bluuebunny/crossref_metadata_2025 huggingface dataset:
Modification of the antibiotic, colistin, with dextrin causes enhanced cytotoxicity and triggers apoptosis in myeloid leukemia
Authors: Rizzo Siân , Varache Mathieu , Sayers Edward J. , Jones Arwyn T. , Tonks Alex , Thomas David W. , Ferguson Elaine L.
Published: November 2023

Acute myeloid leukemia (AML) remains difficult to treat due to its heterogeneity in molecular landscape, epigenetics and cell signaling alterations. Precision medicine is a major goal in AML therapy towards developing agents that can be used to treat patients with different ‘subtypes’ in combination with current chemotherapies. We have previously developed dextrin-colistin conjugates to combat the rise in multi-drug resistant bacterial infections and overcome dose-limiting nephrotoxicity. Recent evidence of colistin’s anticancer activity, mediated through inhibition of intracellular lysine-specific histone demethylase 1 (LSD1/KDM1A), suggests that dextrin-colistin conjugates could be used to treat cancer cells, including AML. This study aimed to evaluate whether dextrin conjugation (which reducesin vivotoxicity and prolongs plasma half-life) could enhance colistin’s cytotoxic effects in myeloid leukemia cell lines and compare the intracellular uptake and localization of the free and conjugated antibiotic. Our results identified a conjugate (containing 8,000 g/mol dextrin with 1 mol% succinoylation) that caused significantly increased toxicity in myeloid leukemia cells, compared to free colistin. Dextrin conjugation altered the mechanism of cell death by colistin, from necrosis to caspase 3/7-dependent apoptosis. In contrast, conjugation via a reversible ester linker, instead of an amide, had no effect on the mechanism of the colistin-induced cell death. Live cell confocal microscopy of fluorescently-labelled compounds showed both free and dextrin-conjugated colistin were endocytosed and co-localized in lysosomes and increasing the degree of modification by succinoylation of dextrin significantly reduced colistin internalization. Whilst clinical translation of dextrin-colistin conjugates for the treatment of AML is unlikely due to the potential to promote AMR and the relatively high colistin concentrations required for anticancer activity, the ability to potentiate the effectiveness of an anticancer drug by polymer conjugation, while reducing side effects and improving biodistribution of the drug, is very attractive, and this approach warrants further investigation.

Graphical abstract
Genome folding principles revealed in condensin-depleted mitotic chromosomes
Authors: Zhao Han , Lin Yinzhi , Lin En , Liu Fuhai , Shu Lirong , Jing Dannan , Wang Baiyue , Wang Manzhu , Shan Fengnian , Zhang Lin , Lam Jessica C. , Midla Susannah C. , Giardine Belinda M. , Keller Cheryl A. , Hardison Ross C. , Blobel Gerd A. , Zhang Haoyue
Published: November 2023

During mitosis, condensin activity interferes with interphase chromatin structures. Here, we generated condensin-free mitotic chromosomes to investigate genome folding principles. Co- depletion of condensin I and II, but neither alone, triggered mitotic chromosome compartmentalization in ways that differ from interphase. Two distinct euchromatic compartments, indistinguishable in interphase, rapidly emerged upon condensin loss with different interaction preferences and dependence on H3K27ac. Constitutive heterochromatin gradually self-aggregated and co-compartmentalized with the facultative heterochromatin, contrasting with their separation during interphase. While topologically associating domains (TADs) and CTCF/cohesin mediated structural loops remained undetectable, cis-regulatory element contacts became apparent, providing an explanation for their quick re-establishment during mitotic exit. HP1 proteins, which are thought to partition constitutive heterochromatin, were absent from mitotic chromosomes, suggesting, surprisingly, that constitutive heterochromatin can self-aggregate without HP1. Indeed, in cells traversing from M- to G1-phase in the combined absence of HP1α, HP1Π and HP1γ, re-established constitutive heterochromatin compartments normally. In sum, “clean-slate” condensin-deficient mitotic chromosomes illuminate mechanisms of genome compartmentalization not revealed in interphase cells.
Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models
Authors: Power Saige K , Venkatesan Sridevi , Qu Sarah , McLaurin JoAnne , Lambe Evelyn K
Published: November 2023

Background

Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examineex vivoelectrophysiological evidence for active compensation in Alzheimer’s disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function.

Methods

We functionally interrogate cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.

Results

In two AD models, we find a potentially-compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissect key pre– and post-synaptic components with pharmacological strategies. We identify a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we test cholinergic and nicotinic-selective pro-cognitive treatments. The inhibition of acetylcholinesterase further enhances endogenous cholinergic responses but greatly distorts their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhances endogenous cholinergic responses and retains their rapid kinetics.

