bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of an improved reference freeze-dried direct agglutination test for detecting leishmaniasis in the canine reservoir
Authors: el Harith Abdallah , Abass Elfadil , Martinkovic Franjo , Mansour Durria , Osman Hussam Ali
Published: November 2024

Introduction

Proper identification and management of reservoir post-kala-azar dermal leishmaniasis (PKDL) and canine visceral leishmaniasis (CVL) cases are prerequisites to the effective control of visceral leishmaniasis (VL) worldwide. Unlike PKDL, CVL still awaits effective improvement because of its cryptic nature, absence of Leishmania parasite in lesions or lymph nodes, and insensitivity of tools in current use. Because of the need for certain skills and equipment, both the liquid direct agglutination test (LQ-DAT) and freeze-dried direct agglutination test (FD-DAT) versions, present in comparison with the indirect immunofluorescence (IFAT) or enzyme-linked immunosorbent assay (ELISA), practical and feasible diagnostic alternatives.

Aim

Validate the performance of an improved FD-DAT to suit routine and large-scale applications in CVL endemic areas.

Methodology

Introducing of citrate-saline formaldehyde (CSF) as an anti-clumping agent to replace normal saline for antigen reconstitution and drastically however eligibly lowering the concentration of promastigotes (1.4X107) in comparison with the original reference FD-DAT (> 5X107/ml), To ensure optimal safety, β-mercaptoethanol (β-ME) was replaced by urea or sodium dodecyl sulphate (SDS) as a serum reducing agent.

Results

Through improving the procedure for reconstitution of FD-DAT antigen with CSF a 150% reduction in the test application cost was achieved. Expired test batches (+ 4 years earlier), were successfully revitalized to full validity. As compared to 48-hour shelf-life time for the original, an FD-DAT batch re-constituted here with CSF maintained validity for + 12 months.

Conclusions

The highly concordant results with IFAT and ELISA (One Way ANOVA Test P = 0.142, Homogeneity of Variances P = 0.009) as routine CVL diagnostics further motivate the application of the improved FD-DAT for detection of the disease in endemic areas.
Agarooligosaccharides as a novel concept in prebiotics: selective inhibition of Ruminococcus gnavus and Fusobacterium nucleatum while preserving Bifidobacteria, Lactobacillales in vitro, and inhibiting Lachnospiraceae in vivo
Authors: Fujii Tadashi , Karasawa Koji , Takahashi Hideaki , Shirai Ikuya , Funasaka Kohei , Ohno Eizaburo , Hirooka Yoshiki , Tochio Takumi
Published: November 2024

Recent studies have linked Ruminococcus gnavus to inflammatory bowel disease and Fusobacterium nucleatum to various cancers. Agarooligosaccharides (AOS), derived from the acid hydrolysis of agar, have shown significant inhibitory effects on the growth of R. gnavus and F. nucleatum at concentrations of 0.1 and 0.2%, respectively. RNA sequencing and quantitative reverse-transcription PCR analyses revealed the downregulation of fatty acid biosynthesis genes (fab genes) in these bacteria when exposed to 0.1% AOS. Furthermore, AOS treatment altered the fatty acid composition of R. gnavus cell membranes, increasing medium-chain saturated fatty acids (C8, C10) and C18 fatty acids while reducing long-chain fatty acids (C14, C16). In contrast, no significant growth inhibition was observed in several strains of Bifidobacteria and Lactobacillales at AOS concentrations of 0.2 and 2%, respectively. Co-culture experiments with R. gnavus and Bifidobacterium longum in 0.2% AOS resulted in B. longum dominating the population, constituting over 96% post-incubation. In vivo studies using mice demonstrated a significant reduction in the Lachnospiraceae family, to which R. gnavus belongs, following AOS administration. Quantitative PCR also showed lower levels of the nan gene, potentially associated with immune disorders, in the AOS group. These findings suggest that AOS may introduce a novel concept in prebiotics by selectively inhibiting potentially pathogenic bacteria while preserving beneficial bacteria such as Bifidobacteria and Lactobacillales.
Physicochemical properties of sweet limes (Citrus
limetta) during storage at different temperatures
Authors: Reyna-Gonzales Katherine , Pesantes-Gallardo María G. , Huamán-Grandez Eddy O. , Valdivia-Culqui Jheniffer E. , Paredes-Tarrillo Fredy A. , Raymundo-Vasquez Pedro A. , Medina-Mendoza Marleni , Cayo-Colca Ilse S. , Quispe-Neyra Juan , Maicelo-Quintana Jorge L. , Castro-Alayo Efraín M. , Balcázar-Zumaeta César R.
Published: November 2024

The loss of nutrients from sweet lime (Citrus limetta) by poor
postharvest storage represents a significant problem today, damaging these
fruits’ quality and market value. This study aimed to evaluate the
physicochemical properties of sweet limes during storage at different
temperatures (RT-21°C, 2°C, and 4°C). The limes were
harvested at full physiological maturity. Water activity (Aw), pH, color index,
total soluble solids, titratable acidity, and ripeness index were determined
during 15 days of storage. In addition, antioxidant activity and phenolic
content were determined. The results indicate that keeping the sweet lime at a
temperature of 4°C is the most favorable condition for optimal
conservation, as reflected by the reduction in Aw, titratable acidity, total
soluble solids and ripeness index of the fruit. The values obtained indicate
slower decomposition and conservation of freshness and flavor. In addition, it
was found that at this temperature, the fruit’s antioxidant activity and
phenolic content were significantly increased. In addition, total polyphenols
were better preserved at 2°C compared to room temperature (RT) and
4°C. However, ABTS and DPPH levels remained constant at 4°C and
2°C throughout the study time and were higher than at RT.
Kinetic modeling of ultrasound-assisted extraction of dieckol from
Ecklonia cava using a choline chloride-based natural deep
eutectic solvent
Authors: Cho Ha Seong , Park Gwang Deok , Olawuyi Ibukunoluwa Fola , Park Jong Jin , Lee Won Young
Published: November 2024

