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Cells & Development Publications

See our "Latest Publications" page for a full list of SLS publications

Publications from the Cluster

Acidic polymers reversibly deactivate phages due to pH changes

Huba L. Marton, Antonia P. Sagona, Peter Kilbride and Matthew I. Gibson

Poly(carboxylic acids) have been reported to inhibit phages’ ability to infect their bacterial hosts and hence offer an exciting route to discover additives to prevent infection. Here, we report the role of pH in inactivating phages to determine if the polymers are unique or simply acidic. It is shown that lower pH (= 3) triggered by either acidic polymers or similar changes in pH using HCl lead to inhibition. There is no inhibitory activity at higher pHs (in growth media). It is also shown that poly(acrylic acid) leads to reversible deactivation of phage, but when the pH is adjusted using HCl alone the phage is irreversibly deactivated. Further experiments using metal binders ruled out ion depletion as the mode of action.  These results show that polymeric phage inhibitors may work by unique mechanisms of action and that pH alone cannot explain the observed effects whilst also placing constraints on the practical utility of poly(acrylic acid).

RSC Applied Polymers. August 2024

Structure of the MlaC-MlaD complex reveals molecular basis of periplasmic phospholipid transport

Peter Wotherspoon, Hannah Johnston, David J. Hardy, Rachel Holyfield, Soi Bui, Giedrė Ratkevičiūtė, Pooja Sridhar, Jonathan Colburn, Charlotte B. Wilson, Adam Colyer, Benjamin F. Cooper, Jack A. Bryant, Gareth W. Hughes, Phillip J. Stansfeld, Julien R. C. Bergeron & Timothy J. Knowles

The Maintenance of Lipid Asymmetry (Mla) pathway is a multicomponent system found in all gram-negative bacteria that contributes to virulence, vesicle blebbing and preservation of the outer membrane barrier function. Here, we report the structure of E. coli MlaC in complex with the MlaD hexamer in two distinct stoichiometries. Utilising in vivo complementation assays, an in vitro fluorescence-based transport assay, and molecular dynamics simulations, we confirm key residues, identifying the MlaD β6-β7 loop as essential for MlaCD function. We also provide evidence that phospholipids pass between the C-terminal helices of the MlaD hexamer to reach the central pore, providing insight into the trajectory of GPL transfer between MlaC and MlaD.

Nature Communications. July 2024

Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

Habib Bashour, Eva Smorodina, Matteo Pariset, Jahn Zhong, Rahmad Akbar, Maria Chernigovskaya, Khang Lê Quý, Igor Snapkow, Puneet Rawat, Konrad Krawczyk, Geir Kjetil Sandve, Jose Gutierrez-Marcos, Daniel Nakhaee-Zadeh Gutierrez, Jan Terje Andersen & Victor Greiff

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as “developability”, which reflects an antibody’s ability to progress through development stages based on its physicochemical properties. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We show that sequence DPs are more predictable than structure-based ones across different machine-learning tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies localize within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work quantifies the plasticity of antibody developability, providing a fundamental resource for multi-parameter therapeutic mAb design.

Communications Biology July 2024

Direct water-soluble molecules transfer from transplanted bone marrow mononuclear cell to hippocampal neural stem cells

Okinaka Y, Maeda M, Kataoka Y, Nakagomi T, Doi A, Boltze J, Claussen C, Gul S, Taguchi A

Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. Following transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 minutes after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In-vitro investigations revealed that BM-MNC abolish the expression of HIF1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying repair of brain function.

Stem Cells & Development. July 2024

SpoIIQ-dependent localization of SpoIIE contributes to septal stability and compartmentalization during the engulfment stage of Bacillus subtilis sporulation

Behzad Dehghani, Christopher D. A. Rodrigues

During spore development in bacteria, a polar septum separates two transcriptionally distinct cellular compartments, the mother cell and the forespore. The conserved serine phosphatase SpoIIE is known for its critical role in the formation of this septum and activation of compartment-specific transcription in the forespore. Signaling between the mother cell and forespore then leads to activation of mother cell transcription and a phagocytic-like process called engulfment, which involves dramatic remodeling of the septum and requires a balance between peptidoglycan synthesis and hydrolysis to ensure septal stability and compartmentalization. Using Bacillus subtilis, we identify an additional role for SpoIIE in maintaining septal stability and compartmentalization at the onset of engulfment. Our data support a model whereby SpoIIE and its interactions with the peptidoglycan synthetic machinery contribute to the stabilization of the asymmetric septum early in engulfment, thereby ensuring compartmentalization during spore development.

