bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolving atomic-level dynamics and interactions of high molecular weight hyaluronic acid by multidimensional solid-state NMR
Authors: Rampratap Pushpa , Lasorsa Alessia , Arunachalam Abinaya , Kamperman Marleen , Walvoort Marthe T.C. , van der Wel Patrick C.A. 
Published: March 2024

AbstractHigh molecular weight (HMW) hyaluronic acid (HA) is a highly abundant natural polysaccharide and a fundamental component of the extracellular matrix (ECM). Its size and concentration regulate tissues’ macro- and microenvironments, and its upregulation is a hallmark feature of certain tumors. Yet, the conformational dynamics of HMW-HA and how it engages with components of the ECM microenvironment remain poorly understood on the molecular level. Probing the molecular structure and dynamics of HMW polysaccharides in a hydrated, physiological-like environment is crucial but also technically challenging. Here, we deploy advanced magic-angle-spinning (MAS) solid-state NMR (ssNMR) spectroscopy in combination with isotopic enrichment to enable an in-depth study of HMW-HA to address this challenge. This approach resolves multiple coexisting HA conformations and dynamics as a function of environmental conditions. By combining13C-labeled HA with unlabeled ECM components, we detect by MAS NMR HA-specific changes in global and local conformational dynamics as a consequence of hydration and ECM interactions. These measurements reveal atom-specific variations in dynamics and structure of the N-acetylglucosamine (GlcNAc) moiety of HA. We discuss possible implications for interactions that stabilize the structure of HMW-HA and facilitate its recognition by HA-binding proteins. The described methods apply similarly to studies of the molecular structure and dynamics of HA in tumor contexts and in other biological tissues, as well as HMW-HA hydrogels and nanoparticles used for biomedical and/or pharmaceutical applications.
PI3K-dependant reprogramming of hexokinase isoforms controls glucose metabolism and functional responses of B lymphocytes
Authors: Paradoski Brandon T , Hou Sen , Mejia Edgard M , Olayinka-Adefemi Folayemi , Fowke Danielle , Hatch Grant M , Saleem Ayesha , Banerji Versha , Hay Nissim , Zeng Hu , Marshall Aaron J 
Published: March 2024

AbstractB lymphocyte metabolic reprogramming is essential for B cell differentiation and mounting a healthy immune response. The PI3K signaling pathway regulates B cell metabolism, but the mechanisms involved are not well understood. Here we report that signaling via PI3K8 can impact B cell glucose metabolism and immune functions via selective upregulation of hexokinase 2 (HK2). Three HK enzymes can catalyze the critical first step for glucose utilization and may selectively direct glucose into specific catabolic and anabolic pathways. While HK1 is constitutively expressed in B cells, HK2 is strikingly upregulated during B cell activation in a PI3K8-dependent manner. HK2 shows a unique distribution between mitochondrial and cytoplasmic pools that is also regulated by PI3K. Genetic deletion of HK2 significantly impairs extracellular acidification rate and glycolytic ATP production despite strong expression of HK1. B cell-specific deletion of HK2 in mice caused mild perturbations in B cell development but did not prevent generation of mature B cell subsets. HK2-deficient B cells show altered functional responsesin vitroand evidence of metabolic adaptation to become less dependent on glucose and more dependent on glutamine. HK2-deficient B cells exhibit impaired glycolysis, altered metabolite profiles and altered flux of labeled glucose carbons into the pentose phosphate pathway. Upon immunization, HK2-deficient mice exhibit impaired generation of germinal centre B cells, plasmablasts and antibody responses. We further found that HK2 expression in primary human chronic lymphocytic leukemia (CLL) cells was associated with recent proliferation and could be reduced by PI3K inhibition. Our study identifies hexokinase 2 upregulation as a functionally important component of B cell metabolic reprogramming dependent on the PI3K pathway.
Secondary microglia formation center in the human fetal brain
Authors: Song Chenyun , Chen Xinyu , Ji Rong , Liu Yang , Zhang Ling , Gao Lu , He Qizhi , Ma Lixiang , Saiyin Hexige 
Published: March 2024

AbstractYolk sac-derived microglia migrate and populate the brain during development, constituting 10−15% of the total brain cells. The human brain is the largest and most complex brain with the highest cognitive capacity among all species. Therefore, the limitations of rodent brain studies in interpreting the human brain are evident. By co-immunostaining microglia in 50 µm fetal brain sections from 7.5 to 16 gestational weeks (gw) and combining high-resolution scanning, we identified a highly proliferative microglia aggregate (0.108−2.129 mm2) that expanded in Down’s Syndrome fetal brain (4.168 mm2) and was located near the ganglion eminence, in which Ki67+microglia accounted for 23.4% of total microglia compared to 6.3% in other brain regions. The microglia in the aggregates lack phagocytic bulbs, membrane ruffles, and long/branching processes compared to microglia in other brain regions. Introducing human microglia into cortical organoids, but not macrophages, replicated proliferative microglial aggregates on the brain organoid surface and sufficiently penetrated deeper regions of the cortical organoids. Penetrating microglia display phagocytic capacity, enhance immunity, and accelerate the maturation of brain organoids. The large proliferative microglial aggregate may be a unique secondary microglial formation center in the human fetal brain to compensate for the enormous microglial demands during brain expansion.
Indirect Haptic Disturbances Enhance Motor Variability, with Divergent Effects on Skill Transfer
Authors: Arink Wouter , Poggensee Katherine L. , Beckers Niek , Abbink David A. , Marchal-Crespo Laura 
Published: March 2024

AbstractResearch on motor learning has found evidence that learning rate is positively correlated with the learner’s motor variability. However, it is still unclear how to robotically promote that variability without compromising the learner’s sense of agency and motivation, which are crucial for motor learning. We propose a novel method to enhance motor variability during learning of a dynamic task by applying pseudorandom perturbing forces to the internal degree of freedom of the dynamic system rather than directly applying the forces to the learner’s limb. Twenty healthy participants practiced swinging a virtual pendulum to hit oncoming targets, either with the novel method or without disturbances, to evaluate the effect of the method on motor learning, skill transfer, motivation, and agency. We evaluated skill transfer using two tasks, changing either the target locations or the task dynamics by shortening the pendulum rod. The indirect haptic disturbance method successfully increased participants’ motor variability during training compared to training without disturbance. Although we did not observe group-level differences in learning, we observed divergent effects on skill generalization. The indirect haptic disturbances seemed to promote skill transfer to the altered task dynamics but limited transfer in the task with altered target positions. Motivation was not affected by the haptic disturbances, but future work is needed to determine if indirect haptic noise negatively impacts sense of agency. Increasing motor variability by indirect haptic disturbance is promising for enhancing skill transfer in tasks that incorporate complex dynamics. However, more research is needed to make indirect haptic disturbance a valuable tool for real-life motor learning situations.
Pharmacological Characterization of SDX-7320/Evexomostat: a Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-Tumor and Anti-Metastatic Activity
Authors: Cornelius Peter , Mayes Benjamin A. , Petersen John S. , Turnquist David J. , Dufour Pierre J. , Shanahan James M. , Carver Bradley J. 
Published: March 2024

AbstractMethionine aminopeptidase type 2 (MetAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. MetAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of MetAP2-specific substrates whose biological activity may be altered following MetAP2 inhibition, and additionally, that MetAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of MetAP2 using fumagillin analogs has established the anti-angiogenic and anti-tumor characteristics of these derivatives, however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting CNS toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer-drug conjugate of the novel MetAP2 inhibitor (MetAP2i) SDX-7539.In vitrobinding, enzyme and cell-based assays demonstrated that SDX-7539 is a potent and selective MetAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, MetAP2i SDX-7539, limitations observed with prior generation, small-molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the MetAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer-drug conjugates in general, reductions in small molecule-equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a Phase 1 clinical safety study in late-stage cancer patients and is currently being evaluated in multiple Phase 1b/2 clinical studies in patients with advanced solid tumors.
The influence of scaffold deformation and fluid mechanical stimuli on bone tissue differentiation
Authors: Moliner Laia , Wills Carlos Ruiz , Camara Oscar , Olivares Andy L. 
Published: March 2024

AbstractBone tissue engineering enables the self-healing of bone fractures avoiding the graft surgery risks. Scaffolds are designed to transfer global mechanical load to cells, and the structure-blood flow interaction is crucial for cell differentiation, proliferation, and migration. Numerical models often consider the effect of solid on the fluid or vice-versa, nevertheless, fluid-structure interactions (FSI) are not usually explored. The present study aims to develop in-silico FSI models to evaluate tissue differentiation capability of different scaffold designs. This is accomplished by analyzing the relation between scaffold strain deformation and fluid mechanical stimuli developed at the cell microscopic level. Cubic regular structures with cylinder and sphere pore based of 60%, 70% and 80% porosity were modelled in finite element analysis. Static or dynamic compression and inlet steady state or transient state fluid profile were considered. Fluid-structure interactions have been performed, and cell differentiation studies considering the octahedral shear strain and fluid shear stress have been compared. Results indicate that high porous scaffold with low compression and fluid perfusion rates promote bone tissue proliferation. Moreover, mechanical stimulation seems to help bone formation and to inhibit cartilage phenotype. Results showed that neglecting the interaction between the scaffold and fluid flow could lead to substantial overestimation of bone differentiation. This study enhances our understanding of the role of dynamic mechanical simulations in tissue formation; allowing the improvement of scaffold design to face complex bone fractures.
The molecular landscape of cellular metal ion biology
Authors: Aulakh Simran Kaur , Lemke Oliver , Szyrwiel Lukasz , Kamrad Stephan , Chen Yu , Hartl Johannes , Muelleder Michael , Nielsen Jens , Ralser Markus 
Published: March 2024

SummaryMetal ions play crucial roles in cells, yet the broader impact of metal availability on biological networks remains underexplored. We generated genome-wide resources, systematically quantifying yeast cell growth, metallomic, proteomic, and genetic responses upon varying each of its essential metal ions (Ca, Cu, Fe, K, Mg, Mn, Mo, Na, Zn), over several orders of magnitude. We find that metal ions deeply impact cellular networks, with 57.6% of the proteome, including most signalling pathways, responding. While the biological response to each metal is distinct, our data reveals common properties of metal responsiveness, such as concentration interdependencies and metal homeostasis. We describe a compendium of metal-dependent cellular processes and reveal that several understudied genes can be functionally annotated based on their metal responses. Furthermore, we report that metalloenzymes occupy central nodes in the metabolic network and are more likely to be encoded by isozymes, resulting in system-wide responsiveness to metal availability.
Gene expression and eQTL analysis reflect the heterogeneity in the inflammatory status of the duodenal epithelial lining in coeliac disease
Authors: Ramírez-Sánchez Aarón D. , Zühlke Stephanie , Aguirre-Gamboa Raúl , Vochteloo Martijn , Franke Lude , Lundin Knut E.A. , Withoff Sebo , Jonkers Iris H. 
Published: March 2024

AbstractIn coeliac disease (CeD), the epithelial lining (EL) of the small intestine is severely damaged through a complex auto-inflammatory response that results in intraepithelial lymphocytes (IELs) attacking epithelial cells (ECs). To better understand the changes occurring in the EL in CeD, including after initiation of a gluten-free diet, and the regulatory mechanisms that affect mucosal homeostasis, we investigated ECs and IELs in the CeD duodenal EL using RNA-seq and eQTL analysis on predicted cell types. The study included 82 duodenal biopsies from volunteers, grouped into controls (CTRL), gluten-free diet treated CeD (TCD) and untreated CeD (UCD). We identified 2,868 differential expressed genes, which clustered into four sets with specific functions related to CeD. Two sets, one upregulated for cell cycle function and one downregulated for digestion, transmembrane transport, and laminin pathways, defined three groups of samples based on inflammation status: non-inflamed, mild inflammation or severe inflammation. These inflammation states correlated with but were not specific to disease state. The remaining two sets of genes were enriched for immune, extracellular matrix, and barrier functions. These latter two sets allowed the classification of samples into their disease conditions: CTRL, TCD, and UCD. Finally, deconvoluting eQTL effects from ECs and immune cells in the EL identified 7 and 9 cell-type-mediated eQTL genes, respectively. In sum, we identified genes expressed in the duodenal EL whose expression might be used as biomarkers to assess CeD condition and its mucosal and immune status.HighlightsGene expression in epithelial lining in CeD patients reflects inflammation statusThe transcriptome can classify epithelium as no, mild, or severe inflammationCell cycle, absorption, and basal lamina genes are indicators of mucosal damageImmune and extracellular matrix genes distinguish untreated from treated casesPredicted-cell-type eQTLs pinpoint effects in immune and epithelial cells
Remembrance with gazes passed: Eye movements precede continuous recall of episodic details of real-life events
Authors: Barker Ryan M. , Armson Michael J. , Diamond Nicholas B. , Liu Zhong-Xu , Wang Yushu , Ryan Jennifer D. , Levine Brian 
Published: March 2024

AbstractAutobiographical memory entails reconstructing the visual features of past events. Eye movements are associated with vivid autobiographical recollection, but this research has yet to capitalize on the high temporal resolution of eye-tracking data. We aligned eye movement data with participants’ simultaneous free recall of a verified real-life event, allowing us to assess the temporal correspondence of saccades to production of episodic and non-episodic narrative content at the millisecond level. Eye movements reliably predicted subsequent episodic – but not non-episodic – details by 250-1100 ms, suggesting that they facilitate episodic recollection by reinstating spatiotemporal context during vivid recollection. Assessing the relationship of oculomotor responses to naturalistic memory informs theory as well as diagnosis and treatment of conditions involving pathological recollection, such as Alzheimer’s disease and post-traumatic stress disorder (PTSD).
The potential of undersown species identity vs. diversity to manage disease in crops
Authors: Cappelli Seraina Lisa , Domeignoz Horta Luiz Alberto , Gerin Stephanie , Heinonsalo Jussi , Lohila Annalea , Raveala Krista , Schmid Bernhard , Shrestha Rashmi , Tiusanen Mikko Johannes , Thitz Paula , Laine Anna-Liisa 
Published: March 2024

AbstractIn the absence of chemical control with its negative side effects, fungal pathogens can cause large yield losses, requiring us to develop agroecosystems that are inherently disease resistant. Grassland biodiversity experiments often find plant species diversity to reduce pathogen pressure, but whether incorporating high biodiversity levels in agricultural fields have similar effects remains largely unknown.We tested if undersown plant species diversity could reduce barley disease, and whether the effect was mediated through above- or belowground mechanisms, by combining an agricultural field trial with a soil transplant experiment.As predicted, barley disease decreased in the presence of undersown plants. Undersown species richness had no effect, but their abundance led to early season disease reduction. Aboveground mechanisms underpinned this disease reduction. Barley yield slightly decreased with increasing undersown species richness, and undersown species varied in their impact on yield.We identified two undersown species with similar functional traits that contributed most to disease reduction and had the potential to increase barley yield. Furthermore, our results indicate that aboveground mechanisms caused this. We show that agroecosystem functioning can be improved without trade-offs on yield by targeted selection of undersown species.
Direct retino-iridal projections and intrinsic iris contraction mediate the pupillary light reflex in early vertebrates
Authors: Jiménez-López Cecilia , Rivas-Ramírez Paula , Barandela Marta , Núñez-González Carmen , Megías Manuel , Pérez-Fernández Juan 
Published: March 2024

AbstractThe pupillary light reflex (PLR) adapts the amount of light reaching the retina, protecting it and improving image formation. Two PLR mechanisms have been described in vertebrates. First, the pretectum receives retinal inputs and projects to the Edinger-Westphal nucleus (EWN), which targets the ciliary ganglion through the oculomotor nerve (nIII). Postganglionic fibers enter the eye-globe, travelling to the iris sphincter muscle. Additionally, some vertebrates exhibit an iris-intrinsic PLR mechanism mediated by sphincter muscle cells that express melanopsin inducing muscle contraction. Given the high degree of conservation of the lamprey visual system, we investigated the mechanisms underlying the PLR to shed light onto their evolutionary origins. Recently, a PLR mediated by melanopsin was demonstrated in lampreys, suggested to be brain mediated. Remarkably, we found that PLR is instead mediated by direct retino-iridal cholinergic projections, a mechanism not demonstrated before, although suggested to be present in mice. This retina-mediated PLR acts synergistically with the iris-intrinsic mechanism mediated by melanopsin, which has contribution of gap junctions, as in other vertebrates. In contrast, we show that lampreys lack the brain-mediated PLR. Our results suggest that two eye-intrinsic PLR mechanisms were present in early vertebrate evolution, whereas the brain-mediated PLR has a more recent origin.
Evaluating the representational power of pre-trained DNA language models for regulatory genomics
Authors: Tang Ziqi , Somia Nirali , Yu Yiyang , Koo Peter K 
Published: March 2024

ABSTRACTThe emergence of genomic language models (gLMs) offers an unsupervised approach to learning a wide diversity ofcis-regulatory patterns in the non-coding genome without requiring labels of functional activity generated by wet-lab experiments. Previous evaluations have shown that pre-trained gLMs can be leveraged to improve predictive performance across a broad range of regulatory genomics tasks, albeit using relatively simple benchmark datasets and baseline models. Since the gLMs in these studies were tested upon fine-tuning their weights for each downstream task, determining whether gLM representations embody a foundational understanding ofcis-regulatory biology remains an open question. Here we evaluate the representational power of pre-trained gLMs to predict and interpret cell-type-specific functional genomics data that span DNA and RNA regulation. Our findings suggest that probing the representations of pre-trained gLMs do not offer substantial advantages over conventional machine learning approaches that use one-hot encoded sequences. This work highlights a major gap with current gLMs, raising potential issues in conventional pre-training strategies for the non-coding genome.
Beta Cells Deficient forRenalaseCounteract Autoimmunity by Shaping Natural Killer Cell Activity
Authors: Bode Kevin , Wei Siying , Gruber Isabella , Kissler Stephan , Yi Peng 
Published: March 2024

ABSTRACTType 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating of theRenalase(Rnls) gene. Here we demonstrate thatRnlsloss-of-function in beta cells shape autoimmunity by mediating a regulatory Natural Killer (NK) cell phenotype important for the induction of tolerogenic antigen presenting cells.Rnls-deficient beta cells mediate cell-cell-contact-independent induction of hallmark anti-inflammatory cytokine Tgfβ1 in NK cells. In addition, surface expression of key regulatory NK immune checkpoints CD47 and Ceacam1 are markedly elevated on beta cells deficient forRnls. Enhanced glucose metabolism inRnlsmutant beta cells is responsible for upregulation of CD47 surface expression. These findings are crucial to a better understand how genetically engineered beta cells shape autoimmunity giving valuable insights for future therapeutic advancements to treat and cure T1D.Graphical summary