bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-specific α-tubulin TBA-6 and pan-ciliary IFT cargo RAB-28 generate a non-canonical transition zone
Authors: Akella Jyothi Shilpa , Silva Malan S. , Nguyen Ken C. Q. , Hall David H. , Barr Maureen M.
Published: November 2023

The transition zone (TZ) regulates cilia composition and function. Canonical TZs with 9 doublet microtubules (MTs) are common but non-canonical TZs that vary from 9 MT symmetry also occur and arise through unknown mechanisms. Cilia on the quadrant inner labial type 2 (IL2Q) neurons ofC. eleganshave a specialized non-canonical TZ with fewer than 9 doublet MTs. We previously showed that non-canonical TZs in IL2Q cilia arise via MT loss and reorganization of canonical TZs. Here, we identify structural events and mechanisms that generate non-canonical TZs. Cell-specific α-tubulin TBA-6 and pan-ciliary IFT cargo RAB-28 regulate IL2QTZ MT loss without affecting ciliary assembly. Our results reveal a role for the tubulin code in generating non-canonical TZs and contribute towards understanding ciliary functional specialization.

Author summary

Ciliary microtubules are exquisitely diverse in arrangements and composition. Studies on how ciliary ultrastructural diversity is generated are essential to our understanding of cilia function in diverse healthy and pathological contexts. Despite its clinical relevance, the ultrastructural diversity of the transition zone and its microtubules remains understudied. Here, we uncover mechanisms contributing to generating ultrastructural diversity in the transition zone and in cilia. A subset of sensory cilia inC. eleganscontain a non-canonical transition zone with 7 and fewer doublet microtubules. We previously showed that this distinct transition zone is generated through microtubule loss in a canonical transition zone with 9 doublet microtubules, a process that occurs asynchronously during animal development. Here, we identify roles for the tubulin code and for an IFT cargo in generating a distinct transition zone. Sculpting of the distinct transition zone occurs in fully assembled cilia and transition zones and is independent of general ciliogenesis mechanisms. Our results demonstrate how specialized transition zones can be generated from canonical transition zones and provide insight into mechanisms of ciliary ultrastructural diversity and post-ciliogenesis restructuring. Such mechanisms hold the key to understanding ciliary function and to restoration of function in ciliopathies with ciliary ultrastructural defects.
The explosive radiation of the NeotropicalTillandsiasubgenusTillandsia(Bromeliaceae) has been facilitated by pervasive hybridization
Authors: Yardeni Gil , Barfuss Michael H. J. , Till Walter , Thornton Matthew R. , Groot Crego Clara , Lexer Christian , Leroy Thibault , Paun Ovidiu
Published: November 2023

The recent rapid radiation ofTillandsiasubgenusTillandsia(Bromeliaceae) provides an attractive system to study the drivers and limits of species diversification. This species-rich Neotropical monocot clade includes predominantly epiphytic species displaying vast phenotypic diversity. Recent in-depth phylogenomic work revealed that the subgenus originated within the last 7 MY while expanding through one major event from South into Central America within the last 5 MY. However, disagreements between phylogenies and lack of resolution at shallow nodes suggested that hybridization occurred throughout the radiation, together with frequent incomplete lineage sorting and/or considerable gene family evolution. We used whole-genome resequencing data and a newly available reference genome to explore the evolutionary history of 34 representative ingroup species employing both a tree-based and a network approach. Our results indicate that lineage co-occurrence does not predict relatedness and confirm significant deviations from a tree-like structure, coupled with pervasive gene tree discordance. Focusing on hybridization, ABBA-BABA and related statistics were used to infer the rates and relative timing of introgression, while topology weighting uncovered high heterogeneity of the phylogenetic signal along the genome. High rates of hybridization within and among clades suggest that, in contrast to previous hypotheses, the expansion of subgenusTillandsiainto Central America proceeded in several dispersal events, punctuated by episodes of diversification and gene flow. Network analysis revealed reticulation as a prominent propeller during radiation and establishment in different ecological niches. This work contributes a plant example of prevalent hybridization during rapid species diversification, supporting the hypothesis that interspecific gene flow facilitates explosive diversification.
Microinjection, gene knockdown, and CRISPR-mediated gene knock-in in the hard coral,Astrangia poculata
Authors: Warner Jacob F. , Besemer Ryan , Schickle Alicia , Borbee Erin , Changsut Isabella V. , Sharp Koty , Babonis Leslie S.
Published: November 2023

Cnidarians have become valuable models for understanding many aspects of developmental biology including the evolution of body plan diversity, novel cell type specification, and regeneration. Most of our understanding of gene function during early development in cnidarians comes from a small number of experimental systems including the sea anemone,Nematostella vectensis. Few molecular tools have been developed for use in hard corals, limiting our understanding of this diverse and ecologically important clade. Here, we report the development of a suite of tools for manipulating and analyzing gene expression during early development in the northern star coral,Astrangia poculata. We present methods for gene knockdown using short hairpin RNAs, gene overexpression using exogenous mRNAs, and endogenous gene tagging using CRISPR-mediated gene knock-in. Combined with our ability to control spawning in the laboratory, these tools makeA. poculataa tractable experimental system for investigative studies of coral development. Further application of these tools will enable functional analyses of embryonic patterning and morphogenesis across Anthozoa and open new frontiers in coral biology research.

Summary Statement

This study reports the development of the first transgenic knock-in coral, providing the opportunity to track the behavior of various cell types during early coral development.
Monocyte-derived microglia withDnmt3amutation cause motor pathology in aging mice
Authors: Kim Jung-Seok , Trzebanski Sébastien , Shin Sun-Hye , Ilani Noa Chapal , Kaushansky Nathali , Scheller Marina , Solomon Aryeh , Liu Zhaoyuan , Aust Oliver , Boura-Halfon Sigalit , Amann Lukas , Prinz Marco , Ginhoux Florent , Avraham Roi , Müller-Tidow Carsten , Uderhardt Stefan , Milenkovic Ivan , Shlush Liran , Jung Steffen
Published: November 2023

Microglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦ) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoMΦ adoptbona fidemicroglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3AR822H, a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.
Glia detect and mount a protective response to loss of dendrite substructure integrity inC. elegans
Authors: Varandas Katherine C. , Hodges Brianna M. , Lubeck Lauren , Farinas Amelia , Liang Yupu , Lu Yun , Shaham Shai
Published: November 2023

Neurons have elaborate structures that determine their connectivity and functions. Changes in neuronal structure accompany learning and memory formation and are hallmarks of neurological disease. Here we show that glia monitor dendrite structure and respond to dendrite perturbation. InC. elegansmutants with defective sensory-organ dendrite cilia, adjacent glia accumulate extracellular matrix-laden vesicles, secrete excess matrix around cilia, alter gene expression, and change their secreted protein repertoire. Inducible cilia disruption reveals that this response is acute. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, and exhibit mutually-dependent localization to and around cilia, respectively. While inhibiting glial secretion disrupts dendritic cilia properties, hyperactivating the glial response protects against dendrite damage. Our studies uncover a homeostatic protective dendrite-glia interaction and suggest that similar signaling occurs at other sensory structures and at synapses, which resemble sensory organs in architecture and molecules.
Whole-brain Mechanism of Neurofeedback Therapy: Predictive Modeling of Neurofeedback Outcomes on Repetitive Negative Thinking in Depression
Authors: Misaki Masaya , Tsuchiyagaito Aki , Guinjoan Salvador M. , Rohan Michael L. , Paulus Martin P.
Published: November 2023

Real-time fMRI neurofeedback (rtfMRI-NF) has emerged as a promising intervention for psychiatric disorders, yet its clinical efficacy remains underexplored due to limited controls and an incomplete mechanistic understanding. This study aimed to elucidate the whole-brain mechanisms underpinning the effects of rtfMRI-NF on repetitive negative thinking in depression. In a double-blind randomized controlled trial, forty-three depressed individuals underwent NF training targeting the functional connectivity (FC) between the posterior cingulate cortex and the right temporoparietal junction, linked to rumination severity. Participants were randomly assigned to active or sham groups, with the sham group receiving synthesized feedback mimicking real NF signal patterns. The active group demonstrated a significant reduction in brooding rumination scores (p<0.001, d=-1.52), whereas the sham group did not (p=0.503, d=- 0.23). While the target FC did not show discernible training effects or group differences, we found that the interaction between brain activities during regulation and the response to the feedback signal was the critical factor in explaining treatment outcomes. Connectome-based predictive modeling (CPM) analysis, incorporating this interaction, successfully predicted rumination changes across both groups. The FCs significantly contributing to the prediction were distributed across broad brain regions, notably the frontal control, salience network, and subcortical reward processing areas. These results underscore the importance of considering the interplay between brain regulation activities and brain response to the feedback signal in understanding the therapeutic mechanisms of rtfMRI-NF. The study not only affirms the potential of rtfMRI-NF as a therapeutic intervention for repetitive negative thinking in depression but also highlights the need for a more nuanced understanding of the whole-brain mechanisms contributing to its efficacy.
Intranasal GHK peptide enhances resilience to cognitive decline in aging mice
Authors: Tucker Matthew , Keely Addison , Park Joo Young , Rosenfeld Manuela , Wezeman Jackson , Mangalindan Ruby , Ratner Dan , Ladiges Warren
Published: November 2023

