bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lens Placode Modulates Extracellular Matrix Formation During Early Eye Development
Authors: De Magalhães Cecília G. , Cvekl Ales , Jaeger Ruy G. , Yan C. Y. Irene 
Published: December 2023

ABSTRACTThe role extracellular matrix (ECM) in multiple events of morphogenesis has been well described, little is known about its specific role in early eye development. One of the first morphogenic events in lens development is placodal thickening, which converts the presumptive lens ectoderm from cuboidal to pseudostratified epithelium. This process occurs in the anterior pre-placodal ectoderm when the optic vesicle approaches the cephalic ectoderm. Since cells and ECM have a dynamic relationship of interdependence and modulation, we hypothesized that the ECM evolves with cell shape changes during lens placode formation. This study investigates changes in optic ECM including both protein distribution deposition, extracellular gelatinase activity and gene expression patterns during early optic development using chicken and mouse models. In particular, the expression ofTimp2, a metalloprotease inhibitor, corresponds with a decrease in gelatinase activity within the optic ECM. Furthermore, we demonstrate that optic ECM remodeling depends on BMP signaling in the placode. Together, our findings suggest that the lens placode plays an active role in remodeling the optic ECM during early eye development.
Diploid genome assembly of the Malbec grapevine cultivar enables haplotype-aware analysis of transcriptomic differences underlying clonal phenotypic variation
Authors: Calderón Luciano , Carbonell-Bejerano Pablo , Muñoz Claudio , Bree Laura , Sola Cristobal , Bergamin Daniel , Tulle Walter , Gomez-Talquenca Sebastian , Lanz Christa , Royo Carolina , Ibáñez Javier , Martinez-Zapater José Miguel , Weigel Detlef , Lijavetzky Diego 
Published: December 2023

AbstractGrapevine cultivars (Vitis viniferaL. ssp.vinifera) must be clonally propagated because of their highly heterozygous genomes. Malbec, a France-originated cultivar appreciated for the production of high-quality wines, is the offspring of cultivars Prunelard and Magdeleine Noire des Charentes. Here, we have built a diploid genome assembly of Malbec, after trio binning of PacBio long reads into the two haploid complements inherited from either parent. After haplotype-aware deduplication and corrections, complete assemblies for the two haplophases were obtained with very low haplotype switch-error rate (<0.025). The haplophases alignment identified >25% of polymorphic regions. Gene annotation including RNA-seq transcriptome assembly andab initioprediction evidence resulted in similar gene model numbers for both haplophases. The annotated diploid assembly was exploited in the transcriptomic comparison of four clonal accessions of Malbec that exhibited variation in berry composition traits. Analysis of the ripening pericarp transcriptome using either haplophases as reference yielded similar results, although some differences were observed. Particularly, among the differentially expressed genes in the Magdeleine-inherited haplotype, we observed an over-representation of hypothetically hemizygous genes. The higher berry anthocyanin content of clonal accession 595 was associated with increased abscisic acid responses, leading to overexpression of secondary metabolism genes and deregulation of genes associated to abiotic stress response. Overall, the results highlight the importance of producing diploid assemblies to fully represent the genomic diversity of highly heterozygous woody crop cultivars and to unveil the molecular bases of clonal phenotypic variation.
The ALS-associated TDP-43M337Vmutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner
Authors: Christoforidou Eleni , Moody Libby , Joilin Greig , Simoes Fabio A. , Gordon David , Talbot Kevin , Hafezparast Majid 
Published: December 2023

AbstractEvidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation may originate from microglia. Furthermore, TDP-43, involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337Vmutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia, and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of two candidate miRNAs, miR-16-5p and miR-99a-5p by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and identified their predicted targets, which include primarily genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia in a sex dependent manner, which may in turn influence disease progression in ALS. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
Testing SIPA1L2 as a modifier of CMT1A using mouse models
Authors: Murray George C. , Hines Timothy J. , Tadenev Abigail L.D. , Xu Isaac , Züchner Stephan , Burgess Robert W. 
Published: December 2023

ABSTRACTCharcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validateSIPA1L2as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion inSIPA1L2and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction betweenSipa1l2deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement ofSipa1l2in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions betweenSipa1l2deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.
Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival inAR-altered lethal prostate cancer
Authors: Chauhan Pradeep S. , Alahi Irfan , Sinha Savar , Shiang Alexander L. , Mueller Ryan , Webster Jace , Dang Ha X. , Saha Debanjan , Greiner Lilli , Yang Breanna , Ni Gabris , Ledet Elisa M. , Babbra Ramandeep K. , Feng Wenjia , Harris Peter K. , Qaium Faridi , Jaeger Ellen B. , Miller Patrick J. , Caputo Sydney A. , Sartor Oliver , Pachynski Russell K. , Maher Christopher A. , Chaudhuri Aadel A. 
Published: December 2023

SummaryMetastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor (AR)-targeted agents is often lethal. Unfortunately, biomarkers for this deadly disease remain under investigation, and underpinning mechanisms are ill-understood. Here, we applied deep sequencing to ∼100 mCRPC patients prior to the initiation of first-line AR-targeted therapy, which detectedAR/enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-freeAR/enhancer alterations developed more lethal prostate cancer, we next performed genome-wide cell-free DNA epigenomics. Strikingly, we found that binding sites for transcription factors associated with developmental stemness were nucleosomally more accessible. These results were corroborated using cell-free DNA methylation data, as well as tumor RNA sequencing from a held-out cohort of mCRPC patients. Thus, we validated the importance ofAR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
Gut microbial changes associated with obesity in youth with type 1 diabetes
Authors: Ismail Heba M , Perera Dimuthu , Mandal Rabindra , DiMeglio Linda A , Evans-Molina Carmella , Hannon Tamara , Petrosino Joseph , Javornick CreGreen Sarah , Schmidt Nathan W 
Published: December 2023

AbstractObesity is increasingly prevalent in type 1 diabetes (T1D) and is associated with management problems and higher risk for diabetes complications. Gut microbiome changes have been described separately in each of T1D and obesity, however, it is unknown to what extent gut microbiome changes are seen when obesity and T1D concomitantly occur. Objective: To describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized significant gut microbial and metabolite differences between T1D youth who are lean (BMI: 5-<85%) vs. those with obesity (BMI: ≥95%). Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) metabolite differences in lean (n=27) and obese (n=21) T1D youth. The mean±SD age was 15.3±2.2yrs, A1c 7.8±1.3%, diabetes duration 5.1±4.4yrs, 42.0% females, and 94.0% were White. Linear discriminant analysis (LDA) effect size (LEfSe) was used to identify taxa that best discriminated between the BMI groups. Results: Bacterial community composition showed differences in species type (β-diversity) by BMI group (p=0.013). At the genus level, there was a higher ratio ofPrevotellatoBacteroidesin the obese group (p=0.0058). LEfSe analysis showed a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance ofPrevotella copri, among other taxa in the obese group. Functional profiling showed that pathways associated with decreased insulin sensitivity were upregulated in the obese group. Stool SCFAs (acetate, propionate and butyrate) were higher in the obese compared to the lean group (p<0.05 for all). Conclusions: Our findings identify gut microbiome, microbial metabolite and functional pathways differences associated with obesity in T1D. These findings could be helpful in identifying gut microbiome targeted therapies to manage obesity in T1D.
Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with intensified electrical stimulation in two dosages: A randomized, controlled trial
Authors: Alizadehgoradel Jaber , Molaei Behnam , Jalali Khandan Barzegar , Pouresmali Asghar , Sharifi Kiomars , Hallajian Amir-Homayun , Nejati Vahid , Glinski Benedikt , Vicario Carmelo M , Nitsche Michael A. , Salehinejad Mohammad Ali 
Published: December 2023

AbstractObsessive-Compulsive Disorder (OCD) is associated with a high disease burden, and treatment options are limited. We used intensified electrical stimulation in two dosages to target a main circuitry associated with the pathophysiology of OCD, left dorsolateral prefrontal cortex (l- DLPFC) and supplementary motor area (SMA) and assessed clinical outcomes, neuropsychological performance and brain physiology. In a double-blind, randomized-controlled trial, thirty-nine patients with OCD were randomized to sham, 2-mA or 1-mA transcranial direct current stimulation (tDCS) targeting the l-DLPFC (F3) and SMA (FC2) with anodal and cathodal stimulation respectively. The treatment included 10 sessions of 20-minute stimulation delivered twice per day with 20-min between-session intervals. Outcome measures were reduction in OCD symptoms, anxiety and depressive states, performance on a neuropsychological test battery of response inhibition, working memory, attention, and oscillatory brain activities and functional connectivity. All outcome measures except EEG were examined at pre-intervention, post- intervention and 1-month follow-up times. The 2-mA protocol significantly reduced OCD symptoms, anxiety, depression states, and improved quality of life after the intervention up to 1- month follow-up compared to the sham group, while the 1-mA protocol reduced OCD symptoms only in the follow-up and depressive state immediately after and 1-month following the intervention. Both protocols partially improved response inhibition and the 2-mA protocol reduced attention bias to OCD-related stimuli and improved reaction time in working memory performance. Both protocols increased alpha oscillatory power and the 2-mA intensified protocol decreased delta power as well. Both protocols increased connectivity in higher frequency bands at frontal-central areas compared to the sham. Modulation of the prefrontal-supplementary motor network with intensified tDCS ameliorates OCD clinical symptoms and results in beneficial cognitive effects. The 2-mA intensified stimulation resulted in larger symptom reduction and improved more converging outcome variables related to therapeutic efficacy. These results support applying the intensified prefrontal-SMA tDCS in larger trials.
A Systematic Review and Dose-Response Meta-Analysis of the Association Between Nitrate & Nitrite intake and Gastroesophageal Cancer Risk: A Study Protocol
Authors: Ghasemi Mohammadreza , Bahrami koutenaei Mohammad , Ghasemi Alireza , Alizadeh-navaei Reza , Moosazadeh Mahmood 
Published: December 2023

