bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic off-resonance correction improves functional image analysis in fMRI of awake behaving non-human primates
Authors: Shahdloo Mo , Khalighinejad Nima , Priestley Luke , Rushworth Matthew , Chiew Mark
Published: October 2023

Use of functional MRI in awake non-human primate (NHPs) has recently increased. Scanning animals while awake makes data collection possible in the absence of anaesthetic modulation and with an extended range of possible experimental designs. Robust awake NHP imaging however is challenging due to the strong artifacts caused by time-varying off-resonance changes introduced by the animal’s body motion. Recently, an image reconstruction technique has been proposed to estimate these off-resonance changes using the navigator data that is typically collected during fMRI scans to correct the data and compensate for the changes. In this study, we sought to thoroughly investigate the effect of this correction on the brain activation estimates using extended awake NHP data. Our results show significant improvements in image fidelity using our proposed correction strategy, as well as greatly enhanced and more reliable activation estimates in GLM analyses.
Open-source LED lamp for the LI-6800 photosynthesis system
Authors: Vélez Ramírez Aarón I. , Moreno Juan de Dios , Pérez-Guerrero Uriel G. , Juarez Antonio M. , Castillo-Arriaga Hector , Vázquez-Medrano Josefina , Hernández-Morales Ilane
Published: October 2023

Premise

Controlling light flux density during carbon dioxide assimilation measurements is essential in photosynthesis research. Commercial lamps are expensive and are based on monochromatic light emitting diodes (LEDs), which deviate significantly in their spectral distribution compared to sunlight.

Methods and Results

Using a LED emitting white light with a color temperature similar to sunlight, we developed a cost-effective lamp compatible with the LI-6800 photosynthesis measuring system. When coupled with customized software, the lamp can be controlled via the LI-6800 console by a user or Python scripts. Testing and calibration show that the lamp meets the quality needed to estimate photosynthesis parameters.

Conclusions

The lamp can be built using a basic electronics lab and a 3D printer. Calibration instructions are supplied and only require equipment commonly available at plant science laboratories. The lamp is a cost-effective alternative to perform photosynthesis research coupled with the popular LI-6800 photosynthesis measuring system.
BayesKAT: Bayesian Optimal Kernel-based Test for genetic association studies reveals joint genetic effects in complex diseases
Authors: Das Adhikari Sikta , Cui Yuehua , Wang Jianrong
Published: October 2023

GWAS methods have identified individual SNPs significantly associated with specific phenotypes. Nonetheless, many complex diseases are polygenic and are controlled by multiple genetic variants that are usually non-linearly dependent. These genetic variants are marginally less effective and remain undetected in GWAS analysis. Kernel-based tests (KBT), which evaluate the joint effect of a group of genetic variants, are therefore critical for complex disease analysis. However, choosing different kernel functions in KBT can significantly influence the type I error control and power, and selecting the optimal kernel remains a statistically challenging task. A few existing methods suffer from inflated type 1 errors, limited scalability, inferior power, or issues of ambiguous conclusions. Here, we present a new Bayesian framework, BayesKAT(https://github.com/wangjr03/BayesKAT), which overcomes these kernel specification issues by selecting the optimal composite kernel adaptively from the data while testing genetic associations simultaneously. Furthermore, BayesKAT implements a scalable computational strategy to boost its applicability, especially for high-dimensional cases where other methods become less effective. Based on a series of performance comparisons using both simulated and real large-scale genetics data, BayesKAT outperforms the available methods in detecting complex group-level associations and controlling type I errors simultaneously. Applied on a variety of groups of functionally related genetic variants based on biological pathways, co-expression gene modules, and protein complexes, BayesKAT deciphers the complex genetic basis and provides mechanistic insights into human diseases.
De novogeneration of T-cell receptors with desired epitope-binding property by leveraging a pre-trained large language model
Authors: Yang Jiannan , He Bing , Zhao Yu , Jiang Feng , Wang Zhonghuang , Guo Yixin , Xu Zhimeng , Yuan Bo , Song Jiangning , Zhang Qingpeng , Yao Jianhua
Published: October 2023

Generating T-cell receptors (TCRs) with desired epitope-binding properties is a fundamental step in the development of immunotherapies, yet heavily relies on laborious and expensive wet experiments. Recent advancements in generative artificial intelligence have demonstrated promising power in protein design and engineering. In this regard, we propose a large language model, termed Epitope-Receptor-Transformer (ERTransformer), for thede novogeneration of TCRs with the desired epitope-binding property. ERTransformer is built on EpitopeBERT and ReceptorBERT, which are trained using 1.9 million epitope sequences and 33.1 million TCR sequences, respectively. To demonstrate the model capability, we generate 1000 TCRs for each of the five epitopes with known natural TCRs. The artificial TCRs exhibit low sequence identity (average Bit-score 27.64 with a standard deviation of 1.50) but high biological function similarity (average BLOSUM62 score 32.32 with a standard deviation of 12.01) to natural TCRs. Furthermore, the artificial TCRs are not very structurally identical to natural ones (average RMSD 2.84 Å with a standard deviation of 1.21 Å) but exhibit a comparable binding affinity towards the corresponding epitopes. Our work highlights the tremendous potential of applying ERTransformer to generate novel TCRs with desired epitope-binding ability.
Random Walk with Restart on multilayer networks: from node prioritisation to supervised link prediction and beyond
Authors: Baptista Anthony , Brière Galadriel , Baudot Anaïs
Published: October 2023

