bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant splicing in Huntington’s disease via disrupted TDP-43 activity accompanied by altered m6A RNA modification
Authors: Nguyen Thai B. , Miramontes Ricardo , Chillon-Marinas Carlos , Maimon Roy , Vazquez-Sanchez Sonia , Lau Alice L. , McClure Nicolette R. , England Whitney E. , Singha Monika , Stocksdale Jennifer T. , Jang Ki-Hong , Jung Sunhee , McKnight Jharrayne I. , Ho Leanne N. , Faull Richard L.M. , Steffan Joan S. , Reidling Jack C. , Jang Cholsoon , Lee Gina , Cleveland Don W. , Lagier-Tourenne Clotilde , Spitale Robert C. , Thompson Leslie M. 
Published: November 2023

AbstractHuntington’s disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of theHTTgene encoding huntingtin. Prior reports have established a correlation between CAG expandedHTTand altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.
Peptide aggregation-induced immunogenic cell death in a breast cancer spheroid model
Authors: Gunay Gokhan , Maier Katelyn N. , Hamsici Seren , Carvalho Filipa , Timog Tristan A. , Acar Handan 
Published: November 2023

AbstractUtilizing multicellular aggregates (spheroids) for in vitro cancer research offers a physiologically relevant model that closely mirrors the intricate tumor microenvironment, capturing properties of solid tumors such as cell interactions and drug resistance. In this research, we investigated the Peptide-Aggregation Induced Immunogenic Response (PAIIR), an innovative method employing engineered peptides we designed specifically to induce immunogenic cell death (ICD). We contrasted PAIIR-induced ICD with standard ICD and non-ICD inducer chemotherapeutics within the context of three-dimensional breast cancer tumor spheroids. Our findings reveal that PAIIR outperforms traditional chemotherapeutics in its efficacy to stimulate ICD. This is marked by the release of key damage-associated molecular patterns (DAMPs), which bolster the phagocytic clearance of dying cancer cells by dendritic cells (DCs) and, in turn, activate powerful anti-tumor immune responses. Additionally, we observed that PAIIR results in elevated dendritic cell activation and increased antitumor cytokine presence. This study not only showcases the utility of tumor spheroids for efficient high-throughput screening but also emphasizes PAIIR’s potential as a formidable immunotherapeutic strategy against breast cancer, setting the stage for deeper exploration and potential clinical implementation.
Engineering microvascular networks using a KLF2 reporter to probe flow-dependent endothelial cell function
Authors: Blazeski Adriana , Floryan Marie A. , Fajardo-Ramírez Oscar R. , Meibalan Elamaran , Ortiz-Urbina Jesús , Angelidakis Emmanouil , Shelton Sarah E. , Kamm Roger D. , García-Cardeña Guillermo 
Published: November 2023

AbstractShear stress generated by the flow of blood in the vasculature is a potent regulator of endothelial cell phenotype and vascular structure. While vascular responses to flow are complex and context-dependent, endothelial cell signaling in response to shear stress induced by laminar flows is coordinated by the transcription factor KLF2. The expression of KLF2 in endothelial cells is associated with a quiescent, anti-inflammatory phenotype and has been well characterized in two-dimensional systems, but has not been studied in three-dimensionalin vitrosystems. Here we develop engineered microvascular networks (MVNs) with a KLF2-based endothelial cell sensor within a microfluidic chip, apply continuous flow using an attached microfluidic pump, and study the effects of this flow on vascular structure and function. We found that culture of MVNs exposed to flow for 48 hours that resulted in increased expression of the KLF2-GFP-reporter display larger vessel diameters and decreased vascular branching and resistance. Additionally, vessel diameters after the application of flow were independent of initial MVN morphologies. Finally, we found that MVNs exposed to flow have improved vascular barrier function and decreased platelet adhesion. The MVNs with KLF2-based flow sensors represent a powerful tool for evaluating the structural and functional effects of flow on engineered three-dimensional vascular systems.
Auditory cues modulate the short timescale dynamics of STN activity during stepping in Parkinson’s disease
Authors: Yeh Chien-Hung , Xu Yifan , Shi Wenbin , FitzGerald James J. , Green Alexander L. , Fischer Petra , Tan Huiling , Oswal Ashwini 
Published: November 2023