Brain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimer’s Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery.
Functional Screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair
Authors: Perez-Bermejo Juan A. , Efagene Oghene , Matern William M. , Holden Jeffrey K. , Kabir Shaheen , Chew Glen M. , Andreoletti Gaia , Catton Eniola , Ennis Craig L. , Garcia Angelica , Gerstenberg Trevor L. , Hill Kaisle A. , Jain Aayami , Krassovsky Kristina , Lalisan Cassandra D. , Lord Daniel , Quejarro B. Joy , Sales-Lee Jade , Shah Meet , Silva Brian J. , Skowronski Jason , Strukov Yuri G. , Thomas Joshua , Veraz Michael , Vijay Twaritha , Wallace Kirby A. , Yuan Yue , Grogan Jane L. , Wienert Beeke , Lahiri Premanjali , Treusch Sebastian , Dever Daniel P. , Soros Vanessa B. , Partridge James R. , Seim Kristen L.
Published: November 2023

Homology Directed Repair (HDR) enables precise genome editing and holds great promise in the gene therapy field. However, the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we demonstrate the development of a functional, pooled screening platform utilizing an HDR-based readout to identify protein-based reagents that improve HDR outcomes in human hematopoietic stem and progenitor cells (HSPCs), a clinically relevant cell type for gene therapy. We leveraged this screening platform to explore sequence diversity at the binding interface of the NHEJ inhibitor i53 and its target, 53BP1, and we identified optimized i53 variants that enable new intermolecular bonds and robustly increase HDR. These variants specifically reduce insertion-deletion outcomes and also synergize with a DNAPK inhibitor to increase HDR rates. When applied at manufacturing scale, the incorporation of improved variants results in a significant increase in cells with at least one repaired allele and improved HDR in long-term HSPCs subpopulations, while not increasing off-target editing or gross chromosomal rearrangements. We anticipate the pooled screening platform will enable discovery of future gene editing reagents that improve HDR outcomes, such as the i53 variants reported here.
Phylogenetic Biogeography Inference Using Dynamic Paleogeography Models and Explicit Geographic Ranges
Authors: Arias J. Salvador
Published: November 2023

Most popular methods of phylogenetic biogeography discard the spatial component of geographic distributions, dividing Earth into a handful of predefined areas. Other methods use explicit geographic ranges, but unfortunately, these methods assume a static Earth, ignoring the effects of plate tectonics and the changes in the landscape. To address this limitation, I propose a method that uses explicit geographic ranges and incorporates a plate motion model and a paleolandscape model directly derived from the models used by geologists in their tectonic and paleogeographic reconstructions. The underlying geographic model is a high-resolution pixelation of a spherical Earth. Biogeographic inference is based on diffusion, approximates the effects of the landscape, uses a time-stratified model to take into account the geographic changes, and directly integrates over all probable histories. By using a simplified stochastic mapping algorithm, it is possible to infer the ancestral locations as well as the distance and speed traveled by the ancestral lineages. For illustration, I applied the method to an empirical phylogeny of the Sapindaceae plants. This example shows that methods based on explicit geographic data, coupled with high-resolution paleogeographic models, can provide detailed reconstructions of the ancestral areas but also include inferences about the probable dispersal paths and traveling speed across the taxon history that are not possible with current methods based on predefined areas.
Krisp: A python package for designing CRISPR and amplification-based diagnostic assays from whole genome data
Authors: Foster Zachary S. L. , Tupper Andrew S. , Press Caroline M. , Grünwald Niklaus J.
Published: November 2023