Background

Biological networks have proven invaluable ability for representing biological knowledge. Multilayer networks, which gather different types of nodes and edges in multiplex, heterogeneous and bipartite networks, provide a natural way to integrate diverse and multi-scale data sources into a common framework. Recently, we developed MultiXrank, a Random Walk with Restart algorithm able to explore such multilayer networks. MultiXrank outputs scores reflecting the proximity between an initial set of seed node(s) and all the other nodes in the multilayer network. We illustrate here the versatility of bioinformatics tasks that can be performed using MultiXrank.

Results

We first show that MultiXrank can be used to prioritise genes and drugs of interest by exploring multilayer networks containing interactions between genes, drugs, and diseases. In a second study, we illustrate how MultiXrank scores can also be used in a supervised strategy to train a binary classifier to predict gene-disease associations. The classifier performance are validated using outdated and novel gene-disease association for training and evaluation, respectively. Finally, we show that MultiXrank scores can be used to compute diffusion profiles and use them as disease signatures. We computed the diffusion profiles of more than 100 immune diseases using a multilayer network that includes cell-type specific genomic information. The clustering of the immune disease diffusion profiles reveals shared shared phenotypic characteristics.

Conclusion

Overall, we illustrate here diverse applications of MultiXrank to showcase its versatility. We expect that this can lead to further and broader bioinformatics applications.
The IRE1-bZIP60 branch of Unfolded Protein Response is required forArabidopsisimmune response toBotrytis cinerea
Authors: Cécile Blanchard , Sébastien Aimé , Amélie Ducloy , Siham Hichami , Marianne² Azzopardi , Jean-Luc Cacas , Olivier Lamotte
Published: October 2023

The Unfolded Protein Response (UPR) is a retrograde signalling pathway which is activated when endoplasmic reticulum (ER) proteostasis is disturbed. Here, we have investigated by reverse genetics the contribution of such pathway inArabidopsis thalianaresponse to two necrotrophic fungi of agricultural importance,Botrytis cinerea which is responsible for the development of grey mold disease, andAlternaria brassicicolawhich triggers black spot disease. We found that the branch of UPR dependent on the INOSITOL-REQUIRING ENZYME 1 (IRE1) and the transcription factor (TF) bZIP60 is required to restrict foliar necrotic symptoms induced by both fungi. Accordingly, focussing onB. cinerea, we provided evidence for the production of the active bZIP60 form during infection. This activation was accompanied by an increased expression of UPR-responsive genes coding for ER-localized chaperones and co-chaperones that belong to the ER-Quality Control (ER-QC) system. Furthermore, mutants deficient for two ER-QC components were also more susceptible to infection. By contrast, investigating the involvement of CELL DIVISION CYCLE 48 (CDC48) AAA+-ATPAses that assist ER-Associated Degradation (ERAD) pathway for disposal of luminal unfolded proteins, we showed that a series of mutants and transgenics are more resistant to grey mold disease. Seeking for molecular insights into how the ER could shape Arabidopsis immune response toB. cinerea, we quantified the expression of defence gene and cell death markers in singlebzip60and doubleire1mutants. However, none of those genes were mis-regulated in mutant genetic backgrounds, indicating that IRE1-bZIP60 branch of UPR modulates the Arabidopsis response toB. cinereaby a yet-to-be-identified mechanism. Interestingly, we identified the NAC053/NTL4 TF as a potential actor of this unknown mechanism, linking the UPR and proteasome stress regulon.

Author summary

Necrotrophic fungi are one of the most economically significant plant pathogens worldwide, inflicting massive pre- and post-harvest losses on a wide range of fruit and vegetable crops. They adopt a necrotrophic lifestyle, deriving their nutrients predominantly from dead plant tissues to complete their life cycle.Botrytis cinereais the causal agent of grey mold and no plant shows complete resistance towards this pathogen. The use of genetic models such as the plantArabidopsis thalianahas partially enabled the understanding of the immunity mechanisms involved in the plant’s response toB. cinerea. Our work provides new insights into the cellular mechanisms of how plants cope with this pathogen. In this context, by means of a reverse genetic approach, we explored the role of the Unfolded Protein Response (UPR), a cell signalling pathway regulating protein homeostasis within the endoplasmic reticulum (ER) and thus protecting cells from a harmful over-accumulation of aberrant or misfolded proteins.
Allopolyploidization from two dioecious ancestors leads to recurrent evolution of sex chromosomes and reversion to autosomes
Authors: He Li , Wang Yuàn , Wang Yi , Zhang Ren-Gang , Wang Yuán , Hörandl Elvira , Mank Judith E. , Ming Ray
Published: October 2023

