bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood-based biomarkers of frailty in older patients with cancer
Authors: Akagunduz Baran , Ergün Yakup , Dog˘an Akagündüz Dig˘dem , Akbas¸ Nergis , Akagündüz Dilara , Karaog˘lu Aziz , Soysal Pinar 
Published: January 2025

Purpose of review
This review aims to evaluate the current evidence on blood-based biomarkers for frailty detection in older cancer patients. It explores the potential of various biomarkers, including inflammatory markers and microRNAs (miRNAs), to serve as indicators of frailty and examines the limitations of existing studies. The review also highlights the need for further research to validate these biomarkers and improve their clinical applicability.

Recent findings
Recent studies have examined blood biomarkers associated with frailty in older cancer patients. Findings suggest that elevated granulocyte levels and lower macrophage-derived stem cells and regulatory T cells are linked to frailty. Inflammatory biomarkers such as interleukin-6 and specific miRNAs, as well as higher neutrophil-to-lymphocyte ratios, have also been identified as potential indicators of frailty. While these biomarkers show promise, no single marker has proven sufficient, and combining them may improve frailty detection. Further research is needed to validate their clinical usefulness in this population.

Summary
Blood-based biomarkers show potential for detecting frailty in older patients with cancer, but further research is needed, particularly beyond an inflammatory focus and with more robust study designs.
Effect of Social Restriction Due to the COVID-19 Pandemic on Activity of Daily Living and Disease Severity of Patients With Alzheimer Disease: Sub-analysis of a Double-blinded Noninferiority Study of Donepezil Patches and Donepezil Tablets
Authors: Nakamura Yu , Omori Takumi , Nishiyama Kenichi , Ishikawa Ichiro , Aoki Hiroshi , Nagakura Naoki 
Published: January 2025

Background:
We previously reported that social restrictions due to the COVID-19 pandemic led to a decline in cognitive function in patients with Alzheimer disease (AD). Here, we assessed the effects of COVID-19 restrictions on the activities of daily living (ADL) and disease severity in patients by comparing them to a control group.

Methods:
We examined the impact on ADL, evaluated using disability assessment for dementia (DAD), and disease severity, evaluated using the ABC dementia scale, in patients with mild-to-moderate AD. We conducted a post hoc subgroup analysis of a double-blinded, noninferiority study of donepezil 27.5 mg patches and donepezil hydrochloride 5 mg tablets (JapicCTI-194582). After showing the noninferiority of both treatments, we combined the data from both groups for analysis.

Results:
The subpopulation of the per-protocol set grouped by completing the double-blinded evaluation before and on/after the mild lockdown was balanced (n=136 and n=120). Patient demographics were similar between the subgroups. The decline in the DAD and ABC dementia scale scores [least-squares mean (SE)] was ameliorated by social restriction [−3.810 (0.743) and −1.871 (0.697) and −1.147 (0.285) and −0.419 (0.267), respectively (not significant)].

Conclusion:
Normalcy and expectation biases can affect the evaluation of ADL and disease severity by caregivers under high stress and deterioration of mental conditions.
Fine-scale variation in pollen availability influencesBombus terrestriscolony behaviour, development and fitness
Authors: Lambert Harriet , Kopp Emanuel , Pashalidou Foteini , De Moraes Consuelo M. , Mescher Mark C. 
Published: January 2025

