bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s disease histopathology in the human Down syndrome retina and in hiPSC‐derived retinal organoids
Authors: Vergara M. Natalia , James Ethan , Ha Michael , Aguilera‐Rico Citlali 
Published: January 2025

AbstractBackgroundDown Syndrome (DS) is a genetic disorder caused by the triplication of human chromosome 21 that affects approximately 1 in 700 people born in the U.S. People with DS are at a greater risk of developing Alzheimer’s disease (AD), with practically all individuals developing AD histopathology and more than half progressing to dementia. However, the histopathological manifestations of AD in the DS retina have not yet been investigated. Closing this knowledge gap could lead to improved AD diagnosis and treatment for individuals with DS, since retinal structural and functional features are increasingly being explored as biomarkers of AD. In this study, we evaluated the presence of AD histopathology in human cadaver retinas from donors with DS as well as disomic controls. Moreover, we developed the first retinal organoid (RO) models of DS using patient‐derived induced pluripotent stem cells (iPSC) and evaluated their ability to recapitulate AD histopathology.MethodDe‐identified human cadaver eyes from individuals with DS and disomic controls were obtained from the Miracles in Sight Eye Bank, fixed, embedded in paraffin or OCT, and sectioned for histopathological analysis. Human iPSC‐derived ROs were generated from disomic controls and donors with DS using the Zhong et al. (2014) protocol and collected at 100 days of differentiation. AD histopathology was assessed by immunoblotting and immunofluorescence staining, including retinal cell type‐specific markers and amyloid‐β (Aβ), phosphorylated Tau (pTau), and NIAD‐4 staining for amyloid plaques.ResultHistopathological analysis of human cadaveric donor retinas indicated an increased deposition of Aβ plaques and pTau in retinas from individuals with DS compared to control donor retinas, consistent with the pathology observed in the brain. DS‐ROs developed a full component of neural retinal cell types and exhibited elevated levels of Aβ plaques and pTau compared to control ROs, mirroring the phenotype observed in the native DS retina.ConclusionAD histopathology can be observed in the human DS retina and in stem cell‐derived RO models of DS. These DS‐RO models may open new opportunities for drug screening and biomarker discovery, as well as enable comparative pathophysiological studies between DS‐ROs and the recently developed AD‐ROs.
Modeling sex differences in Alzheimer’s Disease using isogenic hiPSC lines with different sex chromosome complements and APOE alleles
Authors: Filippova Gala N , Casad Michelle , Groneck Camille , Hui Katherine , Mishra Swati , MacDonald James W , Bammler Theo , Van Dyke Daniel L , Skakkebaek Anna , Gravholt Claus H , Mathieu Julie , Deng Xinxian , Berletch Joel B , Jayadev Suman , Disteche Christine M , Young Jessica E. 
Published: January 2025

AbstractBackgroundLate Onset Alzheimer’s Disease (LOAD) is the most common neurodegenerative disorder. Carriers of an ɛ4 allele of the apolipoprotein E gene (APOE) have significantly increased risk of developing LOAD. LOAD is also strongly sex biased. Besides the well‐established role of sex hormones, the impact of genetic sex combined with APOE genotypes has not been studied. Sex chromosome dosage (SCD) is the main genetic difference between females (XX) and males (XY). Despite dosage compensation by X chromosome inactivation (XCI), some X‐linked genes remain expressed from the inactive X (Xi) and are female biased in expression. Many of these genes are related to neurological and immune functions and could contribute to neuroinflammation in AD.MethodTo understand the genetic interactions between autosomal risk (APOE) and sex‐bias in AD, we are generating isogenic sets of hiPSCs with various sex chromosome complements and APOE genotypes. We have derived XXY/XY, XY/X, and XX/X isogenic pairs by reprogramming cells from naturally mosaic individuals or by selective removal of the Xi in vitro. These lines uniquely position us to differentiate the effects of X chromosome dosage and/or presence of a Y chromosome, while minimizing genetic variability and environmental or hormonal confounders. Currently, we are also constructing APOE ɛ3 and ɛ4 alleles in our paired hiPSC lines with differing sex chromosome content using gene editing.ResultStarting from an XXY/XY isogenic pair, we have generated an hiPSC series with six different genotypes of APOE ɛ3/ɛ3, ɛ3/ɛ4 or ɛ4/ɛ4 alleles with either the XXY or XY genotype. Preliminary results in differentiated neural precursor cells show differential expression of sex‐linked genes in relation to SCD. We also observed genome‐wide changes in gene expression and DNA methylation. Subsets of autosomal sex‐biased genes were differentially affected either by X chromosome dosage, presence of a Y, or both.ConclusionThe new hiPSC lines are being differentiated to AD‐relevant cell types, including neurons, microglia, and cortical organoids, for transcriptomic and functional analyses to elucidate how APOE alleles and genetic sex interact to modulate risk in LOAD pathology.
Comparison among three kinds of assessment for the Mild Behavioral Impairment Checklist (MBI‐C)
Authors: Hwang Tzung‐Jeng , Yang Cho‐Hsiang , Lin Yi‐Ting 
Published: January 2025

AbstractBackgroundMild Behavioral Impairment (MBI) is a construct that describes the emergence of sustainable and at least mildly impactful neuropsychiatric symptoms (NPS) after age 50. The Mild Behavioral Impairment Checklist (MBI‐C) is a provisional tool used to measure the NPS of MBI. However, who should provide the information for the assessment of the NPS remained unclear.MethodWe recruited 123 MBI participant‐informant dyads from a psychiatric outpatient clinic of a university medical center. The MBI‐C was administered to both the participant (MBI‐self) and informant (MBI‐I). Then, a researcher (psychologist) compared the two results, clarified the differences, and made the final assessment (MBI‐R).ResultThere were 49 with MBI only and 74 with MBI plus MCI. Among the 123 MBI subjects, the mean MBI‐C total score was 6.06 (SD 6.7), 5.27 (SD 7.67), and 6.34 (SD 6.4) for MBI‐S, MBI‐I, and MBI‐R. There was no significant difference among the three. However, for the motivation domain, the MBI‐S and MBI‐R scoring was significantly higher than the MBI‐I scoring (p < 0.001). For the affect domain, the MBI‐R scoring was significantly higher than the MBI‐I scoring (p = 0.019). For the social domain, the MBI‐I scoring was significantly higher than the MBI‐S scoring (p = 0.012). There were no significant differences among the 3 scorings for the impulse or psychosis domains. When we examined each item in the 5 domains, the general tendency was consistent with the findings mentioned above, except that there were 3 items in the impulse domain showing a significant difference among the 3 scorings (MBI‐I, MBI‐R > MBI‐S).ConclusionOur findings showed there might be differences among the 3 kinds of scorings for the 5 MBI domains. If the MBI‐R scoring was treated as the gold standard, it was close to the MBI‐S scoring but higher than the MBI‐I scoring for the motivation and affect domain. For the social domain, the MBI‐R scoring was close to the MBI‐I but higher than the MBI‐S.
Identifying medical phenotypes associated with microglia‐expressing AD risk genes
Authors: Zhong Xue , Zhou Dan , Li Bingshan , Cox Nancy J 
Published: January 2025

AbstractBackgroundA recent study with large samples of electronic health records (EHRs) suggested Shingles vaccination may reduce dementia risk. Although further investigation is needed to pinpoint the underlying mechanism, such observation adds to the evidence for a connection between peripheral and central nervous system immunity. Since microglia is the major cell type implicated in AD genetics, here, we set out to probe the shared biology between microglia in human brain and macrophages in peripheral system, through the common genes that express in both cell types.MethodFirst, we identified a set of high‐confidence AD risk genes through integrative analysis of AD GWAS and human‐brain‐related genomic features. Then, we used eQTLs from human microglia to derive the eGene direction affected by AD risk alleles. For these AD‐associated eGenes, we predicted their expressions in peripheral tissues (whole blood, gut, lung, liver etc.) known to be enriched for macrophages with the use of UK biobank (UKB) data and prediction models pre‐trained by Genotype‐Expression project (GTEx) data. Finally, we tested the association of these genetically‐predicted gene expressions across ∼1000 medical phenotypes in UKB., followed by a replication analysis in the biobank of Vanderbilt University Medical Center (VUMC) to identify robust gene‐phenotype associations.ResultThe resulting associations (after adjustment for multiple testing), implicated inflammatory phenotypes, which include the association of connective tissue diseases with increased expression of CTSH, Emphysema with increased expression of TSPAN14, Edema with increased expression of PTK2B, Herpes simplex with reduced expression of PLCG2, and uterine inflammatory disease with increased expression of CD79B. The directions of these associations are all consistent with the regulatory direction in gene expression in human microglia by AD risk alleles.ConclusionWe demonstrated that in peripheral tissues enriched for macrophages, AD risk genes that function in microglia were associated with inflammatory phenotypes in directions consistent with that observed in microglia, suggesting shared immune biology.
Cognitive impairment due to ischemic stroke in female rats is associated with secondary neurodegeneration, and attenuated with microRNA‐20a‐3p as assessed by diffusion tensor MR imaging and histological analysis
Authors: Sampath Dayalan , Singer Jacob , Gopalakrishnan Balaji , Akbari Zara , Villarreal Monserrat , Hurst David A , Noarbe Brenda P , Obenaus Andre , Sohrabji Farida 
Published: January 2025

AbstractBackgroundOur studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke in the acute phase and also attenuates long term cognitive decline in middle‐aged female rats. Cognitive decline due to vascular diseases, such as stroke, is associated with secondary neurodegeneration in cortex and limbic structures. In this study, we assessed the volume of white matter, ventricles and regional diffusion‐weighted MR imaging measures to delineate pathological tissue characteristics from the postmortem brain of stroke rats.MethodMiddle‐aged females were subjected to ischemic stroke using the vasoconstrictor endothelin 1, injected adjacent to the left middle cerebral artery (MCA). Mir‐20a‐3p mimic (n = 10) or scrambled oligo (n = 8) was administered i.v. 4h, 24h and 70d post stroke. Animals were assessed periodically for cognitive performance up to 100d after stroke using both the cued fear conditioning test and the novel object recognition test (NORT). After perfusion fixation, T2 and diffusion tensor imaging (DTI) magnetic resonance imaging were performed on postmortem tissue. Subsequently, brains were processed for histology, including the Weil myelin stain.ResultStroke resulted in impairment in both the cued fear conditioning test and the NORT, which was attenuated by mir‐20a‐3p treatment (Sampath et al., 2023). Weil myelin‐stained sections showed that both the corpus callosum and internal capsule had a reduction in volume in the ischemic hemisphere as compared to non‐ischemic hemisphere in vehicle treated (scrambled oligo) MCAo animals. In contrast, sham and MCAo+Mir‐20a‐3p animals displayed no hemispheric differences in the volume in either tract. A similar volume asymmetry was also observed in the ventricles in the MCA0+ Scrambled group. Entorhinal cortex volume (diffusion tensor MR images) was also asymmetric in the MCAo+scrambled oligo group.ConclusionCognitive changes measured with remote fear memory retrieval and NORT were associated with reduced density of major forebrain white matter tracts due to stroke and enlarged ventricular volume indicative of cell loss. This was observed in the entorhinal cortex, a region involved with contextual memory processing. These stroke‐induced deficits were attenuated in Mir‐20‐3p treated animals, indicating that microRNA treatment attenuated secondary neurodegeneration.
Epigenomics and single cell CRISPR screening to investigate the risk‐modifying role of microglia in Alzheimer’s disease and multiple sclerosis
Authors: Gallagher Michael D , Du Wenjuan , Hazel Katheryn EA , Aydin Zeynep , Cheng Yiran , Yuan Bingbing , Bell George W , Young Richard A , Jaenisch Rudolf , Corradin Olivia 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and other neurodegenerative diseases (NDs) cause substantial health‐related and economic burdens, but progress towards preventative or ameliorative treatments has been limited. Genome‐wide association studies have identified hundreds of risk loci containing single nucleotide polymorphisms (SNPs) that alter risk for these diseases, but >90% of these SNPs are in noncoding regions, which are cell type‐specific and difficult to study. To address this gap, we have characterized the epigenomes of iPSC‐derived neuronal and glial cells and performed CRISPRi single cell screening to dissect the molecular and cellular mechanisms underlying 10 ND risk loci.MethodWe generated neural progenitors, excitatory neurons, astrocytes and microglia from male and female iPSCs and performed RNA‐seq, H3K27ac ChIP‐seq, and Promoter Capture Hi‐C. We compared these data to those from primary uncultured (ex vivo) human neurons, astrocytes and microglia to compare their enhancer landscapes and ND risk SNP enrichment patterns. To perform CRISPRi single cell screening we integrated a dCas9‐KRAB transgene into an iPSC safe harbor locus and developed a novel lentiviral method that allows for efficient and well‐tolerated delivery of sgRNAs to iPSC‐derived microglia‐like cells (iMGLs).ResultiMGLs displayed the strongest correlation of their enhancer landscapes with those of their ex vivo counterparts, as well as highly consistent enrichment of AD and multiple sclerosis (MS) risk SNPs in microglia‐specific enhancers. Enhancer/promoter interactions in iMGLs also overlapped significantly with those from ex vivo microglia. As these results suggest that iMGLs are a suitable model for studying ND risk loci, we performed a CRISPRi single cell screen to identify the target genes and pathways affected at 10 AD and MS risk loci.ConclusionWhile the enhancer landscapes of iPSC‐derived neuronal and glial cells vary in similarity to their ex vivo counterparts, they display similar ND risk SNP enrichments in cell type‐specific enhancers, suggesting that disease risk SNP mechanisms are largely recapitulated in iPSC‐derived cells. The iMGL epigenome is notably similar to ex vivo microglia, and CRISPRi screening of AD and MS risk loci in these cells will advance our understanding of these diseases and nominate potential therapeutic targets.
Carbon Defects as Highly Active Sites for Gold Detection and Recovery
Authors: Zhang Ting , Xu Zhenmin , Xie Ya , Dong Shuyuan , Guo Zhenpeng , Wang Wanting , Chen Yao , Qian Xufang , Yu Han , Bian Zhenfeng 
Published: January 2025

AbstractThe use of precious metals (PMs) in many areas, such as printed circuit boards, catalysts, and target drugs, is increasing due to their unique physical and chemical properties, but their recovery remains a great challenge in terms of zero‐valent PMs as the final product. We report a highly hydrophilic carbon dot (CD) as a reductant (electron donor), in which the defects in CD served as efficient active sites for zero‐valent PMs recovery with an electron‐donating capacity of ~1.7 mmol g−1. The reduction of gold follows a two‐step dynamic model characterized by the formation of nano‐gold nuclei (initial rapid electron transfer process) followed by an Ostwald ripening process (subsequent slow process). Finite element method (FEM) simulation shows that the reaction efficiency and confinement effect of AuCl4− ions are positively correlated with defect density, indicating that the quantitative control of carbon defect density is the key to enhancing reduction activity. Combining density functional theory (DFT) with XPS and FTIR technology, we found that the electron is transferred from CD to Au(III) via hydrogen bonding. This nano carbon material can be exploited to recover gold from e‐waste water directly, with the characteristics of reducing energy consumption and avoiding environmental pollution.
Über die Rolle von Wasserstoffwanderungen im Taxadiensystem
Authors: Li Heng , Goldfuss Bernd , Dickschat Jeroen S. 
Published: January 2025

AbstractTaxa‐4,11‐dien wird durch die Taxa‐4,11‐dien‐Synthase (TxS) aus Taxus brevifolia hergestellt. Die einzigartige Reaktivität des Taxansystems ist durch weitreichende Wasserstoffwanderungen bei der Biosynthese gekennzeichnet. Diese Studie zeigt, dass selektive Wasserstoffwanderungen über große Entfernungen auch eine Rolle im Hochenergieprozess der EI‐MS‐Fragmentierung von Taxa‐4,11‐dien spielen. Es wurde eine TxS‐Enzymvariante generiert, die Cyclophomacten produziert, eine Verbindung, die durch einen konzertierten Prozess gebildet wird, der eine weitreichende Protonenverschiebung und einen Ringschluss umfasst, der auch als Addition eines Methylcarbinylkations an ein Olefin beschrieben werden kann. Basierend auf einer früheren rechnerischen Studie wurde vorgeschlagen, dass der Cyclisierungsmechanismus zu Taxa‐4,11‐dien zwei Protonenwanderungen über große Entfernungen anstelle eines direkten Transfers umfasst. Ein Substratanalogon mit einer verschobenen Doppelbindung wurde mit TxS umgewandelt, um experimentelle Beweise für diesen Vorschlag zu erhalten.
Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles
Authors: Buffa Vanessa , Walz Carlo , Meyners Christian , Zheng Min , Oki Sugiarto Wisely , Repity Maximilian , Achaq Hanaa , Brudy Christian , Spiske Moritz , Cica Matijas , Hausch Felix 
Published: January 2025

AbstractMacrocycles are abundantly used by nature to enable cell‐permeable bioactive molecules. Synthetic non‐peptidic macrocycles are also increasingly considered as modalities for difficult‐to‐bind proteins but guidelines for macrocyclization are only beginning to emerge. Macrocycles are thought to constrain the available conformations but also to allow for residual flexibility, the latter being poorly understood. Here we show that even medium‐sized macrocycles display an unexpected high conformational plasticity, even when bound to their protein target. Minor modification of the linker region of macrocycles can shift the conformational ensemble to distinct conformational subclasses, each constituting distinct three‐dimensional scaffolds for further optimization. This led to several new ligands with improved affinity and beneficial physicochemical parameters for the FK506‐binding protein 51, a promising target for depression, obesity and chronic pain. Importantly, none of the beneficial modifications could have been identified by classical medicinal chemistry as they only work in the macrocyclic context.Our results show that macrocyclization can do more than keeping loose ends together but rather provide a platform for multiple series of macrocycles with distinct binding modes.
Stimuli‐Responsive Polyurethane Actuator Triggered by Light and Heat Reinforced With Disulfide Bonds
Authors: Ren Zhi‐Hui , Cui Zhishuai , Li Naqi , Yue Xiaolei , Zhang Yujie , Li Peng , Zeng Wen , Guan Zheng‐Hui 
Published: January 2025

ABSTRACTThe photoisomerization behavior of mesogenic azobenzene makes it possible to convert light energy into mechanical action. However, achieving durability, configurability, and flexibility of light‐responsive actuators for artificial intelligence applications remains challenging. Here, a light responsive polyurethane (AzoPU‐SS) with remarkable anti‐fatigue and anti‐stress properties has been synthesized through the combination of dynamic disulfide bonds and mesogenic azobenzene functional groups. The AzoPU‐SS film demonstrated excellent photo‐induced bending, under ultraviolet (UV) light exposure, indicating effective transfer of molecular deformation from the microscopic to the macroscopic level. Moreover, the AzoPU‐SS material's elongation at break was greatly increased, due to the dynamic and reversible nature of the flexible S‐S and H bonds, enabling the coordinated motion of azobenzene groups and producing significant deformation. Such a reinforced strategy could be used to design smart actuators with superior stretchability and toughness, helping to broaden the applications of light‐responsive actuator materials.
Degradation Behavior of Rice Husk Fiber‐Reinforced PLA/PBAT Composites in Short‐Term Hydrothermal Environment
Authors: Wang Lei , Wang Zidong , Peng Lian , Wang Liping , Deng Bo 
Published: January 2025

ABSTRACTThe rice husk fiber‐reinforced polylactic acid (PLA)/polybutylene adipate terephthalate (PBAT) composites were prepared by using an injection molding technique. An in‐depth investigation into degradation behavior within a short‐term hydrothermal environment, which encompassed a multi‐faceted analysis that included surface analysis, degradation process analysis, microstructure analysis, and structure strength analysis. Results show that performance of composites could be attributed to the weak interfacial adhesion, these interfacial defects can be seen as observed in the electron micrographs. In the presence of water molecules, it was observed that available interfacial bonds were susceptible to water during deformation. Moreover, the degradation behavior of the resultant network from the filler‐polymer composites could be monitored through available functional groups changes, which could provide an insight into the degradation pattern.
Haemato‐biochemistry, erythromorphology, and histopathology of Oreochromis niloticus as influenced by Aeromonas hydrophila infection and florfenicol therapy
Authors: Sharon Joshi , Abraham Thangapalam Jawahar , Sen Arya , Das Ratnapriya , Sinha Priyanka , Boda Satyanarayana , Patil Prasanna Kumar 
Published: January 2025

AbstractAeromonas hydrophila infection is one of the key factors limiting tilapia production, and antibiotics play important roles in the control of diseases. This study evaluated the effectiveness of florfenicol (FFC) when administered orally at the therapeutic dose of 15 mg/kg fish biomass/day for 10 days against A. hydrophila infection in Oreochromis niloticus in terms of survival, changes in haemato‐biochemistry, erythrocyte morphology, and histoarchitecture of the vital organs. A. hydrophila was moderately virulent to tilapia with an LD50 of 1.15 × 107 cells/fish. When challenged, it caused systemic infection in fish. The challenged fish were lethargic, wandered around the corners, rested at the bottom, swam vertically, and darkly pigmented. The FFC therapy effectively reduced bacteria‐induced mortalities and physiological stress as the measured haemato‐biochemical parameters indicated. The histopathological findings suggested alterations in tissue architecture of the kidney and liver tissues, which improved in the treated fish. Erythrocytes of the challenged fish showed elongated, irregular‐shaped, tear‐drop‐shaped, crenated, and hypochromic erythrocytes, ragged cytoplasmic membranes, vacuolation, hypertrophied nucleus, and eccentric nucleus. These morphological alterations were reduced with FFC therapy. Compared to the untreated group, the FFC treatment normalized the haemato‐biochemical parameters, improved wound healing, and promoted fish recovery against bacterial infections. The results hinted at the effectiveness of FFC against A. hydrophila infection in O. niloticus juveniles at the therapeutic dose. However, care must be taken for its judicious aquacultural application to avoid its negative impacts on fish, the environment, and consumers.