Recent pandemics such as COVID-19 have highlighted the importance of rapidly developing diagnostics to detect and monitor evolving pathogens. CRISPR-Cas technology, combined with isothermal DNA amplification methods, has recently been used to develop diagnostic assays for sequence-specific recognition of DNA or RNA. These assays have similar sensitivity to the gold standard qPCR but can be deployed as easy to use and inexpensive test strips. However, the discovery of diagnostic regions of a genome flanked by conserved regions where primers can be designed requires extensive bioinformatic analyses of genome sequences. We developed the python packagekrispto find primers and diagnostic sequences that differentiate groups of samples from each other at any taxonomic scale, using either unaligned genome sequences or a variant call format (VCF) file as input.Krisphas been optimized to handle large datasets by using efficient algorithms that run in near linear time, use minimal RAM, and leverage parallel processing when available. The validity ofkrispresults has been demonstrated in the laboratory with the successful design of SHERLOCK assays to distinguish the sudden oak death pathogenPhytophthora ramorumfrom closely relatedPhytophthoraspecies.Krispis released open source under a permissive license with all the documentation needed to quickly design CRISPR-Cas diagnostic assays.

Author summary

Pathogens continue to emerge at accelerated rates affecting animals, plants, and ecosystems. Rapid development of novel diagnostic tools is needed to monitor novel pathogen variants or groups. We developed the computational toolkrispto identify genetic regions suitable for development of CRISPR diagnostics and traditional amplification-based diagnostics such as PCR.Krispscans whole genome sequence data for target and non-target groups to identify diagnostic regions based on DNA or RNA sequences. This computational tool has been validated using genome data for the sudden oak death pathogenPhytophthora ramorum.Krispis released open source under a permissive license with all the documentation needed to quickly design CRISPR-Cas diagnostic assays and other amplification-based assays.
SMAD4 promotes formation of terminally differentiated CTLs that localize in the microvasculature of the lungs but are excluded from the lumen of the airways
Authors: Suarez-Ramirez Jenny , Chandiran Karthik , Cauley Linda S
Published: November 2023

Cytotoxic T lymphocytes (CTLs) circulate around the body searching for infected and transformed cells, that undergo apoptosis when lytic granules are delivered into the cytoplasm. To find pathogens that propagate in different tissues, naïve CD8 T cells differentiate into heterogeneous populations of effector (TEFF) and memory CD8 T cells with different migratory properties. Several subsets can be identified using antibodies that recognize surface receptors that are expressed at specific stages during CD8 T cell differentiation. Although flow cytometry is a powerful method for tracking antigen specific CTLs during a dynamic immune response, the data provide little information about the distribution of cells in specific anatomical compartments. In this study, confocal imaging was used to explore how signaling via SMAD4 influenced the tissue-tropism of antigen specific CTLs during respiratory infection. During microbial infection, wildtype CTLs gave rise to terminally differentiated TEFFcells that expressed KLRG1 and CX3CR1 at high levels and localized in the microvasculature of the lungs. However, both markers were expressed at reduced levels on SMAD4-deficient CTLs, which preferentially entered the lumen of the airways. These disparate homing properties emphasize the important contributions of SMAD signaling pathways to cell-mediated immunity.
Modeling spatial evolution of multi-drug resistance under drug environmental gradients
Authors: Freire Tomas , Hu Zhijian , Wood Kevin B. , Gjini Erida
Published: November 2023

Multi-drug combinations to treat bacterial populations are at the forefront of approaches for infection control and prevention of antibiotic resistance. Although the evolution of antibiotic resistance has been theoretically studied with mathematical population dynamics models, extensions to spatial dynamics remain rare in the literature, including in particular spatial evolution of multi-drug resistance. In this study, we propose a reaction-diffusion system that describes the multi-drug evolution of bacteria, based on a rescaling approach (Gjini and Wood, 2021). We show how the resistance to drugs in space, and the consequent adaptation of growth rate is governed by a Price equation with diffusion. The covariance terms in this equation integrate features of drug interactions and collateral resistances or sensitivities to the drugs. We study spatial versions of the model where the distribution of drugs is homogeneous across space, and where the drugs vary environmentally in a piecewise-constant, linear and nonlinear manner. Applying concepts from perturbation theory and reaction-diffusion equations, we propose an analytical characterization ofaverage mutant fitnessin the spatial system based on the principal eigenvalue of our linear problem. This enables an accurate translation from drug spatial gradients and mutant antibiotic susceptibility traits, to the relative advantage of each mutant across the environment. Such a mathematical understanding allows to predict the precise outcomes of selection over space, ultimately from the fundamental balance between growth and movement traits, and their diversity in a population.
Astyanax mexicanus surface and cavefish chromosome-scale assemblies for trait variation discovery
Authors: Warren Wesley C. , Rice Edward S. , Maggs X , Roback Emma , Keene Alex , Martin Fergal , Ogeh Denye , Haggerty Leanne , Carroll Rachel A. , McGaugh Suzanne , Rohner Nicolas
Published: November 2023