AbstractClimate change threatens the long-established synchronization of seasonal pollinator activity and flowering time. Bumble bees are particularly vulnerable to these shifts, with resource availability playing a significant role in colony establishment and success. Recently, we documented a mechanism whereby pollen-deprived bumble bees deliberately damaged plant leaves, speeding up the production of flowers in two different species. However, it is unknown whether bumble bees obtain a benefit through this behaviour, both on a spatial and temporal scale. In the current study, we evaluate the effects of pollen availability on colony development, behaviour and reproductive fitness inBombus terrestrisusing semi-natural and laboratory experiments. We find that the close proximity of flowers has significant effects on reproductive investment and output ofB. terrestriscolonies in a small-scale rooftop experiment. Moreover, we find that small shifts in the timing of pollen availability (5 days) shape the behaviour and development of the first generation of offspring, with significant carry-over effects on reproductive fitness forB. terrestrismicrocolonies. This suggests that small changes in the distribution of food may have significant impacts on colony success that cannot be compensated for over the course of the season. Furthermore, our findings suggest bumble bee colonies can feasibly profit by altering the timing of pollen resources, even by a few days.
Endogenous recovery of hippocampal function following global cerebral ischemia in juvenile female mice is influenced by neuroinflammation and circulating sex hormones
Authors: Vigil Jose J. , Tiemeier Erika , Orfila James E. , Chalmers Nicholas E. , Chang Victoria N. , Mitchell Danae , Veitch Isobella , Falk Macy , Dietz Robert M. , Herson Paco S. , Quillinan Nidia 
Published: January 2025

AbstractCardiac arrest-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal dependent behavior to assess hippocampal function. LTP was and contextual fear were impaired 7-days after GCI and endogenously recovered by 30-days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice which differs mechanistically from juvenile males and does not occur in adults of either sex.
Spatially-structured inflammatory response in the presence of a uniform stimulus
Authors: Jerison Elizabeth R. , Romeo Nicolas , Quake Stephen R. 
Published: January 2025

AbstractInflammatory responses occur within the complex spatial context of tissues and organs, and many questions remain about how tissue structure and cellular communication shape their spatiotemporal dynamics. Here, we use a multiplexed RNA in situ hybridization approach, together with analytical tools, to study inflammatory gene expression in the larval zebrafish tailfin in response to a bath of lipopolysaccharide (LPS). We use this model system to address whether spatial structure emerges in the tissue response even absent the spatial variation introduced by a pathogen. We find that epithelial cells in the tailfin express several pro-inflammatory genes, and that across these genes, the uniform stimulus triggers a spatially non-uniform response. We use a graph-based spectral decomposition method to analyze its structure, and find that long modes dominate, creating zones of activation. Overall, these zones account for a majority of the variation in gene expression. Our results show that epithelial cells are important producers of pro-inflammatory effector molecules in this system, and that tissue induces spatial correlations even absent a structured input.
Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation
Authors: Jami Khaled M. , Farb Daniel C. , Osumi Kayla M. , Shafer Catelynn C. , Criscione Sophie , Murray Dylan T. 
Published: January 2025

AbstractThe loss of cellular proteostasis through aberrant stress granule formation is implicated in neurodegenerative diseases. Stress granules are formed by biomolecular condensation involving protein-protein and protein-RNA interactions. These assemblies are protective, but can rigidify, leading to amyloid-like fibril formation, a hallmark of the disease pathology. Key proteins dictating stress granule formation and disassembly, such as TDP43, contain low-complexity (LC) domains that drive fibril formation. HSPB8, a small heat shock protein, plays a critical role modulating stress granule fluidity, preventing aggregation and promoting degradation of misfolded proteins. We examined the interaction between HSPB8 and the TDP43 LC using thioflavin T (ThT) and fluorescence polarization (FP) aggregation assays, fluorescence microscopy and photobleaching experiments, and crosslinking mass spectrometry (XL-MS). Our results indicate that HSPB8 delays TDP43 LC aggregation through domain-specific interactions with fibril nucleating species, without affecting fibril elongation rates. These findings provide mechanistic insight into how ATP-independent chaperones mediate LC domain aggregation and provide a basis for investigating how the TDP43 LC subverts chaperone activity in neurodegenerative disease.Significance StatementATP-independent chaperones facilitate clearance of aggregated proteins through autophagy. This study provides insight into the molecular mechanism by which small heat shock proteins interact with the aggregation-prone low complexity protein domains of RNA-binding proteins linked to neurodegenerative disease pathologies. The results provide a foundation for designing improved chaperones as therapeutics and illustrate a methodology to identify regions in low complexity domains for targeted drug development in the context of neurodegenerative disease.
Matrix stiffness induces heritable changes in chromosome numbers, consistent with solid tumor heterogeneity
Authors: Anlaş Alişya A. , Sprenger Markus T. , Wang Mai , Ontko Nick , Phan Steven , Discher Dennis E. 
Published: January 2025

AbstractSolid tumors often have an abundance of collagen-I that stiffens the tissue, and they are invariably driven by mutations that include chromosome losses and gains. These observations are linked here by showing that 3D matrix stiffness induces heritable changes to a cell’s DNA. We use live-cell chromosome reporters (ChReporters) and hydrogels of tunable stiffness to show mitotic compression, micronuclei counts, ChReporter losses and heterogeneity all increase as functions of stiffness. Increased mistakes occur despite suppressed cell division in stiff matrix and minimal size variation between spheroids. Colonies of ChReporter-negative cells within cancer spheroids align with Luria-Delbruck’s seminal theory for heritable mutations, which predicts inter-spheroid variances that exceed Poisson statistics. Suppression of the contractility motor Myosin-II also increases chromosome loss in 3D but not 2D and does not affect spheroid growth – thus clarifying Myosin-II’s putative role as a tumor suppressor. Consistent with experiments, pan-cancer analyses of clinical data associates chromosome losses and gains with collagen-I levels and genetic variation. Stiff extracellular matrix thus drives mechano-evolution of solid tumors as a Darwin-Lamarck process with heterogeneity that complicates therapy.
Microscopic and structural observations of actin filament capping and severing by Cytochalasin D
Authors: Mitani Takahiro , Takeda Shuichi , Oda Toshiro , Narita Akihiro , Maéda Yuichiro , Honda Hajime , Fujiwara Ikuko 
Published: January 2025

AbstractCytochalasin D (CytoD) is widely used to inhibit actin polymerization, but the underlying regulatory mechanism is unclear. We addressed this using Total Internal Reflection Fluorescence (TIRF) microscopy. Our time course depolymerization assay of individual actin filaments showed that CytoD tightly caps the barbed end, with an estimated Kmvalue for inhibition of 4.1 nM and a duration time of ∼1 min. Consistently, in polymerization assays, CytoD at concentrations near the Kmvalue completely suppressed barbed end elongation. Interestingly, at lower concentrations, CytoD acted as a leaky capper, allowing actin monomer addition by rapidly binding to and dissociating from barbed ends. We interpreted this contradictory behavior as arising from differences in binding modes: capping one strand (fast dissociation) or both strands (slow dissociation). CytoD severs actin filaments at micromolar levels, a concentration range commonly used in cell biological studies. Although the severing rate is slower than cofilin, the frequency is higher, resulting in the fragmentation of filaments into shorter pieces. Severing activity was suppressed by inorganic phosphate or cofilin. We determined the crystal structure of CytoD bound to filamentous conformation (F-form) actin and found that CytoD fits better in the hydrophobic cleft of F-form actin than in the monomeric conformation actin, explaining the preferential binding towards barbed end subunits. The structure further indicates that CytoD prevents barbed end depolymerization by stabilizing the terminal subunits in the F-form, which is supported by our MD simulations. Collectively, our results demonstrate how CytoD regulates actin dynamics at the molecular level.
Structural basis of undecaprenyl phosphate glycosylation leading to polymyxin resistance in Gram-negative bacteria
Authors: Ashraf Khuram U , Bunoro-Batista Mariana , Ansell T. Bertie , Punetha Ankita , Rosario-Garrido Stephannie , Firlar Emre , Kaelber Jason T. , Stansfeld Phillip J. , Petrou Vasileios I. 
Published: January 2025

