bluuebunny/crossref_metadata_2025 huggingface dataset:
Time of arrival during plant disease progression and humidity additively influenceSalmonella entericacolonization of lettuce
Authors: Dixon Megan H. , Nellore Dharshita , Zaacks Sonia C. , Barak Jeri D.
Published: February 2024

The interplay between plant host, phytopathogenic bacteria, and enteric human pathogens in the phyllosphere have consequences for human health.Salmonella entericahas been known to take advantage of phytobacterial infection to increase its success on plants, but there is little knowledge of additional factors that may influence the relationship between enteric pathogen and plant disease. In this study, we investigated the role of humidity and the extent of plant disease progression onS. entericacolonization of plants. We found that high humidity was necessary for replication ofS. entericaon diseased lettuce, but not required forS. entericaingress into the UV-protected apoplast. Additionally, theXanthomonas hortorumpv. vitians (hereafter,X. vitians)-infected lettuce host was found to be a relatively hostile environment forS. entericawhen it arrived prior to the development of watersoaking or following necrosis onset, supporting the existence of an ideal window duringX. vitiansinfection progress that maximizesS. entericasurvival. In vitrogrowth studies in sucrose media suggest thatX. vitiansmay allowS. entericato benefit from cross-feeding during plant infection. Overall, this study emphasizes the role of phytobacterial disease as a driver ofS. entericasuccess in the phyllosphere, demonstrates how time of arrival during disease progress can influenceS. enterica’sfate in the apoplast, and highlights the potential for humidity to transform an infected apoplast into a growth-promoting environment for bacterial colonizers.

Importance:

Bacterial leaf spot of lettuce caused byX. vitiansis a common threat to leafy green production. The global impact caused by phytopathogens, includingX. vitians, is likely to increase with climate change. We found that even under a scenario where increased humidity did not enhance plant disease, high humidity had a substantial effect on facilitatingS. entericagrowth onXanthomonas-infected plants. High humidity climates may directly contribute to the survival of human enteric pathogens in crop fields or indirectly affect bacterial survival via changes to the phyllosphere brought on by phytopathogen disease.
Deciphering the History of ERK Activity from Fixed-Cell Immunofluorescence Measurements
Authors: Ram Abhineet , Pargett Michael , Choi Yongin , Murphy Devan , Cabel Markhus , Kosaisawe Nont , Quon Gerald , Albeck John
Published: February 2024

The Ras/ERK pathway drives cell proliferation and other oncogenic behaviors, and quantifying its activity in situ is of high interest in cancer diagnosis and therapy. Pathway activation is often assayed by measuring phosphorylated ERK. However, this form of measurement overlooks dynamic aspects of signaling that can only be observed over time. In this study, we combine a live, single-cell ERK biosensor approach with multiplexed immunofluorescence staining of downstream target proteins to ask how well immunostaining captures the dynamic history of ERK activity. Combining linear regression, machine learning, and differential equation models, we develop an interpretive framework for immunostains, in which Fra-1 and pRb levels imply long term activation of ERK signaling, while Egr-1 and c-Myc indicate recent activation. We show that this framework can distinguish different classes of ERK dynamics within a heterogeneous population, providing a tool for annotating ERK dynamics within fixed tissues.
Highly efficient in vivo mutagenesis method based on the endonuclease and exonuclease activity of Bacillus alcalophilus RecJ (BaRecJ)
Authors: Shang Jixiang , Zhang Yanchao , Xu Zongjun , Sun Zhongtao , Zheng Minggang , Zhang Shouqing
Published: February 2024

With the continual advancement of technologies such as microbial cultivation, DNA sequencing, bioinformatics, and genetic engineering, methods for microbial breeding have become increasingly diverse. We identified a RecJ enzyme (BaRecJ) with both endonuclease and exonuclease activities from B. alcalophilus. Differing from traditional physical-chemical mutagenesis approaches and the methods based on perturbation factor. this research established a novel mutagenesis method utilizing the endonuclease and exonuclease activities of BaRecJ. Mutagenesis of E. coli was conducted using the BaRecJ method, followed by screening for rifampicin-resistant mutants, rpoB sequencing results demonstrated a broader, more uniform spectrum of mutations and a higher frequency of substitution mutations with this mutagenesis approach. Furthermore, this mutagenesis method was applied to S cerevisiae, resulting in mutants with enhanced tolerance to acetic acid and ethanol, exhibiting improved fermentation performance and flocculation abilities Genomic resequencing analysis summarized genes possibly associated with the tolerance of mutants. Therefore, this approach not only holds immense potential in microbial mutagenesis breeding and adaptive evolution but also, when coupled with genomic resequencing, allows for the rapid identification of genetic loci associated with specific traits.
Using structure prediction of negative sense RNA virus nucleoproteins to assess evolutionary relationships
Authors: Sabsay Kimberly R. , te Velthuis Aartjan J.W.
Published: February 2024