AbstractObjectivesThe global burden of cancer underscores the necessity for evidence-based strategies to identify and manage risk factors. Nitrate and nitrite are inherent byproducts resulting from microbial-mediated nitrogen oxidation in plants, soil, or water. Fruits, vegetables, and combinations thereof are integral constituents of a nutritious diet. Despite the potential carcinogenicity of N-nitroso compounds (NOCs), certain epidemiological investigations have reported a lack of correlation between the dietary intake of nitrate, nitrite, and NOCs and the occurrence of cancer in human subjects.MethodsPubMed/MEDLINE, Embase, WoS (Clarivate Analytics), Proquest, Scopus, and Google Scholar as electronic databases will be precisely searched for observational studies that assessed the relationship between nitrate/nitrite levels and gastric/esophageal cancer. In this study, an assessment will be conducted on studies spanning January 1, 1980, to October 30, 2023. The inclusion criteria will not restrict language. Discrepancies among the reviewers at various stages of the study, including screening, selection, quality assessment, and data extraction, will be resolved through consensus. In instances where disagreements persist unresolved, a third reviewer will decide. The combination method will be employed based on methodological similarities in the chosen articles, utilizing either the Random Effect Model or the Fixed Effect Model. Additionally, forest plots will be generated for the included articles. Statistical heterogeneity will be evaluated using the I2 statistic and the Q-statistic test. Furthermore, funnel plots will be employed to assess non-significant study effects and potential reporting bias. Eggers and Beggs tests will be executed, and the identification of publication bias will rely on significant findings (P < 0.05).ConclusionThe findings of this study should be of benefit to governments and researchers in maintaining safe levels of nitrate and nitrite in drinking water as well as preventing Gastroesophageal cancers.
Aberration correction for deformable mirror based remote focusing enables high-accuracy whole-cell super-resolution imaging
Authors: Shi Wei , He Yingchuan , Wang Jianlin , Zhou Lulu , Chen Jianwei , Zhou Liwei , Xi Zeyu , Wang Zhen , Fang Ke , Li Yiming 
Published: December 2023

AbstractSingle-molecule localization microscopy (SMLM) enables three-dimensional (3D) investigation of nanoscale structures in biological samples, offering unique insights into their organization. However, traditional 3D super-resolution microscopy using high numerical aperture (NA) objectives is limited by imaging depth of field (DOF), restricting their practical application to relatively thin biological samples. Here, we developed a unified solution for thick sample super-resolution imaging using a deformable mirror (DM) which was served for fast remote focusing, optimized point spread function (PSF) engineering and accurate aberration correction. By effectively correcting the system aberrations introduced during remote focusing and sample aberrations at different imaging depths, we achieved high-accuracy, large DOF imaging of the whole-cell organelles [i.e. nuclear pore complex (NPC), microtubules, and mitochondria] with a nearly uniform resolution of approximately 30 nm across the entire cellular volume.
In-depth characterization of HINT1 pathogenic variants
Authors: Amor-Barris Silvia , Lazar Tamas , Peeters Kristien , Wodak Shoshana J. , Jordanova Albena 
Published: December 2023

ABSTRACTLoss-of-function variants in HINT1 were identified to cause axonal recessive peripheral neuropathy with neuromyotonia (NMAN). Patients suffer from motor-greater-than-sensory polyneuropathy with an age of onset, mainly within the first decade of life. Currently, nearly 30 NMAN disease-causing variants have been described, predominantly in sporadic cases and small families, most of them with limited functional evidence of pathogenicity. We systematically characterized all reported pathogenic missense mutations in HINT1, aiming to dissect their underlying loss-of-function mechanism. Individual variants were mapped onto the crystal structure of the HINT1 protein, and their potential effect on protein stability was computed. These variants were grouped into three main clusters: around the catalytic pocket, at the dimer interface, and in the β-sheet behind the catalytic pocket of the protein. The stability and functionality of the corresponding altered proteins were testedin vivousing HINT1 KO cells and a yeast model deficient for the orthologous gene (HNT1), providing insights into the structure-function relations. Our findings support the pathogenic character of most of the variants and uncover their differential effect on HINT1 function. Classifying the variants in three clusters sets the basis for patient stratification strategies for future therapeutic development.
PURA and GLUT1: Sweet partners for brain health
Authors: Colombo Rocío B. , Maxit Clarisa , Martinelli Diego , Anderson Mel , Masone Diego , Mayorga Lía 
Published: December 2023

ABSTRACTPURA, also known as Pur-alpha, is an evolutionarily conserved DNA/RNA-binding protein crucial for various cellular processes, including DNA replication, transcriptional regulation, and translational control. Comprising three PUR domains, it engages with nucleic acids and has a role in protein-protein interactions. The manifestation of PURA syndrome, arising from mutations in the PURA gene, presents neurologically with developmental delay, hypotonia, and seizures. In our prior work from 2018, we highlighted the unique case of a PURA patient displaying hypoglycorrhachia, suggesting a potential association with GLUT1 dysfunction in this syndrome.In this current study, we expand the patient cohort with PURA mutations exhibiting hypoglycorrhachia and aim to unravel the molecular basis of this phenomenon. We established an in vitro model in HeLa cells to modulate PURA expression and investigated GLUT1 function and expression. Our findings indicate that PURA levels directly impact glucose uptake through the functioning of GLUT1, without influencing significantly GLUT1 expression. Moreover, our study reveals convincing evidence for a physical interaction between PURA and GLUT1, demonstrated by colocalization and co-immunoprecipitation of both proteins. Computational analyses, employing molecular dynamics, further corroborates these findings, demonstrating that PURA:GLUT1 interactions are plausible, and that the stability of the complex is altered when PURA is truncated and/or mutated.In conclusion, our results suggest that PURA plays a pivotal role in driving the function of GLUT1 for glucose uptake, potentially forming a regulatory complex. Additional investigations are warranted to elucidate the precise mechanisms governing this complex and its significance in ensuring proper GLUT1 function.
Differential Effects of Posttranslational Modifications on the Membrane Interaction of Huntingtin Protein
Authors: Zhang Zhidian , Gehin Charlotte , Abriata Luciano A , Peraro Matteo Dal , Lashuel Hilal 
Published: December 2023

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine stretch near the N-terminus of the huntingtin (HTT) protein, rendering the protein more prone to aggregate. The first 17 residues in HTT (Nt17) interact with lipid membranes and harbor multiple posttranslational modifications (PTMs) that can modulate HTT conformation and aggregation. In this study, we used a combination of biophysical studies and molecular simulations to investigate the impact of PTMs on the helicity of Nt17 in the presence of various lipid membranes. We demonstrate that anionic lipids such as PI4P, PI(4,5)P2, and GM1 significantly enhance the helical structure of unmodified Nt17. This effect is attenuated by single acetylation events at K6, K9, or K15, whereas tri-acetylation at these sites abolishes Nt17 membrane interaction. Similarly, single phosphorylation at S13 and S16 decreased but did not abolish the POPG and PIP2-induced helicity, while dual phosphorylation at these sites markedly diminished Nt17 helicity, regardless of lipid composition. The helicity of Nt17 with phosphorylation at T3 is insensitive to the membrane environment. Oxidation at M8 variably affects membrane-induced helicity, highlighting a lipid-dependent modulation of Nt17 structure. Altogether, our findings reveal differential effects of PTMs and crosstalks between PTMs on membrane interaction and conformation of HTT. Intriguingly, the effects of phosphorylation at T3 or single acetylation at K6, K9, and K15 on Nt17 conformation in the presence of certain membranes do not mirror that observed in the absence of membranes. Our studies provide novel insight into the complex relationship between Nt17 structure, PTMs and membrane binding.TOC figure
Multifrequency control of Faraday wave bioassembly for constructing multiscale hPSC-derived neuronal networks
Authors: Gu Longjun , Zhao Wen , Fan Yuhang , Shang Jia , Zhao Yang , Wang Jibo , Chen Tao , Liu Peidi , Chen Pu 
Published: December 2023

AbstractBioassembly is recently regarded as a critical alternative biofabrication technical route to bioprinting since it can directly manipulate millions of live cells to form multicellular structures with close intercellular proximity, improving contact-dependent cell communication and promoting the emergence of tissue-specific functions. However, acoustic bioassembly techniques are currently limited to generating cytoarchitecture with a single characteristic length which cannot faithfully mimic the multiscale cellular structures in native tissues. To overcome this challenge, herein we report a novel acoustic bioassembly technique that employs multifrequency control of Faraday waves to form multiscale cellular structures. By superimposing multiple sine wave signals with proper amplitude ratios, Faraday waves containing multiple wavelengths can be induced and enabled to generate multiscale structures in few seconds. Using this technique, we construct functional neuronal networks with multiscale connectivity that display spontaneous neuroelectrical activities. We anticipate this technique will find wide applications in tissue engineering and regenerative medicine.