Natural deep eutectic solvents (NADES) are promising green and sustainable
solvents for efficient extraction of bioactive compounds. We employed
ultrasound-assisted extraction (UAE) to extract dieckol from Ecklonia
cava (EC) using choline chloride-based NADES. Eight different NADES
(comprising sugars, alcohols, and organic acids) and a conventional solvent were
screened to select the best eutectic solvent for dieckol extraction. Among the
organic acid-based NADES, choline chloride–acetic acid (CCAC; 1:1 molar
ratio with a 50% [v/v] water content) exhibited a higher dieckol content
(31.45 mg/g) than other NADES and ethanol. Second-order kinetic modeling was
applied using CCAC with varying water content (40–80%, v/v) to
confirm the extraction efficiency and underlying mechanism. The kinetic model
showed that CCAC with 40% water content (v/v) exhibited the highest
capacity (Ce=29.67 mg/g), while CCAC with 60% water
content (v/v) yielded a superior extraction rate constant
(k=0.12 mg/g min). Moreover, the dieckol extract
displayed potent DPPH and ABTS+ antioxidant activities.
Furthermore, structural and viscosity changes between the synthesized CCAC with
and without water addition were compared. Our study proposes an eco-friendly and
efficient extraction alternative for the extraction of dieckol from EC using
NADES.
Effect of red ginseng extract on the quality characteristics of
mayonnaise
Authors: Kim Jung Soo , Kim Jiyoon , Nam Inju , Kim Soo Hyun , Seo Yu Min , Lim Jeong-Ho , Moon Kwang-Deog
Published: November 2024

Increasing consumer demand for healthy food leads to the pursuit of mayonnaise
with fewer egg yolks. This study investigated the possibility of red ginseng
extract (RGE) as an egg yolk alternative in mayonnaise. Mayonnaises were
prepared by replacing different ratios (0%, 25%, 50%,
75%, and 100%) of RGE to egg yolks, and quality characteristics
were analyzed. RGE was confirmed to have 17.51 mg/g of crude saponin, a water
holding capacity of 0.21 g/g, and an oil holding capacity of 1.82 g/g.
Antioxidant activities of mayonnaise were significantly increased by RGE
content. In texture profile analysis, the cohesiveness, gumminess, and
adhesiveness of mayonnaise decreased with the addition of RGE. Mayonnaise with
0% and 25% RGE substitution for egg yolk showed smaller oil
droplets and higher viscosity and, therefore, the highest emulsion stability
(p<0.05). In mayonnaises incorporated with high RGE concentrations
(>75%), larger oil droplets increased, and emulsion properties
were rapidly weakened. RGE also affected the sensory evaluation of mayonnaise;
mayonnaises incorporated with 0% and 25% RGE showed high
preference. RGE can be expected to play a positive role as a supplemental
emulsifier and may expand the utility of red ginseng.
Discovering plasticity rules that organize and maintain neural circuits
Authors: Bell David , Duffy Alison , Fairhall Adrienne
Published: November 2024

Intrinsic dynamics within the brain can accelerate learning by providing a prior scaffolding for dynamics aligned with task objectives. Such intrinsic dynamics should self-organize and self-sustain in the face of fluctuating inputs and biological noise, including synaptic turnover and cell death. An example of such dynamics is the formation of sequences, a ubiquitous motif in neural activity. The sequence-generating circuit in zebra finch HVC provides a reliable timing scaffold for motor output in song and demonstrates a remarkable capacity for unsupervised recovery following perturbation. Inspired by HVC, we seek a local plasticity rule capable of organizing and maintaining sequence-generating dynamics despite continual network perturbations. We adopt a meta-learning approach introduced by Confavreux et al, which parameterizes a learning rule using basis functions constructed from pre- and postsynaptic activity and synapse size, with tunable time constants. Candidate rules are simulated within initially random networks, and their fitness is evaluated according to a loss function that measures the fidelity with which the resulting dynamics encode time. We use this approach to introduce biological noise, forcing meta-learning to find robust solutions. We first show that, in the absence of perturbation, meta-learning identifies a temporally asymmetric generalization of Oja’s rule that reliably organizes sparse sequential activity. When synaptic turnover is introduced, the learned rule incorporates an additional form of homeostasis, better maintaining sequential dynamics relative to other previously proposed rules. Additionally, inspired by recent findings demonstrating plasticity in synapses from inhibitory interneurons in HVC, we explore the role of inhibitory plasticity in sequence-generating circuits. We find that learned plasticity adjusts both excitation and inhibition in response to manipulations, outperforming rules applied only to excitatory connections. We demonstrate how plasticity acting on both excitatory and inhibitory synapses can better shape excitatory cell dynamics to scaffold timing representations.
A phased chromosome-level genome of the annelid tubewormGaleolaria caespitosa
Authors: van Dorssen Monique , Belcher Emily K. , Gallegos Cristóbal , Hodgins Kathryn A. , Monro Keyne
Published: November 2024