Conclusions

We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.
Genetic factors acting prior to dormancy in sour cherry influence bloom time the following spring
Authors: Goeckeritz Charity Z. , Grabb Chloe , Grumet Rebecca , Iezzoni Amy F. , Hollender Courtney A.
Published: November 2023

Bloom time is central to tree fruit production, and forPrunusspecies floral development leading up to bloom spans four seasons. Understanding this entire process is crucial for developing strategies to manipulate bloom time to prevent crop loss due to climate change. Here, we present a detailed examination of flower development from initiation until bloom for early- and late-blooming sour cherries (Prunus cerasus) from a population segregating for a major bloom time QTL on chromosome 4. Using a new staging system, we identified floral buds from early-blooming trees were persistently more advanced than those from late-blooming siblings. A gDNA coverage analysis revealed the late-blooming haplotype of this QTL,k, is located on a subgenome originating from the late-bloomingP. fruticosaprogenitor. Transcriptome analyses identified a large number of genes within this QTL as differentially expressed between early- and late-blooming trees during the vegetative-to-floral transition. From these, we identified candidate genes for the late bloom phenotype, including multiple transcription factors homologous to REproductive Meristem (REM) B3 domain-containing proteins. Additionally, we determined the basis ofkin sour cherry is likely separate from candidate genes found in sweet cherry – suggesting several major regulators of bloom time are located onPrunuschromosome 4.

HIGHLIGHT

Dormancy is a main effector of bloom time in fruit trees. However, developmental, genetic, and transcriptomic analyses indicate differences in flower development before dormancy significantly influence flowering time in cherry.
Single cell spatial transcriptomic profiling of childhood-onset lupus nephritis reveals complex interactions between kidney stroma and infiltrating immune cells
Authors: Danaher Patrick , Hasle Nicholas , Nguyen Elizabeth D. , Hayward Kristen , Rosenwasser Natalie , Alpers Charles E. , Reed Robyn C. , Okamura Daryl M. , Baxter Sarah K. , Jackson Shaun W.
Published: November 2023

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single cell resolution atlas of kidney tissue (>400,000 cells) from eight cLN patients and two controls. Annotated cells were assigned to 35 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localize to specific regions in cLN kidneys, including myeloid cells trafficking to inflamed glomeruli and B cells clustering within tubulointerstitial immune hotspots. Notably, gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Finally, we identified modules of spatially-correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. In summary, single cell spatial transcriptomics allows unprecedented insights into the molecular heterogeneity of cLN, paving the way towards more targeted and personalized treatment approaches.
Characterisation and correction of polarisation effects in fluorescently labelled fibres
Authors: Aggarwal Nandini , Marsh Richard , Marcotti Stefania , Shaw Tanya J , Stramer Brian , Cox Susan , Culley Siân
Published: November 2023

Many biological structures take the form of fibres and filaments, and quantitative analysis of fibre organisation is important for understanding their functions in both normal physiological conditions and disease. In order to visualise these structures, fibres can be fluorescently labelled and imaged, with specialised image analysis methods available for quantifying the degree and strength of fibre alignment. Here we show that fluorescently labelled fibres can display polarised emission, with the strength of this effect varying depending on structure and fluorophore identity. This can bias automated analysis of fibre alignment and mask the true underlying structural organisation. We present a method for quantifying and correcting these polarisation effects without requiring polarisation resolved microscopy, and demonstrate its efficacy when applied to images of fluorescently labelled collagen gels, allowing for more reliable characterisation of fibre microarchitecture.
The effects of paroxetine-induced transient apoptosis and brain remodeling on social behavior in developing zebrafish
Authors: Sato Tomomi , Saito Kaito , Oyu Tsubasa , Tsuda Sachiko , Kurisaki Tomohiro , Kajihara Takeshi , Nagashima Masabumi
Published: November 2023

Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by various genetic and environmental factors. This disorder has the cardinal symptoms including impaired social behavior involving the amygdala. Antidepressants such as paroxetine in early pregnancy increase the risk of ASD in offspring. However, a comprehensive picture of the underlying pathogenic mechanisms remains elusive. Here, we demonstrate that early exposure of zebrafish embryos to paroxetine suppresses neurogenesis in the optic tectum and the dorsal telencephalon which corresponds to the human amygdala. Paroxetine-treated embryos exhibit impaired growth, with small heads and short body lengths resulting from transient apoptosis. This is reminiscent of the early-onset fetal growth restriction (FGR) associated with ASD. Interestingly, the suppressed neurogenesis in the small heads was found to be restored after the cessation of paroxetine. This was accompanied by extended retinotectal projections, suggesting brain-preferential remodeling. Finally, the paroxetine-treated fish exhibited impaired social behavior, further supporting the correspondence with ASD. Our findings offer new insights into the early neurodevelopmental etiology of ASD.
Evaluation of the Diuretic Activities of 80% Methanol Leaf Extract and Solvent Fractions ofRumex nepalensisin Mice
Authors: Tafesse Fasika Argaw , Asrie Assefa Belay , Belete Tafere Mulaw
Published: November 2023