Journal of Bacteriology. July 2024

An atlas of the tomato epigenome reveals that KRYPTONITE shapes TAD-like boundaries through the control of H3K9ac distribution

Jing An, Rim Brik Chaouche, Leonardo I Pereyra-Bistraín, Hugo Zalzalé, Qingyi Wang, Ying Huang, Xiaoning He, Chloé Dias Lopes, Javier Antunez-Sanchez, Catherine Bergounioux, Claire Boulogne, Cynthia Dupas, Cynthia Gillet, José Manuel Pérez-Pérez, Olivier Mathieu, Nicolas Bouché, Sotirios Fragkostefanakis, Yijing Zhang, Shaojian Zheng, Martin Crespi, Magdy M Mahfouz, Federico Ariel, Jose Gutierrez-Marcos, Cécile Raynaud, David Latrasse, Moussa Benhamed

In recent years, the exploration of genome three-dimensional (3D) conformation has yielded profound insights into the regulation of gene expression and cellular functions in both animals and plants. Employing advanced high-throughput sequencing and microscopy techniques, we investigated the landscape of 26 histone modifications and RNA polymerase II distribution in tomato (Solanum lycopersicum). Our study unveiled a rich and nuanced epigenetic landscape, shedding light on distinct chromatin states associated with heterochromatin formation and gene silencing. Moreover, we elucidated the intricate interplay between these chromatin states and the overall topology of the genome. Employing a genetic approach, we delved into the role of the histone modification H3K9ac in genome topology. Notably, our investigation revealed that the ectopic deposition of this chromatin mark triggered a reorganization of the 3D chromatin structure, defining different TAD-like borders. Our work emphasizes the critical role of H3K9ac in shaping the topology of the tomato genome, providing valuable insights into the epigenetic landscape of this agriculturally significant crop species.

PNAS. July 2024

Johannes Boltze publications

Perioperative stroke deteriorates white matter integrity by enhancing cytotoxic CD8 + T‐cell activation

Yuxi Zhou, Xin Wang, Wen Yin, Yan Li, Yunlu Guo, Chen Chen, Johannes Boltze, Arthur Liesz, Tim Sparwasser, Daxiang Wen, Weifeng Yu, and Peiying Li

Here we explore the regulatory mechanisms of microglia‐mediated cytotoxic CD8+ T‐cell infiltration in the white matter injury of perioperative stroke (PIS). We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8+ T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8+ T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor‐interacting protein kinase 1 (RIPK1) activity could alleviate CD8+ T‐cell infiltration and demyelination in PIS mice. Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8+ T cells and microglia necroptosis, suggesting that modulating interactions of CD8+ T cells and microglia could be a novel therapeutic target of long‐term neurological deficits of PIS.. CNS Neuroscience and Therapeutics. July 2024

The association between air pollutant exposure and cerebral small vessel disease imaging markers with modifying effects of PRS-defined genetic susceptibility

Xiaowei Sun, Shiyang Ma, Yunlu Guo, Caiyang Chen, Lijun Pan, Yidan Cui, Zengai Chen, Rick M. Dijkhuizen, Yan Zhou, Johannes Boltze, Zhangsheng Yu, Peiying Li


Studies have highlighted a possible link between air pollution and cerebral small vessel disease (CSVD) imaging markers. However, the exact association and effects of polygenic risk score (PRS) defined genetic susceptibility remains unclear. This cross-sectional study used data from the UK Biobank. Participants aged 40–69 years were recruited between the year 2006 and 2010. The annual average concentrations of NOX, NO2, PM2.5, PM2.5–10, PM2.5 absorbance, and PM10, were estimated, and joint exposure to multiple air pollutants was reflected in the air pollution index (APEX). Air pollutant exposure was classified into the low (T1), intermediate (T2), and high (T3) tertiles.. Our study demonstrated that air pollutant exposure may be associated with CSVD imaging markers, with females being more susceptible, and that PRS-defined genetic susceptibility may modify the associations of air pollutants.