Haplotype-resolved (phased) genome assemblies are emerging as important assets for genomic studies of species with high heterozygosity, but remain lacking for key animal lineages. Here, we use PacBio HiFi and Omni-C technologies to assemble the first phased, annotated, chromosome-level genome for any annelid: the reef-building tubewormGaleolaria caespitosa(Serpulidae). The assembly is 803.5 Mbp long (scaffold N50 = 76.5 Mbp) for haplotype 1 and 789.3 Mbp long (scaffold N50 = 75.4 Mbp) for haplotype 2, which are arranged into 11 pairs of chromosomes showing no sign of sex chromosomes. This compares with cytological analyses reporting 12–13 pairs inGaleolaria’s closest relatives, including species that are protandrous hermaphrodites. We combined long-read and short-read transcriptome sequencing to annotate both haplotypes, resulting in 43,191 predicted proteins for haplotype 1, 39,675 proteins for haplotype two, and 55.5% of proteins with at least one functional annotation. We also assembled a mitochondrial genome 23 Kbp long, annotating all genes typically found in mitochondrial DNA apart from those coding the16Sribosomal subunit and the proteinatp8— a short, fast-evolving mitochondrial gene missing in other metazoans. ComparingGaleolaria’s genome to those of three other annelids reveals limited collinearity despite 32.2% of shared orthologous gene clusters (4,248 of 13,174 clusters counted inGaleolaria), suggesting extensive chromosomal rearrangements among lineages. New high-quality annelid genomes may help resolve the genetic and evolutionary basis of this diversity.
Unveiling the Hidden Feast: from molecular detection to predation rate – An example on biological control by generalist predators
Authors: Masson Abel Louis , Rastello Kevan , Sacco-Martret de Preville Ambre , Tricault Yann , Poggi Sylvain , Canard Elsa , Etienne Marie-Pierre , Plantegenest Manuel
Published: November 2024

Very few processes are as decisive as predation in shaping the structure and dynamics of ecological communities. For most predator species, the number of prey items killed by a predator in a day (predation rate) remains impossible to assess because direct observations are scarce or impossible to acquire. To fill this gap, we propose here a Hierarchical Bayesian Model that integrates data on the molecular detection of prey in predators (e.g. PCR results), on individuals captured in the field on the one hand, and on individuals fed in the laboratory, on the other, in a novel mechanistic framework. By explicitly combining the processes of predation and digestion, model fit provides an estimate of the slope and intercept of the digestion curve, and an estimate of the number of prey consumed by a predator in a day. In a case study targeting 25 carabid beetle species and 5 types of prey in agricultural fields (winter wheat), we use our model to estimate predation rates at species and community scales and demonstrate its advantages for studies on biocontrol and beyond.

Code and Data are available on this repository :/r/HBM_PredationCode-C725/
Striking Departures from Polygenic Architecture in the Tails of Complex Traits
Authors: Souaiaia Tade , Wu Hei Man , Ori Anil P.S. , Choi Shing Wan , Hoggart Clive J. , O’Reilly Paul F.
Published: November 2024

Understanding the genetic architecture of human traits is of key biological, medical and evolutionary importance[1]. Despite much progress, little is known about how genetic architecture varies across the trait continuum and, in particular, if it differs in the tails of complex traits, where disease often occurs. Here, applying a novel approach based on polygenic scores, we reveal striking departures from polygenic architecture across 148 quantitative trait tails, consistent with distinct concentrations of high-impact rare alleles in one or both tails of most of the traits. We demonstrate replication of these results across ancestries, cohorts, repeat measures, and using an orthogonal family-based approach[2]. Furthermore, trait tails with inferred enrichment of rare alleles are associated with more exome study hits, reduced fecundity, advanced paternal age, and lower predictive accuracy of polygenic scores. Finally, we find evidence of ongoing selection consistent with the observed departures in polygenicity and demonstrate, via simulation, that traits under stabilising selection are expected to have tails enriched for rare, large-effect alleles. Overall, our findings suggest that while common variants of small effect likely account for most of the heritability in complex traits[3], rare variants of large effect are often more important in the trait tails, particularly among individuals at highest risk of disease. Our study has implications for rare variant discovery, the utility of polygenic scores, the study of selection in humans, and for the relative importance of common and rare variants to complex traits and diseases.
Cancer-associated DAXX mutations reveal a critical role for ATRX localization in ALT suppression
Authors: Clatterbuck Soper Sarah F. , Walker Robert L. , Pineda Marbin A. , Zhu Yuelin J. , Dalgleish James L. T. , Wang Jasmine , Meltzer Paul S.
Published: November 2024

To maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors maintain telomeres through the action of telomerase, a subset of tumors utilize a DNA-templated process termed Alternative Lengthening of Telomeres or ALT. ALT is associated with mutations in the ATRX/DAXX/H3.3 histone chaperone complex, which is responsible for deposition of non-replicative histone variant H3.3 at heterochromatic regions of the genome including telomeres. We wished to better understand the role DAXX plays in ALT suppression, and to determine which disease-associated DAXX mutations are unable to suppress ALT. To answer this question, we have leveraged the G292 cell line, in which ATRX is wild type but DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. Restoration of wild-type DAXX in G292 localizes ATRX and abrogates ALT. Using this model system, we tested the ability of a panel of disease-associated DAXX missense variants to suppress ALT. Missense mutations in the ATRX binding domain, the histone binding domain, and the C-terminal SUMO interaction motif reduce the ability of DAXX to suppress ALT. Unexpectedly, we find that mutations in the DAXX histone binding domain lead to failure of ATRX localization. We conclude that a key function of DAXX in ALT suppression is the localization of ATRX to nuclear foci.
Network toxicology focused investigation on the impacts of inorganic arsenic and cadmium on human and ecosystem health
Authors: Chivukula Nikhil , Madgaonkar Shreyes Rajan , Ramesh Kundhanathan , Mangot Swetha , Karthikeyan Panneerselvam , Marigoudar Shambanagouda Rudragouda , Sharma Krishna Venkatarama , Samal Areejit
Published: November 2024

Heavy metals like arsenic and cadmium are persistent environmental pollutants that pose serious health risks to humans and ecosystems due to their toxicity, bioaccumulation potential, and frequent presence in consumer products. Network toxicology offers a holisticin silicoframework to elucidate the complex biological mechanisms of toxicity, thereby supporting New Approach Methodologies (NAMs) for toxicity assessment. In this study, network toxicological tools were utilized to investigate arsenic- and cadmium-induced toxicities. Toxicity endpoints associated with inorganic arsenic and cadmium compounds were curated from six exposome-relevant databases and mapped to key events (KEs) across adverse outcome pathways (AOPs) cataloged in AOP-Wiki. This led to construction of stressor-AOP networks, revealing 51 AOPs associated with arsenic and 78 with cadmium, and facilitated mechanistic case studies of pathways relevant to human and ecological health. Toxicity concentrations and bioconcentration factors from the ECOTOX database were then used to construct stressor-species networks, that helped identify species that are vulnerable and potentially bioaccumalate these chemicals. Further, the construction of species sensitivity distributions (SSDs) and toxicity-normalized SSDs (SSDn), provided a comparative framework for prioritizing these compounds in risk assessments. Further, integrating SSD data with stressor-species networks identified species groups particularly sensitive to arsenic and cadmium exposure, enhancing these networks’ utility for ecological risk assessment. The networks and related data generated in this study are freely available for further research athttps://cb.imsc.res.in/heavymetaltox/. Overall, this study offers a comprehensive perspective on the toxicological impact of inorganic arsenic and cadmium compounds, supporting a One Health approach to their regulatory and mitigation strategies.
A proposed framework for evaluating meat alternatives
Authors: Semper Cameron , Kolta Caroline , Kinney MJ , Giali Jordan , Rogers Michaella , Blaustein-Rejto Dan , Rowat Amy C. , Ogilvie Olivia J. , Hutmacher Ryan , Wee Josephine , Emery Isaac , Domigan Laura J. , Shelke Kantha
Published: November 2024

Concerns surrounding the environmental, economic, and ethical consequences of meat production and industrial agriculture have prompted substantial research and capital investment into the production of meat alternatives. Alternative meat production encompasses a variety of technological approaches including plant-based meats, cell-based or cultivated meats, meat alternatives relying on fungal protein sources, and hybrids thereof; each of which offers unique advantages and disadvantages and has been associated with a myriad of claims supporting it as the preferred alternative to animal-derived meats. As part of XPRIZE Foundation’s Feed the Next Billion competition, we developed a framework for evaluating meat alternatives by measuring their structural, nutritional, and organoleptic properties while also assessing safety and their purported environmental and economic benefits compared to animal-derived meats. The framework is technologically agnostic and can be used to evaluate meat alternatives of all types. The output of the framework enables a data-driven comparison to animal-derived meat and/or other alternative meats, allowing a range of stakeholders (e.g., food startups, investors, government) to assess technological readiness, competitive advantage, and impact potential. This framework can assist this nascent industry as it moves towards standardizing approaches to evaluating the quality, safety and proposed benefits of meat alternatives.
The role of secondary structures of peptide polymers on antimicrobial efficacy and antibiotic potentiation
Authors: Barman Swagatam , Abiodun Alimi , Hossain Md Waliullah , Parris Adam , Chandrasseril Aiswarya Banshidhar , Older Ethan A. , Li Jie , Decho Alan W. , Tang Chuanbing
Published: November 2024

The rise of antibiotic resistance, biofilm formation, and dormant bacterial populations poses serious global health threats. Synthetic antimicrobial peptide (AMP) mimics offer promising alternatives, though the impact of secondary structures in polymeric AMP mimics on antimicrobial efficacy is underexplored. This study investigates chirality-controlled α-peptide polymers (D-PP and DL-PP), synthesized via ring-opening polymerization of allylglycineN-carboxy anhydrides and post-polymerization modification through thiol-ene click chemistry. D-PP adopts a stable helical structure under biomimetic conditions, whereas DL-PP remains random. This helical structure enhanced D-PP’s antibacterial and antibiotic potentiation activities, amplifying antibiotic efficacy by 2- to 256-fold across various classes—including tetracyclines, ansamycins, fusidanes, macrolides, cephalosporins, and monobactams—against multidrug-resistant Gram-negative pathogens, while maintaining low hemolytic activity and high protease stability. Mechanistic investigations revealed that D-PP exhibited greater membrane interaction. D-PP and antibiotic combinations eradicated dormant bacterial populations and disrupted biofilms with minimal antimicrobial resistance development. This study paves the way for the rational design of polypeptide-based antimicrobial agents, harnessing chirality and secondary structural features to enhance the efficacy of synthetic antimicrobial peptide mimics.
Engineered mitochondrial A-to-G editors with enhanced efficiency and targeting scope
Authors: Chen Liang , Hong Mengjia , Luan Changming , Yuan Meng , Wang Yiming , Guo Xinyuan , Fang Yue , Huang Hao , Dong Xiaohua , Gao Hongyi , Zhang Dan , Chen Xi , Meng Dihao , Huang Molin , Yi Zongyi , Liu Mingyao , Gao Liangcai , Song Gaojie , Zhou Xiaoming , Wei Wensheng , Li Dali
Published: November 2024

Mitochondrial base editing is a powerful technology, but the current A-to-G mitochondrial DNA (mtDNA) base editors are reluctant to achieve high efficiency, which is critical for mtDNA engineering. Through laboratory evolution, TadA-8e variants were discovered with substantially increased activity and expanded targeting compatibility, especially for previously unfavorite sequence contexts, when applied to both nuclear and mitochondrial ABEs. Further engineering of the mtDNA editors (eTd-mtABEs) dramatically reduced both DNA and RNA off-targeting effects and enhanced strand-selective A-to-G editing with substitution of DddA to DNA nickases. Moreover, the eTd-mtABEs induced up to 145-fold editing frequencies compared to previous mtDNA adenine base editors in rat cells, and installed targeted mutations in all injected rat embryos with up to 74% efficiency in founders, resulting generation of SNHL and Leigh syndrome models with severe defects. It suggests that eTd-mtABEs are promising mtDNA engineering technology for basic research and for translational studies.

Highlights

Engineered TadA variants enhance nuclear and mitochondrial ABE activity in all sequence contexts.

Additional mutations in eTd-mtABEs further minimize both DNA and RNA off-targeting effects.

Engineered TadA variants are compatible to DNA nickase assisted strand-selective mtDNA editing.

eTd-mtABEs enable highly efficient generation of rat mtDNA disease models with severe phenotypes.
Golgins support extracellular matrix secretion by collectively maintaining the Golgi structure-function relationship
Authors: Thompson George , Hoyle Anna , Lewis Philip A. , Esther Prada-Sanchez M. , Swift Joe , Heesom Kate , Lowe Martin , Stephens David , Stevenson Nicola
Published: November 2024

The secretion of extracellular matrix (ECM) proteins is vital to the maintenance of tissue health. One major control point of this process is the Golgi apparatus, whose dysfunction causes numerous connective tissue disorders. Golgi function is tightly linked to its structure, which is maintained by the cytoskeleton and Golgi organising proteins. We sought to investigate the role of two of these organising proteins, the golgins GMAP210 and Golgin-160, in ECM secretion. We found that loss of either protein had distinct impacts on Golgi organisation. GMAP210 loss caused cisternal fragmentation and dilation, alongside the accumulation of tubulovesicular structures. Meanwhile, Golgin-160 knockout lead to Golgi fragmentation and vesicle build-up. Nonetheless, loss of each protein had a similar impact on ECM secretion and glycosaminoglycan synthesis. We therefore propose that golgins are collectively required to create the correct physical-chemical space to support efficient ECM protein secretion and modification. This is the first time that Golgin-160 has been shown to be required for ECM secretion.

In this study, Thompsonet aldemonstrate that two cis-Golgi golgins, GMAP210 and Golgin-160, have distinct, non-redundant roles in maintaining Golgi organisation and that both are required to support the efficient secretion, assembly, and modification of extracellular matrix proteins.
Sensitivity to Vγ9Vδ2TCR T cells is imprinted after single mutations during early oncogenesis
Authors: Cleven Astrid , Meringa Angelo D. , Brazda Peter , Fasci Domenico , Koorman Thijs , Aarts Tineke , Johanna Inez , Beringer Dennis X , Hernandez-Lopez Patricia , Heijhuurs Sabine , Mizutani Tomohiro , Lim Sangho , Huismans Maarten , Bernink Jochem , Diaz David Vargas , Wu Wei , Jose Esther San , Schipper Jelle , Tsakirakis Nikos , Hoorens van Heyningen Lauren , Nouwens Annick , Gatti Lucrezia , Straetemans Trudy , Snippert Hugo , Roodhart Jeanine , Derksen Patrick W.B. , Drost Jarno , Altelaar Maarten , Heck Albert J.R. , Clevers Hans , Kuball Juergen , Sebestyen Zsolt
Published: November 2024