The ability of organisms to adapt to sudden extreme environmental changes produces some of the most drastic examples of rapid phenotypic evolution. The Mexican Tetra,Astyanax mexicanus, is abundant in the surface waters of northeastern Mexico, but repeated colonizations of cave environments have resulted in the independent evolution of troglomorphic phenotypes in several populations. Here, we present three chromosome-scale assemblies of this species, for one surface and two cave populations, enabling the first whole-genome comparisons between independently evolved cave populations to evaluate the genetic basis for the evolution of adaptation to the cave environment. Our assemblies represent the highest quality of sequence completeness with predicted protein-coding and non-coding gene metrics far surpassing prior resources and, to our knowledge, all long-read assembled teleost genomes, including zebrafish. Whole genome synteny alignments show highly conserved gene order among cave forms in contrast to a higher number of chromosomal rearrangements when compared to other phylogenetically close or distant teleost species. By phylogenetically assessing gene orthology across distant branches of amniotes, we discover gene orthogroups unique toA. mexicanus.

When compared to a representative surface fish genome, we find a rich amount of structural sequence diversity, defined here as the number and size of insertions and deletions as well as expanding and contracting repeats across cave forms. These new more complete genomic resources ensure higher trait resolution for comparative, functional, developmental, and genetic studies of drastic trait differences within a species.
Vascularized Liver Tissue Embedded Bioprinting Utilizing GelMA/Nanoclay-based Composite hydrogels
Authors: Rezaei Nima Tabatabaei , Dixit Kartikeya , Kumar Hitendra , John Jacob , Natale Giovanniantonio , Park Simon S. , Kim Keekyoung
Published: November 2023

As the aging population grows, the need to regenerate non-self-repairing tissues becomes increasingly crucial for enhancing our quality of life. Tissue engineering offers a promising solution, particularly in recreating the intricate networks of blood vessels crucial for tissue vitality. These tissues rely on effective nutrient and oxygen circulation, with an optimal oxygen diffusion range of 100–200 µm. Yet, crafting vascularized in vitro tissues remains a significant challenge. This study addresses the challenge by using GelMA-based hydrogels as a photocrosslinkable support bath, a biocompatible and versatile choice for biological applications. To enhance the rheological properties for in vitro tissue engineering, Laponite (LPN) is introduced as a rheology modifier. The study optimizes the GelMA-LPN nanocomposite hydrogel composition, ensuring the desired physical, mechanical, and rheological properties, including recovery. The research also explores the biological implications, encapsulating liver cells within the nanocomposite hydrogel, and studying their behavior under perfusion conditions. This research presents a promising avenue for creating vascularized in vitro tissues, potentially advancing tissue engineering and regenerative medicine.
Unveiling the Burden of Drug-Induced Impulsivity: A Network Analysis of the FDA Adverse Event Reporting System
Authors: Fusaroli Michele , Polizzi Stefano , Menestrina Luca , Giunchi Valentina , Pellegrini Luca , Raschi Emanuel , Weintraub Daniel , Recanatini Maurizio , Castellani Gastone , De Ponti Fabrizio , Poluzzi Elisabetta
Published: November 2023

Introduction

Impulsivity induced by dopaminergic agents, like pramipexole and aripiprazole, can lead to behavioral addictions impacting social functioning and quality of life of patients and families (e.g., resulting in unemployment, marital problems, anxiety). These secondary effects, interconnected in networks of signs and symptoms, are usually overlooked by clinical trials, not reported in package inserts, and neglected in clinical practice.

Objective

This study explores the syndromic burden of impulsivity induced by pramipexole and aripiprazole, pinpointing key symptoms for targeted mitigation.

Methods

An event-event Information Component (IC) on the FDA Adverse Event Reporting System (January 2004 – March 2022) identified the syndrome of events disproportionally co-reported with impulsivity, separately for pramipexole and aripiprazole. A greedy-modularity clustering on composite network analyses (PPMI, Ising, Φ) identified subsyndromes. Bayesian network modeling highlighted possible precipitating events.