Toxicology and Environmental Safety. June 2024

Structures of wild-type and a constitutively closed mutant of connexin26 shed light on channel regulation by CO2

Deborah H. Brotherton, Sarbjit Nijjar, Christos G. Savva, Nicholas Dale, Alexander D. Cameron

Connexins allow intercellular communication by forming gap junction channels (GJCs) between juxtaposed cells. Connexin26 (Cx26) can be regulated directly by CO2. This is proposed to be mediated through carbamylation of K125. We show that mutating K125 to glutamate, mimicking the negative charge of carbamylation, causes Cx26 GJCs to be constitutively closed. Through cryo-EM we observe that the K125E mutation pushes a conformational equilibrium towards the channel having a constricted pore entrance, similar to effects seen on raising the partial pressure of CO2. In previous structures of connexins, the cytoplasmic loop, important in regulation and where K125 is located, is disordered. Through further cryo-EM studies we trap distinct states of Cx26 and observe density for the cytoplasmic loop. The interplay between the position of this loop, the conformations of the transmembrane helices and the position of the N-terminal helix, which controls the aperture to the pore, provides a mechanism for regulation.

eLife. June 2023

Membraneless channels sieve cations in ammonia-oxidizing marine archaea

Andriko von Kügelgen, C. Keith Cassidy, Sofie van Dorst, Lennart L. Pagani, Christopher Batters, Zephyr Ford, Jan Löwe, Vikram Alva, Phillip J. Stansfeld & Tanmay A. M. Bharat

Nitrosopumilus maritimus is an ammonia-oxidizing archaeon that is crucial to the global nitrogen cycle. A critical step for nitrogen oxidation is the entrapment of ammonium ions from a dilute marine environment at the cell surface and their subsequent channelling to the cell membrane of N. maritimus. Here we elucidate the structure of the molecular machinery responsible for this process, comprising the surface layer (S-layer), using electron cryotomography and subtomogram averaging from cells. We supplemented our in situ structure of the ammonium-binding S-layer array with a single-particle electron cryomicroscopy structure, revealing detailed features of this immunoglobulin-rich and glycan-decorated S-layer. This in situ structural study illuminates the biogeochemically essential process of ammonium binding and channelling, common to many marine microorganisms that are fundamental to the nitrogen cycle.

Nature. May 2024

Astrocyte ryanodine receptors facilitate gliotransmission and astroglial modulation of synaptic plasticity

Ulyana Lalo, Yuriy Pankratov

Intracellular Ca2+-signaling in astrocytes is instrumental for their brain “housekeeping” role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca2+ level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca2+-sensitive ryanodine receptors (RyRs). We explored the role for ryanodine receptors in the modulation of cytosolic Ca2+-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data demonstrate that ryanodine receptors are essential for astrocytic Ca2+-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.

Frontiers in Cellular Neuroscience. May 2024

Detection of membrane fission in single Bacillus subtilis cells during endospore formation with high temporal resolution

Ane Landajuela, Martha Braun, Christopher D.A. Rodrigues, Erdem Karatekin

Membrane fission is an essential process in all domains of life. The underlying mechanisms remain poorly understood in bacteria, partly because suitable assays are lacking. Here, we describe an assay to detect membrane fission during endospore formation in single Bacillus subtilis cells with a temporal resolution of ∼1 min. Other cellular processes can be quantified and temporally aligned to the membrane fission event in individual cells, revealing correlations and causal relationships.