Background

The leaf ofRumex nepalensishas historically been employed to treat urinary retention and as a diuretic. Despite these assertions, there has been very little research addressing the diuretic effect of the leaves ofR. nepalensis. Therefore, this study was done to examine the diuretic properties of R. nepalensis leaves.

Methods

Cold maceration with 80% methanol was used to extract the coarsely powdered leaves ofR. nepalensis. The extract was separated using increasing polarity solvents, beginning with n-hexane, ethyl acetate, and water. Mice were split into sections to test the plant’s diuretic properties. The negative control groups were given either distilled water or 2% tween 80; the positive control groups were given furosemide (10 mg/kg); and the test groups were given the 80% methanol extract and solvent fractions orally at dosages of 100, 200, and 400 mg/kg. The urine volume was determined, and urine analysis was performed on each extract.

Results

At dosage levels of 200 mg/kg and 400 mg/kg, the 80% methanol extract, ethyl acetate fraction, and aqueous fraction all produced substantial diuresis (p<0.001) as compared to the negative control. Similarly, mice given the 80% methanol extract, ethyl acetate fraction, and aqueous fraction demonstrated substantial natriuresis (p<0.001) and kaliuresis (p<0.001) at dosages of 200 mg/kg and 400 mg/kg, respectively, in comparison to the negative control.

Conclusion

The diuretic activity ofR. nepalensiswas significantly seen in the 80% methanol extract, ethyl acetate, and aqueous fractions, which corroborated the plant’s traditional use.
Computational Design of Periplasmic Binding Protein Biosensors Guided by Molecular Dynamics
Authors: O’Shea Jack M. , Richardson Annis , Doerner Peter , Wood Christopher W.
Published: November 2023

Periplasmic binding proteins (PBPs) are bacterial proteins commonly used as scaffolds for substrate-detecting biosensors. In such biosensors, effector proteins, for example circularly permuted green fluorescent protein (cpGFP), are inserted into a PBP such that the effector protein’s output changes upon PBP-substate binding. The insertion site is often determined by comparison of PBPapo/holocrystal structures, but random insertion libraries have shown that this can miss the best sites. Here, we present a PBP biosensor design method based on residue contact analysis from molecular dynamics. This computational method identifies the best previously known insertion sites in the maltose binding PBP, and suggests further previously unknown sites. We experimentally characterise cpGFP insertions at these new sites, finding they too give functional biosensors. Our method is sufficiently flexible to both suggest insertion sites compatible with a variety of effector proteins and be applied to binding proteins beyond PBPs.
Oncogenic RAS drives rapid onset cellular plasticity and elicits a tumour-promoting neutrophil response at the inception of preneoplastic development
Authors: Elliot Abigail M. , Ribeiro Bravo Isabel , Astorga Johansson Jeanette , Hutton Esme , Cunningham Richard , Myllymäki Henna , Chang Kai Yee , Beltran Mariana , Dobie Ross , Elks Phil , Hansen Carsten Gram , Henderson Neil , Feng Yi
Published: November 2023