Results

Suspected drug-induced impulsivity was documented in 7.49% pramipexole and 4.50% aripiprazole recipients. The highest IC concerned obsessive-compulsive disorder (reporting rate = 26.77%; IC median = 3.47, 95%CI = 3.33-3.57) and emotional distress (21.35%; 3.42, 3.26-3.54) for pramipexole, bankruptcy (10.58%; 4.43, 4.26-4.55) and divorce (7.59%; 4.38, 4.19-4.53) for aripiprazole. The network analysis identified delusional jealousy and dopamine dysregulation subsyndromes for pramipexole, obesity-hypoventilation and social issues for aripiprazole. The Bayesian network highlighted anxiety and economic problems as potentially precipitating events.

Conclusion

The under-explored consequences of drug-induced impulsivity significantly burden patients and families. Network analyses, exploring syndromic reactions and potential precipitating events, complement traditional techniques and clinical judgment. Characterizing the secondary impact of reactions will support informed patient-centered decision-making.

Highlights

Drug-induced impulsivity significantly impacts patients’ lives. Network analyses help characterize reactions as syndromes.

We explore the impulsivity syndrome and subsyndromes resulting from pramipexole and aripiprazole.

The manifestation of drug-induced impulsivity was different for the two drugs. Anxiety and economic problems bridge between other symptoms and could be important therapeutical targets.
Estimating Demand for Potential Disease modifying Therapies for Alzheimer’s Disease in the UK
Authors: Laurell Axel AS , Venkataraman Ashwin V , Schmidt Tatjana , Montagnese Marcella , Mueller Christoph , Stewart Robert , Lewis Jonathan , Mundell Clare , Isaacs Jeremy D , Krishnan Mani S , Barber Robert , Rittman Timothy , Underwood Benjamin R
Published: November 2023

Background

Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical endpoints in early Alzheimer’s disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments considering the resources required for their administration and monitoring.

Aim

To estimate the scale of real-world demand for monoclonal antibodies for AD in the United Kingdom.

Method

We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab with consideration given to diagnosis, cognitive performance, cerebrovascular disease, and willingness to receive treatment.

Results

We examined the records of 82,386 people referred to services covering some 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30,200 people if extrapolated nationally.

Conclusions

Monoclonal antibody treatments for AD are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.
Distinct Functions for Beta and Alpha Bursts in Gating of Human Working Memory
Authors: Liljefors Johan , Almeida Rita , Rane Gustaf , Lundström Johan N. , Herman Pawel , Lundqvist Mikael
Published: November 2023

Multiple neural mechanisms underlying gating to and from working memory (WM) have been proposed, with divergent results obtained in human and animal studies. Previous results from non-human primate studies suggest information encoding and retrieval is regulated by high-power bursts in the beta frequency range, whereas human studies suggest that alpha power in sensory regions filters out unwanted stimuli from entering WM. Discrepancies between studies, whether due to differences in analysis, species, or cortical regions, remain unexplained. We addressed this by performing similar single-trial burst analysis we earlier deployed on non-human primates on human whole-brain electrophysiological activity. Participants performed a sequential working memory task that allowed us to track the distinct electrophysiological activity patterns associated with neural processing of targets and distractors. Intriguingly, our results reconcile earlier findings by demonstrating that both alpha and beta bursts are involved in the filtering and control of WM items, but with region and task-specific differences between the two rhythms. Occipital beta burst patterns regulate the transition from sensory processing to WM retention whereas prefrontal and parietal beta bursts track sequence order and proactively suppress retained information prior to upcoming target encoding. Occipital alpha bursts instead suppress unwanted sensory stimuli during their presentation. These results suggest that human working memory is regulated by multiple neural mechanisms that operate in different cortical regions and serve distinct computational roles.
Distinct roles of monkey OFC-subcortical pathways in adaptive behavior
Authors: Oyama Kei , Majima Kei , Nagai Yuji , Hori Yukiko , Hirabayashi Toshiyuki , Eldridge Mark A G , Mimura Koki , Miyakawa Naohisa , Fujimoto Atsushi , Hori Yuki , Iwaoki Haruhiko , Inoue Ken-ichi , Saunders Richard C , Takada Masahiko , Yahata Noriaki , Higuchi Makoto , Richmond Barry J , Minamimoto Takafumi
Published: November 2023

To be the most successful, primates must adapt to changing environments and optimize their behavior by making the most beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task’s rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate a dissociable contribution of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates.
Chromosome Structure I: Loop extrusion or boundary:boundary pairing?
Authors: Bing Xinyang , Ke Wenfan , Fujioka Miki , Kurbidaeva Amina , Levitt Sarah , Levine Michael , Schedl Paul , Jaynes James B
Published: November 2023

