive disease, or a benign or even favorable outcome. We have used Aurora B kinase (AURKB) inhibitors that efficiently promote polyploidy in many cell types to investigate the fate of polyploid cells. We demonstrate AURKB inhibitor treatment of cells that have loss of RB and p53 function causes them to become hyper-polyploid, undergoing continuous rounds of growth, replication and failed mitosis/cytokinesis (endomitosis), whereas RB and p53 functional cells will eventually exit the cell cycle. These hyper-polyploid cells (>4n DNA content) are viable and undergo continuous endomitotic cycles, but have lost the ability to form viable coloniesin vitroor form tumoursin vivo. Investigation of mitosis in these cells revealed that centrosome duplication remained coupled to DNA replication, with the hyper-polyploid cells containing high numbers of centrosome that were capable of supporting functional mitotic spindle poles, but these failed to progress to anaphase/telophase structures even when AURKB inhibitor was removed after 2-3 days. However, when AURKB inhibitor was removed after 1 day and cells had failed a single cytokinesis to become tetraploid, they retained long term colony forming ability. Collectively, these findings demonstrate that tetraploidy is well tolerated by tumour cells but higher ploidy states are incompatible with long term proliferative potential.
Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis
Authors: Lauer David , Magnin Cheryl Yael , Kolly Luca , Wang Huijuan , Brunner Matthias , Charbria Mamta , Cereghetti Grazia Maria , Gabryś Hubert , Tanadini-Lang Stephanie , Uldry Anne-Christine , Heller Manfred , Verleden Stijn E , Klein Kerstin , Sarbu Adela-Cristina , Funke-Chambour Manuela , Ebner Lukas , Distler Oliver , Maurer Britta , Gote-Schniering Janine
Published: March 2024

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.
PTENandARID1Ahaploinsufficiency equip colonic epithelium for oncogenic transformation
Authors: Skoufou-Papoutsaki Nefeli , Adler Sam , Mehmed Shenay , Tume Claire , Olpe Cora , Morrissey Edward , Kemp Richard , Girard Anne-Claire , Moutin Elisa B , Chilamakuri Chandra Sekhar Reddy , Miller Jodi L , Lindskog Cecilia , Werle Fabian , Marks Kate , Perrone Francesca , Zilbauer Matthias , Tourigny David S , Winton Douglas J
Published: March 2024

Normal aged tissues are thought to exist as a patchwork of mutant clones. However, the relevance of driver mutations in normal tissue in terms of cancer initiation has not been well described. Here, we sought a quantitative understanding of how different cancer drivers achieve an age-related mutational footprint in the human colonic epithelium and to relate the clonal behaviours they generate to cancer risk. Metanalysis of contemporary multiregional sampling studies of colorectal tumours revealed many of the weak or moderate cancer drivers are trunk mutations present in the last common ancestor from which cancers arise. To study the processes by which such driver mutations could contribute to cancer predisposition, immunohistochemistry was used to detect PTEN, SMAD4 and ARID1A deficient clones in normal colon FFPE surgical resection samples (N=182 patients). Age-related changes in clone size and frequency identified positive biases in clone dynamics that acted to increase the mutational footprint for ARID1A and PTEN but not SMAD4.In vitroengineered monoallelic loss ofPTENandARID1Aimplicated specific altered downstream pathways and acquired pro-oncogenic cellular fates corresponding to haploinsufficiency for these genes.In situanalysis confirmed enhanced proliferation in both PTEN and ARID1A deficient clones and creation of an immune exclusive microenvironment associated with ARID1A deficiency. The behaviours resulting from haploinsufficiency ofPTENandARID1Aexemplify how priming of the tissue through somatic mosaicism could contribute alternative combinations of genetic events leading to transformation.
Altruistic feeding and cell-cell signaling during bacterial differentiation actively enhance phenotypic heterogeneity
Authors: Updegrove Taylor B. , Delerue Thomas , Anantharaman Vivek , Cho Hyomoon , Chan Carissa , Nipper Thomas , Choo-Wosoba Hyoyoung , Jenkins Lisa M. , Zhang Lixia , Su Yijun , Shroff Hari , Chen Jiji , Bewley Carole A. , Aravind L. , Ramamurthi Kumaran S.
Published: March 2024