Negative sense RNA viruses (NSV) include some of the most detrimental human pathogens, including the influenza, Ebola and measles viruses. NSV genomes consist of one or multiple single-stranded RNA molecules that are encapsidated into one or more ribonucleoprotein (RNP) complexes. These RNPs consist of viral RNA, a viral RNA polymerase, and many copies of the viral nucleoprotein (NP). Current evolutionary relationships within the NSV phylum are based on alignment of conserved RNA-directed RNA polymerase (RdRp) domain amino acid sequences. However, the RdRp domain-based phylogeny does not address whether NP, the other core protein in the NSV genome, evolved along the same trajectory or whether several RdRp-NP pairs evolved through convergent evolution in the segmented and non-segmented NSV genomes architectures. Addressing how NP and the RdRp domain evolved may help us better understand NSV diversity. Since NP sequences are too short to infer robust phylogenetic relationships, we here used experimentally-obtained and AlphaFold 2.0-predicted NP structures to probe whether evolutionary relationships can be estimated using NSV NP sequences. Following flexible structure alignments of modeled structures, we find that the structural homology of the NSV NPs reveals phylogenetic clusters that are consistent with RdRp-based clustering. In addition, we were able to assign viruses for which RdRp sequences are currently missing to phylogenetic clusters based on the available NP sequence. Both our RdRp-based and NP-based relationships deviate from the current NSV classification of the segmentedNaedrevirales, which cluster with the other segmented NSVs in our analysis. Overall, our results suggest that the NSV RdRp and NP genes largely evolved along similar trajectories and that even short pieces of genetic, protein-coding information can be used to infer evolutionary relationships, potentially making metagenomic analyses more valuable.
Architecture of the spinach plastid-encoded RNA polymerase
Authors: Wang Tongtong , Wang Guanglei , Fang Ying , Zhang Yi , Peng Wenxin , Zhou Yue , Zhang Aihong , Yu Long-Jiang , Lu Congming
Published: February 2024

The plastid-encoded RNA polymerase (PEP) serves as the principal transcription machinery within chloroplasts and is responsible for transcribing over 80% of primary plastid transcripts. Plant PEP is composed of a prokaryotic-like multisubunit core enzyme known as the PEP core, supplemented by newly evolved PEP-associated proteins (PAPs). In this study, we present the cryo-electron microscopy (cryo-EM) structure of a PEP complex derived from spinach (Spinacia oleracea). Our structural analysis unveils the presence of 14 PAPs closely associated with the PEP core complex consisting of 5 subunits, forming an irregular-shaped supercomplex. We provide a detailed depiction of the PEP core subunits and the 14 PAPs, elucidating their precise spatial arrangement and interactions. This research offers a crucial structural basis for future investigations into the functions and regulatory mechanisms governing plastid transcription.
SISTR: Sinus and Inferior alveolar nerve Segmentation with Targeted Refinement on Cone Beam Computed Tomography images
Authors: Misrachi Laura , Covili Emma , Mayard Hippolyte , Alaka Christian , Rousseau Jérémy , Au Willy
Published: February 2024

Background

Accurate delineation of the maxillary sinus and inferior alveolar nerve (IAN) is crucial in dental implantology to prevent surgical complications. Manual segmentation from CBCT scans is labor-intensive and error-prone.

Methods

We introduce SISTR (Sinus and IAN Segmentation with Targeted Refinement), a deep learning framework for automated, high-resolution instance segmentation of oral cavity anatomies. SISTR operates in two stages: first, it predicts coarse segmentation and offset maps to anatomical regions, followed by clustering to identify region centroids. Subvolumes of individual anatomical instances are then extracted and processed by the model for fine structure segmentation. Our model was developed on the most diverse dataset to date for sinus and IAN segmentation, sourced from 11 dental clinics and 10 manufacturers (358 CBCTs for sinus, 499 for IAN).

Results

SISTR shows robust generalizability. It achieves strong segmentation performance on an external test set (98 sinus, 91 IAN CBCTs), reaching average DICE scores of 96.64% (95.38-97.60) for sinus and 83.43% (80.96-85.63) for IAN, representing a significant 10 percentage point improvement in Dice score for IAN compared to single-stage methods. Chamfer distances of 0.38 (0.24-0.60) mm for sinus and 0.88 (0.58-1.27) mm for IAN confirm its accuracy. Its inference time of 4 seconds per scan reduces time required for manual segmentation, which can take up to 28 minutes.

Conclusions

SISTR offers a fast, accurate, and efficient solution for the segmentation of critical anatomies in dental implantology, making it a valuable tool in digital dentistry.

Plain text summary

Accurately determining the locations of important structures such as the maxillary sinus and inferior alveolar nerve is crucial in dental implant surgery to avoid complications. The conventional method of manually mapping these areas from CBCT scans is time-consuming and prone to errors. To address this issue, we have developed SISTR, an AI-based framework that efficiently and accurately automates this process, trained on extensive datasets, sourced from 11 dental clinics and 10 manufacturers. It surpasses conventional methods by identifying anatomical regions within seconds. SISTR provides a rapid and accurate solution for high-resolution segmentation of critical anatomies in dental implantology, making it a valuable tool in digital dentistry.
No clear evidence for relationships of Apolipoprotein E genotype with measures of common infections in three UK cohorts
Authors: Green Rebecca E. , Fernández-Sanlés Alba , Felici Caterina , Warren-Gash Charlotte , Butt Julia , Waterboer Tim , Richards Marcus , Schott Jonathan M. , Hughes Alun D. , Chaturvedi Nish , Williams Dylan M.
Published: February 2024

APOEgenotype is the strongest genetic risk factor for late onset Alzheimer’s disease, with the ε2 and ε4 alleles decreasing and increasing risk relative to the ε3 allele, respectively. Although evidence has been conflicting, several common infections have been associated with Alzheimer’s disease risk, and interactions byAPOEε4 carriage have also been reported. Nevertheless, to date, no study has examined relationships betweenAPOEgenotype and measures of multiple common infections among large population-based studies.

We investigated associations ofAPOEε2 and ε4 carriage (i.e. non-carrier vs carrier) with serostatus and antibody titers to 14 common pathogens – encompassing herpesviruses, human polyomaviruses,C.trachomatis, H.pylori, andT.gondii– in three population-based cohorts (UK Biobank, National Survey of Health and Development, Southall and Brent Revisited). Pathogen serostatus was derived using validated antibody cut-offs for relevant antigens and included as an outcome assessing previous infection. Antibody titers were dichotomised among the seropositive subset for each antigen and included as binary outcomes assessing recent immunological responses. We conducted analyses in each cohort using mixed-models, including age, sex and genetic principal components as fixed-effects, and genetic relatedness as a random-effect. In secondary analyses, we additionally assessed i) relationships ofAPOEε2 and ε4 dosage (i.e. number of copies of the allele of interest), and ii) relationships ofAPOEgenotype with continuous antibody titers (rank-based inverse normal transformed). Findings were meta-analysed across cohorts (n=10,059) using random-effects models and corrected for multiple tests using the false discovery rate.

We found no clear evidence of relationships betweenAPOEgenotype and serostatus or antibody titers to any pathogen, with no strong associations observed in any of our analyses following multiple testing correction. Investigations ofAPOEgenotypes with the clinical manifestations of these pathogens, as well as expanding to include other viruses such as SARS-CoV-2, would also be warranted.
Predicting gestational age at birth in the context of preterm birth from multi-modal fetal MRI
Authors: Fajardo-Rojas Diego , Hall Megan , Cromb Daniel , Rutherford Mary A. , Story Lisa , Robinson Emma , Hutter Jana
Published: February 2024

Preterm birth is associated with significant mortality and a risk for lifelong morbidity. The complex multifactorial aetiology hampers accurate prediction and thus optimal care. A pipeline consisting of bespoke machine learning methods for data imputation, feature selection, and regression models to predict gestational age (GA) at birth was developed and evaluated from comprehensive multi-modal morphological and functional fetal MRI data from 176 control cases and 67 preterm birth cases. The GA at birth predictions were classified into term and preterm categories and their accuracy, sensitivity, and specificity were reported. An ablation study was performed to further validate the design of the pipeline. The pipeline achieves an R2 score of 0.51 and a mean absolute error of 2.22 weeks. It also achieves a 0.88 accuracy, 0.86 sensitivity, and 0.89 specificity, outperforming previous classification efforts in the literature. The predominant features selected by the pipeline include cervical length and various placental T2* values. The confluence of fast, motion-robust and multi-modal fetal MRI techniques and machine learning prediction allowed the prediction of the gestation at birth. This information is essential for any pregnancy. To the best of our knowledge, preterm birth had only been addressed as a classification problem in the literature. Therefore, this work provides a proof of concept. Future work will increase the cohort size to allow for finer stratification within the preterm birth cohort.
Increased reproductive tract infections among secondary school girls during the COVID-19 pandemic: associations with pandemic related stress, mental health, and domestic safety
Authors: Mehta Supriya D , Nandi Debarghya , Otieno Fredrick , Zulaika Garazi , Nyothach Elizabeth , Agingu Walter , Bhaumik Runa , Mason Linda , van Eijk Anna M , Phillips-Howard Penelope A
Published: February 2024

Background: Kenya, like many countries, shuttered schools during COVID–19, with subsequent increases in poor mental health, sexual activity, and pregnancy. We sought to understand how the COVID–19 pandemic may mediate risk of reproductive tract infections. We hypothesized that greater COVID–19 related stress would mediate risk via mental health, feeling safe inside the home, and sexual exposure, given the pandemic mitigation–related impacts of school closures on these factors. Methods: We analyzed data from a cohort of 436 girls enrolled in secondary school in rural western Kenya. Baseline, 6–, 12–, and 18– month study visits occurred April 2018 – December 2019 (pre–COVID), and 30–, 36–, and 48– month study visits occurred September 2020 – July 2022 (COVID period). At study visits, participants self–completed a survey for sociodemographics and sexual practices, and provided self–collected vaginal swabs for Bacterial vaginosis (BV) testing, with STI testing at annual visits. COVID–related stress was measured with a standardized scale and dichotomized at highest quartile. Mixed effects modeling quantified how BV and STI changed over time, and longitudinal mediation analysis quantified how the relationship between COVID–19 stress and increased BV was mediated. Findings: BV and STI prevalence increased from 12.1% and 10.7% pre–COVID to 24.5% and 18.1% during COVID, respectively. This equated to a 26% (95% CI 1.00 – 1.59) and 36% (95% CI 0.98 – 1.88) increased relative prevalence of BV and STIs, respectively, in the COVID–19 period compared to pre–COVID, adjusted for numerous sociodemographic and behavioral factors. Higher COVID–related stress was associated with elevated depressive symptoms and feeling less safe inside the home, which were each associated with increased likelihood of having a boyfriend. In longitudinal mediation analyses, the direct effect of COVID–related stress on BV was small and non–significant, indicating increased BV was due to the constellation of factors that were impacted during the COVID pandemic. Conclusions: In this cohort of adolescent girls, BV and STIs increased following COVID–related school closures. These results highlight modifiable factors to help maintain sexual and reproductive health resiliency, such as anticipating and mitigating mental health impacts, domestic safety concerns, and maintaining sexual health services to prevent and treat reproductive tract infections.
Automated Diagnostic Reports from Images of Electrocardiograms at the Point-of-Care
Authors: Khunte Akshay , Sangha Veer , Oikonomou Evangelos K , Dhingra Lovedeep Singh , Aminorroaya Arya , Coppi Andreas , Vasisht Shankar Sumukh , Mortazavi Bobak J , Bhatt Deepak L , Krumholz Harlan M , Nadkarni Girish , Vaid Akhil , Khera Rohan
Published: February 2024

Timely and accurate assessment of electrocardiograms (ECGs) is crucial for diagnosing, triaging, and clinically managing patients. Current workflows rely on a computerized ECG interpretation using rule-based tools built into the ECG signal acquisition systems with limited accuracy and flexibility. In low-resource settings, specialists must review every single ECG for such decisions, as these computerized interpretations are not available. Additionally, high-quality interpretations are even more essential in such low-resource settings as there is a higher burden of accuracy for automated reads when access to experts is limited. Artificial Intelligence (AI)-based systems have the prospect of greater accuracy yet are frequently limited to a narrow range of conditions and do not replicate the full diagnostic range. Moreover, these models often require raw signal data, which are unavailable to physicians and necessitate costly technical integrations that are currently limited. To overcome these challenges, we developed and validated a format-independent vision encoder-decoder model - ECG-GPT - that can generate free-text, expert-level diagnosis statements directly from ECG images. The model shows robust performance, validated on 2.6 million ECGs across 6 geographically distinct health settings: (1) 2 large and diverse US health systems- Yale-New Haven and Mount Sinai Health Systems, (2) a consecutive ECG dataset from a central ECG repository from Minas Gerais, Brazil, (3) the prospective cohort study, UK Biobank, (4) a Germany-based, publicly available repository, PTB-XL, and (5) a community hospital in Missouri. The model demonstrated consistently high performance (AUROC≤0.81) across a wide range of rhythm and conduction disorders. This can be easily accessed via a web-based application capable of receiving ECG images and represents a scalable and accessible strategy for generating accurate, expert-level reports from images of ECGs, enabling accurate triage of patients globally, especially in low-resource settings.
MicroRNAs as diagnostic biomarkers and predictors of antidepressant response in major depressive disorder: a systematic review. Running title: miRNAs as biomarkers of MDD
Authors: Carneiro Beatriz A , Guerreiro-Costa Lívia N. F. , Lins-Silva Daniel H. , Faria-Guimarães Daniela , Souza Lucca S. , Leal Gustavo C. , Caliman-Fontes Ana Teresa , Beanes Graziele , Costa Ryan S. , Quarantini Lucas C.
Published: February 2024

Despite the hardships of major depressive disorder (MDD), biomarkers for the diagnosis and pharmacological management of this condition are lacking. MicroRNAs are epigenetic mechanisms that could provide promising MDD biomarkers. Our aim was to summarize the findings and provide validation for the selection and use of specific microRNAs as biomarkers in the diagnosis and treatment of MDD. A systematic review was conducted using the PubMed/MEDLINE, Cochrane, PsycINFO, Embase, and LILACS databases from March to May 2022, with clusters of terms based on microRNA and antidepressant. Studies involving human subjects, animal models, and cell cultures were included, whereas those that evaluated herbal medicines, non-pharmacological therapies, or epigenetic mechanisms other than miRNA were excluded. The review revealed differences in the expression of various microRNAs when considering the time of assessment (before or after antidepressant treatment) and the population studied. However, due to the heterogeneity of the microRNAs investigated, the limited size of the samples, and the wide variety of antidepressants used, few conclusions could be made. Despite the observed heterogeneity, the following microRNAs were determined to be important factors in MDD and the antidepressant response: mir-1202, mir-135, mir-124, and mir-16. The findings indicate the potential for the use of microRNAs as biomarkers for the diagnosis and treatment of MDD; however, more homogeneous studies are needed.
Longitudinal Case-Control Study of Active and Passive Dense Mammographic Breast Tissue
Authors: Batchelder Kendra A , White Basel , Cinelli Christina , Harrow Amy , Lary Christine , Khalil Andre
Published: February 2024

Mammography is used as secondary prevention for breast cancer. Computer-aided detection and image-based short-term risk estimation were developed to improve the accuracy of mammography. However, most approaches inherently lack the ability to connect observations at the mammography level to observations of cancer onset and progression seen at a smaller scale, which can occur years before imageable cancer and lead to primary prevention. The Hurst exponent (H) can quantify mammographic tissue into regions of dense tissue undergoing active restructuring and regions that remain passive, with amounts of active and passive dense tissue that differ between cancer and controls at diagnosis. A longitudinal retrospective case-control study was conducted to test the hypothesis that differences can be detected before diagnosis and changes could signal developing cancer. Mammograms and reports were collected from 50 patients from Maine Medical Center in 2015 with at least a 5-year screening history. Age-matching patients within 2 years created a primary dataset, and within 5 years, a secondary dataset was created to test for sensitivity. The amount of passive (H≥0.55) and active dense tissue (0.45<H<0.55) was calculated for each breast and was predicted by creating a linear mixed-effects model. Cancer status was a predictor for passive (p=0.036) and active (p=0.025) dense tissue using the primary dataset. However, when increasing the power, cancer status was a predictor for active dense tissue (p=0.013), while breast status (p=0.004), time (p=0.009), and interaction (p=0.038) were predictors for passive dense tissue. This suggests active dense tissue is a risk for cancer and passive dense tissue is an indication of developing cancer.
Disease progression strikingly differs in research and real-world Parkinson's populations
Authors: Beaulieu-Jones Brett , Frau Francesca , Bozzi Sylvie , Chandross Karen J , Peterschmitt M Judith , Cohen Caroline , Coulovrat Catherine , Kumar Dinesh , Kruger Mark J , Lipnick Scott L , Fitzsimmons Lane , Kohane Isaac , Scherzer Clemens
Published: February 2024

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data and recent advances in natural language processing, particularly large language models, allow for a more granular comparison of populations and the methods of data collection describing these populations than previously possible. This study includes two research populations and two real-world data derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using natural language processing with a large language model to extract measurements of PD progression. This extraction process is manually validated for accuracy. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p<0.001; mini-mental state exam median decline 0.28 vs. 0.11, p<0.001; and clinically recognized cognitive decline, p=0.001). In the real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p<0.001). After diagnosis, in real-world cohorts, treatment with PD medications is initiated 2.3 years later on average (95% CI: [2.1-2.4]; p<0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging using existing data. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.
Elucidating effects of single and multiple resistance mechanisms on bacterial response to meropenem by quantitative and systems pharmacology modeling and population genomics
Authors: Fuhs Dominika T , Cortés-Lara Sara , Tait Jessica R , Rogers Kate E , López-Causapé Carla , Lee Wee Leng , Shackleford David M , Nation Roger L , Oliver Antonio , Landersdorfer Cornelia B
Published: February 2024

Meropenem is commonly used againstPseudomonas aeruginosa; however, resistance is emerging. Traditionally, the time unbound antibiotic concentration exceeds the MIC (fT>MIC) is used to select carbapenem regimens. We aimed to 1) characterize the effects of different resistance mechanisms on bacterial killing and resistance emergence, 2) evaluate whetherfT>MICcan predict these effects, and 3) develop a novel quantitative and systems pharmacology model to elucidate effects of baseline resistance mechanisms on the time-course of bacterial response. Seven isogenicP. aeruginosastrains with a range of resistance mechanisms and MICs were used in 10-day hollow-fibre infection model studies (HFIM). Meropenem pharmacokinetic profiles were simulated for various regimens (t1/2,meropenem=1.5h). All viable counts on drug-free, 3xMIC and 5xMIC meropenem-containing agar across all strains, five regimens and control (n=90 profiles) were modelled simultaneously. Whole genome sequencing was completed for resistant colonies and total population samples at 239h. Regimens achieving ≥98%fT>1xMICsuppressed resistance emergence of the mexR knockout strain. Even 100%fT>5xMICfailed to achieve this against the strain with OprD loss and the ampD and mexR double-knockout strain. The model well characterized total and less-susceptible bacteria for all strains. Supported by genomic analysis, pre-existing resistant subpopulations drove resistance emergence in the model. During meropenem exposure, mutations in mexR were selected in strains with baseline oprD mutations, and vice versa, confirming these as major mechanisms of resistance emergence. Secondary mutations occurred in lysS or argS, coding for lysyl and arginyl tRNA synthetases, respectively. The model well characterized all bacterial outcomes of seven strains simultaneously, whichfT>MICcould not.
Prevalence and preferred niche of small eukaryotes with mixotrophic potentials in the global ocean
Authors: Dong Kaiyi , Wang Ying , Zhang Wenjing , Li Qian
Published: February 2024