To date, very little is known regarding the earliest cellular and molecular events within the initial preneoplastic cell (PNC) niche that might determine the outcome of PNC development. Here, we combinein vivolive imaging and single cell transcriptomics to investigate the immediate cellular and molecular changes that occur in PNCs and responding innate immune cells within the first 24 hours following tumour initiation. We do so using an inducible transgenic zebrafish model of tumour initiation, in which oncogenic HRAS is conditionally expressed within the zebrafish epidermis. We found that, when expressed within basal keratinocytes, oncogenic HRAS was sufficient to drive several cancer hallmarks in nascent PNCs and their niche. Within 8 hours of oncogenic HRAS induction, basal keratinocytes began to dedifferentiate, followed by a bifurcation in PNC fate towards either a cellular state characterised by partial Epithelial-Mesenchymal-Transition (pEMT) and cancer stem cell features or a more differentiated cell state resembling suprabasal keratinocytes. By directly integrating data from PNCs and human SCC patients we show that both of these PNC states likely persist with established tumours, whilst the pEMT state corresponded with a more aggressive phenotype. Strikingly, markers of the PNC subpopulation that underwent pEMT correlated with poor prognosis in multiple human cancer types in the TCGA database. In addition, the pEMT PNC subpopulation expressed higher levels of cytokines that modulate neutrophil development and function, suggesting a major role for these cells in governing pro-tumour neutrophil responses. Indeed, we found that granulopoiesis was altered within PNC-bearing larvae, with a large proportion of neutrophils switching to an Arginase 2 positive phenotype that functioned to promote PNC proliferation. Similar to tumour associated neutrophils in the mammalian system, the cxcr1/2 – Il8 axis is involved in mediating the PNC-promoting function of neutrophils in our model. Thus, oncogenic RAS, when activated in the permissive cellular environment is sufficient to drive enabling cancer hallmarks, such as cellular plasticity and inflammation from the inception of the preneoplastic stage of cancer development. Furthermore, these same features may persist to drive malignant progression.
An Arabidopsis leaf expression atlas across diurnal and developmental scales
Authors: Vong Gina , McCarthy Kayla , Claydon Will , Davis Seth J. , Redmond Ethan J. , Ezer Daphne
Published: November 2023

Mature plant leaves are a composite of distinct cell types, including epidermal, mesophyll and vascular cells. Notably the proportion of these cells, and the relative transcript concentrations within different cell types may change over time. While gene expression data at a single-cell level can provide cell-type specific expression values, it is often too expensive to perform this on high resolution time series. Although bulk RNA-seq can be performed in a high resolution time series, the RNA-seq in whole leaves measures the average gene expression values across all cell types in each sample. In this study, we combined single cell RNA-seq data with time-series data from whole leaves to infer an atlas of cell type-specific gene expression changes over time forArabidopsis thaliana. We inferred how relative transcript concentrations of cell types vary across diurnal and developmental time scales. Importantly this analysis revealed three sub-groups of mesophyll cells that have distinct temporal profiles of expression. Finally, we develop tissue-specific gene networks that form a new community resource: An Arabidopsis Leaf Time-Dependent Atlas (AraLeTa), which allows users to extract gene networks that are confirmed by transcription factor binding data and specific to certain cell types, at certain times of day and certain developmental stages, which is available at:https://regulatorynet.shinyapps.io/araleta/.
Stable Equilibria under Random Fitness and Recombination Rates
Authors: Babel Noah
Published: November 2023

We develop and analyze a two-locus biallelic genetic model with randomized recombination rates and fitness matrices. While deterministic models reveal a trajectory toward the simplex center before stabilizing at polymorphisms, introducing random recombination pinpointed regions of attraction dependent on the fitness matrix and recombination fraction range. As recombination randomness intensifies, transitions in these attraction regions are observed. Analysis with random fitness matrices highlighted genotype attraction towards the tetrahedron vertices with edges guiding genotypic clustering.
Threat of water hyacinth (Eichhornia crassipes) on socio-economic and environmental sustainability of Koka and Ziway lakes, Ethiopia
Authors: Churko Esayas Elias , Nhamo Luxon , Chitakira Munyaradzi
Published: November 2023

Invasive alien plant species cause severe socio-economic and environmental damage. In particular, the water hyacinth (Eichhornia crassipes) is an aggressive alien aquatic macrophyte that affects the socio-hydrologic and social environment in many parts of the globe. This study assessed the socio-economic and ecological impacts of the water hyacinth (WH) in Koka and Ziway Lakes in Ethiopia and recommends novel management practices. Purposive sampling design method was used to select households using systematic random sampling. The household sample size was determined with 95% confidence level. Data were collected through key informant interviews, focus group discussion and household surveys, prepared using the Kobo Toolbox which monitors data collectors online. A total of 413 households were sampled and the data were analysed through descriptive statistics and the ANOVA statistical package. At Lake Koka districts that the WH has caused 51% food insecurity by reducing food productivity, and 98.5% health distress through exposure to vector disease. At Lake Ziway districts it caused 81.6% food insecurity and 99.5% health distress. At both lakes, the WH affected the fishing industry by almost 100%. In terms of crop production, maize was significantly affected at Koka,ᵡ2(1, = 413) = 117.01, p<.001 and cabbage was significantly affected at Ziway,ᵡ2(1, N= 413) =6.36, p<.001. There was a statistically significant difference in annual income level, age of the household leader, and cost of recovery at household family size, F (9, 623.18) =14.38, p<.001; Wilk’s Λ=.632, partial η2=.14. Therefore, 195 (99.5%) households at Lake Koka and 215 (99.1%) at Lake Ziway illustrated the need for intervention to reduce health impacts and food insecurity. Despite the negative impact, at Lake Koka districts, 86.7% of the plant is used as cattle feed and 28.1% as fertilizer. At Lake Ziway, 42.9% of the plant is used as forage and 39.2%, as a fertilizer.
Automated classification of giant virus genomes using a random forest model built on trademark protein families
Authors: Ha Anh D. , Aylward Frank O.
Published: November 2023