Vγ9Vδ2T cells have the unique ability to recognize a broad range of malignant transformed cells. The tumor targeting event involving BTN2A1 and BTN3A1 dimers on the tumor cell surface is critical, leading to full activation of the TCR. Although the molecular mechanisms governing TCR engagement and T cell activation are well-characterized, the role of Vγ9Vδ2 T cells in cancer immune surveillance remains to be fully elucidated, particularly the mechanisms that enable these cells to discriminate between healthy and malignant cells at an early stage of malignant transformation. We employed two independent, genetically engineered step-wise mutagenesis models of human colorectal and breast cancer that mimic the transformation steps leading to tumor formation. We demonstrate that various single oncogenic mutations introduced into healthy organoids or cells, are sufficient to upregulate surface expressed BTN2A1 and enable Vγ9Vδ2 TCR binding to tumor cells. However, full activation of T cells through a Vγ9Vδ2TCR required additional subsequent phosphorylation of juxtamembrane (JTM) amino acids of BTN3A1, leading to the activating heterodimerization of BTN2A1 and 3A1. Using a protein interactome mapping pipeline, we identified PHLDB2, SYNJ2 and CARMIL1 as key players in controlling these delicate dual surface dynamics of BTN2A1 and 3A1 during early transformation. This mode of action allowed Vγ9Vδ2TCR T cells to control tumorsin vitroand in vivo, emphasizing the crucial role of these molecules from early mutagenesis, to advanced cancer stages, and highlighting the therapeutic potential of a Vγ9Vδ2TCR.
Quiescent neural stem cells transiently become ‘neurons’ to coordinate reactivation
Authors: Gherghina Laura-Yvonne , Tang Jocelyn L.Y. , Brand Andrea H.
Published: November 2024

Reactivation of quiescent neural stem cells (qNSCs) is a coordinated process that generates new neurons and glia. Here, we show that during development reactivation follows a hierarchical sequence, whereby anteriorly located qNSCs control the reactivation of more posterior qNSCs in the central nervous system (CNS). Electrical communication between qNSCs and neurons enables this precise spatial and temporal control of reactivation throughout the entire span of the CNS. Using single-cell RNA-seq we discovered that, remarkably, qNSCs switch on a host of neuronal genes while maintaining a stem cell identity. This transient mixed identity is specific to qNSCs, as neuronal genes are turned off after stem cells resume proliferation. Our results uncover long-range communication between qNSCs to coordinate reactivation, enabled by a transient ‘stem cell-neuron’ fate.
Revealing complex relationships between sex, individuals’ phenotype variation and social signalling in foraging strategies
Authors: Leitão Ana V. , Funghi Caterina , Mota Paulo G.
Published: November 2024

In social living animals, individuals typically use two main strategies to find food: either by exploiting social information (scrounger) or relying on personal knowledge (producer). These tactics are often linked to different life-history strategies. Access to foraging patches in hierarchical social groups may constrain the use of the producer-scrounger strategies, selecting for colour ornaments to act as status badges. In sexual dimorphic species, males and females may exhibit distinct life-history strategies, with females often lacking a clear badge-of-status and occupying subordinate roles. Here we address the question of how differences in social signalling and personality influence foraging behaviour and the individual’s decision to play producer or scrounger, using males and females European serins,Serinus serinus.Specifically, we analysed how individual traits such as sex, plumage colouration, and boldness, relate with foraging strategies in both solitary and social contexts. In solitary contexts, colourful individuals, regardless of sex, were faster to find food, as were bolder males and shyer females. In social contexts, less colourful males and more colourful females adopted the producer strategy, while males’ foraging ability was influenced by their companion’s boldness. Our results reveal that personality and colour differences are linked to social foraging tactics in serins in a sex-dependent manner, highlighting the adaptive value of individual traits in both sexes, and their potential implications for social evolution.
Alcohol Withdrawal Alters the Inhibitory Landscape of the Prelimbic Cortex in an Interneuron- and Sex-specific Manner
Authors: Quadir Sema G , Danyal Zaidi S. , Cone Meredith G , Patel Sachin
Published: November 2024

Alcohol use disorder (AUD) is highly prevalent and associated with substantial morbidity and high mortality among substance use disorders. While there are currently three FDA-approved medications for treating AUDs, none specifically target the withdrawal/negative affect stage of AUD, underscoring the need to understand the underlying neurobiology during this critical stage of the addiction cycle. One key region involved in alcohol withdrawal and negative affect is the prelimbic cortex, a subregion of the medial prefrontal cortex. While previous studies have examined alcohol-related adaptations in prefrontal cortical principal glutamatergic neurons, here we used male and female PV:Ai14, SOM:Ai14 and VIP:Ai14 mice to examine synaptic adaptations in all three major classes of prelimbic cortex interneurons following 72 hour withdrawal from a continuous access to two bottle choice model of EtOH drinking in male and female mice. We found that alcohol withdrawal increased excitability of prelimbic PV interneurons in males, but decreased excitability in prelimbic VIP interneurons in females. Additionally, alcohol withdrawal reduced GABA release onto PV interneurons in males while increasing glutamate release onto VIP interneurons in females. In SOM interneurons, alcohol withdrawal had no effect on excitability, but decreased glutamate release onto SOM interneurons in males. Together, our studies identified sex-specific alcohol withdrawal-induced synaptic plasticity in three different types of interneurons and could provide insight into the cellular substrates of negative affective states associated with alcohol withdrawal.
Mating and ecdysone signaling modify growth, metabolism, and digestive efficiency in the femaleDrosophilagut
Authors: Kandelouei Tahmineh , Houghton Madeline E. , Lewis Mitchell R. , Keller Caroline C. , Marchetti Marco , Kang Xiaoyu , Edgar Bruce A.
Published: November 2024