AbstractBackgroundGait impairment has a major impact on motor performance and quality of life in patients with Parkinson’s disease (PD). The neurophysiological mechanisms of gait impairment remain poorly understood, meaning that treatment options are currently limited. It is believed that basal ganglia oscillatory activity at β frequencies (15-30 Hz) may be a contributor to gait impairment in PD, but the precise dynamics of this oscillatory activity during gait remain unclear. Auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using brain-computer interface (BCI) technologies.ObjectiveWe aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait.MethodsWe used local field potentials (LFPs) to study STN oscillatory activity in eight PD patients while stepping in place with auditory cueing. Hidden Markov Models (HMMs) were used to discover dynamic brain states that occurred pre-sound, on-sound, and post-sound cues.ResultsThe occurrence of β bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, α transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues.ConclusionsWe found transient oscillatory states in the STN LFP during stepping and showed that α and β oscillations are differentially modulated by auditory cues during stepping in PD.
Targeted Deletion of All Known Thyroid Hormone Receptors Causes Maturation Retardation and Early-onset Degeneration of Cochlear Outer Sulcus
Authors: Ma XianHua , Jiang Fei , Wei Chunchun , Han Shuang , Zhang Yuqing , Sun Lianhua , Qu Jiaxi , Ying Hao , Chen Yuxia , Tang Jie , He David Z. , Zhang Weiping J. , Xie Zhifang 
Published: November 2023

AbstractThyroid hormone (TH) and its receptors (TRs) are crucial for cochlear late-stage development and endocochlear potential (EP) maintenance. However, the mechanism underlying EP reduction in the absence of TH or TRs remains elusive. Cochlear outer sulcus root cells undergo significant morphological changes during late-stage cochlear development and are believed to play a role in maintaining endolymph homeostasis and EP. Yet, it is unknown whether TH and/or TRs are necessary for root cell differentiation and function. Here, we elucidate the essential role of TH or TRs in postnatal root cell development and survival in mice. TH deficiency significantly delayed root cell differentiation. Otocyst-selective deletion of bothThraandThrb, but notThrbalone, leads to a similar impairment, accompanied by early degeneration of root cells, with the stria vascularis remaining unaffected. Furthermore, a 22% reduction in mean EP magnitudes was observed in conditionalTRsdouble knockout mice at 4 months of age, less pronounced than in globalTRsknockout mice. Transcriptome analysis reveals that TH deficiency downregulates a significant portion of root cell-enriched genes. These findings underscore the redundant roles of TRα and TRβ in promoting the late-stage differentiation and survival of root cells. Additionally, they suggest that the expression of TRs in cochlear epithelium is crucial for maintaining an optimal EP magnitude, while TRs expressed in areas outside cochlear epithelium, particularly in spiral ligament fibrocytes, may also significantly contribute to EP maintenance. This study advances our understanding of TH in cochlear outer sulcus development and EP maintenance.
Adult Human Heart ECM Improves Human iPSC-CM Function via Mitochondrial and Metabolic Maturation
Authors: Ozcebe S. Gulberk , Tristan Mateo , Zorlutuna Pinar 
Published: November 2023

AbstractMyocardial infarction can lead to the loss of billions of cardiomyocytes, and while cell-based therapies are a promising option, the immature nature of in vitro-generated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) is a significant roadblock to their development. Through the years, various approaches have emerged to improve iCM maturation, yet none could fully recapitulate the complexity of cardiac development and were not enough to achieve full cardiac maturityin vitro.Cardiac differentiation occurs at the early stages of development in a highly dynamic environment. Although significantly improved over the past two decades, small molecule-based iPSC differentiation protocols don’t go beyond producing high purity fetal iCMs. Recently adult extracellular matrix (ECM) was shown to retain tissue memory and has shown some success in driving tissue-specific differentiation in unspecified cells in various organ systems. Therefore, here, we first characterized the adult human heart left ventricle components. We then investigated the effect of adult human heart-derived ECM on iPSC cardiac differentiation and subsequent maturation. By preconditioning iPSCs with ECM, we tested whether creating a cardiac environment around iPSCs would drive them toward cardiac fate before small molecule mediated differentiation. Ultimately, we investigated ECM components that might be responsible for the observed effects.We identified critical glycoproteins and proteoglycans involved in early cardiac development in the adult heart ECM. Namely, adult ECM had extracellular galactin-1, fibronectin, fibrillins, and basement-membrane-specific heparan-sulfate proteoglycan (HSPG), which have been implicated in normal heart development and associated with various embryonic developmental processes.Relatedly, we showed that preconditioning iPSCs with adult ECM resulted in enhanced cardiac differentiation, yielding iCMs with higher functional maturity. Further investigation revealed that a more developed mitochondrial network and coverage as well as enhanced metabolic maturity and a shift towards a more energetic profile allowed the observed functional enhancement in ECM pretreated iCMs.These findings demonstrate the potential of using cardiac ECM for promoting iCM maturation and suggest a promising strategy for improving the development of iCM-based therapies and in vitro cardiac disease modeling and drug screening studies. Upon manipulating ECM, such as heat denaturation and sonication to eliminate protein components and release ECM bound vesicle contents, respectively, we concluded that the beneficial effects that we observed are not solely due to the ECM proteins, and might be related to the decorative units attached to them.
Better therapeutic efficiency of omnidirectional than directional subthalamic deep brain stimulation in Parkinson’s disease
Authors: Scherer Maximilian , Milosevic Luka , Cebi Idil , Bookjans Patrick , Brunett Bastian , Guggenberger Robert , Weiss Daniel , Gharabaghi Alireza 
Published: November 2023