Viruses of the phylumNucleocytoviricota, often referred to as “giant viruses,” are prevalent in various environments around the globe and play significant roles in shaping eukaryotic diversity and activities in global ecosystems. Given the extensive phylogenetic diversity within this viral group and the highly complex composition of their genomes, taxonomic classification of giant viruses, particularly incomplete metagenome-assembled genomes (MAGs) can present a considerable challenge. Here we developed TIGTOG (Taxonomic Information ofGiant viruses usingTrademarkOrthologousGroups), a machine learning-based approach to predict the taxonomic classification of novel giant virus MAGs based on profiles of protein family content. We applied a random forest algorithm to a training set of 1,531 quality-checked, phylogenetically diverseNucleocytoviricotagenomes using pre-selected sets of giant virus orthologous groups (GVOGs). The classification models were predictive of viral taxonomic assignments with a cross-validation accuracy of 99.6% to the order level and 97.3% to the family level. We found that no individual GVOGs or genome features significantly influenced the algorithm’s performance or the models’ predictions, indicating that classification predictions were based on a comprehensive genomic signature, which reduced the necessity of a fixed set of marker genes for taxonomic assigning purposes. Our classification models were validated with an independent test set of 823 giant virus genomes with varied genomic completeness and taxonomy and demonstrated an accuracy of 98.6% and 95.9% to the order and family level, respectively. Our results indicate that protein family profiles can be used to accurately classify large DNA viruses at different taxonomic levels and provide a fast and accurate method for the classification of giant viruses. This approach could easily be adapted to other viral groups.
Experimental design impacts the vector competence ofOrnithodorosticks for African swine fever virus: a meta-analysis of published evaluations
Authors: Bernard Jennifer , Madeira Sara , Otte Joachim , Boinas Fernando , Le Potier Marie-Frédérique , Vial Laurence , Jourdan-Pineau Hélène
Published: November 2023

African Swine Fever (ASF) is a highly economically devastating viral disease for swine. Soft ticks of the genusOrnithodorosare involved in its epidemiology, as vectors and natural reservoirs of African Swine Fever Virus (ASFV). The vector competence ofOrnithodorosticks for ASFV has been mainly studied by mimicking natural tick-to-pig transmission pathways through experimental infections in the laboratory. By reviewing the original research studies dating back to the 1960s on the vector competence ofOrnithodorosfor ASFV, we estimated the vector competence of 10 tick species in association with 38 viral strains resulting in 51 tick-virus associations. This assessment emphasized the extensive range of protocol designs employed and their impact on the success of tick infection with ASFV. Our results call for standardised procedures in vector competence experiments to facilitate further investigation and reduce potential experimental bias. In particular, we recommend the use of late nymphs or adult ticks from a laboratory colony to achieve efficient infection rates. In addition, viral inoculation should be carried out by blood meal rather than by injection, and preference should be given to high titre blood. Finally, detection of viral DNA should be performed 2 months after inoculation to distinguish between successful replication and residual virus in the tick.
Cingulate cortex facilitates auditory perception under challenging listening conditions
Authors: Anbuhl Kelsey L. , Diez Castro Marielisa , Lee Nikki A. , Lee Vivian S. , Sanes Dan H.
Published: November 2023

We often exert greater cognitive resources (i.e., listening effort) to understand speech under challenging acoustic conditions. This mechanism can be overwhelmed in those with hearing loss, resulting in cognitive fatigue in adults, and potentially impeding language acquisition in children. However, the neural mechanisms that support listening effort are uncertain. Evidence from human studies suggest that the cingulate cortex is engaged under difficult listening conditions, and may exert top-down modulation of the auditory cortex (AC). Here, we asked whether the gerbil cingulate cortex (Cg) sends anatomical projections to the AC that facilitate perceptual performance. To model challenging listening conditions, we used a sound discrimination task in which stimulus parameters were presented in either ‘Easy’ or ‘Hard’ blocks (i.e., long or short stimulus duration, respectively). Gerbils achieved statistically identical psychometric performance in Easy and Hard blocks. Anatomical tracing experiments revealed a strong, descending projection from layer 2/3 of the Cg1 subregion of the cingulate cortex to superficial and deep layers of primary and dorsal AC. To determine whether Cg improves task performance under challenging conditions, we bilaterally infused muscimol to inactivate Cg1, and found that psychometric thresholds were degraded for only Hard blocks. To test whether the Cg-to-AC projection facilitates task performance, we chemogenetically inactivated these inputs and found that performance was only degraded during Hard blocks. Taken together, the results reveal a descending cortical pathway that facilitates perceptual performance during challenging listening conditions.