Adaptive changes in organ size and physiology occur in most adult animals, but how these changes are regulated is not well understood. Previous research found that mating inDrosophilafemales drives not only increases in gut size and stem cell proliferation but also alters feeding behavior, intestinal gene expression, and whole-body lipid storage, suggesting altered gut metabolism. Here, we show that mating dramatically alters female gut metabolism and digestive function. In addition to promoting a preference for a high-protein diet, mating also altered levels of TCA cycle intermediates and fatty acids in the gut, increased total gut lipids and protein, reduced relative carbohydrate levels, and enhanced the efficiency of protein digestion relative to carbohydrate digestion. The expression of genes that mediate each of these metabolic processes was similarly altered. In addition, we noted the mating-dependent downregulation of oxidative stress response and autophagy genes. Mating-dependent increases in ecdysone signaling played an important role in re-programming many, but not all, of these changes in the female gut. This study contributes to our understanding of how steroid signaling alters gut physiology to adapt to the demands of reproduction.
Medication and pharmacogenomic effects on cross-sectional symptom severity and cognitive ability in schizophrenia
Authors: Lock Siobhan K. , Kappel Djenifer B. , Owen Michael J. , Walters James T.R. , O’Donovan Michael C. , Pardiñas Antonio F. , Legge Sophie E.
Published: November 2024

Background

People with schizophrenia differ in the type and severity of symptoms experienced, as well as their response to medication. A better understanding of the factors that influence this heterogeneity is necessary for the development of individualised patient care. Here, we sought to investigate the relationships between phenotypic severity and both medication and pharmacogenomic variables in a cross-sectional sample of people with schizophrenia or schizoaffective disorder depressed type.

Methods

Confirmatory factor analysis derived five dimensions relating to current symptoms (positive symptoms, negative symptoms of diminished expressivity, negative symptoms of reduced motivation and pleasure, depression and suicide) and cognitive ability in participants prescribed with antipsychotic medication. Linear models were fit to test for associations between medication and pharmacogenomic variables with dimension scores in the full sample (N = 585), and in a sub-sample of participants prescribed clozapine (N = 215).

Outcomes

Lower cognitive ability was associated with higher chlorpromazine-equivalent daily antipsychotic dose and with the prescription of clozapine and anticholinergic medication. We also found associations between pharmacogenomics-inferred cytochrome P450 (CYP) enzyme activity and symptom dimensions. Increased genotype-predicted CYP2C19 and CYP3A5 activity were associated with reduced severity of positive and negative symptoms, respectively. Faster predicted CYP1A2 activity was associated with higher cognitive dimension scores in people taking clozapine.

Interpretation

Our results confirm the importance of taking account of medication history (and particularly antipsychotic type and dose) in assessing potential causes of cognitive impairment or poor functioning in patients with schizophrenia. We also highlight the potential for pharmacogenomic variation to be a useful tool to help guide drug prescription, although these findings require further validation.
Model-based evaluation of the impact of a potential HIV cure on HIV transmission dynamics
Authors: De Bellis Alfredo , Willemsen Myrthe , Guzzetta Giorgio , van Sighem Ard , Romijnders Kim , Reiss Peter , Schim van der Loeff Maarten F. , van de Wijgert Janneke HHM , Nijhuis Monique , Kretzschmar Mirjam E , Rozhnova Ganna E
Published: November 2024

Biomedical research and clinical trials for curative HIV interventions are advancing rapidly. Understanding the potential impact of an HIV cure on transmission dynamics is key for its successful implementation at the population level. Using a mathematical model calibrated to the HIV epidemic among men who have sex with men (MSM) in the Netherlands as a case study, we tested the common hypothesis that an effective cure will contribute to HIV control and help end the epidemic. Guided by the target product profile (TPP) for an HIV cure, we evaluated the impact of two cure scenarios: (i) HIV remission, which entails suppression of the virus in the absence of ongoing antiretroviral treatment (ART) but carries a risk of viral rebound, and (ii) HIV eradication, which aims for complete removal of the virus. We found that either sustained HIV remission (with no risk of rebound) or HIV eradication could consistently reduce cumulative HIV incidence among MSM in the Netherlands by up to 50% for optimum TPP within eight years, relative to the baseline scenario without a cure. In contrast, transient HIV remission with a risk of rebound may drastically increase cumulative HIV incidence and disrupt the progress made toward HIV control under the current standard of care and prevention. These findings underscore the importance of the characteristics of curative HIV interventions in maximizing their benefits for public health and highlight the need to align HIV cure research with public health objectives to end the HIV epidemic.
Understanding the influence of leadership, organisation, and policy on delivering an integrated child health and social care service in community settings: A qualitative exploration using the SELFIE framework
Authors: Litchfield I , Harper L , Abbas S , Dutton F , Wolhuter C , Bird C
Published: November 2024

Introduction

It’s understood in the UK that integrated care is well-placed to address the prevalence of chronic conditions, obesity, and mental ill health in children and young people (CYP) living in minoritized and economically-marginalised communities in high-income countries. The Sparkbrook Childrens’ Zone is an example of a place-based integrated health and social care service situated in a super-diverse community in a large post-industrial city, developed to support children and young people. To realise its potential, it’s important to understand the organizational and infrastructural requirements of a service combining clinical and non-clinical staff from a range of organisations and backgrounds. This will improve the current service offer and inform the design and delivery of similar initiatives.