Starvation triggers bacterial spore formation, a committed differentiation program that transforms a vegetative cell into a dormant spore. Cells in a population enter sporulation non-uniformly to secure against the possibility that favorable growth conditions, which puts sporulation-committed cells at a disadvantage, may resume. This heterogeneous behavior is initiated by a passive mechanism: stochastic activation of a master transcriptional regulator. Here, we identify a cell-cell communication pathway that actively promotes phenotypic heterogeneity, whereinBacillus subtiliscells that start sporulating early utilize a calcineurin-like phosphoesterase to release glycerol, which simultaneously acts as a signaling molecule and a nutrient to delay non-sporulating cells from entering sporulation. This produced a more diverse population that was better poised to exploit a sudden influx of nutrients compared to those generating heterogeneity via stochastic gene expression alone. Although conflict systems are prevalent among microbes, genetically encoded cooperative behavior in unicellular organisms can evidently also boost inclusive fitness.
A Novel Liver Cancer-Selective Histone Deacetylase Inhibitor Is Effective Against Hepatocellular Carcinoma and Induces Durable Responses with Immunotherapy
Authors: Wu Bocheng , Tapadar Subhasish , Ruan Zhiping , Sun Carrie Q. , Arnold Rebecca S. , Johnston Alexis , Olugbami Jeremiah O. , Arunsi Uche , Gaul David A. , Petros John A. , Kobayashi Tatsuya , Duda Dan G. , Oyelere Adegboyega K.
Published: March 2024

Hepatocellular cancer (HCC) progression is facilitated by gene-silencing chromatin histone hypoacetylation due to histone deacetylases (HDACs) activation. However, inhibiting HDACs — an effective treatment for lymphomas — has shown limited success in solid tumors. We report the discovery of a class of HDAC inhibitors (HDACi) that demonstrates exquisite selective cytotoxicity against human HCC cells. The lead compoundSTR-V-53(3) showed a favorable safety profile in mice and robustly suppressed tumor growth in orthotopic xenograft models of HCC. When combined with the anti-HCC drug sorafenib,STR-V-53showed greater in vivo efficacy. Moreover,STR-V-53combined with anti-PD1 therapy increased the CD8+to regulatory T-cell (Treg) ratio and survival in an orthotopic HCC model in immunocompetent mice. This combination therapy resulted in durable responses in 40% of the mice. Transcriptomic analysis revealed thatSTR-V-53primed HCC cells to immunotherapy through HDAC inhibition, impaired glucose-regulated transcription, impaired DNA synthesis, upregulated apoptosis, and stimulated the immune response pathway. Collectively, our data demonstrate that the novel HDACiSTR-V-53is an effective anti-HCC agent that can induce profound responses when combined with standard immunotherapy.

Graphical Abstract
A Health Economic Evaluation for Implementing an Extended Half-life Monoclonal Antibody for All Infants vs. Standard Care for Respiratory Virus Syncytial Prophylaxis in Canada
Authors: Shin Thomas , Lee Jason KH , Kieffer Alexia , Greenberg Michael , Wu Jianhong
Published: March 2024