Significance Statement

Sensory perception often occurs under challenging conditions, such a noisy background or dim environment, yet stimulus sensitivity can remain unaffected. One hypothesis is that cognitive resources are recruited to the task, thereby facilitating perceptual performance. Here, we identify a top-down cortical circuit, from cingulate to auditory cortex in the gerbils, that supports auditory perceptual performance under challenging listening conditions. This pathway is a plausible circuit that supports effortful listening, and may be degraded by hearing loss.
LMD: Cluster-Independent Multiscale Marker Identification in Single-cell RNA-seq Data
Authors: Li Ruiqi , Qu Rihao , Parisi Fabio , Strino Francesco , Lam Hainan , Stanley Jay S. , Cheng Xiuyuan , Myung Peggy , Kluger Yuval
Published: November 2023

Identifying accurate cell markers in single-cell RNA-seq data is crucial for understanding cellular diversity and function. Localized Marker Detector (LMD) is a novel tool to identify “localized genes” - genes exclusively expressed in groups of highly similar cells - thereby characterizing cellular diversity in a multi-resolution and fine-grained manner. LMD constructs a cell-cell affinity graph, diffuses the gene expression value across the cell graph, and assigns a score to each gene based on its diffusion dynamics. LMD’s candidate markers can be grouped into functional gene modules, which accurately reflect cell types, subtypes, and other sources of variation such as cell cycle status.

We apply LMD to mouse bone marrow and hair follicle dermal condensate datasets, where LMD facilitates cross-sample comparisons, identifying shared and sample-specific gene signatures and novel cell populations without requiring batch effect correction or integration methods. Furthermore, we assessed the performance of LMD across nine single-cell RNA sequencing datasets, compared it with six other methods aimed at achieving similar objectives, and found that LMD outperforms the other methods evaluated.
UBTFTandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis
Authors: Barajas Juan M. , Umeda Masayuki , Contreras Lisett , Khanlari Mahsa , Westover Tamara , Walsh Michael P. , Xiong Emily , Yang Chenchen , Otero Brittney , Arribas-Layton Marc , Abdelhamed Sherif , Song Guangchun , Ma Xiaotu , Thomas Melvin E. , Ma Jing , Klco Jeffery M.
Published: November 2023

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features ofUBTF-TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 ofUBTF. We demonstrate thatUBTF-TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm thatUBTF-TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition ofFLT3orWT1mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 ofUBTFthat phenocopy exon 13 duplications, expanding the spectrum ofUBTFalterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS withUBTF-TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.

Key Points

Largest cohort of pediatricUBTF-TD in myeloid neoplasms reported to date.

Use of single-cell DNA+protein sequencing technology in 3UBTF-TD samples reveals a clonal evaluation pattern characterized by sequential acquisition ofWT1andFLT3mutations and a more stem cell-like protein expression pattern.

Pediatric MDS and AML patients withUBTF-TD alterations dysplastic features with an increase erythroid precursors.

Tandem duplications in exon 9 ofUBTFrepresent a rare but functionally equivalent subgroup ofUBTF-TD myeloid neoplasms.

Impact Statement

UBTFtandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatricUBTF-TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.
A TWO PARAMETER CLOSED FORM SOLUTION TO KERMACK AND MCKENDRICK’S INTEGRO-DIFFERENTIAL EQUATIONS
Authors: Duclos Ted , Reichert Tom
Published: November 2023

A closed form solution of the full Kermack and McKendrick (K&M) integro-differential equations (Kermack and McKendrick 1927), called the KMES, is presented and verified. Intuitively, the KMES states that the total case count in an epidemic is the integral of the product of the probability rate of transmission and the number of infectious contacts from the epidemic start to the current point in time.

This solution was derived by pursuing the logical consequences of a construct that combines network concepts with the recognition that the infectiousness of an individual depends on their exposure to susceptible persons. The KMES has two parameters: the probability rate of disease transmission, and the basic reproduction number. The proof of the solution uses the weighted averages of K&M’s rate parameters, and a restatement of the proper integral limits in their recovery function.