Polyploidization presents an unusual challenge for species with sex chromosomes, as it can lead to complex combinations of sex chromosomes that disrupt reproductive development. This is particularly true for allopolyploidization between species with different sex chromosome systems. Here we assemble haplotype-resolved chromosome-level genomes of a female allotetraploid weeping willow (Salix babylonica) and a male diploidSalix dunniiusing Hi-C and PacBio HiFi reads. We use phylogenomics of nuclear and plastid genomes to show that weeping willow arose from crosses between female ancestor from theSalixclade, having XY sex chromosomes on chromosome 7, with a male ancestor from theVetrixclade, having ancestral XY sex chromosomes on chromosome 15. Our analysis reveals that weeping willow has one pair sex chromosomes, ZW on chromosome 15, that derive from the ancestral XY sex chromosomes in theVetrix-clade male ancestor, and the X chromosomes on chromosome 7 from theSalix-clade female ancestor has reverted to an autosome. Taken together, our results point to rapid evolution and reversion of sex chromosomes following allopolyploidization in weeping willow.

Significance Statement

We assembled haplotype-resolved genomes and obtained gap-free sex chromosomes of a female allotetraploid weeping willow (Salix babylonica) and a male diploidSalix dunnii. The weeping willow arose from two dioecious ancestors, that have XY sex chromosomes on chromosome 7 and 15, respectively. The one pair sex chromosomes 15W and 15Z in weeping willow derived from ancestral 15X and 15Y, respectively. Inversions contributed to the evolutions of sex-linked regions (SLRs) of diploid and polyploid willows.
Pathophysiological Significance of Impaired KAT7-Dependent Histone H3K14 Acetylation During Zinc Deficiency
Authors: Fujisawa Takao , Takenaka Satoshi , Maekawa Lila , Kowada Toshiyuki , Matsui Toshitaka , Mizukami Shin , Kato Yugo , Suzuki Michio , Noma Hisashi , Naguro Isao , Ichijo Hidenori
Published: October 2023

Zinc is an indispensable micronutrient for optimal physiological functions, and zinc deficiency has been implicated in the pathogenesis of various human diseases. One potential mechanism underlying such pathogenic effects is the alteration of gene expression caused by zinc deficiency; however, the details of this process remain largely unexplored. Here, we show that during zinc deficiency, the histone acetyltransferase KAT7 loses its enzymatic activity, leading to the attenuated acetylation of histone H3 at Lys14 (H3K14ac) at enhancer regions. Physiologically, the decrease in H3K14ac leads to the upregulation of the expression of ZIP10, a plasma membrane-localized zinc transporter, thereby facilitating the import of extracellular zinc to maintain cellular zinc homeostasis. Moreover, prolonged zinc deficiency in mice induced by a zinc-deficient diet or high-fat diet, accompanied by decreased H3K14ac levels in the liver, upregulated the expression of genes associated with intracellular lipid droplet formation, leading to the accumulation of lipids within liver tissue. Our findings demonstrate that cells respond to zinc deficiency by converting it into an epigenetic signal that drives physiological or pathophysiological biological processes.
A specific innate immune response silences the virulence ofPseudomonas aeruginosain a latent infection model in theDrosophila melanogasterhost
Authors: Chen Jing , Lin Guiying , Ma Kaiyu , Li Zi , Liégeois Samuel , Ferrandon Dominique
Published: October 2023

Microbial pathogenicity often depends on the route of infection. For instance,P. aeruginosaorS. marcescenscause acute systemic infections when low numbers of bacteria are injected intoD. melanogasterflies whereas flies succumb much slower to the continuous ingestion of these pathogens, even though both manage to escape from the gut compartment and reach the hemocoel. Here, we have developed a latentP. aeruginosainfection model by feeding flies on the bacteria for a short period. The bacteria stably colonize internal tissues yet hardly cause any damage since latently-infected flies live almost as long as noninfected control flies. The apparently dormant bacteria display particular characteristics in terms of bacterial colony morphology, composition of the outer cell wall, and motility. The virulence of these bacteria can however be reactivated upon wounding the host. We show that melanization but not the cellular or the systemic humoral response is the predominant host defense that establishes latency and may coerce the bacteria to a dormant state. In addition, the lasting activation of the melanization responses in latently-infected flies provides a degree of protection to the host against a secondary fungal infection. Latent infections by an ingested pathogen protects against a variety of homologous or heterologous systemic secondary infectious challenges, a situation previously described for the endosymbiotic Wolbachia bacteria, a guard against viral infections.
Mathematical Preconditions for Existence of the Stock-Recruitment Function
Authors: Schaarschmidt Ute , Frank Anna S. J. , Subbey Sam
Published: October 2023

For marine species, several life stages link parents to their progeny (recruits), through a process referred to as recruitment. Current stock recruitment (SR) functions encapsulate this multi-stage relationship in a closed-form mathematical expression, which explicitly relates the biomass of parents, to the number of recruits. This functional relationship (between parents and recruits) is required for management purposes. No study, however, has investigated the conditions that validate the existence of the SR functions when all life history stages are incorporated into a model.

In this study, we represent the processes leading to recruitment by a stage-and age-structured discrete-time population dynamic model. We show that in general, a SR function does not correctly represent the parent-progeny relationship. A valid relationship must incorporate information across the complete life cycle over several time periods. For populations with simple life cycle history, a functional relationship may result, which is not necessarily consistent with current SR functions.

We present a brief discussion of the relevance of our results to effective management of fisheries.
Low-invasive sampling method for taxonomic for the identification of archaeological and paleontological bones by proteomics of their collagens
Authors: Fabrizi Isabelle , Flament Stéphanie , Delhon Claire , Gourichon Lionel , Vuillien Manon , Oueslati Tarek , Auguste Patrick , Rolando Christian , Bray Fabrice
Published: October 2023

Collagen from paleontological bones is an important organic material for isotopic measurement, radiocarbon and paleoproteomic analyzes, to provide information on diet, dating and taxonomy. Current paleoproteomics methods are destructive and require from a few milligrams to several tenths of milligrams of bone for analysis. In many cultures, bones are raw materials for artefact which are conserved in museum which hampers to damage these precious objects during sampling. Here, we describe a low-invasive sampling method that identifies collagen, taxonomy and post-translational modifications from Holocene and Upper Pleistocene bones dated to 130,000 and 150 BC using dermatological skin tape-discs for sampling. The sampled bone micro-powders were digested following our highly optimized eFASP protocol, then analyzed by MALDI FTICR MS and LC-MS/MS for identifying the genus taxa of the bones. We show that this low-invasive sampling does not deteriorate the bones and achieves results similar to those obtained by more destructive sampling. Moreover, this sampling method can be performed at archaeological sites or in museums.
Detecting the genetic variants associated with key culinary traits inDioscorea alata
Authors: Dossa Komivi , Houngbo Mahugnon Ezékiel , Lechaudel Mathieu , Malédon Erick , Zoclanclounon Yedomon Ange Bovys , Irep Jean-Luc , Nasir Mian Faisal , Chair Hâna , Cornet Denis
Published: October 2023

Quality attributes play a pivotal role in determining consumers’ acceptability and market value of food crops.Dioscorea alatais a major yam species for food security in tropical areas, but our understanding of the genetic factors underlying tuber culinary traits is limited. This study aimed at elucidating the genetic basis of key culinary attributes, including dry matter content, cooking time, boiled yam hardness, and moldability, through genome-wide association studies (GWAS). Phenotypic assessments revealed notable variations among theD. alatagenotypes across two locations as well as significant correlations among the quality traits. The GWAS identified 25 significant associations distributed across 14 chromosomes. Allele segregation analysis of the identified loci highlighted favorable alleles associated with desired traits, such as reduced cooking time, increased dry matter content, enhanced hardness, and good moldability. Within the set of 42 putative candidate genes, we identified specific genes differentially expressed in tubers of distinct genotypes with contrasting quality attributes. Furthermore, we conducted a comparative analysis with previously reported quantitative trait loci for dry matter content and showed that multiple genomic regions govern this trait inD. alata. Our study offers valuable insights into the links between these key culinary traits and the underlying genetic basis inD. alata. These findings have practical implications for breeding programs aimed at enhancing the quality attributes of greater yam.
T-cell commitment inheritance – an agent-based multi-scale model
Authors: Andersson Emil , Rothenberg Ellen V. , Peterson Carsten , Olariu Victor
Published: October 2023

T-cell development provides an excellent model system for studying lineage commitment from a multipotent progenitor. The intrathymic development process has been thoroughly studied. The molecular circuitry controlling it has been dissected and the necessary steps like programmed shut off of progenitor genes and T-cell genes upregulation have been revealed. However, the exact timing between decision-making and commitment stage remains unexplored. To this end, we implemented an agent-based multi-scale model to investigate inheritance in early T-cell development. Treating each cell as an agent provides a powerful tool as it tracks each individual cell of a simulated T-cell colony, enabling the construction of lineage trees. Based on the lineage trees, we introduce the concept of the last common ancestors (LCA) of committed cells and analyse their relations, both at single-cell level and population level. In addition to simulating wild-type development, we also conduct knockdown analysis. Our simulations showed that the commitment is a three-step process over several cell generations where a cell is first prepared by a transcriptional switch. This is followed by the loss of the Bcl11b-opposing function two to three generations later which is when the decision to commit is taken. Finally, after another one to two generations, the cell becomes committed by transitioning to the DN2b state. Our results showed that there is inheritance in the commitment mechanism.
Deciphering circulating tumor cells binding in a microfluidic system thanks to a parameterized mathematical model
Authors: Ciavolella Giorgia , Granet Julien , Goetz Jacky G. , Osmani Naël , Etchegaray Christèle , Collin Annabelle
Published: October 2023

The spread of metastases is a crucial process in which some questions remain unanswered. In this work, we focus on tumor cells circulating in the bloodstream, the so-called Circulating Tumor Cells (CTCs). Our aim is to characterize their trajectories under the influence of hemodynamic and adhesion forces. We focus on already availablein vitromeasurements performed with a microfluidic device corresponding to the trajectories of CTCs – without or with different protein depletions – interacting with an endothelial layer. A key difficulty is the weak knowledge of the fluid velocity that has to be reconstructed. Our strategy combines a differential equation model – a Poiseuille model for the fluid velocity and an ODE system for the cell adhesion model – and a robust and well-designed calibration procedure. The parameterized model quantifies the strong influence of fluid velocity on adhesion and confirms the expected role of several proteins in the deceleration of CTCs. Finally, it enables the generation of synthetic cells, even for unobserved experimental conditions, opening the way to a digital twin for flowing cells with adhesion.
Genetic deficiency of ribosomal rescue factor HBS1L causes retinal dystrophy associated with Pelota and EDF1 depletion
Authors: Luo Shiyu , Alwattar Bilal , Li Qifei , Bora Kiran , Blomfield Alexandra K. , Lin Jasmine , Fulton Anne , Chen Jing , Agrawal Pankaj B.
Published: October 2023

Inherited retinal diseases (IRDs) encompass a genetically diverse group of conditions in which mutations in genes critical to retinal function lead to progressive loss of photoreceptor cells and subsequent visual impairment. A handful of ribosome-associated genes have been implicated in retinal disorders alongside neurological phenotypes. This study focuses on theHBS1Lgene, encoding HBS1 Like Translational GTPase which has been recognized as a critical ribosomal rescue factor. Previously, we have reported a female child carrying biallelicHBS1Lmutations, manifesting growth restriction, developmental delay, and hypotonia. In this study, we describe her ophthalmologic findings, compare them with theHbs1ltm1a/tm1ahypomorph mouse model, and evaluate the underlying microscopic and molecular perturbations. The patient was noted to have impaired visual function observed by electroretinogram (ERG), with dampened amplitudes of a- and b-waves in both rod- and cone-mediated responses.Hbs1ltm1a/tm1amice exhibited profound retinal thinning of the entire retina, specifically of the outer retinal photoreceptor layer, detected using in vivo imaging of optical coherence tomography (OCT) and retinal cross sections. TUNEL assay revealed retinal degeneration due to extensive photoreceptor cell apoptosis. Loss of HBS1L resulted in comprehensive proteomic alterations in mass spectrometry analysis, with169 proteins increased and 480 proteins decreased including many critical IRD-related proteins. GO biological process and GSEA analyses reveal that these downregulated proteins are primarily involved in photoreceptor cell development, cilium assembly, phototransduction, and aerobic respiration. Furthermore, apart from the diminished level of PELO, a known partner protein, HBS1L depletion was accompanied by reduction in translation machinery associated 7 homolog (Tma7), and Endothelial differentiation-related factor 1(Edf1) proteins, the latter of which coordinates cellular responses to ribosome collisions. This novel connection between HBS1L and ribosome collision sensor (EDF1) further highlights the intricate mechanisms underpinning ribosomal rescue and quality control that are essential to maintain homeostasis of key proteins of retinal health, such as rhodopsin.
Nutritional sex-specificity on bacterial metabolites during mosquito development leads to adult sex-ratio distortion
Authors: Romoli Ottavia , Serrato-Salas Javier , Gapp Chloé , Epelboin Yanouk , Figueras Ivern Pol , Barras Frédéric , Gendrin Mathilde
Published: October 2023

Mosquitoes rely on their microbiota for B vitamin synthesis. We previously found thatAedes aegyptithird-instar larvae cleared of their microbiota were impaired in their development, notably due to a lack of folic acid (vitamin B9). In this study, we found that diet supplementation using a cocktail of seven B vitamins did not improve mosquito developmental success, but rather had a significant impact on the sex-ratio of the resulting adults, with an enrichment of female mosquitoes emerging from B vitamin-treated larvae. A transcriptomic analysis of male and female larvae identified some sex-specific regulated genes upon vitamin treatment. When treating germ-free larvae with individual B vitamins, we detected a specific toxic effect related to biotin (vitamin B7) exposure at high concentrations. We then provided germ-free larvae with varying biotin doses and showed that males are sensitive to biotin toxicity at a lower concentration than females. Gnotobiotic larvae exposed to controlled low bacterial counts or with bacteria characterized by slower growth, show a male-enriched adult population, suggesting that males require less bacteria-derived nutrients than females. These findings shed new light on sex-specific nutritional requirements and toxicity thresholds during the development of insect larvae, which impact the sex ratio of adults.
Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer
Authors: Barr Jeffrey , Walz Austin , Restaino Anthony C. , Amit Moran , Barclay Sarah M. , Vichaya Elisabeth G. , Spanos William C. , Dantzer Robert , Talbot Sebastien , Vermeer Paola D.
Published: October 2023

Cancer patients often experience changes in mental health, prompting an exploration into whether nerves infiltrating tumors contribute to these alterations by impacting brain functions. Using a mouse model for head and neck cancer and neuronal tracing we show that tumor-infiltrating nerves connect to distinct brain areas. The activation of this neuronal circuitry altered behaviors (decreased nest-building, increased latency to eat a cookie, and reduced wheel running). Tumor-infiltrating nociceptor neurons exhibited heightened calcium activity and brain regions receiving these neural projections showed elevated Fos as well as increased calcium responses compared to non-tumor-bearing counterparts.

The genetic elimination of nociceptor neurons decreased brain Fos expression and mitigated the behavioral alterations induced by the presence of the tumor. While analgesic treatment restored nesting and cookie test behaviors, it did not fully restore voluntary wheel running indicating that pain is not the exclusive driver of such behavioral shifts. Unraveling the interaction between the tumor, infiltrating nerves, and the brain is pivotal to developing targeted interventions to alleviate the mental health burdens associated with cancer.

Significance Statement

Head and neck cancers are infiltrated by sensory nerves which connect to a pre-existing circuit that includes areas in the brain. Neurons within this circuit are altered and mediate modifications in behavior.
Influenza Hospitalisations in England during the 2022/23 Season: do different data sources drive divergence in modelled waves? A comparison of surveillance and administrative data
Authors: Mellor Jonathon , Christie Rachel , Guilder James , Paton Robert S , Elgohari Suzanne , Watson Conall , Deeny Sarah , Ward Thomas
Published: October 2023

Background

Accurate and representative data is vital for precisely reporting the impact of influenza in healthcare systems. Northern hemisphere winter 2022/23 experienced the most substantial influenza wave since the COVID-19 pandemic began in 2020. Simultaneously, new data streams become available within health services because of the pandemic. Comparing these data, surveillance and administrative, supports the accurate monitoring of population level disease trends.

Methods

We analysed admissions rates per capita from four different collection mechanisms covering National Health Service hospital Trusts in England over the winter 2022/23 wave. We adjust for difference in reporting and extracted key epidemic characteristics including the maximum admission rate, peak timing, cumulative season admissions and growth rates by fitting generalised additive models at national and regional levels.

Results

By modelling the admission rates per capita across surveillance and administrative data systems we show that different data measuring the epidemic produce different estimates of key quantities. Nationally and in most regions the data correspond well for the maximum admission rate, date of peak and growth rate, however, in subnational analysis discrepancies in estimates arose, particularly for the cumulative admission rate.

Interpretation

This research shows that the choice of data used to measure seasonal influenza epidemics can influence analysis substantially at sub-national levels. For the admission rate per capita there is comparability in the sentinel surveillance approach (which has other important functions), rapid situational reports, operational databases and time lagged administrative data giving assurance in their combined value. Utilising multiple sources of data aids understanding of the impact of seasonal influenza epidemics in the population.
Distinct longitudinal brain white matter microstructure changes and associated polygenic risk of common psychiatric disorders and Alzheimer’s disease in the UK Biobank
Authors: Korbmacher Max , van der Meer Dennis , Beck Dani , Askeland-Gjerde Daniel E. , Eikefjord Eli , Lundervold Arvid , Andreassen Ole A. , Westlye Lars T. , Maximov Ivan I.
Published: October 2023

During the course of adulthood and ageing, white matter (WM) structure and organisation are characterised by slow degradation processes such as demyelination and shrinkage. An acceleration of such ageing process has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, in particular, in terms of WM features, provides a cornerstone in the understanding of ageing. We use longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) (N=2,678; agescan1=62.38±7.23 years; agescan2=64.81±7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores (PGRS) for the most common neurodegenerative disorder, Alzheimer’s disease, and common psychiatric disorders (uniand bipolar depression, anxiety, obsessive-compulsive, autism, schizophrenia, attention-deficit-hyperactivity) in longitudinal (N=2,329) and crosssectional UKB validation data (N=31,056). Global and regional single and multi-compartment fractional anisotropy, intra-axonal water fraction, and kurtosis metrics decreased, whereas diffusivity metrics, and free water increased with age, with the annual rate of WM change (ARoC) accelerating at higher ages for both globaland regional WM metrics. Voxel-level trends indicated decreasing anisotropy, and variable spatial patterns for other diffusion metrics, suggesting differential changes in frontal compared to other brain regions. Although effect sizes were small, ARoC in middle cerebral peduncle WM had the strongest association with PGRS, especially for Alzheimer’s:. PGRS were more strongly related to ARoC than cross-sectional measures (dscan1=0.03,dscan2=0.03,dvalidation=0.03). Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of PGRS with WM. Importantly, brain longitudinal changes reflected the genetic risk for disorder development better than the utilised cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages.
Sex-specific effects of birth weight on longitudinal behavioural outcomes in children and adolescents
Authors: Byg Lars Meinertz , Wang Carol , Attia John , Pennell Craig
Published: October 2023

Introduction

Previous cross-sectional studies suggest that birth weight (BW) affects the development of aggression-, social- and attention problems differently in boys and girls. We sought to test if these differences could be confirmed in a longitudinal study.

Methods

The Raine Study provided prospectively collected data on perinatal variables and repeated child behaviour checklist assessments from ages five to seventeen. We used linear mixed effects model to determine crude and adjusted relationships between BW and childhood behaviour at a conservative significance threshold. Sensitivity analyses included an age ten teacher assessment.

Results

Data on behaviour, BW and sex, was available in 2269 participants. Male sex was associated with increased aggression problems at lower BW compared to females in the crude model (β: -0.436, 98.3%CI: [-0.844, - 0.0253]), but not the adjusted model (β: -0.310, 98.3%CI: [-0.742, 0.140]). Male sex was associated with increased attention problems at lower BW compared to females in both the crude model (β: -0.334, 98.3%CI: [- 0.530, -0.137]) and the adjusted model (β: -0.274, 98.3%CI: [-0.507, -0.0432]). Male sex was associated with increased social problems at lower BW compared to females in both the crude model (β: -0.164, 98.3%CI: [- 0.283, -0.0441]) and the adjusted model (β: -0.148, 98.3%CI: [-0.285, -0.00734]).

Conclusion

Using repeated measures from ages 5-17 we were able to show a crude and adjusted male vulnerability to lower BW in the development of attention problems and social problems. We did not find a BW x sex interaction for the development of aggressive behaviour.
Legal Frameworks Upholding Deceased Individuals’ Rights and Enabling the Use of Cadavers in Anatomy Education and Research: A Systematic Review
Authors: Charmode Sundip H. , Sheikh Nishat , Ravi Satish Kumar , Mehra Simmi
Published: October 2023

The study of human cadavers is essential for teaching, advanced training, and research in medical and anatomical sciences. Medical institutions, around the globe presently face the scarcity of cadaver supply. For the majority of countries, unclaimed bodies are still the primary source of cadavers despite guidelines issued by the International Federation of Associations of Anatomists which discourage the use of unclaimed bodies. This study aims to conduct a review of the existing national and international laws safeguarding the several rights of a deceased person. The study also reviews the existing anatomy acts (and related acts) across various countries that facilitate cadaver supply for anatomy education and research. According to PRISMA guidelines an online search was publications in four medical databases (PubMed, Scopus, Web of Sciences, and Google Scholar) was conducted from 1950 till 2022. A research review protocol was registered in PROSPERO prospectively. Using the Mesh terms like cadaver, anatomy education, dead person and rights, body donation program, unclaimed bodies, and anatomy acts. After the application of the eligibility criteria, 149 publications were shortlisted. After review of all the shortlisted articles, laws, and guidelines, using the data extraction checklist prepared by both authors, five (5) international laws; three (3) supreme court case decisions; two (2) high court case decisions; four (4) Indian penal Code Sections and 22 anatomy acts were selected. The review findings will emphasize the distinctions between India’s anatomy acts and those of other developed nations, thereby broadening our perspective as we propose a model anatomy act for uniform implementation across the country with the goal of streamlining the procurement of cadavers.
Integrin-like adhesin CglD confers traction and stabilizes bacterial focal adhesions involved in myxobacterial gliding motility
Authors: Jolivet Nicolas Y. , Han Endao , Belgrave Akeisha M. , Saïdi Fares , Koushki Newsha , Lemon David J. , Faure Laura M. , Fleuchot Betty , Mahanta Utkarsha , Jiang Heng , Sharma Gaurav , Fiche Jean-Bernard , Bratton Benjamin P. , Diallo Mamoudou , Nan Beiyan , Zusman David R. , Sudre Guillaume , Garza Anthony , Nollmann Marcelo , Ehrlicher Allen J. , Théodoly Olivier , Shaevitz Joshua W. , Mignot Tâm , Islam Salim T.
Published: October 2023

Abstract

Integrins are crucial for eukaryotic cell attachment and motility within the extracellular matrix (ECM) via focal-adhesion formation, with their evolutionary emergence important for the development of multicellularity. Intriguingly, single gliding cells of the predatory deltaproteobacteriumMyxococcus xanthusform bacterial focal-adhesion (bFA) sites; therein, helically-trafficked motors become immobilized at anchored locations through Glt apparatus association with cell-surface integrin αI-domain-like adhesin CglB. Using traction-force, bead-force, and total internal reflection-fluorescence microscopies combined with biochemical approaches, we herein identify the von Willebrand A domain-containing cell-surface lipoprotein CglD to be a β-integrin-like outer-membrane lipoprotein that functionally associates with and anchors the trans-envelope Glt–CglB gliding apparatus, stabilizing and efficiently anchoring this assembly at bFAs. Calcium dependence governs CglD importance, consistent with its integrated ECM eukaryotic cartilage oligomeric matrix protein domains. CglD thus confers mechanosensory and mechanotransductory capabilities to the gliding apparatus, helping explain bFA-mediated trans-envelope force transduction, from inner-membrane-embedded motors to the cell surface.
Applying the area fraction fractionator (AFF) probe for total volume estimations of somatic, dendritic and axonal domains of the nigrostriatal dopaminergic system in a murine model
Authors: Oñate-Ponce Alejandro , Muñoz Catalina , Catenaccio Alejandra , Court Felipe A. , Henny Pablo
Published: October 2023

Using the nigrostriatal dopaminergic system as a case example, we describe a protocol based on Cavalieri’s principle to estimate the total volume of its somatic, nuclear, dendritic and axonal domains in the adult mouse. This protocol requires serial section analysis, a confocal laser scanning microscope (CLSM), and a stereological software combining the serial section manager (SSM) tool and the area fraction fractionator (AFF) probe. The protocol consists of the following steps: 1) systematic random sampling (SRS) of sites across sections for relevant regions of interest (ROI), which in this study included the substantia nigra pars compacta (SNc) and pars reticulata (SNr), the nigrostriatal tract, and the caudate-putamen complex (CP), 2) high resolution image acquisition of all SRS sites within and across sections, 3) loading of images on the previously defined SRS sites, 4) marking of all cellular structures of interest (cSOI) in the images, including perikarya and cell nuclei, dendrites, axonal segments and varicosities, using Cavalieri’s point-counting grids, and 5) estimation of cSOI total volume using the estimated area of each cSOI in every brain section, and the distance between sections. The added volume for all cSOI comprising the nigrostriatal dopaminergic system, in this murine model is around 0.37 mm3, with approximately 5% corresponding to perikarya and cell nuclei, 10% to neuropil/dendrites in substantia nigra, and 85% to axonal segments and varicosities within the CP. The use of a simple quantitative approach to assess the global state of a system may allow quantification of compartment-specific changes that may accompany neurodegenerative processes.
Trypanosoma brucei gambiensegroup 2 experimentalin vivolife cycle: from procyclic to bloodstream form
Authors: Juban Paola , Bart Jean-Mathieu , Segard Adeline , Jamonneau Vincent , Ravel Sophie
Published: October 2023

Trypanosoma brucei gambiense(Tbg) group 2 is a subgroup of trypanosomes able to infect humans in West and Central Africa. Unlike other agents causing sleeping sickness such asTbggroup 1 andTrypanosoma brucei rhodesiense, Tbg2 lacks the typical molecular markers associated with resistance to human serum. Only thirty-six strains ofTbg2 have been documented, and therefore, very limited research has been conducted despite its zoonotic nature. Some of these strains are only available in their procyclic form which hinders human serum resistance assays and mechanistic studies. Furthermore, the understanding ofTbg2’s potential to infect tsetse flies and mammalian hosts is limited. In this study, 165Glossina palpalis gambiensisflies were experimentally infected with procyclicTbg2 parasites. 35 days post-infection, 43 flies out of the 80 still alive flies were foundTbg2PCR-positive in the saliva. These flies were able to infect 3 out of the 4 mice used for blood-feeding. Dissection revealed that only six flies really carried mature infections in their midguts and salivary glands. Importantly, a single fly with a mature infection was sufficient to infect a mammalian host. ThisTbg2transmission success confirms thatTbg2 strains can establish in tsetse flies and infect mammalian hosts. The study describes an effectivein vivoprotocol for transformingTbg2 from procyclic to bloodstream form, reproducing the completeTbg2 cycle fromG. p. gambiensisto mice. These findings provide valuable insights intoTbg2’s host infectivity, and will facilitate further research on mechanisms of human serum resistance.
Single cell profiling of del(5q) MDS unveils its transcriptional landscape and the impact of lenalidomide
Authors: Serrano Guillermo , Berastegui Nerea , Díaz-Mazkiaran Aintzane , García-Olloqui Paula , Huerga-Dominguez Sofia , Alfonso-Pierola Ana , Ainciburu Marina , Vilas-Zornoza Amaia , Martin Patxi San , Aguirre-Ruiz Paula , Ullate-Agote Asier , Ariceta Beñat , Lamo de Espinosa Jose , Acha Pamela , Calvete Oriol , Jimenez Tamara , Molero Antonieta , Montoro Julia , Díez-Campelo Maria , Valcarcel David , Solé Francisco , Ochoa Idoia , Prósper Felipe , Ezponda Teresa , Hernaez Mikel
Published: October 2023

While del(5q) MDS patients comprise a well-defined hematological subgroup, the molecular basis underlying its origin, and the reason behind the relapse after lenalidomide remains unknown. Using scRNA-seq on CD34+progenitor cells from patients with del(5q) MDS we were able to identify cells harboring the deletion, enabling us to deeply characterize the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. We found, across all patients, an enrichment of del(5q) cells in GMP and megakaryocyte-erythroid progenitors not described to date. Interestingly, both del(5q) and non-del(5q) cells presented similar transcriptional lesions when compared to progenitors from healthy individuals, indicating that all cells, and not only those harboring the deletion, are altered in these patients and may contribute to aberrant hematopoietic differentiation. However, GRN analysis revealed a group of regulons with aberrant activity in del(5q) cells that could be responsible for triggering altered hematopoiesis, pointing to a more prominent role of these cells in the phenotype of these patients. An analysis of del(5q) MDS patients achieving hematological response upon lenalidomide treatment showed that the drug reverted several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remained, which may be responsible for potential future relapses. Moreover, lack of hematological response was associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study provides a deep characterization of del(5q) and non-del(5q) cells at single-cell resolution, revealing previously unknown transcriptional alterations that could contribute to disease pathogenesis, or lack of responsiveness to lenalidomide.

KEY POINTS

– Del(5q) and non-del(5q) CD34+ cells share similar transcriptional alterations, with del(5q) cells presenting additional lesions.

– Hematological response to lenalidomide is associated with the reversal of some transcriptional lesions in del(5q) and non-del(5q) cells