AbstractBackgroundDeep brain stimulation (DBS) using segmented electrode contacts allows for directionally steered stimulation (DS), while the conventional ring mode provides omnidirectional stimulation (OS). However, with regard to achieving better effects with the same stimulation intensity or equivalent effects with lower intensity, the comparative therapeutic efficiency of these approaches remains unclear.ObjectiveTo compare the therapeutic efficiency of subthalamic DBS using segmented and ring contacts in Parkinson’s disease (PD) patients with akinetic-rigid symptoms.MethodsA double-blind, randomized monopolar review was conducted with patients in the dopaminergic medication-off state at 10 weeks postoperatively on three upper ring contacts and three contacts of the upper segmented level. Impedance measurements were obtained, and the therapeutic threshold (current strength for complete biceps brachii muscle rigidity resolution) was estimated by increasing stimulation intensity in 0.2 mA increments.ResultsOS with ring contacts showed an improved therapeutic threshold compared to DS with segmented contacts. At 1.1 mA stimulation intensity, complete rigidity resolution was achieved in 90% of patients with the best ring contact, whereas only 40% achieved the same outcome with the best segmented contact. In addition, OS with ring contacts exhibited 50% lower impedance than DS with segmented contacts.ConclusionsIncremental adjustments in current intensity during parameter titration generate valuable stimulus-response curves for assessing therapeutic efficiency. In clinical practice, the monopolar review should give priority to identifying the optimal ring level and therapeutic threshold. Segmented contacts should be carefully considered as a potential alternative when side effects limit the feasibility of other options.
Comparison of body composition measures assessed by bioelectrical impedance analysis versus dual-energy X-ray absorptiometry in UK Biobank
Authors: Feng Qi , Bešević Jelena , Conroy Megan , Omiyale Wemimo , Lacey Ben , Allen Naomi 
Published: November 2023

AbstractBackgroundBioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) are used commonly for assessing body composition. This study aimed to evaluate the agreement between BIA and DXA measures to assess the validity of BIA measures in UK Biobank.MethodsUK Biobank participants with body fat mass (FM) and fat free mass (FFM) estimates derived from BIA and DXA measures performed on the same date were included. BIA and DXA-derived estimates were compared using Pearson correlation coefficients. Bland-Altman analysis was performed to quantify the differences and its distribution. Multivariable linear regression was used to identify predictors for the difference between the two measures. Finally, prediction models were developed to calibrate BIA measures against DXA measures.Results34437 participants (female 51.4%, mean age 55.2 years) were included. BIA and DXA measurements were highly correlated (correlation coefficient 0.96 for FM and 0.97 for FFM), with similar values in males and females and across body mass index subgroups. BIA underestimates FM by 1.84 kg (23.77 vs. 25.61), but overestimated FFM by 2.56 kg (52.49 vs. 49.93). The BIA-DXA difference was associated with individual FM, FFM, BMI and waist circumference. Prediction models showed overall good model performance in the training and testing data.ConclusionWe found good agreement between BIA-and DXA-derived body composition measures at a population level in UK Biobank. However, BIA-DXA difference existed at individual level, and was associated with anthropometric measures. Future studies may consider using prediction models to calibrate BIA measures.
sLOX-1 as a differential diagnostic biomarker for acute pulmonary embolism
Authors: Wu Jianing , Rong Wei , Ma Ke , Ma Jie , Mi Yuhong , Jing Zhi-Cheng , Zhang Hui , Li Ping , Du Jie , Li Yulin 
Published: November 2023