Practical analytical expressions, including novel expressions for the effective reproduction number, time to peak in new infections, and the final size flow directly from the solution. Notably, the latter two expressions project phenomena antithetical to currently accepted epidemic concepts. Using early COVID-19 pandemic data from six different countries to estimate the model parameters, the KMES accurately projects case data from the COVID-19 pandemic in the following 60-day period with R2values > 0.78. In addition, the projection of a typical individual’s contagiousness, derived from the KMES, closely approximates the time course of viral shedding as measured in infected persons.
Genotype-microbiome-metabolome associations in early childhood, and their link to BMI and childhood obesity
Authors: Aparicio Andrea , Sun Zheng , Gold Diane R. , Litonjua Augusto A. , Weiss Scott T. , Lee-Sarwar Kathleen , Liu Yang-Yu
Published: November 2023

The influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10−6. We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children’s BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children’s BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.
Connectome reorganization associated with temporal lobe pathology and its surgical resection
Authors: Larivière Sara , Park Bo-yong , Royer Jessica , DeKraker Jordan , Ngo Alexander , Sahlas Ella , Chen Judy , Rodríguez-Cruces Raúl , Weng Yifei , Frauscher Birgit , Liu Ruoting , Wang Zhengge , Shafiei Golia , Mišić Bratislav , Bernasconi Andrea , Bernasconi Neda , Fox Michael D. , Zhang Zhiqiang , Bernhardt Boris C.
Published: November 2023

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain’s structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n= 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age-and sex-matched healthy controls who underwent comparable imaging (n= 31). Core to our analysis was the projection of high-dimensional structural connectome data—derived from diffusion MRI tractography from each subject—into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre-to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical-imaging signature underlying this pre-to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency, and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and inter-individual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.
Management of Antipsychotics in Primary Care: Insights from Healthcare Professionals and Policy Makers in the UK
Authors: Woodall Alan A. , Abuzour Aseel S. , Wilson Samantha A. , Mair Frances S. , Buchan Iain , Sheard Sally B. , Atkinson Paul , Joyce Dan W. , Symon Pyers , Walker Lauren E.
Published: November 2023

Introduction

Antipsychotic medication is increasingly prescribed to patients with serious mental illness. Patients with serious mental illness often have cardiovascular and metabolic comorbidities, and antipsychotics independently increase the risk of cardiometabolic disease. Despite this, many patients prescribed antipsychotics are discharged to primary care without planned psychiatric review. We explore perceptions of healthcare professionals and managers/planners of policy regarding management of antipsychotics in primary care.

Methods

Qualitative study using semi-structured interviews with 11 general practitioners (GPs), 8 psychiatrists, and 11 managers/planners of policy in the United Kingdom. Interviews were studied using inductive thematic analysis.

Results

Respondents reported competency gaps that impaired ability to manage patients prescribed antipsychotic medications holistically, arising from inadequate postgraduate training and professional development. GPs lacked confidence to manage antipsychotic medications alone; psychiatrists lacked skills to address cardiometabolic risks and did not perceive this as their role. Communication barriers, lack of integrated care records, limited psychology provision, lowered expectation of patients with serious mental illness by professionals, and pressure to discharge from hospital resulted in patients in primary care becoming ‘trapped’ on antipsychotics, inhibiting opportunities to deprescribe. Organisational and contractual barriers between organisations exacerbate this risk, with socioeconomic deprivation and lack of access to non-pharmacological alternatives driving overprescribing. GPs and psychiatrists voiced professional fears of being blamed if an event causing harm occurred after stopping an antipsychotic, which inhibited deprescribing. A range of actions to overcome these barriers were suggested.

Conclusions

People prescribed antipsychotics experience a fragmented health system and suboptimal care. Many simple steps could be taken to improve quality of care for this population but inadequate availability of non-pharmacological alternatives and socioeconomic factors increasing mental distress need key policy changes to improve the current situation.
Prognostic Value of Angiography-derived Microcirculatory Resistance in Patients undergoing Rotational Atherectomy
Authors: Zhang Xi , Jin Qing , He Jiaji , Zhao Tao , He Guiping , Xue Qiang , Guang Xuefeng
Published: November 2023

BACKGROUND

Rotational atherectomy (RA) is predominantly employed in the treatment of severe calcification lesions in patients with coronary atherosclerotic heart disease (CAD). Studies focusing on the assessment of postoperative microvascular dysfunction (CMD) after RA and related prognosis are scarce.

