bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression
Authors: Zhu Yining , Shen Ruochen , Vuong Ivan , Reynolds Rebekah A. , Shears Melanie J. , Yao Zhi-Cheng , Hu Yizong , Cho Won June , Kong Jiayuan , Reddy Sashank K. , Murphy Sean C. , Mao Hai-Quan 
Published: July 2022

AbstractLipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compositions for plasmid DNA delivery. Here, we report a multi-step screening platform to identify optimized plasmid DNA lipid nanoparticles for liver-targeted transgene expression. To achieve this, we analyze the role of different helper lipids and component ratios in plasmid DNA lipid nanoparticle-mediated gene delivery in vitro and in vivo. Compared to mRNA LNPs and in vivo-jetPEI/DNA nanoparticles, the identified plasmid DNA lipid nanoparticles successfully deliver transgenes and mediate prolonged expression in the liver following intravenous administration in mice. By addressing different physiological barriers in a stepwise manner, this screening platform can efficiently down select effective lipid nanoparticle candidates from a lipid nanoparticle library of over 1000 formulations. In addition, we substantially extend the duration of plasmid DNA nanoparticle-mediated transgene expression using a DNA/siRNA co-delivery approach that targets transcription factors regulating inflammatory response pathways. This lipid nanoparticle-based co-delivery strategy further highlights the unique advantages of an extended transgene expression profile using plasmid DNA delivery and offers new opportunities for DNA-based gene medicine applications.
DNA nicks induce mutational signatures associated with BRCA1 deficiency
Authors: Feng Yi-Li , Liu Qian , Chen Ruo-Dan , Liu Si-Cheng , Huang Zhi-Cheng , Liu Kun-Ming , Yang Xiao-Ying , Xie An-Yong 
Published: July 2022

AbstractAnalysis of human cancer genome sequences has revealed specific mutational signatures associated withBRCA1-deficient tumors, but the underlying mechanisms remain poorly understood. Here, we show that one-ended DNA double strand breaks (DSBs) converted from CRISPR/Cas9-induced nicks by DNA replication, not two-ended DSBs, cause more characteristic chromosomal aberrations and micronuclei inBrca1-deficient cells than in wild-type cells. BRCA1 is required for efficient homologous recombination of these nick-converted DSBs and suppresses bias towards long tract gene conversion and tandem duplication (TD) mediated by two-round strand invasion in a replication strand asymmetry. However, aberrant repair of these nick-converted one-ended DSBs, not that of two-ended DSBs inBrca1-deficient cells, generates mutational signatures such as small indels with microhomology (MH) at the junctions, translocations and small MH-mediated TDs, resembling those inBRCA1-deficient tumors. These results suggest a major contribution of DNA nicks to mutational signatures associated withBRCA1deficiency in cancer and the underlying mechanisms.
Lead federated neuromorphic learning for wireless edge artificial intelligence
Authors: Yang Helin , Lam Kwok-Yan , Xiao Liang , Xiong Zehui , Hu Hao , Niyato Dusit , Vincent Poor H. 
Published: July 2022

AbstractIn order to realize the full potential of wireless edge artificial intelligence (AI), very large and diverse datasets will often be required for energy-demanding model training on resource-constrained edge devices. This paper proposes a lead federated neuromorphic learning (LFNL) technique, which is a decentralized energy-efficient brain-inspired computing method based on spiking neural networks. The proposed technique will enable edge devices to exploit brain-like biophysiological structure to collaboratively train a global model while helping preserve privacy. Experimental results show that, under the situation of uneven dataset distribution among edge devices, LFNL achieves a comparable recognition accuracy to existing edge AI techniques, while substantially reducing data traffic by >3.5× and computational latency by >2.0×. Furthermore, LFNL significantly reduces energy consumption by >4.5× compared to standard federated learning with a slight accuracy loss up to 1.5%. Therefore, the proposed LFNL can facilitate the development of brain-inspired computing and edge AI.
Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain
Authors: Chen Hongwen , Qi Xiaofeng , Faulkner Rebecca A. , Schumacher Marc M. , Donnelly Linda M. , DeBose-Boyd Russell A. , Li Xiaochun 
Published: July 2022

Abstract3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme in cholesterol synthesis and target of cholesterol-lowering statin drugs. Accumulation of sterols in endoplasmic reticulum (ER) membranes accelerates degradation of HMGCR, slowing the synthesis of cholesterol. Degradation of HMGCR is inhibited by its binding to UBIAD1 (UbiA prenyltransferase domain-containing protein-1). This inhibition contributes to statin-induced accumulation of HMGCR, which limits their cholesterol-lowering effects. Here, we report cryo-electron microscopy structures of the HMGCR-UBIAD1 complex, which is maintained by interactions between transmembrane helix (TM) 7 of HMGCR and TMs 2–4 of UBIAD1. Disrupting this interface by mutagenesis prevents complex formation, enhancing HMGCR degradation. TMs 2–6 of HMGCR contain a 170-amino acid sterol sensing domain (SSD), which exists in two conformations—one of which is essential for degradation. Thus, our data supports a model that rearrangement of the TMs in the SSD permits recruitment of proteins that initate HMGCR degradation, a key reaction in the regulatory system that governs cholesterol synthesis.
Structural basis of human TREX1 DNA degradation and autoimmune disease
Authors: Zhou Wen , Richmond-Buccola Desmond , Wang Qiannan , Kranzusch Philip J. 
Published: July 2022

AbstractTREX1 is a cytosolic DNA nuclease essential for regulation of cGAS-STING immune signaling. Existing structures of mouse TREX1 establish a mechanism of DNA degradation and provide a key model to explain autoimmune disease, but these structures incompletely explain human disease-associated mutations and have limited ability to guide development of small-molecule therapeutics. Here we determine crystal structures of human TREX1 in apo and DNA-bound conformations that provide high-resolution detail of all human-specific features. A 1.25 Å structure of human TREX1 establishes a complete model of solvation of the exonuclease active site and a 2.2 Å structure of the human TREX1–DNA complex enables identification of specific substitutions involved in DNA recognition. We map each TREX1 mutation associated with autoimmune disease and establish distinct categories of substitutions predicted to impact enzymatic function, protein stability, and interaction with cGAS-DNA liquid droplets. Our results explain how human-specific substitutions regulate TREX1 function and provide a foundation for structure-guided design of TREX1 therapeutics.
Optimized intramuscular immunization with VSV-vectored spike protein triggers a superior immune response to SARS-CoV-2
Authors: Taddeo Adriano , Veiga Inês Berenguer , Devisme Christelle , Boss Renate , Plattet Philippe , Weigang Sebastian , Kochs Georg , Thiel Volker , Benarafa Charaf , Zimmer Gert 
Published: July 2022

AbstractImmunization with vesicular stomatitis virus (VSV)-vectored COVID-19 vaccine candidates expressing the SARS-CoV-2 spike protein in place of the VSV glycoprotein relies implicitly on expression of the ACE2 receptor at the muscular injection site. Here, we report that such a viral vector vaccine did not induce protective immunity following intramuscular immunization of K18-hACE2 transgenic mice. However, when the viral vector was trans-complemented with the VSV glycoprotein, intramuscular immunization resulted in high titers of spike-specific neutralizing antibodies. The vaccinated animals were fully protected following infection with a lethal dose of SARS-CoV-2-SD614G via the nasal route, and partially protected if challenged with the SARS-CoV-2Delta variant. While dissemination of the challenge virus to the brain was completely inhibited, replication in the lung with consequent lung pathology was not entirely controlled. Thus, intramuscular immunization was clearly enhanced by trans-complementation of the VSV-vectored vaccines by the VSV glycoprotein and led to protection from COVID-19, although not achieving sterilizing immunity.
Logic-gated antibody pairs that selectively act on cells co-expressing two antigens
Authors: Oostindie Simone C. , Rinaldi Derek A. , Zom Gijs G. , Wester Michael J. , Paulet Desiree , Al-Tamimi Kusai , van der Meijden Els , Scheick Jennifer R. , Wilpshaar Tessa , de Jong Bart , Hoff-van den Broek Marloes , Grattan Rachel M. , Oosterhoff Janita J. , Vignau Julie , Verploegen Sandra , Boross Peter , Beurskens Frank J. , Lidke Diane S. , Schuurman Janine , de Jong Rob N. 
Published: July 2022

AbstractThe use of therapeutic monoclonal antibodies is constrained because single antigen targets often do not provide sufficient selectivity to distinguish diseased from healthy tissues. We present HexElect®, an approach to enhance the functional selectivity of therapeutic antibodies by making their activity dependent on clustering after binding to two different antigens expressed on the same target cell. lmmunoglobulin G (lgG)-mediated clustering of membrane receptors naturally occurs on cell surfaces to trigger complement- or cell-mediated effector functions or to initiate intracellular signaling. We engineer the Fc domains of two different lgG antibodies to suppress their individual homo-oligomerization while promoting their pairwise hetero-oligomerization after binding co-expressed antigens. We show that recruitment of complement component C1q to these hetero-oligomers leads to clustering-dependent activation of effector functions such as complement mediated killing of target cells or activation of cell surface receptors. HexElect allows selective antibody activity on target cells expressing unique, potentially unexplored combinations of surface antigens.
Change-detection training and its effects on visual processing skills
Authors: Truong Jennifer , Buschkuehl Martin , Smith-Peirce Rachel N. , Carrillo Audrey A. , Seitz Aaron R. , Jaeggi Susanne M. 
Published: July 2022

AbstractPrevious cognitive training research with the change-detection paradigm found only sparse effects that went beyond improvements in the training task but stressed an increase in fidelity of internal memory representations. Motivated by the demanding visual processing requirements of change-detection training, we extended this work by focusing on whether training on a change-detection task would improve visual processing skills. Fifty participants were randomly assigned to train on a change-detection task or on a control task for seven sessions. Participants’ visual processing skills were assessed before and after the intervention, focusing on visual search, contrast sensitivity, and contour integration. Our results suggest a general improvement in perceptual skills that was primarily driven by a conjunction search task and to a much lesser extent by a complex visual search task and a contrast sensitivity task. The data from the conjunction search task further suggest a causal link between training and improvements of perceptual as opposed to attentional processes. Since the change-detection paradigm is commonly used to assess working memory capacity, future research needs to investigate how much of its variance is explained by memory performance and how much is explained by perceptual processes.
Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction
Authors: Urata Ryota , Ikeda Koji , Yamazaki Ekura , Ueno Daisuke , Katayama Akiko , Shin-Ya Masaharu , Ohgitani Eriko , Mazda Osam , Matoba Satoaki 
Published: July 2022

AbstractThe coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.
The clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinomas
Authors: Li Yangsen , Wang Yuanyuan , Li Liwen , Qiu Xinguang 
Published: July 2022

AbstractThis study aimed to review the clinical significance of BRAFV600E mutations in pediatric papillary thyroid carcinoma (PTC). From 2018 to 2021, 392 pediatric thyroid operations were performed in the first affiliated Hospital of Zhengzhou University. Of these, 169 patients underwent their first operation in our hospital and were histopathologically diagnosed as papillary thyroid carcinoma. BRAFV600E gene mutation detection was performed in these 169 pediatric patients to investigate the correlation between BRAF gene mutations and clinicopathological features. Ninety-seven of our 169 patients had a BRAFV600E mutation, with a mutation rate of 57.4%. The incidence of BRAFV600E was higher in boys than in girls, and in the 13–18-year age group as compared with the 6–12-year age group (P < 0.05). The positivity rate of BRAFV600E in unilateral PTC (67.7%) was significantly higher than the ones in bilateral PTC (28.9%). The occurrence of diffuse microcalcification of the thyroid negatively correlated with the presence of BRAFV600E mutations. BRAFV600E mutations were found more frequently in patients with smaller tumor size, a lack of multifocality, lower TSH levels and central lymph node metastasis. During the follow-up time, 70 patients were treated with iodine-131. Eight patients required a second surgery (All had cervical lymph node recurrence). BRAFV600E mutations do not suggest a more aggressive course in papillary thyroid carcinoma in pediatric patients in the short term.
Analysis of family stigma and socioeconomic factors impact among caregivers of patients with early- and late-onset Alzheimer's disease and frontotemporal dementia
Authors: Velilla Lina , Acosta-Baena Natalia , Allen Isabel , Lopera Francisco , Kramer Joel 
Published: July 2022

AbstractTo the best of our knowledge, there are no research studies about socioeconomic factors, family stigma, and their psychological impact on early-onset dementia caregivers. We assessed the impact of family stigma and socioeconomic factors on psychological outcomes, quality of life (QoL), and caregiver burden among 150 caregivers of patients with early-onset Alzheimer’s disease due to E280A mutation in presenilin 1 (EOAD), frontotemporal dementia (FTD), and late-onset Alzheimer’s disease (LOAD). Caregivers of patients with EOAD presented a higher frequency of socioeconomic risk factors. Caregivers of FTD presented higher levels of family stigma and a higher prevalence of negative outcomes. We found family stigma to be a more suitable predictor of all outcomes. After adjusting for the type of dementia, dementia stage and behavioral changes, and caregiver age and education, family stigma was the most important factor associated with a higher risk of caregiver burden and a reduction in QoL in terms of energy fatigue and emotional wellbeing among early-onset dementia caregivers.
New energy power system operation security evaluation based on the SWOT analysis
Authors: Maihemuti Saniye , Wang Weiqing , Wu Jiahui , Wang Haiyun 
Published: July 2022

AbstractGrid-connection of new energy is highly important in promoting the use of clean and renewable energy. However, it will bring huge risks to the power grid operation security, such as frequency stability, voltage stability, small signal stability, and transient stability, etc.,. In the study, SWOT (Strengths, Weaknesses, Opportunities, and Threats) analysis has been employed to construct 24 kinds of internal and external evaluation factors and 8 kinds of improvement strategies, for assessing operation security prospective with new energy power system of HM in China. The weights of SWOT factors are determined with the fuzzy-AHP method. Moreover, the fuzzy-MARCOS approach is used to select the most suitable strategies for power system operation security effective implementation. The reported research reveals that new energy in HM area not only has an ample potential for full development and generating electricity, but also brings operation security problems due to large-scale grid connection. Therefore, 8 kinds of improvement strategies are suggested to encourage the government to exploit and develop new resources, improve the investment pay, power generation and transmission technologies to mitigate the current energy crisis, and increase the energy security for sustainable development of the country. The methodology proposed herein is applicable with a case study concerning the operation security prospective of HM power grid, and all phases of the comparative analysis and sensitivity analysis illustrate the validity of MARCOS method. Furthermore, the ranked order of strategies is obtained as A2 > A6 > A5 > A1 > A8 > A7 > A4 > A3. The three most important strategies are A2, A6 and A5, i.e., “improving the technical establishment to encourage efficient and cheap electricity production”, “strive to build local permanent load, and reduce the risk of long-distance and high-capacity transmission”, “taking advantage of government incentives and investment to modify the irrational energy policies and energy planning”, respectively.
QRS detection and classification in Holter ECG data in one inference step
Authors: Ivora Adam , Viscor Ivo , Nejedly Petr , Smisek Radovan , Koscova Zuzana , Bulkova Veronika , Halamek Josef , Jurak Pavel , Plesinger Filip 
Published: July 2022

AbstractWhile various QRS detection and classification methods were developed in the past, the Holter ECG data acquired during daily activities by wearable devices represent new challenges such as increased noise and artefacts due to patient movements. Here, we present a deep-learning model to detect and classify QRS complexes in single-lead Holter ECG. We introduce a novel approach, delivering QRS detection and classification in one inference step. We used a private dataset (12,111 Holter ECG recordings, length of 30 s) for training, validation, and testing the method. Twelve public databases were used to further test method performance. We built a software tool to rapidly annotate QRS complexes in a private dataset, and we annotated 619,681 QRS complexes. The standardised and down-sampled ECG signal forms a 30-s long input for the deep-learning model. The model consists of five ResNet blocks and a gated recurrent unit layer. The model's output is a 30-s long 4-channel probability vector (no-QRS, normal QRS, premature ventricular contraction, premature atrial contraction). Output probabilities are post-processed to receive predicted QRS annotation marks. For the QRS detection task, the proposed method achieved the F1 score of 0.99 on the private test set. An overall mean F1 cross-database score through twelve external public databases was 0.96 ± 0.06. In terms of QRS classification, the presented method showed micro and macro F1 scores of 0.96 and 0.74 on the private test set, respectively. Cross-database results using four external public datasets showed micro and macro F1 scores of 0.95 ± 0.03 and 0.73 ± 0.06, respectively. Presented results showed that QRS detection and classification could be reliably computed in one inference step. The cross-database tests showed higher overall QRS detection performance than any of compared methods.
Population-based screening for celiac disease reveals that the majority of patients are undiagnosed and improve on a gluten-free diet
Authors: Kvamme Jan-Magnus , Sørbye Sveinung , Florholmen Jon , Halstensen Trond S. 
Published: July 2022

AbstractThe impact of a gluten-free diet (GFD) on screen-detected celiac disease (CD) is currently ambiguous. We aimed to identify the population-based prevalence of undiagnosed adult CD and examine the impact of a GFD on screen-detected CD. In total, 12,981 adults participated in a population-based health study in Tromsø, Norway. Participants with increased levels of anti-tissue transglutaminase-2 IgA or anti-deamidated gliadin peptide IgG were invited to undergo gastroduodenoscopy with both histological and immunohistochemical examination of small-bowel biopsies. The prevalence of previously diagnosed CD was 0.37%. Additionally, the prevalence of previously undiagnosed CD was 1.10%. Thus, 1.47% of the population had CD, of whom 75% were previously undiagnosed. A GFD resulted in significant improvements in overall gastrointestinal symptoms, diarrhea, and health-related quality of life, with reduced abdominal discomfort (76%) and improved levels of energy (58%). The large majority of patients with adult CD were undiagnosed and benefited from a GFD with reduced gastrointestinal symptoms and improved health-related quality of life. In clinical practice, there should be a low threshold for CD testing even in the absence of abdominal complaints because most adult patients appear to consider their symptoms a part of their normal state and therefore remain untested and undiagnosed.Trial registration: Clinical Trials. Gov Identifier: NCT01695681.
A model for the development of binocular congruence in primary visual cortex
Authors: Somaratna Manula A. , Freeman Alan W. 
Published: July 2022

AbstractNeurons in primary visual cortex are selective for stimulus orientation, and a neuron’s preferred orientation changes little when the stimulus is switched from one eye to the other. It has recently been shown that monocular orientation preferences are uncorrelated before eye opening; how, then, do they become aligned during visual experience? We aimed to provide a model for this acquired congruence. Our model, which simulates the cat’s visual system, comprises multiple on-centre and off-centre channels from both eyes converging onto neurons in primary visual cortex; development proceeds in two phases via Hebbian plasticity in the geniculocortical synapse. First, cortical drive comes from waves of activity drifting across each retina. The result is orientation tuning that differs between the two eyes. The second phase begins with eye opening: at each visual field location, on-centre cortical inputs from one eye can cancel off-centre inputs from the other eye. Synaptic plasticity reduces the destructive interference by up-regulating inputs from one eye at the expense of its fellow, resulting in binocular congruence of orientation tuning. We also show that orthogonal orientation preferences at the end of the first phase result in ocular dominance, suggesting that ocular dominance is a by-product of binocular congruence.