AbstractObjectiveDiagnosing acute pulmonary embolism (PE) is challenging because of nonspecific clinical symptoms. Soluble lectin-type oxidized low-density lipoprotein receptor (sLOX-1) has differential expression in arterial and venous disease. This study aimed to evaluate the relevance of soluble lectin-type oxidized low-density lipoprotein receptor (sLOX-1) as a diagnostic biomarker for acute PE.MethodsThis observational study was performed at Beijing Anzhen Hospital in China. Patients with PE, aortic dissection (AD), myocardial infarction (MI) and healthy controls were enrolled in this cross-sectional study (n=90 each). Moreover, 730 patients with suspected PE were enrolled in this prospective study. The diagnostic performance of sLOX-1 was assessed using the receiver operating characteristic curve analysis.ResultsIn the development set, sLOX-1 levels were significantly lower in patients with PE than in those with AD, MI, or healthy controls. In the validation cohort, the area under the curve (AUC) of sLOX-1 for patients with PE from other chest pain diseases, particularly from AD was significantly higher than that of D-dimer (ΔAUC=0.32; 95%CI, 0.26-0.37; P<0.0001) with 77.0% specificity and 74.5% positive predictive value at the threshold of 600 pg/mL derived from the development set. By integrating sLOX-1 into existing diagnosis strategy (Wells rules combined D-dimer), the number of patients who were further categorized as workup for PE decreased from 417 to 209, with the positive detection rate of computed tomographic pulmonary angiography increased from 35.1% to 67.0%. Six patients with PE were missed in 208 excluded patients at a failure rate of 2.88%.ConclusionsPlasma sLOX-1 is a novel diagnostic tool that can rapidly categorize suspected PE as a workup for PE based on existing diagnostic strategy.
Outcomes in patients with ischemic stroke and newly diagnosed atrial fibrillation after stroke
Authors: Chang Yu-Kang , Hsu Chih-Cheng , Huang Chi-Ting , Lien Chi-Hsun , Hsu Hung-Yi 
Published: November 2023

ABSTRACTBACKGROUNDThe clinical characteristics and long-term outcomes of patients with ischemic stroke (IS) and newly diagnosed atrial fibrillation after stroke (NAF) have not been clearly established. Previous studies evaluating patients with NAF were limited by the low prescription rates of anticoagulants and short follow-up periods.METHODSConsecutive patients hospitalized for IS between 2014 and 2017 were identified from a National Health Insurance Research Database. The included patients were categorized into three groups: (1) known diagnosis of AF (KAF) before the index stroke, (2) NAF, and (3) without AF (non-AF). Univariable and multivariable Cox regression analyses were performed to estimate the hazard ratio (HR) for independent variables and recurrent IS, hemorrhagic stroke, or death.RESULTSWe identified 158,909 patients with IS of whom 16,699 (10.5%) had KAF and 7,826 (4.9%) had NAF. The patients with NAF were younger, more often male, and had lower CHA2DS2-VASc scores (3.8 ± 1.9 versus 4.9 ± 1.8,p< 0.001) than the patients with KAF. Anticoagulant treatment significantly reduced the risks of all outcomes. Compared with NAF, KAF was associated with lower risks of recurrent IS [hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.86–0.97,p< 0.01] and hemorrhagic stroke (HR: 0.88, 95% CI: 0.79–0.99,p< 0.01) and a higher risk of all-cause mortality (HR: 1.11, 95% CI: 1.07–1.16,p< 0.001). The risks of all three outcomes were significantly higher for both NAF and KAF than for non-AF.CONCLUSIONSThe risks of recurrent IS and hemorrhagic stroke were higher and of all-cause mortality was lower for patients with NAF than with KAF. Anticoagulant therapy significantly reduced the risks of recurrent IS, hemorrhagic stroke, and all-cause mortality.
Loss of Purkinje cells in the developing cerebellum strengthens the cerebellothalamic synapses
Authors: Nishiyama Hiroshi , Nishiyama Naoko , Zemelman Boris V. 
Published: November 2023

AbstractCerebellar damage early in life often causes long-lasting motor, social, and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviors. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviors. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is the direct postsynaptic target of the cerebellum, sending cerebellar outputs to the cerebral cortex. Despite its crucial position in cerebello-cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The hemizygous deletion of the tuberous sclerosis complex-1 (Tsc1) gene in the Purkinje cell—known to cause Purkinje cell hypoactivity and autistic behaviors—did not alter cerebellothalamic synapses or intrinsic membrane properties of thalamic neurons. However, the ablation of Purkinje cells in the developing cerebellum strengthened the cerebellothalamic synapses and enhanced thalamic suprathreshold activities. These results suggest that the cerebellothalamic circuit is resistant to moderate perturbation in the developing cerebellum, such as the reduced firing rate of Purkinje cells, and that autistic behaviors are not necessarily linked to thalamic abnormality. Still, Purkinje cell loss alters the thalamic circuit, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum.