bluuebunny/crossref_metadata_2025 huggingface dataset:
Unveiling unique metabolomic and transcriptomic profiles in three Brassicaceae crops
Authors: Zhang Liyong , Parkin Isobel A. P.
Published: December 2024

Brassica napus,Camelina sativaand field pennycress (Thlaspi arvense), represent one highly economically valuable crop and two emerging oilseed crops of the Brassicaceae family, respectively. As sessile organisms, these crops are continuously exposed to various stresses when grown in the field. Interestingly, the responses of these three crops to different environmental stimuli vary to a great extent, but there is very limited knowledge about the molecular basis of these differential responses. In this study, we employed untargeted metabolomics to compare the metabolic profile of these crops, and examined the potentially related genes through further integration with transcriptomic analysis. Our data revealed distinctive overall metabolic profiles among these three crops, where in particular, a variety of phenylpropanoids showed differential accumulation and the corresponding putative genes’ expression varied significantly. The results provide a valuable resource for those studying Brassicaceae species and will provide insight into the understanding of metabolic variation among these three important oilseed crops, and provide potential targets for the future breeding of stress tolerant crops.
Association between surgical aortic valve replacement and long-term outcomes in 50 to 65-year-olds: Results of the AUTHEARTVISIT study
Authors: Florian A. , Auer J. , Reichardt B. , Krotka P. , Wagenlechner C. , Wendt R. , Mildner M. , Mascherbauer J. , Ankersmit HJ , Zimpfer D. , Graf A.
Published: December 2024

Objectives

During the last years, age recommendations for the use of biological prostheses rather than mechanical prostheses for surgical aortic valve replacement (sAVR) have been lowered considerably. We evaluated survival rates, major adverse cardiac events (MACEs), and reoperation risks after surgical (sM-AVR) and biological (sB-AVR) AVR, to provide data for the optimal prosthesis choice for middle aged patients between 50 and 65 years.

Methods

We performed a population-based cohort study using Austrian Health System data from 2010–2020. Patients undergoing isolated sAVR (n=3761) were categorized into sM-AVR (n=1018) and sB-AVR (n=2743) groups. Propensity score matching (PSM) was applied to balance covariates. The primary endpoint was all-cause mortality. Secondary endpoints included MACEs, reoperation, stroke, bleeding, and survival post-reoperation. Outcomes were assessed using Cox regression and Kaplan-Meier analyses.

Results

Patients undergoing sM-AVR had significantly lower all-cause mortality compared to sB-AVR (HR=1.352, p=0.003). sB-AVR was associated with higher risks of MACEs (HR=1.182, p=0.03) and reoperation (HR=2.338, p=0.002). Stroke and bleeding rates were comparable. All results were sustained after PSM.

Conclusion

The findings highlight increased mortality, MACEs and reoperation risks associated with sB-AVR compared to sM-AVR. We observed superior long-term outcomes after sM-AVR, suggesting the need to reevaluate the expanding use of sB-AVR in younger patients.

Graphical Abstract
Vaccine Confidence and Intention-to-Vaccinate Children against COVID-19 among Parents in Mysore, India: Insights from the BeSD Framework
Authors: Muralidhar Kiranmayee , Ngaybe Maiya G Block , Nanjaiah Shivamma , Pope Benjamin , Coursey Kate , Jaykrishna Poornima , Ningaiah Nagalambika , Edwards Todd L. , Edwards Digna R. Velez , Madhivanan Purnima , Somaiya Devanshi , Krupp Karl
Published: December 2024

Background

India rolled out COVID-19 vaccinations for adults in January 2021 and children aged 12-18 in early 2022. A 2021 survey indicated that 63% of Indian parents were willing to vaccinate their children against COVID-19, with few studies examining vaccine hesitancy and acceptability. The the Behavioral and Social Drivers of Vaccination (BeSD) framework helps demonstrate which factors may affect vaccination uptake. Our study examined parents’ intentions-to-vaccinate their children below 18 years of age against COVID-19 in Mysore, India and their decision-making process using the BeSD framework.

Methods

From November 2021 to May 2022, 506 parents/guardians of children below 18 years of age living in Mysore district, India were consented and interviewed by phone or face-to-face. We assessed their own COVID-19 vaccination status, vaccine confidence (Vaccine Confidence Index), intention-to-vaccinate their child against COVID-19, and other factors affecting vaccination such as demographic variables. Multivariable ordinal logistic regression was conducted to examine the association of influencing factors based on the literature and BeSD framework using Stata version 16.1. Intention-to-vaccinate was presented as odds ratios (OR) with associated 95% confidence intervals (95%CI).

Results

The majority (91.3%) of the 503 participants fully trusted COVID-19 vaccines for their children. The same number (91.3%) had been fully vaccinated themselves, and 78.3% reported being (very) likely to vaccinate their children against COVID-19. Vaccine-hesitant and vaccine-confident groups were not significantly different socio-demographically. As parental age increased, parents had higher odds to express intention-to-vaccinate their child (OR: 1.04, 95%CI: 1.01-1.08). Parents from urban Mysore had lower odds to vaccinate their child compared to those from rural areas (OR: 0.53, 95%CI: 0.35-0.82).

Conclusion

Most parents expressed vaccine confidence and intention-to-vaccinate their child against COVID-19. Exploring decision-making processes among parents is a crucial strategy to ensure effective implementation of vaccination programs.
Characterising Representations of Hue and Saturation in the Cortex Using Information Decoding
Authors: Rozman Ana , Chauhan Tushar , Martinovic Jasna
Published: December 2024

One of the enduring questions in the field of colour vision research revolves around how features of colour appearance, such as hue and saturation are represented in the brain. While considerable progress has been made in understanding the transformation of physical colour signals during early processing stages, the mechanisms by which these signals are recombined in later processing, ultimately giving rise to our perceptual experience of colour, remain elusive. A promising avenue for capturing these representations involves decoding from EEG signals. We captured EEG signals in response to 8 evenly spaced isoluminant colours at two saturation levels, taken from a perceptually uniform CIE Lab colour space. Surprisingly, our main finding challenges the expectation that representations of colours that are perceptually more similar elicit more similar signals. Instead, our results show that isoluminant hues perceived as maximally dissimilar tend to evoke the most similar EEG signals, which is in line with predictions derived from opponent theory. Additionally, decoding performs better for lower saturation than for higher saturation hues, contrary to expectations that more distinct hue representations would be associated with highly saturated hues but in line with prediction of magnified differences in latency and amplitude of EEG signals between low-level opponent mechanisms at lower contrast levels. Finally, our findings also highlight the non- uniformity of the cortical representation space for isoluminant colour, indicating that neighbouring hues exhibit varying degrees of similarity. Put together, the results show that low-level features, such as contrast and cone-opponency, drive the EEG response to colour.
Chemogenetic tuning reveals optimal MAPK signaling for cell-fate programming
Authors: Lende-Dorn Brittany A. , Atkinson Jane C. , Bae Yunbeen , Galloway Kate E.
Published: December 2024

Cell states evolve through the combined activity of signaling pathways and gene regulatory networks. While transcription factors can direct cell fate, these factors rely on a cell state that is receptive to transitions in cell identity. How signaling levels contribute to the emergence of receptive cell states remains poorly defined in primary cells. Using a well-defined model of direct conversion, we examined how levels of the MAPK-activating oncogene HRASG12Vinfluence direct conversion of primary fibroblasts to induced motor neurons. We demonstrate that an optimal ‘Goldilocks’ level of MAPK signaling efficiently drives cell-fate programming. Rates of direct conversion respond biphasically to increasing HRASG12Vlevels. While intermediate HRASG12Vlevels increase the rate of conversion, high levels of HRASG12Vinduce senescence. Through chemogenetic tuning, we set optimal MAPK activity for high rates of conversion in the absence of HRAS mutants. As MAPK pathways influence cell-fate transitions in development and disease, our results highlight the need to tune therapeutic interventions within a non-monotonic landscape that is shaped by genetics and levels of gene expression.

Highlights

MAPK signaling drives proliferation and conversion of fibroblasts to motor neurons

Cell-fate programming responds biphasically to HRASG12Vexpression

High HRASG12Vexpression induces senescence, which reduces conversion

Chemogenetic tuning of MAPK activity increases conversion rates

A small-molecule MAPK inducer drives high rates of conversion in the absence of HRASG12V
Investigating the performance of Oxford Nanopore long-read sequencing with respect to Illumina microarrays and short-read sequencing
Authors: Santos Renato , Lee Hyunah , Williams Alexander , Baffour-Kyei Anastasia , Breen Gerome , Iacoangeli Alfredo
Published: December 2024

Oxford Nanopore Technologies (ONT) long-read sequencing (LRS) has emerged as a promising tool for genomic analysis, but comprehensive comparisons with established platforms across diverse datasets remain limited. In this study, we present a comprehensive comparison of ONT long-read sequencing (LRS) against Illumina short- read sequencing (SRS) and microarray platforms across 14 human genomes.

We performed ONT sequencing using both multiplexed and singleplexed approaches and compared the results with matched Illumina microarray and SRS data. We assessed sequencing quality metrics, variant detection performance for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), while examining the impact of sequencing depth, read length, and multiplexing.

ONT LRS demonstrated competitive performance with SRS for SNV detection, particularly in low complexity regions (F-measure: 0.763 vs 0.770), though with slightly lower performance in high complexity regions (F-measure: 0.954 vs 0.968). For indel detection, LRS showed robust performance in high complexity regions (F-measure: 0.850) which, however, decreased in low complexity regions (F-measure: 0.453). LRS identified 2.82 times more structural variants than SRS and detected variants across a broader size range (8 bp to 129 Mb vs 2 bp to 6 kb). Sequencing depth strongly correlated with variant calling performance across all variant types, with correlation coefficients of 0.80 for SNVs in high complexity regions, 0.84 for SNVs in low complexity regions, and exceeding 0.9 for indels. SV detection in LRS showed strong depth dependence (r = 0.939), while SRS SV calls remained stable across depths.

Our findings demonstrate that ONT LRS complements existing sequencing technologies, offering advantages in detecting structural variants and analysing low complexity regions, while maintaining competitive performance in standard variant detection. This study provides practical insights for optimising ONT sequencing strategies and highlights areas for future methodological improvement.
Cardiac Pacemaker Cells Harness Stochastic Resonance to Ensure Fail-Safe Operation at Low Rates Bordering on Sinus Arrest
Authors: Okamura Akihiro , He Isabella K , Wang Michael , Maltsev Alexander V , Maltsev Anna V , Stern Michael D , Lakatta Edward G , Maltsev Victor A
Published: December 2024

BACKGROUND

The sinoatrial node (SAN) is primary pacemaker of the heart. Recent high-resolution imaging showed that synchronized action potentials (APs) that exit the SAN emerge from heterogeneous signals, including subthreshold signals in non-firing (dormant) cells. This sets up a new problem in cardiac biology of how these signals contribute to heartbeat generation. Here we tested a hypothesis that pacemaker cells harness stochastic resonance to ensure their fail-safe operation, especially at low rates bordering on sinus arrest.

METHODS

We measured membrane potential and Ca signals in SAN cells isolated from rabbit hearts in response to external currents in the form of sine waves or white noise. Protocols were applied via a perforated patch while cells were either in the basal state or in the presence of cholinergic receptor stimulation. Additionally, we performed multiscale model simulations at respective sub-cellular, cellular, and tissue levels.

RESULTS

Noise currents awakened dormant cells to fire APs and substantially improved the rate and rhythm of cells firing infrequent, dysrhythmic APs. Rhythmic AP generation in response to applications of sine wave currents of different frequencies outlined a resonance spectrum in SAN cells: their capability of responding, via stochastic resonance, to specific frequency components embedded in the noise. Cholinergic stimulation shifted the resonance spectrum towards lower frequencies, i.e. cells responded to lower frequency signals but could not process higher frequency signals. Noise currents added to SAN single cell– and tissue-models substantially expanded the parametric space of AP firing beyond the bifurcation line where cells failed to operate without noise. Both the numerical models and our simultaneous recordings of membrane potential and Ca dynamics also demonstrated that stochastic resonance in SAN cells is amplified by coupled electrical and Ca signaling, enhancing AP generation at low noise levels.

CONCLUSIONS

SAN cells harness stochastic resonance amplified by coupled membrane-Ca signaling to ensure rhythmic heartbeat initiation especially at low rates, providing a last-resort signaling mechanism to avoid sinus arrest when signal synchronization decreases but noise substantially increases, such as during strong parasympathetic stimulation, disease or aging when the heart slows and high-frequency signaling wanes.
Large complex structural rearrangements in human genomes harbor cryptic structures
Authors: Audano Peter A. , Paisie Carolyn ,   The Human Genome Structural Variation Consortium (HGSVC), Beck Christine R.
Published: December 2024

Structural variation is a major contributor to human diversity, adaptation, and disease. Simple structural variant (SV) types include deletions, insertions, duplications, inversions, and translocations, and SVs account for most of the variable bases between genomes. Complex structural variants (CSVs) that consist of one or more simple eventsin cisappear more frequently in diseases and cancers where DNA repair, apoptosis, and cell cycle checkpoints are compromised, although CSVs can also appear in germline genome sequences of healthy individuals. CSVs are often characterized by short tracts of homology or no homology, and while CSVs are more prevalent in complex regions that contain large repeats, smaller stretches of homology can also enable their formation across more unique loci. Long-read assemblies have increased the size of detectable SVs and expanded variant detection into more complex regions of the genome, and while they reconstruct CSVs, methods for identifying CSVs from assemblies is limited. Here, we have developed a new assembly-based approach to trace through complex loci rather than relying upon reference representations of alignments. We can now access CSVs in large complex segmental duplications, reveal structures that were previously unknown, and identify SV breakpoints with greater accuracy. We find 72 large CSVs per genome and 128 unique complex structures and CSVs in highly repetitive regions can now be detected including several distinct complex events in repetitiveNBPFgenes that was not previously callable with short-read or long-read CSV methods. This approach is implemented within a key assembly-based variant calling tool, PAV, and represents a substantial improvement identifying complex variants now ascertainable from contiguous genome assemblies.
A proteomic map of B cell activation and its shaping by mTORC1, MYC and iron
Authors: James Olivia , Sinclair Linda V. , Lefter Nadia , Salerno Fiamma , Brenes Alejandro , Howden Andrew J.M.
Published: December 2024

Using high resolution quantitative mass spectrometry, we have explored how immune activation and the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) regulate the proteome of B lymphocytes. B cell activation via the B cell receptor, CD40 and the IL-4 receptor induced considerable re-modelling of the B cell protein landscape, with a 5-fold increase in total cellular protein mass within 24 hours of activation. Analysis of copy numbers per cell of >7,500 proteins revealed increases in the metabolic machinery that supports B cell activation and nutrient and amino acid transporters that fuel B cell biosynthetic capacity. We reveal that mTORC1 controls activation-induced cell growth and B cell proteome remodelling and inhibiting mTORC1 impairs the expression of amino acid transporters that fuel B cell protein production. We also show that mTORC1 activity regulates the expression of the transcription factor MYC and the transferrin receptor CD71. Blocking MYC activity phenocopied mTORC1 inhibition in many ways including impaired CD71 expression, while limiting iron availability during B cell activation impaired B cell growth and protein synthesis. This work provides a detailed map of naïve and immune activated B cell proteomes and a greater understanding of the cellular machinery that direct B cell phenotypes. This work also provides new insights into the role of mTORC1, MYC and iron in regulating activation-induced proteome remodelling and protein production in B cells.
MrHAMER2: high-accuracy long-read RNA sequencing to decode isoform-specific variation in viral transcripts during latency
Authors: Gallardo Christian M. , Albert Jessica L. , Qazi Andrew A. , Ventura Roni Lobato , Deshmukh Savitha , Beliakova-Bethell Nadejda , Torbett Bruce E.
Published: December 2024

Alternative splicing (AS) greatly expands the repertoire of proteins encoded by the human genome. Viruses have been shown to hijack AS to sustain replication or lead to latency. In HIV infection, the virus integrates into the host genome, becoming a transcriptional unit that directly engages in AS to regulate its gene expression. Sequencing advances have enabled insights into HIV gene expression dynamics during productive replication. However, viral isoform dynamics during latency remain largely uncharacterized due to the low abundance of both spliced viral transcripts and their originating cellular subsets, making their accurate detection and quantification challenging. To address current gaps, we developed MrHAMER2, a high-accuracy long-read RNA sequencing method that leverages dual Unique Molecular Identifier (UMI) tagging of cDNA to accurately capture and quantify full-length isoforms with high dynamic range and 99.968% single-nucleotide accuracy. We then use MrHAMER2 to decode the spliced HIV transcriptome in a primary cell model of latency and show substantial changes in viral isoforms bearing intron retentions accompanied by changes in their potential to generate translatable protein.
Provides Apparent Predictive Biomarker in a Phase I/II Study of Pembrolizumab With Gemcitabine in Patients with Previously-Treated Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: Sanborn Rachel E. , Jensen Shawn M. , Paustian Christopher , Chang Shu-Ching , Vetto Eloy , Vu Quyen , Rajamanickam Venkatesh , Bernard Brady , Koguchi Yoshinobu , Redmond William , Fox Bernard A.
Published: December 2024

Retrospective characterization of cell-cell relationships in the tumor microenvironment provides significantly better predictive power than PD-L1 expression, tumor mutational burden (TMB), or gene expression profiles. In this small study assessing the safety and possible efficacy of gemcitabine and pembrolizumab in immunotherapy-naïve patients with NSCLC who have received prior treatment, we investigated both standard and novel immune parameters on 16 enrolled patients. The combination of gemcitabine and pembrolizumab could be administered safely but did not demonstrate synergism compared with historical controls. Novel findings of this study are that elevated frequencies of Tregulatory cells near CD3 T cells at baseline was associated with improved outcome to treatment (p<0.05). Integrating this Treg / T cell relationship metric together with overall T cell density yielded a tumor inflammation score which correlated (p<0.002) with disease response. We postulate this is indicative of ongoing anti-cancer immune response. Additionally, while prior studies documented that IgG Ab responses to TAA can identify targets of a coordinated T and B cell response and evidence of immune surveillance, this study found that high autoantibody responses, while not statistically significant, trended towards a worse outcome (p=0.06). This suggests to us that tumors may have developed mechanisms to escape the immune response to these TAAs.
Chlorhexidine Bathing for Candida auris Decolonization among Adult Patients in Healthcare Settings: Protocol for a Systematic Review and Meta-Analysis
Authors: Belfakir Messaouda , Sherif Moustafa , Adam Balazs
Published: December 2024

Background

Candida auris (C. auris) poses a significant threat in healthcare settings, characterized by its high morbidity and mortality rates. While the use of chlorhexidine bathing has been suggested as a potential strategy for C. auris decolonization in adult patients within healthcare settings, a comprehensive and systematic evaluation of its effectiveness and associated outcomes is notably lacking.

Aim

This study seeks to systematically assess the effectiveness of daily chlorhexidine bathing for Candida auris decolonization in adult patients within healthcare settings. The study’s primary objectives are to evaluate the impact of this intervention on reducing colonization rates, infection occurrences, and outbreak incidences, while concurrently evaluating any associated adverse events. The study’s secondary objectives are to identify adverse events, and to explore and quantify the effect sizes of potential risk factors, if identified, that may influence the outcomes of chlorhexidine bathing for C. auris decolonization.

Methods and Analysis

In adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines, this protocol outlines the methodology for our systematic review and meta-analysis. The study commenced with an extensive presearch conducted from June to August 2023 on PubMed, followed by searches across other three key databases: Embase, Web of Science, and Scopus, in September 2023. The systematic search will encompass all available years of publication without applying any publication date filters. Records located in the literature search will be uploaded to the systematic review software Covidence to facilitate deduplication, blinded screening, and the selection of eligible studies. Two independent reviewers will rigorously screen records, extract data, and perform risk of bias assessments, with a third researcher resolving conflicts. The results will be synthesized narratively in summary tables, with the potential for meta-analysis contingent upon the findings, focusing on the effectiveness and adverse events of daily chlorhexidine bathing for C. auris decolonization in adult patients within healthcare settings. Additionally, we will investigate whether certain risk factors, if identified, have an impact on the outcomes by quantifying their effect sizes.

Ethics and Dissemination

The ethical framework of this systematic review obviates the need for ethics approval, as it relies exclusively on published research. The outcomes of this study will be disseminated via publication in a peer-reviewed journal, shared with stakeholders, and made publicly accessible.