AbstractIn Gram-negative bacteria, the enzymatic modification of Lipid A with aminoarabinose (L-Ara4N) leads to resistance against polymyxin antibiotics and cationic antimicrobial peptides. ArnC, an integral membrane glycosyltransferase, attaches a formylated form of aminoarabinose to the lipid undecaprenyl phosphate, enabling its association with the bacterial inner membrane. Here, we present cryo-electron microscopy structures of ArnC fromS. entericainapoand nucleotide-bound conformations. These structures reveal a conformational transition that takes place upon binding of the partial donor substrate. Using coarse-grained and atomistic simulations, we provide insights into substrate coordination before and during catalysis, and we propose a catalytic mechanism that may operate on all similar metal-dependent polyprenyl phosphate glycosyltransferases. The reported structures provide a new target for drug design aiming to combat polymyxin resistance.
High-Throughput Glycan Array Screening Reveals Rhamnogalacturonan-I as a Ligand for Arabidopsis Leucine-Rich Repeat Receptor Kinases
Authors: Lee Du-Hwa , Ruprecht Colin , Lee Jung-Min , Choi Min-Soo , Hrovat Tobias , Heo Geon , Edelbacher Natalie , Enugutti Balaji , Blaukopf Markus , Cho Chung Hyun , Lee Ho-Seok , Belkhadir Youssef , Smakowska-Luzan Elwira , Pfrengle Fabian 
Published: January 2025

AbstractThe plant cell wall not only serves as a physical barrier against pathogens but, when damaged, also functions as a source of cell wall-derived molecules that play crucial roles in plant immunity as damage-associated molecular patterns (DAMPs). While oligogalacturonides from homogalacturonan are well-studied DAMPs, the immune-signaling potential of other cell wall components remains largely unexplored. Conventional genetic and biochemical approaches aimed at identifying ligand-receptor pairs in plant immunity have been limited by the vast diversity of potential ligand molecules and functional redundancy of putative receptors. Here, we developed a high-throughput screening pipeline that simultaneously examines multiple interactions between plant cell wall-derived glycans and >350 extracellular domains (ECDs) of receptor kinases and receptor like proteins in Arabidopsis, resulting in the screening of >40,000 interactions. We discovered a group of leucine-rich repeat receptor kinases named ARMs (AWARENESS of RG-I MAINTENANCES) that interact with rhamnogalacturonan-I (RG-I), a major component of pectin. RG-I treatment induced pattern-triggered immunity responses, with distinct kinetics compared to oligogalacturonide responses. We identified RG-I oligosaccharide structures required for interaction with ARM receptors and immune activation, and found that ARM receptors are redundantly involved in plant immunity. Thus, our approach provides a powerful platform for discovering glycan-receptor pairs in plants.
Aging: an inevitable road toward gut microbiota pathoadaptation
Authors: Melo-Miranda Rita , Pinto Ana , Barreto Hugo C. , Jesus Catarina , Gordo Isabel , Duarte Iola , Sousa Ana 
Published: January 2025

SUMMARYLaboratory-raised mice live approximately seven times longer and healthier lives compared to their wild counterparts, due to a standardized healthy diet and limited exposure to environmental stressors1.Aging is associated with increased inflammation and microbial dysbiosis2–4. Collectively, these influence microbiota evolution and may contribute to the enrichment in pathobiont frequency observed in old age4. Alternatively, this increase could stem from a decline in colonization resistance5,6, creating favorable conditions for pathobiont invasion.Here, we sought to test whether aging in healthy, controlled conditions, could prevent the selection of age-associated pathobionts.We have followed the adaptive evolution of a commensal strain ofEscherichia coliin the guts of mice of advanced age and found that it acquired several mutations common to bacteria colonizing young mice, which were absent in old animals. This, together with the increase inAkkermansia muciniphilain mice of advanced age, suggest healthy aging7,8.However, mutations acquired exclusively in the older were mainly pathoadaptive, tuning the metabolism to oxygen and iron availability, hypermotility, and biofilm formation.In summary, while the evolutionary signature in the guts of very old mice shows youth-like features that may be associated with longevity, the selection of pathoadaptive traits is magnified in very old age.While suggesting that a breach in colonization resistance is not needed to justify the abundance of age-associated pathobionts, our findings raise the question whether specialized bacteria, as opposing to generalists such asE. coli, will display the same ability to evolve pathoadaptive traits.HighlightsGut commensals face increasingly personalized selective pressures in the aging gutEven healthy aging selects for pathoadaptive traits in the gut microbiotaE. coli‘s adaptive pattern better reflects the metabolome than microbiota compositionIn BriefPathobionts are often enriched in the microbiota of the elderly. Melo-Miranda et al. showed that irrespectively of limiting the opportunity for gut invasion, the strength of selection for pathoadaptation increases with aging. Yet, the gut environment of extreme ages seems to converge, highlighting the discontinuity of the aging process.
High-Throughput Site-Specific N-Glycosylation Profiling of Human Fibrinogen in Atrial Fibrillation
Authors: Šoić Dinko , Kifer Domagoj , Szavits-Nossan Janko , Blivajs Aleksandar , Đerek Lovorka , Rudan Diana , Gornik Olga , Gudelj Ivan , Keser Toma 
Published: January 2025