AIMS

we attempted to investigate the predictive significance of coronary angiography-derived microcirculatory resistance (AMR) in patients with coronary RA.

METHODS

This retrospective study analyzed the data from 114 patients who were successfully treated between January 2019 and September 2022. Coronary microcirculatory function after RA was assessed using AMR. Patients were categorized into CMD and non-CMD groups depending on a postoperative AMR of ≥2.5 mmHg-s/cm. Patients were followed up for postoperative major adverse cardiovascular events (MACE).

RESULTS

We analyzed the data from 114 patients, and post-RA, the mean AMR, mean QFR, and the percentage of CMDs were significantly higher compared to those before RA. MACE occurred in 14 (12.3%) patients after a year of follow-up. A higher proportion of patients in the MACE group showed post-RA AMR of ≥2.5 mmHg-s/cm (57.1% vs. 27.0%, P=0.048). Cox regression analysis showed that AMR ≥2.5 mmHg-s/cm (HR=3.86, 95%CI. 1.28-11.63, P=0.016) and renal insufficiency (HR=9.92, 95%CI: 2.06-47.83, P=0.004) were independent predictors of MACE. Logistic regression analyses showed the length of the RA operative area and diabetes mellitus (DM) were related to post-RA CMD.

CONCLUSION

In patients with CAD treated with RA, AMR ≥2.5 mmHg-s/cm independently predicted post-RA MACE; furthermore, the operative length of RA and the comorbid DM were associated with CMD following RA.
N-terminal toxin signal peptides efficiently load therapeutics into a natural nano-injection system
Authors: Steiner-Rebrova Eva M. , Ejaz Rooshanie N. , Kielkopf Claudia S. , Ruiz Mar Pérez , Marín-Arraiza Leyre , Hendriks Ivo A. , Nissen Jakob Nybo , Pozdnyakova Irina , Pape Tillmann , Regaiolo Alice , Götz Kira , Heermann Ralf , Rasmussen Simon , Nielsen Michael Lund , Taylor Nicholas M. I.
Published: November 2023

Targeted delivery of therapeutics to specific cells is a major bottleneck towards personalized medicine. The extracellular injection system (eCIS) ofSerratia entomophila, the antifeeding prophage (Afp), promises potential for drug delivery purposes. However, the precise mechanism of action, toxin location, and Afp loading remain unclear. Here, we reveal a minimal N-terminal signal peptide (NtSP) of the toxin Afp18, that plays a key role in toxin packing. By engineering fusion proteins, we demonstrate that Afp18’s NtSP can shuttle effectors for Afp loading. We packed non-eCIS effectors, including CRISPR-Cas protein CasΦ-2 from Biggiephage, and a human antimicrobial peptide, LL37, into Afp. Additionally, NtSPs from eCIS effectors of other species facilitate loading of CasΦ-2 into Afp. We observed cargo being packed inside the Afp tail tube through cryo-EM single particle analysis. The presented results enhance our understanding of eCIS toxin packing and contribute to their development as targeted delivery systems.

Teaser

A novel use of the Afp nano injection system’s N-terminal signal peptide in targeted therapeutics delivery
De novobasecalling of m6A modifications at single molecule and single nucleotide resolution
Authors: Cruciani Sonia , Delgado-Tejedor Anna , Pryszcz Leszek P. , Medina Rebeca , Llovera Laia , Novoa Eva Maria
Published: November 2023

RNA modifications hold pivotal roles in shaping the fate and function of RNA molecules. Although nanopore sequencing technologies have proven successful at transcriptome-wide detection of RNA modifications, current algorithms are limited to predicting modifications at a per-site level rather than within individual RNA molecules. Herein, we introducem6ABasecaller, an innovative method enabling direct basecalling of m6A modifications from raw nanopore signals within individual RNA molecules. This approach facilitatesde novoprediction of m6A modifications with precision down to the single nucleotide and single molecule levels, without the need of paired knockout or control conditions. Using them6ABasecaller, we find that the median transcriptome-wide m6A modification stoichiometry is ∼10-15% in human, mouse and zebrafish. Furthermore, we show that m6A modifications affect polyA tail lengths, exhibit a propensity for co-occurrence within the same RNA molecules, and show relatively consistent stoichiometry levels across isoforms. We further validate them6ABasecallerby treating mESC with increasing concentrations of STM2457, a METTL3 inhibitor as well as in inducible METTL3 knockout systems. Overall, this work demonstrates the feasibilityde novobasecalling of m6A modifications, opening novel avenues for the application of nanopore sequencing to samples with limited RNA availability and for which control knockout conditions are unavailable, such as patient-derived samples.