PROSPERO Registration

CRD42023459048.
Frailty in older patients with atrial fibrillation and its relationship with anticoagulant use: a multi-centred observational study in New South Wales
Authors: Nguyen Tu N , Fujita Kenji , Hilmer Sarah N
Published: December 2024

Background and aims

Evidence of the impact of frailty on oral anticoagulant (OAC) prescription in older people with atrial fibrillation (AF) is conflicting. This study aimed to examine the prevalence of frailty in hospitalised older patients with AF and its relationship with OAC prescription during admission. The secondary aim was to examine the association between frailty and rate/rhythm control medication prescriptions.

Methods

This retrospective observational study included adults aged ≥65 with AF admitted to six hospitals in Australia in 2022. Frailty was defined by a Frailty Index ≥0.25. Logistic regression models were applied to examine the association between frailty and the prescriptions of OAC, rate-control and rhythm-control drugs during hospitalisation. Results are presented as odds ratios and 95% confidence intervals (CI).

Results

There were 685 patients, with a mean age of 82.6(SD 8.3), 49.8% female and 42.8% identified as frail. Overall, 75.6% were prescribed OAC (67.9% in the frail versus 81.4% in the non-frail, p<0.001), 37.7% received rate-control drugs (42.0% in the frail versus 34.4% in the non-frail, p=0.044), 27.3% received rhythm-control drugs (22.9% in the frail versus 30.6% in the non-frail, p=0.024). The adjusted odds ratios of frailty on prescriptions were 0.58 (95% CI 0.39-0.86) for OAC, 1.75 (95%CI 1.22-2.52) for rate-control drugs, and 0.83 (95%CI 0.55-1.24) for rhythm-control drugs.

Conclusions

The study revealed a high prevalence of frailty in older inpatients with AF. Frailty was associated with reduced likelihood of prescription of OAC during admission and increased likelihood of prescribing rate-control medications, with no independent impact on rhythm-control therapy. Further studies are needed to understand these prescribing patterns.
A hospital-based cluster-randomized controlled trial of free influenza vaccination before hospital discharge compared to routine care in patients with heart failure (PANDA II): Statistical Analysis Plan
Authors: Shan Sana , Billot Laurent , Du Xin , Dong Jianzeng , Anderson Craig
Published: December 2024

The PANDA II trial aims to evaluate whether a free influenza vaccination program for patients hospitalized in China with acute heart failure provides benefits compared to current routine practice of no influenza vaccination. It is designed as a two-arm, parallel, cluster-crossover randomized trial of 122 hospitals conducted over three influenza seasons. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variable collected in the trial.

The primary outcome is a composite of all-cause mortality and re-admission to hospital within a 12- month period after the initial 30-day post-discharge period. The primary analysis will include all recruited participants analysed according to the intervention allocated to the hospital during their enrolment period. It will consist in an individual-level hierarchical logistic regression adjusted for the effect of the period and for clustering by hospital using both a random hospital effect and a random hospital-period effect. The effect of the influenza vaccination program will be estimated as an odds ratio and 95% confidence interval.

Sensitivity analyses will include covariate adjustments as well as a cluster-level analysis and subgroup analyses according to eight pre-specified subgroups.
Characterizing Population-level Changes in Human Behavior during the COVID-19 Pandemic in the United States
Authors: Urmi Tamanna , Pant Binod , Dewey George , Quintana-Mathé Alexi , Lang Iris , Druckman James N. , Ognyanova Katherine , Baum Matthew , Perlis Roy H. , Riedl Christoph , Lazer David , Santillana Mauricio
Published: December 2024

The transmission of communicable diseases in human populations is known to be modulated by behavioral patterns. However, detailed characterizations of how population-level behaviors change over time during multiple disease outbreaks and spatial resolutions are still not widely available. We used data from 431,211 survey responses collected in the United States, between April 2020 and June 2022, to provide a description of how human behaviors fluctuated during the first two years of the COVID-19 pandemic. Our analysis suggests that at the national and state levels, people’s adherence to recommendations to avoid contact with others (a preventive behavior) was highest early in the pandemic but gradually—and linearly—decreased over time. Importantly, during periods of intense COVID-19 mortality, adherence to preventive behaviors increased—despite the overall temporal decrease. These spatial-temporal characterizations help improve our understanding of the bidirectional feedback loop between outbreak severity and human behavior. Our findings should benefit both computational modeling teams developing methodologies to predict the dynamics of future epidemics and policymakers designing strategies to mitigate the effects of future disease outbreaks.
The genetic architecture of the β-globin chain in individuals with and without sickle cell disease in Nigeria: A case for beta thalassemia?
Authors: Babalola Oluwatoyin Aduke , Fasola Foluke Atinuke , Brown Biobele Jotham , Zhang Jing , Zheng Yonglan , Odetunde Abayomi , Falusi Adeyinka Gladys , Olopade Olufunmilayo
Published: December 2024

Background

Reports on beta thalassemia in the Nigerian population are conflicting, and the prevalence and role of beta thalassemia in Nigerian sickle cell disease (SCD) patients remain unclear. There is a need to set the records straight to ascertain the prevalence and effect of beta thalassemia in these patients.

Methods

123 SCD patients and 117 age- and sex-matched controls were recruited. For the cases, the age range was 3 – 69 years, median(IQR) = 16(9 - 29). A separate cohort of 26 SCD patients were studied along. Full blood count was calculated, and the hemoglobin fractions were estimated by High Performance Liquid Chromatography. The 1.6kb beta-globin gene region was amplified from germline DNA and Sanger sequencing was performed. Single nucleotide polymorphisms (SNPs) were detected and annotated, and haplotypes were constructed.

Results

Contrary to recent reports, the prevalence of beta thalassemia in this population is <1%. Aside the sickle, hemoglobin C and beta thalassemia mutations, eight other variants were identified. Only three of these variants were found in the SCD patients and are in linkage disequilibrium. The sickle and hemoglobin C mutations arose on the major ancestral haplotype, while the beta thalassemia intermedia mutation (rs33915217C>A) was found on the minor ancestral haplotype, atypical of Africa. Two rare variants (rs537944366T>C and rs33915217C>A) are reported for the first time in the Yoruba population.

Conclusion

There is a need for a re-assessment of the diagnosis of beta thalassemia in this and other African populations for the proper management of SCD and other anemia-related cases.
Application of a GRF-GIF chimera enhances plant regeneration for genome editing in tomato
Authors: Swinnen Gwen , Lizé Eléonore , Sánchez Miguel Loera , Stolz Stéphanie , Soyk Sebastian
Published: December 2024

Genome editing has become a routine tool for functionally characterizing plant and animal genomes. However, stable genome editing in plants remains limited by the time- and labor- intensive process of generating transgenic plants, as well as by the efficient isolation of desired heritable edits. In this study, we evaluated the impact of the morphogenic regulatorGRF-GIFon plant regeneration and genome editing outcomes in tomato. We demonstrate that expressing a tomatoGRF-GIFchimera reliably accelerates the onset of shoot regeneration from callus tissue culture by approximately one month and nearly doubles the number of recovered transgenic plants. Consequently, theGRF-GIFchimera enables the recovery of a broader range of edited haplotypes and simplifies the isolation of mutants harboring heritable edits, but without markedly interfering with plant growth and development. Based on these findings, we outline strategies that employ basic or advanced diagnostic pipelines for efficient isolation of single and higher-order mutants in tomato. Our work represents a technical advantage for tomato transformation and genome editing, with potential applications across other Solanaceae species.
Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
Authors: Breves Sarah L. , Campigli Di Giammartino Dafne , Nicholson James , Cirigliano Stefano , Mahmood Syed Raza , Lee Uk Jin , Martinez-Fundichely Alexander , Jungverdorben Johannes , Singhania Richa , Rajkumar Sandy , Kirou Raphael , Studer Lorenz , Khurana Ekta , Polyzos Alexander , Fine Howard A. , Apostolou Effie
Published: December 2024

Dysregulation of enhancer-promoter communication in the context of the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of primary patient-derived glioblastoma stem cells (GSCs) in comparison with neuronal stem cells (NSCs) to identify potential central nodes and vulnerabilities in the regulatory logic of this devastating cancer. Specifically, we focused on hyperconnected 3D regulatory hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and strong association with oncogenic programs that distinguish IDH-wt glioblastoma patients from low-grade glioma. Epigenetic silencing of a recurrent 3D enhancer hub—with an uncharacterized role in glioblastoma—was sufficient to cause concordant downregulation of multiple hub-connected genes along with significant shifts in transcriptional states and reduced clonogenicity. By integrating published datasets from other cancer types, we also identified both universal and cancer type-specific 3D regulatory hubs which enrich for varying oncogenic programs and nominate specific factors associated with worse outcomes. Genetic alterations, such as focal duplications, could explain only a small fraction of the detected hyperconnected hubs and their increased activity. Overall, our study provides computational and experimental support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.

HIGHLIGHTS

- 3D regulatory “hubs” in glioblastoma enrich for highly coregulated genes at a single-cell level and expand oncogenic regulatory networks.

- Targeted perturbation of a highly recurrent 3D regulatory hub in GSCs results in altered transcriptional states and cellular properties.

- 3D regulatory hubs across cancer types associate with tumor-specific and universal oncogenic programs and worse outcomes.

- The majority of hyperconnected hubs do not overlap with structural variants, suggesting epigenetic mechanisms.

eTOC

Here we profile the 3D enhancer connectomes of primary patient-derived human glioblastoma stem cells (GSCs), identify hyperconnected 3D regulatory “hubs”, and examine the impact of 3D hub perturbation on the transcriptional program and oncogenic properties.
The Diverse Phenotypic and Mutational Landscape Induced by Fluoroquinolone Treatment
Authors: Mohiuddin Sayed Golam , Kavousi Pouria , Figueroa Diego , Ghosh Sreyashi , Orman Mehmet A.
Published: December 2024

Despite extensive research on antibiotic resistance, the potential effects of antibiotic treatments on bacterial tolerance and resistance remain a significant concern. Although bacterial cells adopt a variety of mutational strategies to resist unfavorable circumstances, it is still unclear how antibiotic tolerance and resistance mechanisms affect bacterial fitness characteristics and whether evolved mutants exhibit similar properties across different cell populations subjected to the same conditions. Here, we usedEscherichia coli, a fluoroquinolone antibiotic (ofloxacin), and adaptive laboratory evolutionary experiments to demonstrate that ofloxacin tolerance and resistance can evolve independently across different cell populations exposed to identical conditions. Fitness attributes, such as lag score, doubling time, competition score, and other metabolic features, were variably affected by antibiotic tolerance and resistance mechanisms. However, we did not observe strong and apparent correlations between fitness trade-offs and antibiotic tolerance and resistance. While our whole-genome sequencing identified some shared mutations, such as single nucleotide polymorphisms in theicdgene (a crucial citric acid cycle gene), evolved cell populations exhibited diverse genetic mutations without a clear pattern of a conserved evolutionary pathway. Our study also identifies unique phenotypes, such as those displaying significantly lower minimum inhibitory concentration levels compared to the parental strain yet showing remarkably high tolerance to the same antibiotic. Altogether, our study, examining the phenotypic and mutational landscapes of fluoroquinolone-induced strains, contributes to our understanding of complex bacterial adaptation mechanisms.
Association of Bile Acids with Connectivity of Executive Control and Default Mode Networks in Patients with Major Depression
Authors: Dunlop Boadie W. , Cha Jungho , Mayberg Helen S. , Choi Ki Sueng , Edward Craighead W. , MahmoudianDehkordi Siamak , Bhattacharyya Sudeepa , John Rush A. , Kaddurah-Daouk Rima
Published: December 2024

Objective

Bile acids may contribute to pathophysiologic markers of Alzheimer’s disease, including disruptions of the executive control network (ECN) and the default mode network (DMN). Cognitive dysfunction is common in major depressive disorder (MDD), but whether bile acids impact these networks in MDD patients is unknown.

Methods

Resting state functional magnetic resonance imaging (fMRI) scans and blood measures of four bile acids from 74 treatment-naïve adults with MDD were analyzed. Dorsolateral prefrontal cortex (DLPFC) seeds were used to examine connectivity of the ECN and posterior cingulate cortex (PCC) seeds were used for the DMN. Using a whole-brain analysis, the functional connectivity of these seeds was correlated with serum levels chenodeoxycholic acid (CDCA) and its bacterially-derived secondary bile acid, lithocholic acid (LCA).

Results

CDCA levels were strongly and inversely correlated with connectivity between DLPFC regions of the ECN (R2= .401, p<.001). LCA levels were strongly and positively correlated with connectivity of the DLPFC and left inferior temporal cortex of the ECN (R2=.263, p<.001). The LCA/CDCA ratio was strongly and positively correlated with connectivity of the DLPFC with two components of the ECN: bilateral inferior temporal cortex and the left superior and inferior parietal lobules (all R2>.24, all p<.001). For the DMN, the LCA/CDCA ratio was strongly and negatively correlated with connectivity of the PCC with multiple bilateral insula regions (all R2>0.25, all p<.001).

Conclusions

The relationship between LCA and CDCA levels and functional connectivity of the ECN and DMN suggests potential shared pathophysiologic processes between Alzheimer’s disease and MDD.
Automated Analysis of Bird Head Motion from Videos in Unconstrained Settings
Authors: Santos-Lopes Marco , Araújo Ricardo , David Romain , Correia Paulo L.
Published: December 2024

This study introduces a framework applicable to videos of habitual behaviors of multiple bird species to automatically assess head angular velocities and frequencies during various behaviors in natural habitats. The process involves detecting birds, identifying key points on their heads, and tracking changes in their positions over time. Bird detection and key point extraction were trained on publicly available datasets, including Animal Kingdom, NABirds, Birdsnap, CUB-200-2011, and eBird, featuring videos and images of diverse bird species in uncontrolled settings. Initial challenges arose due to the complexity of video backgrounds, leading to misidentifications and inaccurate key point estimates. These issues were addressed through validation, refinement, filtering, and smoothing steps. Head angular velocities and rotation frequencies were computed from the refined key points. The algorithm performed well at moderate speeds but was limited by the 30 Hz frame rate of most eBird videos, which constrained measurable angular velocities and frequencies and caused motion blur, affecting key point detection. Our findings suggest that the framework may provide plausible estimates of head motion but also emphasize the importance of high frame rate videos in future research, including extensive comparisons against ground truth data, to fully characterize bird head movements.
BenchXAI: Comprehensive Benchmarking of Post-hoc Explainable AI Methods on Multi-Modal Biomedical Data
Authors: Metsch Jacqueline Michelle , Hauschild Anne-Christin
Published: December 2024