Respiratory syncytial virus (RSV) is a highly infectious virus, and infants and young children are particularly vulnerable to its progression to severe lower respiratory tract illness (LRTI). Nirsevimab, an extended half-life monoclonal antibody, was recently approved in Canada as a passive immunization intervention for the prevention of RSV LRTI. A static decision tree model was utilized to determine the cost-effectiveness of nirsevimab in Canadian infants compared to current standard of care (palivizumab for infants born preterm, and with specific chronic conditions) and generate an optimal price per dose (PPD) at accepted willingness-to-pay (WTP) thresholds. Various health outcomes (including hospitalization, ICU, and mechanical ventilation) and healthcare costs were calculated over one RSV season, with any necessary follow-up prophylaxis in the second season for three infant categories (palivizumab-eligible, preterm, and term). All health-related parameters and costs were tailored to the Canadian environment. Compared to scenarios where only at-risk segments of the infant population received nirsevimab, the base case (administering nirsevimab to all infants in their first RSV season) was the most cost-effective versus standard care: the PPD was $692 at a $40,000/QALY WTP threshold, using average costing data assumptions across all scenarios. Compared to standard care, the base case scenario could avoid 18,249 RSV-related health outcomes (reduction of 9.96%). Variations in discount rate, distribution of monthly RSV infections, nirsevimab coverage rate for infants born at term, and palivizumab cost had the most significant model impact. Passive immunization of all infants with nirsevimab can significantly reduce RSV-related health and economic burden across Canada.
Topological obstructions to quantum computation with unitary oracles
Authors: Gavorová Zuzana , Seidel Matan , Touati Yonathan
Published: March 2024

Algorithms with unitary oracles can be nested, which makes them extremely versatile. An example is the phase estimation algorithm used in many candidate algorithms for quantum speedup. The search for new quantum algorithms benefits from understanding their limitations: Some tasks are impossible in quantum circuits, although their classical versions are easy, for example, cloning. An example with a unitary oracle U is the if clause, the task to implement controlled U (up to the phase on U). In classical computation the conditional statement is easy and essential. In quantum circuits the if clause was shown impossible from one query to U. Is it possible from polynomially many queries? Here we unify algorithms with a unitary oracle and develop a topological method to prove their limitations: No number of queries to U and U† lets quantum circuits implement the if clause, even if admitting approximations, postselection, and relaxed causality. We also show limitations of process tomography, oracle neutralization, and UdimU, UT, and U† algorithms. Our results strengthen an advantage of linear optics, challenge the experiments on relaxed causality, and motivate new algorithms with many-outcome measurements.

Published by the American Physical Society
2024
Operator growth hypothesis in open quantum systems
Authors: Srivatsa N. S. , von Keyserlingk Curt
Published: March 2024

The operator growth hypothesis (OGH) is a technical conjecture about the behavior of operators—specifically, the asymptotic growth of their —under repeated action by a Liouvillian. It is expected to hold for a sufficiently generic closed many-body system. When it holds, it yields bounds on the high-frequency behavior of local correlation functions and measures of chaos (like OTOCs). It also gives a route to numerically estimating response functions. Here we investigate the generalization of OGH to open quantum systems, where the Liouvillian is replaced by a Lindbladian. For a quantum system with local Hermitian jump operators, we show that the OGH is modified: we define a generalization of the Lanczos coefficient and show that it initially grows linearly as in the original OGH, but experiences exponentially growing oscillations on scales determined by the dissipation strength. We see this behavior manifested in a semi-analytically solvable model (large-q SYK with dissipation), numerically for an ergodic spin chain, and in a solvable toy model for operator growth in the presence of dissipation (which resembles a non-Hermitian single-particle hopping process). Finally, we show that the modified OGH connects to a fundamental difference between Lindblad and closed systems: At high frequencies, the spectral functions of the former decay algebraically, while in the latter they decay exponentially. This is an experimentally testable statement, which also places limitations on the applicability of Lindbladians to systems in contact with equilibrium environments.

Published by the American Physical Society
2024
Emergent symmetries of relativistic fluid dynamics from local ergodicity
Authors: Torrieri Giorgio
Published: March 2024

We show that volume-preserving diffeomorphisms and the chemical shift symmetry defining relativistic Lagrangian ideal fluid dynamics can be derived as an emerging symmetry when ergodicity is assumed to apply locally in a way that is invariant under smooth spacetime foliations. This can be used as a way to derive the ideal hydrodynamic limit in a strongly coupled but strongly fluctuating medium. We comment on the connection with thermalization in small systems, the eigenstate thermalization hypothesis and deviations from the ideal limit.

Published by the American Physical Society
2024