Unicellular eukaryotes that are capable of phago-mixotrophy in the ocean compete for inorganic nutrients and light with autotrophs, and for bacterial prey with heterotrophs. In this study, we ask what are the overall prevalence of eukaryotic mixotrophs in vast open oceans, and how the availability of inorganic nutrients, light, and prey affects their relative success. We utilized theTara Oceanseukaryotic 18S rRNA gene and environmental context variables dataset to conduct large-scale field analysis. We also performed isolate-based culture experiments to verify growth and nutritional resource relationships for representative mixotrophic taxa. The field analysis suggested that the overall prevalence of mixotrophs was negatively correlated with nutrient concentrations and positively associated with light availability. Concentrations of bacterial prey also presented somewhat correlation with mixotrophs but to a less extent. In comparison, the culture experiments demonstrated a taxa-specific relationship between mixotrophic growth and nutrition resources, i.e., the growth of one group was significantly dependent on light availability while the other group was less affected by light when they received sufficient prey. Both groups were capable of growing efficiently with low inorganic nutrients when receiving sufficient prey and light. Therefore, our field analysis and culture experiments both suggest that phago-mixotrophy for ocean eukaryotes is seemingly to be an efficient strategy to compensate nutrient deficiency but unnecessarily light limitation. This study collectively revealed a close relationship between abiotic and biotic nutritional resources and the prevalence of trophic strategies, shedding light on the importance of light and nutrients for determining the competitive success of mixotrophs versus autotrophic and heterotrophic eukaryotes in the ocean.
Loop extrusion-mediated plasmid DNA cleavage by the bacterial SMC Wadjet complex
Authors: Pradhan Biswajit , Deep Amar , Koenig Jessica , Baaske Martin , Corbett Kevin , Kim Eugene
Published: February 2024

Structural maintenance of chromosomes (SMC) protein complexes play pivotal roles in genome organization and maintenance across all domains of life. In prokaryotes, SMC family Wadjet complexes structurally resemble the widespread MukBEF genome-organizing complexes but serve a defensive role by inhibiting plasmid transformation. We previously showed that Wadjet specifically cleaves circular DNA; however, the molecular mechanism underlying DNA substrate recognition remains unclear. Here, we use in vitro single-molecule imaging to directly visualize DNA loop extrusion and plasmid cleavage by Wadjet. We find that Wadjet is a symmetric DNA loop extruder that simultaneously reels in DNA from both sides of a growing loop and that this activity requires a dimeric JetABC supercomplex containing two dimers of the JetC motor subunit. On surface-anchored plasmid DNAs, Wadjet extrudes the full length of a 44 kilobase pair plasmid, stalls, and then cleaves DNA. Our findings reveal the role of loop extrusion in the specific recognition and elimination of plasmids by Wadjet, and establish loop extrusion as an evolutionarily conserved mechanism among SMC complexes across kingdoms of life.
SVarp: pangenome-based structural variant discovery
Authors: Soylev Arda , Ebler Jana , Pani Samarendra , Rausch Tobias , Korbel Jan , Marschall Tobias
Published: February 2024

The linear human reference genome that we use today does not represent the haplotypic diversity of the global human population. This raises bias in genomic read alignment and limits our ability to call large structural variations (SV), especially at highly polymorphic loci. Thus, many SV alleles remain unresolved. Recent efforts to transition to a graph-based reference genome resulted in the generation of the first draft human pangenome reference, but tools to call SVs relative to the pangenome reference are presently lacking. In this study, we present the SVarp algorithm, aiming to discover haplotype resolved SVs on top of a pangenome reference using long sequencing reads. SVarp outputs local assemblies of SV alleles, termed svtigs, instead of a VCF file of SV breakpoints, which we propose as a general exchange format allowing for flexible downstream analyses. In order to assess the accuracy of svtigs, we used simulated and real human genomes. Simulations allowed us to make exact breakpoint comparisons against the true callsets. We observed ~96% recall with deletions, insertions and duplications larger than 1,000bp, showing that SVarp can reliably detect genomic structural variants not yet represented in the graph. On the other hand, we compared SVarp output for ONT sequencing data at 20X coverage against independent genome assemblies of the same samples and found that ~82% of our svtig predictions are validated by the assemblies by a match with more than 85% sequence identity. SVarp was implemented using C++ and its source code is available at https://github.com/asylvz/SVarp under MIT license.
In search of breadth and depth: the origin story of a multidisciplinary faculty of management
Authors: Brooks Kim , Nichini Thomas
Published: February 2024

Purpose

This paper aims to use the origin story of Dalhousie’s Faculty of Management as a foil for unpacking the tensions between deep disciplinary specialization and liberal education in business schools in Canada and the USA. Ultimately, the paper reveals that those tensions are not irreconcilable, and that through the fortunes of historical contingencies and deliberate decision-taking, a faculty can embrace the benefits of both breadth and depth.

Design/methodology/approach

The paper proposes a critical organizational history of management education through a case study. By drawing on secondary literature and archival sources, the authors focus on moments in business education, such as the founding of the Wharton School of Business, the release of the Carnegie and Ford Reports and the trend towards increased specialization to situate a case study of Dalhousie University’s Faculty of Management.

Findings

The authors find that the evolution of business education in North America from its broad, liberal origins towards narrow, specialization has come at a cost to some of the benefits of business and management education. An alternative approach, one reflected in the design of Dalhousie’s Faculty of Management, its programme offerings and its interconnection with other disciplines, enables the advantages of deep disciplinarity to co-exist (and cross-inform) with the advantages of liberal approach to knowledges.

Originality/value

The Dalhousie model offers business schools an example of a faculty that balances the rich insights of liberal interdisciplinarity with the need for sophisticated approaches to more granular, often disciplinary, topics. In addition, the paper offers the story of a multidisciplinary management faculty, some explanation for how that faculty was maintained despite pressures towards specialization; and in doing so, contributes to the limited historical research of management education, particularly in Canada, post-2000.
Quantitative pressure and saturation engineering values from 4D PP and PS seismic data
Authors: Tura Ali , Held Marihelen , Simmons James , Kvilhaug Arnstein , Dhelie Per Eivind
Published: February 2024

For field development and drilling decisions, production assets and reservoir engineers require dynamic reservoir properties, such as saturation and pressure changes of a reservoir from the pre‐production virgin state. To date, geophysicists have produced time‐lapse (4D) seismic attributes (mostly on stacked seismic data) rather than dynamic parameters directly. In this paper, we present a new method to estimate saturation and pressure properties from time‐lapse seismic data to provide to reservoir engineers. This new three‐step method is demonstrated over the Edvard Grieg field in the North Sea. We can realize this method thanks to advanced seismic multi‐component acquisition via PP and PS seismic data and processing that allows accurate estimation of amplitude‐variation‐with‐offset parameters P‐ and S‐impedances. With time‐lapse P‐ and S‐impedances optimally resolved, we estimate a stable set of axes identifying water saturation increase (water replacing oil), gas saturation increase (gas injection or gas out of solution), pressure increase (at injectors) and pressure decrease (at producers). Once these axes are obtained, we convert every 4D P‐ and S‐impedance data points into 4D pseudo‐saturation and pseudo‐pressure using a transformation of coordinates. We next use the rock physics relationships of this field to show that a linear relationship can be used to map any 4D change in the field from impedances to saturations and pressures. Key locations in the field with largest saturation and pressure changes are used to find calibration values at these extreme points. Next, from the pseudo‐seismic 4D data, a linear mapping is used to calculate actual reservoir property changes (fractions for saturation and bars for pressure). This allows us to obtain fieldwide dynamic values for water and gas saturations and injection and production related pressure changes. The results are shown, and dynamic changes are interpreted on the Edvard Grieg field data.
Ehrlich ascites carcinoma provokes renal toxicity and DNA injury in mice: Therapeutic impact of chitosan and maitake nanoparticles
Authors: Abosharaf Hamed A. , Gebreel Doaa T. , Allam Sahar , El‐Atrash Afaf , Tousson Ehab
Published: February 2024

In this study, the impact of chitosan (CS) and maitake (GF) nanoparticles towards the renal toxicity induced by Ehrlich ascites carcinoma (EAC) in vivo model was conducted. Besides benchmark negative control group, EAC model was constructed by intraperitoneal injection (i.p.) of 2.5 × 106 cells. Alongside positive control, two groups of EAC‐bearing mice received 100 mg/kg of CS and GF nanoparticles/body weight daily for 14 days. The kidney function was conducted by measuring urea, creatinine, ions, (anti)/oxidative parameters and DNA damage. Also, measuring immunoreactivity of P53, proliferating cell nuclear antigen (PCNA), and B‐cell lymphoma 2 (Bcl‐2) and apoptosis protein. The outcomes illustrated notable kidney toxicity, which indicated by elevations in urea, creatinine, oxidative stress, DNA damage and induction of apoptosis. These events were supported by the drastic alteration in kidney structure through histological examination. Administration of CS and GF nanoparticles was able to enhance the antioxidant power, which further reduced oxidative damage, DNA injury, and apoptosis. These results indicated the protective and therapeutic role of biogenic chitosan and maitake nanoparticles against nephrotoxicity.
Effective growth hormone replacement with once‐weekly somapacitan in Japanese children with growth hormone deficiency: Results from REAL4, a phase 3 clinical trial
Authors: Mori Jun , Ohata Yasuhisa , Fujisawa Yasuko , Sato Yukihito , Röhrich Sebastian , Rasmussen Michael Højby , Bang Rikke Beck , Horikawa Reiko
Published: February 2024

Objective

Somapacitan is a long‐acting growth hormone (GH) derivative developed for the treatment of GH deficiency (GHD). This study evaluates the efficacy and tolerability of somapacitan in Japanese children with GHD after 104 weeks of treatment and after switch from daily GH.

Design

Subanalysis on Japanese patients from a randomised, open‐labelled, controlled parallel‐group phase 3 trial (REAL4, NCT03811535).

Patients and Measurements

Thirty treatment‐naïve patients were randomised 2:1 to somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day) up to Week 52, after which all patients received somapacitan. Height velocity (HV; cm/year) at Weeks 52 and 104 were the primary measurements. Additional assessments included HV SD score (SDS), height SDS, bone age, insulin‐like growth factor‐I (IGF‐I) SDS, and observer‐reported outcomes.

Results

At Week 52, observed mean HV was similar between treatment groups (10.3 vs. 9.8 cm/year for somapacitan and daily GH, respectively). Similar HVs between groups were also observed at Week 104: 7.4 cm/year after continuous somapacitan treatment (soma/soma) and 7.9 cm/year after 1‐year somapacitan treatment following switch from daily GH (switch). Other height‐related endpoints supported continuous growth. IGF‐I SDS increased in both groups with mean IGF‐I SDS within −2 and +2 during the study. Somapacitan was well tolerated, one mild injection site reaction was reported, with no reports of injection site pain. Patient preference questionnaires showed that most patients and their caregivers (90.9%) who switched treatment at Week 52 preferred once‐weekly somapacitan over daily GH treatment.

Conclusions

Somapacitan showed sustained efficacy in Japanese children with GHD over 104 weeks and for 52 weeks after switching from daily GH. Somapacitan was well tolerated and preferred over daily GH.
Steroidogenic acute regulatory protein (STAR) deficiency: Our experience and systematic review for phenotype–genotype correlation
Authors: Phadte Aditya , Dhole Charushila , Hegishte Samiksha , Sarathi Vijaya , Lila Anurag , Gada Jugal V. , Memon Saba Samad , Arya Sneha , Karlekar Manjiri , Patil Virendra , Varthakavi Premlata K. , Shah Nalini , Bhagwat Nikhil M. , Bandgar Tushar
Published: February 2024

Objective

Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype–genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype–genotype correlation.

Design, Patients and Measurements

Retrospective review of three genetically proven LCAH patients from our centre and per‐patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia).

Results

We report three new LCAH probands from India, all diagnosed post‐infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two‐thirds of LCAH probands were East‐Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice‐site variants and deletion/insertions were present in Group A.

Conclusions

We report three new cases of LCAH from India. We propose a phenotype‐derived genotypic classification of reported STAR variants in 46,XY LCAH.
Trends in contact sensitization, results, and implications from a contact dermatitis clinic in Israel
Authors: Slodownik Dan , Bar Jonathan , Daniely Danny
Published: February 2024

Background

The baseline series includes common allergens, evolves over time, and differs by location. Our study aims to characterize allergen sensitization trends among the Israeli population during the last two decades, compare our results to American and European registries, as well as to highlight significant allergens in additional series outside the European baseline series (OEBS).

Methods

We analysed patch test results of 2086 patients from a designated contact dermatitis clinic in Tel Aviv between 2019 and 2022, compared them to European and North American registries and to 2156 patch test results conducted in Israel two decades ago.

Results

38.6% of patients had at least one positive reaction to an allergen in the European baseline series (EBS), nickel sulphate (14.6%), fragrance mix I (4.6%), and Methylchloroisothiazolinone methylisothiazolinone (MCI/MI; 3.7%) were the most common among them. N‐Isopropyl N‐Phenyl‐4‐Phenylenediamine (NIPPD; 0%), Propolis (0.1%), Sesquiterpene lactone mix (0.1%), and Budesonide (0.1%) elicited a sensitization frequency significantly lower than the proposed threshold for baseline inclusion. Chi‐square test revealed a statistically significant decrease (p < 0.05) in the sensitization frequency of fragrance mix I, Formaldehyde, Potassium dichromate, Neomycin sulphate, Myroxylon pereirae, Sesquiterpene lactone, and NIPPD during the last two decades. The overall sensitization frequency to the majority of allergens was lower in our cohort in comparison to the North American and European registries.

Conclusions

MCI/MI and 2‐hydroxyethyl methacrylate‐2 (HEMA) are common, relevant allergens, with high SPIN (significance and prevalence index number) and should be better regulated by the authorities. While among the EBS, NIPPD, Propolis, Sesquiterpene lactone, and Budesonide usually do not elicit a positive reaction and therefore should be reconsidered in baseline series, among the OEBS, Chloramphenicol, Quaternium 15, Propyl gallate, and Amerchol L101 have elicited high SPIN values and should be vigilantly examined in the suitable clinical scenario. Significantly lower sensitization frequency to propolis raises the possibility of a protective effect due to early oral exposure among the Israeli population.