AbstractFibrinogen is a major plasma glycoprotein involved in blood coagulation and inflammatory responses. Alterations in its glycosylation have been implicated in various pathological conditions, yet its site-specific N-glycosylation profile remains largely unexplored in a clinical context. Here, we present a high-throughput LC-MS workflow for site-specific analysis of fibrinogen N-glycosylation using a cost-effective ethanol precipitation enrichment method. The method demonstrated good intra- and inter-plate repeatability (CV: 5% and 12%, respectively) and was validated through the first assessment of intraindividual temporal stability in healthy individuals, revealing consistent glycosylation patterns within individuals. Application to 181 atrial fibrillation (AF) patients and 52 healthy controls identified three gamma chain glycoforms significantly associated with AF. Most notably, increased levels of the asialylated N4H5, known to enhance fibrin bundle thickness and promote clot formation, suggest a potential mechanism linking glycosylation changes to the prothrombotic state in AF. Furthermore, fibrinogen sialylation showed strong associations with cardiovascular risk factors, including triglycerides, BMI, and glucose levels. Longitudinal analysis of 108 AF patients six months post-catheter ablation showed stability in the AF-associated glycan profile. Our findings establish fibrinogen glycosylation as a potential biomarker for cardiovascular conditions and demonstrate the utility of site-specific glycosylation analysis for clinical applications.
Optimizing DNA origami assembly through selection of scaffold sequences that minimise off-target interactions
Authors: Shirt-Ediss Ben , Torelli Emanuela , Navarro Silvia Adriana , Khamis Hadeel , Kaplan Ariel , Trewby William , Elezgaray Juan , Moradzadeh-Esmaeili Nima , Haydell Michael , Keppner Daniel , Famulok Michael , Krasnogor Natalio 
Published: January 2025

AbstractDNA origami is a mainstay of DNA nanotechnology and several efforts have been devoted to understanding how various factors of the self-assembly reaction affect the final yield of the target origami structure. This study analyses how base sequence affects origami yield through the generation of off-target side reactions during selfassembly. Off-target bindings are an under-explored phenomenon and can potentially introduce unwanted assembly barriers and kinetic traps in the origami folding pathway. We developed a multi-objective computational approach that takes a given origami design and scores different scaffold sequences (and their complementary staples) for the prevalence of four different types of off-target binding events. Using our method on DNA origami, we can select ‘bad’ regions of biological sequences (like lambda DNA phage) that, when used as origami scaffold sequences, have an excessive number of off-target side reactions for each shape. We show, using high-resolution atomic force microscopy (AFM), that these scaffold sequences largely fail to fold into the target triangle or rectangle structurein vitro, despite the scaffold sequence having a fully complementary staple set present. Conversely, using our method we can also select ‘good’ regions of biological sequences. These sequences are deficient in off-target reactions and when used as origami scaffolds, fold more successfully into their target structures as characterised by AFM.These results have been validated in “blind” folding experiments at two different laboratories in which the experimenters did not know which scaffolds were good or bad folders. To further investigate assembly behaviour, optical tweezers experiments revealed distinct mechanical response profiles, correlating with scaffold-specific off-target interactions. While variants with higher GC content show a high mean unfolding force, variants with lower off-target binding demonstrated more uniform force-extension curves. Our analysis confirmed that high off-target binding leads to increased structural heterogeneity, as seen in the clustering behaviour of unfolding traces of OT experiments. Over-all, our work demonstrates how the off-target reactions implicit in base sequences can derail the origami self-assembly process if sufficiently prevalent, and we provide a software tool to select scaffold sequences that minimise off-target reactions for any DNA origami design.