STAR Protocols. March 2024

Peptidoglycan synthesis drives a single population of septal cell wall synthases during division in Bacillus subtilis

Kevin D. Whitley, James Grimshaw, David M. Roberts, Eleni Karinou, Phillip J. Stansfeld & Seamus Holden

Bacterial cell division requires septal peptidoglycan (sPG) synthesis by the divisome complex. Treadmilling of the essential tubulin homologue FtsZ has been implicated in septal constriction, though its precise role remains unclear. Here we used live-cell single-molecule imaging of the divisome transpeptidase PBP2B to investigate sPG synthesis dynamics in Bacillus subtilis. In contrast to previous models, we observed a single population of processively moving PBP2B molecules whose motion is driven by peptidoglycan synthesis and is not associated with FtsZ treadmilling. However, despite the asynchronous motions of PBP2B and FtsZ, a partial dependence of PBP2B processivity on FtsZ treadmilling was observed. Additionally, through single-molecule counting experiments we provide evidence that the divisome synthesis complex is multimeric. Our results support a model for B. subtilis division where a multimeric synthesis complex follows a single track dependent on sPG synthesis whose activity and dynamics are asynchronous with FtsZ treadmilling.

Nature Microbiology. March 2024

The contribution of an X chromosome QTL to non-Mendelian inheritance and unequal chromosomal segregation in A. freiburgense

Talal Al-Yazeedi, Sally Adams, Sophie Tandonnet, Anisa Turner, Jun Kim, Junho Lee, Andre Pires-daSilva

Auanema freiburgense is a nematode with males, females, and selfing hermaphrodites. When XO males mate with XX females, they typically produce a low proportion of XO offspring because they eliminate nullo-X spermatids. This occurs because of an unequal distribution of essential cellular organelles during sperm formation. Intriguingly, the interbreeding of two A. freiburgense strains results in hybrid males capable of producing viable nullo-X sperm. Consequently, when these hybrid males mate with females, they yield a high percentage of male offspring. To uncover the genetic basis of nullo-spermatid elimination and X- chromosome drive, we generated a genome assembly for A. freiburgense, and genotyped the intercrossed lines. This analysis identified a Quantitative Trait Locus spanning several X chromosome genes linked to the non-Mendelian inheritance patterns observed in A. freiburgense. This finding provides valuable clues to the underlying factors involved in asymmetric organelle partitioning during male meiotic division and thus non-Mendelian transmission of the X chromosome and sex ratios.

Genetics. March 2024

Liver sinusoidal cells eliminate blood-borne phage K1F

Javier Sánchez Romano, Jaione Simón-Santamaria, Peter McCourt, Bård Smedsrød, Kim Erlend Mortensen, Antonia P. Sagona, Karen Kristine Sørensen, Anett Kristin Larsen

Blood-borne phages are believed to be captured by macrophages in the liver and spleen. Since liver sinusoids also consist of specialized scavenger liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), this study investigated the contribution of both cell types in the elimination of Escherichia coli phage K1Fg10b::gfp (K1Fgfp) in mice. The results presented herein contribute to increased knowledge about the pharmacokinetics of the T7-like phage K1F in the mammalian system. The cell types of the liver that are responsible for rapid phage blood clearance are identified. Our results highlight the need for more research about appropriate dose regimens when phage therapy is delivered intravenously and advise essential knowledge about cell systems that should be investigated further for detailed phage pharmacodynamics.

mSphere. February 2024

NCAM mimetic peptide P2 synergizes with bone marrow mesenchymal stem cells in promoting functional recovery after stroke

Lan X.Y., Liang X.S., Cao M.X., Qin H.M., Chu C.Y., Boltze J., Li S.

The neural cell adhesion molecule (NCAM) promotes neural development and regeneration. Whether NCAM mimetic peptides could synergize with bone marrow mesenchymal stem cells (BMSCs) in stroke treatment deserves investigation. We found that the NCAM mimetic peptide P2 promoted BMSC proliferation, migration, and neurotrophic factor expression, protected neurons from oxygen-glucose deprivation through ERK and PI3K/AKT activation and anti-apoptotic mechanisms in vitro. Following middle cerebral artery occlusion (MCAO) in rats, P2 alone or in combination with BMSCs inhibited neuronal apoptosis and induced the phosphorylation of ERK and AKT. P2 combined with BMSCs enhanced neurotrophic factor expression and BMSC proliferation in the ischemic boundary zone. Moreover, combined P2 and BMSC therapy induced translocation of nuclear factor erythroid 2-related factor, upregulated heme oxygenase-1 expression, reduced infarct volume, and increased functional recovery as compared to monotreatments. Treatment with LY294002 (PI3K inhibitor) and PD98059 (ERK inhibitor) decreased the neuroprotective effects of combined P2 and BMSC therapy in MCAO rats. Collectively, P2 is neuroprotective while P2 and BMSCs work synergistically to improve functional outcomes after ischemic stroke, which may be attributed to mechanisms involving enhanced BMSC proliferation and neurotrophic factor release, anti-apoptosis, and PI3K/AKT and ERK pathways activation.

Journal of Cerebral Blood Flow & Metabolism. January 2024

Screening of Hydrophilic Polymers Reveals Broad Activity in 2 Protecting Phages during Cryopreservation

Huba L Marton, Apoorva Bhatt, Antonia P Sagona, Peter Kilbride, Matthew I Gibson

Bacteriophages have many biotechnological and therapeutic applications, but as with other biologics, cryopreservation is essential for storage and distribution. Macromolecular cryoprotectants are emerging for a range of biologics, but the chemical space for polymer-mediated phage cryopreservation has not been explored. Here we screen the cryoprotective effect of a panel of polymers against five distinct phages, showing that nearly all the tested polymers provide a benefit. This work shows that phages are amenable to protection with hydrophilic polymers and opens up new opportunities for advanced formulations for future phage therapies and to take advantage of the additional functionality brought by the polymers.

Biomacromolecules. December 2023

Johannes Boltze publications

Mononuclear cell therapy of neonatal hypoxic-ischemic encephalopathy in preclinical versus clinical studies: a systematic analysis of therapeutic efficacy and study design

Scrutton A. M., Ollis F., Boltze J

Hypoxic-ischemic encephalopathy (HIE) is a devastating condition affecting around 8.5 in 1000 newborns globally. Therapeutic hypothermia (TH) can reduce mortality and, to a limited extent, disability after HIE. Nevertheless, there is a need for new and effective treatment strategies. Here, we conducted a systematic review and meta-analysis. and analyzed overall MNC efficacy in preclinical trials, the methodological quality of preclinical trials, and relevant design features in preclinical versus clinical trials. Based on the analyzed data, it is unlikely that therapeutic effect size is massively overestimated in preclinical studies. It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE. Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.

Neuroprotection. December 2023

MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease

Abdul Naeem, Ravi Prakash, Neha Kumari, Mohsin Ali Khan, Abdul Quaiyoom Khan, Shahab Uddin, Sandeep Verma, Avril AB Robertson, Johannes Boltze, Syed Shadab Raza

In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in Alzheimer's disease (AD). . MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome.

Brain, Behavior and Immunity. December 2023

Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controls shade avoidance syndrome in Arabidopsis

María Florencia Mammarella, Leandro Lucero, Nosheen Hussain, Aitor Muñoz-Lopez, Ying Huang, Lucia Ferrero, Guadalupe L Fernandez-Milmanda, Pablo Manavella, Moussa Benhamed, Martin Crespi, Carlos L Ballare, Jose Gutierrez-Marcos, Pilar Cubas, Federico Ariel

The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA–DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant–environment interactions may therefore become a new tool for sustainable agriculture.

EMBO Journal. December 2023

SKN-1/NRF2 up-regulation by vitamin A is conserved from nematodes to mammals and is critical for lifespan extension in Caenorhabditis elegan

Chaweewan Sirakawin, Dongfa Lin, Ziyue Zhou, Xiaoxin Wang, Rhianne Kelleher, Shangyuan Huang, Weimiao Long, Andre Pires-da Silva, Yu Liu, Jingjing Wang, Ilya A. Vinnikov

Vitamin A (VA) is a micronutrient essential for the physiology of many organisms, but its role in longevity and age-related diseases remains unclear. In this work, we used Caenorhabditis elegans to study the impact of various bioactive compounds on lifespan. We demonstrate that VA extends lifespan and reduces lipofuscin and fat accumulation while increasing resistance to heat and oxidative stress. This resistance can be attributed to high levels of detoxifying enzymes called glutathione S-transferases, induced by the transcription factor skinhead-1 (SKN-1). Notably, VA upregulated the transcript levels of skn-1 or its mammalian ortholog NRF2 in both C. elegans, human cells, and liver tissues of mice. Moreover, the loss-of-function genetic models demonstrated a critical involvement of the SKN-1 pathway in longevity extension by VA. Our study thus provides novel insights into the molecular mechanism of anti-aging and anti-oxidative effects of VA, suggesting that this micronutrient could be used for the prevention and/or treatment of age-related disorders.

Aging Cell. December 2023

Activation of neurogenesis in the hippocampus is a novel therapeutic target for Alzheimer’s disease

Taguchi A., Okinaka Y., Takeda A., Okamoto T., Boltze J., Claussen C., Gul S

It is proposed that age-related brain dysfunction may not necessarily result from the accumulation of uncontrollable disorders, but rather the natural deterioration of brain function following expiration of the limited innate program to preserve the brain in a healthy condition. We now have identified a means by which this process could potentially be mitigated or even partially reversed by applying stem cell therapy. Furthermore, we propose that the activation of neurogenesis in the hippocampus, also through stem cell therapy, is a promising therapeutic target in AD.

Neuroprotection. November 2023

LipIDens: Simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins.

T. Bertie Ansell, Wanling Song, Claire E. Coupland, Loic Carrique, Robin A. Corey, Anna L. Duncan, C. Keith Cassidy, Maxwell M. G. Geurts, Tim Rasmussen, Andrew B. Ward, Christian Siebold, Phillip J. Stansfeld, Mark S. P. Sansom

Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures.

Nature Communications. November 2023

Post operative fibrinogen to albumin ratio acting as an indicator of futile recanalization in patients with successful thrombectomy

Tang T., Li D., Fan T.P., Guo L.J., Lan X.Y., Bi C.J., Boltze J., Thomas A.M., Zhao X.S., Mo M., Zhao M.H., Ji X., Li S

Timely recognition of futile recanalization might enable a prompter response and thus improve outcomes in patients receiving successful thrombectomy. This study aims to evaluate whether postoperative fibrinogen-to-albumin ratio (FAR) could act as an indicator of futile recanalization.This is a single-center, retrospective analysis of patients with acute anterior circulation large-vessel occlusion and successful thrombectomy between May 2019 and June 2022. A total of 255 patients were enrolled, amongst which 34.1% had high postoperative FAR. Futile recanalization was more prevalent among patients with high FAR compared to those with low FAR. After adjusting for potential confounders, high postoperative FAR was found to independently correspond with the occurrence of futile. This association was consistently observed regardless of prior antithrombotic therapy, treatment of intravenous thrombolysis, occlusion site, time from symptom onset to groin puncture, and reperfusion status. Our findings support high postoperative FAR serving as an indicator of futile recanalization in patients with anterior circulation large-vessel occlusion and successful thrombectomy.

Brain & Behavior. November 2023

Mechanism of substrate binding and transport in BASS transporters

Patrick Becker, Fiona B. Naughton, Deborah H. Brotherton, Raul Pacheco-Gomez, Oliver Beckstein, Alexander D. Cameron

The bile acid sodium symporter (BASS) family transports a wide array of molecules across membranes, including bile acids in humans, and small metabolites in plants. These transporters, many of which are sodium-coupled, have been shown to use an elevator mechanism of transport, but exactly how substrate binding is coupled to sodium ion binding and transport is not clear. Here, we solve the crystal structure at 2.3 Å of a transporter from Neisseria meningitidis (ASBTNM) in complex with pantoate, a potential substrate of ASBTNM.. Comparison of structures in the presence and absence of pantoate demonstrates that pantoate elicits a conformational change in one of the cross-over helices. This modifies the interface between the two domains that move relative to one another to elicit the elevator mechanism. These results have implications, not only for ASBTNM but for the BASS family as a whole and indeed other transporters that work through the elevator mechanism.

eLife. November 2023