Two different models have been proposed to explain how the endpoints of chromatin looped domains (TADs) in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop. In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized, and experimental manipulations of the even skipped TAD boundary, homie, to test the predictions of the loop-extrusion and the boundary-pairing models. Our findings are incompatible with the loop-extrusion model and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely to require loop extrusion.
Pneumococcal competence, a populational health sensor driving multilevel heterogeneity in response to antibiotics
Authors: Prudhomme Marc , Johnston Calum H. G. , Soulet Anne-Lise , De Lemos David , Campo Nathalie , Polard Patrice
Published: November 2023

Competence for natural transformation is a central driver of genetic diversity in bacteria. In the human pathogenStreptococcus pneumoniae, competence exhibits a populational character mediated by the stress-induced ComABCDE quorum-sensing (QS) system. Here, we explore how this cell-to-cell communication mechanism proceeds and the functional properties acquired by competent cells grown under lethal stress. We show that populational competence development depends on self-induced cells stochastically emerging in response to stresses, including antibiotics. Competence is demonstrated to propagate through the population from a low threshold density of self-induced cells, defining a biphasic Self-Induction and Propagation (SI&P) QS mechanism. We also reveal that a competent population displays either increased sensitivity or improved tolerance to lethal doses of antibiotics, dependent in the latter case on the competence-induced ComM division inhibitor. Remarkably, these surviving competent cells also display an altered transformation potential. Thus, the unveiled SI&P QS mechanism shapes pneumococcal competence as a health sensor of the clonal population, promoting a bet-hedging strategy that both responds to and drives cells towards heterogeneity.
Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice
Authors: Kerp Helena , Gassen Janina , Grund Susanne Camilla , Hönes Georg Sebastian , Dörr Stefanie , Mittag Jens , Härting Nina , Kaiser Frank , Moeller Lars Christian , Lorenz Kristina , Führer Dagmar
Published: November 2023

1

Thyroid hormones (TH) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases are still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure.

Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and after induction of left ventricular pressure overload, received T4 or anti-thyroid medication in the drinking water over the course of 4 weeks.

T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis and interstitial fibrosis) and mortality. This is surprising, because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice.

In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure induced cardiac damage. This suggests that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions.
High prevalence of Prdm9-independent recombination hotspots in placental mammals
Authors: Joseph J. , Prentout D. , Laverré A. , Tricou T. , Duret L.
Published: November 2023

In many mammals, recombination events are concentrated into hotspots directed by a sequence specific DNA-binding protein named Prdm9. This protein facilitates chromosome pairing and its inactivation has been shown to induce fertility losses in mice and rats. Intriguingly,Prdm9has been lost several times in vertebrates, and notably among mammals, it has been pseudogenized in the ancestor of canids (dogs, wolves foxes). When this gene is inactive, either naturally in dogs, or through knock-out experiments in mice, recombination hotspots still exist, but they tend to occur in promoter-like features such as CpG islands. It has thus been proposed that one role ofPrdm9could be to direct recombination away from those Prdm9-independent hotspots. However, the ability of Prdm9 to direct recombination hotspots has been assessed only in a handful of species, and a clear picture of how much recombination occurs outside of Prdm9-directed hotspots in mammals is still lacking. In this study, we derived an estimator of past recombination activity based on signatures of GC-biased gene conversion in substitution patterns. We applied it to quantify recombination activity in Prdm9-independent hotspots in 52 species of boreoeutherian mammals. We observed a wide range of recombination rate at these loci: several species (such as mice, humans, some felids or cetaceans) show a deficit of recombination, while a majority of mammals display a clear peak of recombination. Our results demonstrate that Prdm9-directed and Prdm9-independent hotspots can co-exist in mammals, and that their co-existence seem to be the rule rather than an exception.
Unique Hmgn2 Orthologous Variant Modulates Shape Preference Behavior in Medaka Fish
Authors: Masaki Yume , Inoue Shuntaro , Nakagawa Shinichi , Yokoi Saori
Published: November 2023