The increasing digitalisation of multi-modal data in medicine and novel artificial intelligence (AI) algorithms opens up a large number of opportunities for predictive models. In particular, deep learning models show great performance in the medical field. A major limitation of such powerful but complex models originates from their ’black-box’ nature. Recently, a variety of explainable AI (XAI) methods have been introduced to address this lack of transparency and trust in medical AI. However, the majority of such methods have solely been evaluated on single data modalities. Meanwhile, with the increasing number of XAI methods, integrative XAI frameworks and benchmarks are essential to compare their performance on different tasks. For that reason, we developed BenchXAI, a novel XAI benchmarking package supporting comprehensive evaluation of fifteen XAI methods, investigating their robustness, suitability, and limitations in biomedical data. We employed BenchXAI to validate these methods in three common biomedical tasks, namely clinical data, medical image and signal data, and biomolecular data. Our newly designed sample-wise normalisation approach for post-hoc XAI methods enables the statistical evaluation and visualisation of performance and robustness. We found that the XAI methods Integrated Gradients, DeepLift, DeepLiftShap, and GradientShap performed well over all three tasks, while methods like Deconvolution, Guided Backpropagation, and LRP-α1-β0 struggled for some tasks. With acts such as the EU AI Act the application of XAI in the biomedical domain becomes more and more essential. Our evaluation study represents a first step toward verifying the suitability of different XAI methods for various medical domains.
A biocatalytic platform for the production of substituted 2-quinolones and (thio)coumarins
Authors: Sokolova Nika , Osipyan Angelina , Zhang Lili , Groves Matthew R. , Schmidt Sandy , Haslinger Kristina
Published: December 2024

2-quinolones are privileged scaffolds for drug discovery that are relatively rare in nature. Here, we characterise two promiscuous fungal polyketide synthases AthePKS and FerePKS, which we had previously found to produce quinolonesin vitro. We challenged the enzymes with several substituted anthranilic acid derivatives, revealing their ability to produce precursors of pharmaceutically relevant quinolones. We also discovered that AthePKS and FerePKS accept other 2-substituted benzoic acids, leading to the formation of coumarin and thiocoumarin scaffolds. We applied AthePKS in an artificial enzymatic cascade towards an antimicrobial 4-methoxy-1-methyl-2-quinolone and demonstrated itsin vivofeasibility by successfully expressing the pathway inEscherichia coli. Lastly, we determined the crystal structure of AthePKS, suggesting hotspots for enhancing its catalytic efficiency by enzyme engineering. Our results provide a framework for further engineering of enzymatic routes towards privileged heteroaromatic scaffolds and derivatives thereof.
Photoreceptor cell death mechanism in light damage
Authors: Bruera Manuel G. , Contin María A.
Published: December 2024

Light is one of the most ambient agents harmful to the retina. In Wistar rats prolonged exposure to 200 lux of LED light promotes photoreceptors cells death after 6 days. The possibility to know the cell photoreceptors death mechanism increases the likelihood to find a mixture of therapy with inhibitors or antagonists with anti-inflammatory and antioxidant effects. This study tested the cell death mechanism to elucidate the possible underlying molecular mechanisms. Adult male rats were exposed to 200 lux of LED light by different periods of constant light. The study focused on apoptosis and necroptosis pathways. Our findings reveal that necroptosis is an active pathway in retinal degeneration, occurring in both photoreceptors and glial cells, while apoptosis seem to be inactive during the studied time points.
The Septin Cytoskeleton excludes the Cdc42 GAP Rga4 from growing sites to promote bipolarity in fission yeast
Authors: McDuffie Justin , Chang Goeun , Das Maitreyi
Published: December 2024

The conserved GTPase Cdc42 regulates polarity in most eukaryotes and is spatiotemporally regulated to confine growth to discreet areas throughout the cell cycle. Cdc42 activity stops at the growing ends of fission yeast during mitosis and resumes after division when the ends remove the inactivator/GAP Rga4. In interphase, Rga4 appear punctate at the cell sides restricted from the growing ends. During mitosis, Rga4 appears homogeneous and localizes to the ends. We show that this cell-cycle-dependent Rga4 localization is septin cytoskeleton-dependent. Septins forms linear filaments along the sides during interphase. In mitosis, the septins recede from the sides and form a ring at the division site. In septin mutants, Rga4 is mobile, homogeneously distributed and localizes to the ends, regardless of cell-cycle stage. Accordingly, septin mutants show delayed Cdc42 reactivation after division and are monopolar with disrupted Cdc42 activation dynamics. Our data describe an unusual form of polarity regulation where a septin-dependent physical barrier restricts GAP localization for proper Cdc42 dynamics.

Cell-cycle-dependent Rga4 localization pattern is controlled by the septin cytoskeleton to promote bipolar growth. In interphase, the septin cytoskeleton at the cell sides restricts Rga4 mobility and localization away from the cell ends to promote proper Cdc42 activation dynamics.
Neuronal representation of the decisional reference point in monkeys
Authors: Nguyen Duc , Rich Erin L. , Wallis Joni D. , Louie Kenway , Glimcher Paul W.
Published: December 2024

The reward reference point serves as a hidden benchmark for evaluating options in decision-making. Despite extensive behavioral evidence for reference-dependence, no neural representation of the reference point has been discovered. We analyzed single neuron activity from macaque monkeys performing a decision-making task designed to orthogonalize objective reward values from the reference point. Regression analyses of neuronal activity across six frontal brain regions identified a robust neural representation of the reference point in the ventral bank of anterior cingulate cortex (vbACC). Activity in the dorsal bank of anterior cingulate cortex and the dorsolateral prefrontal cortex, in contrast, encoded the reference-dependent subjective values of the rewards offered or obtained on each trial. The temporal dynamics of these signals and connections between these regions suggest a dedicated neural circuit implementing reference-dependent reward encoding, with the vbACC serving as the reference point signal source modulating activity in other frontal value-encoding areas.