Materials and Methods,

We conducted a qualitative exploration of the experiences of staff delivering the service and used a directed content analysis to populate and present the results within the Sustainable integrated chronic care model for multi-morbidity: delivery, financing, and performance (SELFIE) framework. The analysis presented here focuses on the domains of Leadership and Governance, Workforce, Financing, and Information and Research.

Results

A total of 14 staff were interviewed including clinicians from primary and secondary care, social care providers, local voluntary groups, and school-based family mentors. Staff described the gap between integration at system level and the absence of process and support to deliver a unified health and social care service in real-world environments. The benefits of supportive and accessible leadership, and an open, learning environment were described, as was the trust developed through meaningful consultations with local communities. The lack of administrative support was noticeable, particularly when managing a workforce drawn from multiple organisations, as was the lack of secure funding and the need for reliable long-term evidence to inform decisions on design and funding.

Conclusions

Despite decades of structural reform aimed at integrating the health and social care system in the UK, there was a surprising lack of system-level practical support for delivering a place-based integrated health and care service. The balance remained to be struck between the need to demonstrate benefits for short term funding cycles and the reliability of evidence being gathered from a complex and evolving service.
Profiling Epigenetic Aging at Cell-Type Resolution Through Long-Read Sequencing
Authors: Eames Alec , Moqri Mahdi , Poganik Jesse R. , Gladyshev Vadim N.
Published: November 2024

DNA methylation can give rise to robust biomarkers of aging, yet most studies profile it at the bulk tissue level, which masks cell type-specific alterations that may follow distinct aging trajectories. Long-read sequencing technology enables methylation profiling of extended DNA fragments, which allows mapping to their cell type of origin. In this study, we introduce a framework for evaluating cell type-specific aging using long-read sequencing data, without the need for cell sorting. Leveraging cell type-specific methylation patterns, we map long-read fragments to individual cell types and generate cell type-specific methylation profiles, which are used as input to a newly developed probabilistic aging model, LongReadAge, capable of predicting epigenetic age at the cell-type level. We apply LongReadAge to track aging of myeloid cells and lymphocytes from bulk leukocyte data as well as circulating cell-free DNA, demonstrating robust performance in predicting age despite limited shared features across samples. This approach provides a novel method for profiling the dynamics of epigenetic aging at cell-type resolution.
Histone H3 N-terminal recognition by the PHD finger of PHRF1 is required for proper DNA damage response
Authors: Jain Kanishk , Tchara Pata-Eting Kougnassoukou , Mengistalem Amanuel B. , Holland Aidan P. , Bowman Christopher N. , Marunde Matthew R. , Popova Irina K. , Cooke Spencer W. , Krajewski Krzysztof , Keogh Michael-Christopher , Lambert Jean-Philippe , Strahl Brian D.
Published: November 2024

Plant homeodomain (PHD) fingers are critical effectors of histone post-translational modifications (PTMs), acting as regulators of gene expression and genome integrity, and frequently presenting in human disease. While most PHD fingers recognize unmodified and methylated states of histone H3 lysine 4 (H3K4), the specific functions of many of the over 100 PHD finger-containing proteins in humans remain poorly understood, despite their significant implications in disease processes. In this study, we undertook a comprehensive analysis of one such poorly characterized PHD finger-containing protein, PHRF1. Using biochemical, molecular, and cellular approaches, we show that PHRF1 robustly binds to histone H3, specifically at its N-terminal region. Through RNA-seq and proteomic analyses, we also find that PHRF1 is intricately involved in transcriptional and RNA splicing regulation and plays a significant role in DNA damage response (DDR). Crucially, mutagenesis of proline 221 to leucine (P221L) in the PHD finger of PHRF1 abolishes histone interaction and fails to rescue defective DDR. These findings underscore the importance of PHRF1-H3 interaction in maintaining genome integrity and provide insight into how PHD fingers contribute to chromatin biology.
The nucleocapsid (N) proteins of different human coronaviruses demonstrate a variable capacity to induce the formation of cytoplasmic condensates
Authors: Tikhomirova Maria A. , Kuzmenko Oleg L. , Arifulin Eugene A. , Shirokova Olesya M. , Musinova Yana R. , Sheval Eugene V.
Published: November 2024

To date, seven human coronaviruses (HCoVs) have been identified. Four of these viruses typically manifest as a mild respiratory disease, whereas the remaining three can cause severe conditions that often result in death. The reasons for these differences remain poorly understood, but may be related to the properties of individual viral proteins. The nucleocapsid (N) protein plays a crucial role in the packaging of viral genomic RNA and the modification of host cells during infection, in part due to its capacity to form dynamic biological condensates via liquid-liquid phase separation (LLPS). In this study, we investigated the capacity of N proteins derived from all HCoVs to form condensates when transiently expressed in cultured human cells. A fraction of the transfected cells were observed to contain cytoplasmic granules in which the most of the N proteins were accumulated. Notably, the N proteins of SARS-CoV and SARS-CoV-2 showed a significantly reduced tendency to form cytoplasmic condensates. The condensate formation was not a consequence of overexpression of N proteins, as is typical for LLPS-inducing proteins. These condensates contained components of stress granules (SGs), indicating that the expression of N proteins caused the formation of SGs, which integrate N proteins. Thus, the N proteins of two closely related viruses, SARS-CoV and SARS-CoV-2, have the capacity to antagonize SG induction and/or assembly, in contrast to all other known HCoVs.