Diversification of protein sequences contributes to the variation of physiological traits. In this study, using medaka fish (Oryzias latipes) as a model, we identified a novel protein variant influencing shape preference behavior. Re-analysis of sequencing data revealed thatLOC101156433, previously annotated as a non-protein- coding gene, encodes a divergent Hmgn2 variant undetectable by standard homology searches. This unique Hmgn2 in medaka shows non-standard subnuclear localization, and mutants exhibited a reduction in certain regions of the telencephalon and a loss of shape preference. These results not only establish a direct association between amino acid sequence variation and the development of new molecular properties and behavioral adaptations but also highlight new clues toward understanding the visual shape perception system in fish.
Osteoblast-Induced Collagen Alignment in a 3Din vitroBone Model
Authors: Schaart Judith M. , Lindert Mariska Kea-te , Roverts Rona , Nijhuis Wouter H. , Sommerdijk Nico , Akiva Anat
Published: November 2023

The bone extracellular matrix consists of a highly organized collagen matrix that is mineralized by hydroxyapatite. Even though the structure and composition of bone have been studied extensively, the mechanisms underlying collagen matrix organization remain elusive. In this study, we developed a 3D cell culture system in which osteogenic cells deposit an oriented collagen matrix, that is subsequently mineralized. Using live fluorescence imaging combined with volume electron microscopy, we visualize the organization of the cells and collagen in the cell culture. We show that the osteogenic cells are organizing the collagen matrix during development. Based on the observation of tunnel-like structures surrounded by aligned collagen in the center of the culture, we propose that osteoblasts organize the deposited collagen during migration towards the periphery of the culture. Overall, we show that cell-matrix interactions are involved in collagen alignment during early-stage osteogenesis and that the matrix is organized by the osteoblasts in the absence of osteoclast activity.
Restaurant food waste among Chinese consumers in a group context: an extended value-attitude-behaviour (VAB) hierarchy with information publicity
Authors: Long Fei , Ooi Can-Seng , Gui Ting , Ngah Abdul Hafaz
Published: November 2023

Purpose

The objective of this study is to examine Chinese consumers' behavioural intentions to reduce restaurant food wastage (i.e. intentions to order moderate meal size, and to pack leftovers) in a group context from both psychological and cultural perspectives.

Design/methodology/approach

This paper used an online self-administered survey for data collection. The measurements were either adopted or adapted from prior studies on pro-environmental behaviours. Using data from 311 Chinese consumers, the authors analysed restaurant food wastage in China by utilising PLS-SEM.

Findings

By applying an extended value-attitude-behaviour (VAB) hierarchy with information publicity, it is found that materialism, frugality consciousness, information publicity and environmental concern are important factors in influencing individuals' behavioural intentions to reduce food waste in a group dining-out context.

Originality/value

Drawing upon perspectives of Chinese consumers, this paper outlines key promoters and barriers to food waste mitigation, and provides meaningful insights to policymakers, NGOs, industry stakeholders and even consumers on how to effectively overcome the food waste challenge at the consumption stage in the context of Chinese culture.
A fuzzy multiobjective linear programming approach for green multiechelon distribution network design
Authors: Tai Pham Duc , Jinawat Krit , Buddhakulsomsiri Jirachai
Published: November 2023

Purpose

Distribution network design involves a set of strategic decisions in supply chains because of their long-term impacts on the total logistics cost and environment. To incorporate a trade-off between financial and environmental aspects of these decisions, this paper aims to determine an optimal location, among candidate locations, of a new logistics center, its capacity, as well as optimal network flows for an existing distribution network, while concurrently minimizing the total logistics cost and gas emission. In addition, uncertainty in transportation and warehousing costs are considered.

Design/methodology/approach

The problem is formulated as a fuzzy multiobjective mathematical model. The effectiveness of this model is demonstrated using an industrial case study. The problem instance is a four-echelon distribution network with 22 products and a planning horizon of 20 periods. The model is solved by using the min–max and augmented ε-constraint methods with CPLEX as the solver. In addition to illustrating model’s applicability, the effect of choosing a new warehouse in the model is investigated through a scenario analysis.

Findings

For the applicability of the model, the results indicate that the augmented ε-constraint approach provides a set of Pareto solutions, which represents the ideal trade-off between the total logistics cost and gas emission. Through a case study problem instance, the augmented ε-constraint approach is recommended for similar network design problems. From a scenario analysis, when the operational cost of the new warehouse is within a specific fraction of the warehousing cost of third-party warehouses, the solution with the new warehouse outperforms that without the new warehouse with respective to financial and environmental objectives.

Originality/value

The proposed model is an effective decision support tool for management, who would like to assess the impact of network planning decisions on the performance of their supply chains with respect to both financial and environmental aspects under uncertainty.