bluuebunny/crossref_metadata_2025 huggingface dataset:
Expanding access to rectal spacers in the United Kingdom: an examination of current evidence and an early review of data from a single institution
Authors: Watts Isabella , Clifford Amy , Needleman Sarah , Roy Ashoke , Hartill Clare , Gore Alexandra , Prentice Mark
Published: July 2022

Background:

Prostate cancer is a common malignancy with rising incidence in Western countries such as the United Kingdom. In localised disease there are a variety of curative treatment modalities. Patients can be referred for surgery, or for a combination of hormonal therapies and radiotherapy (external beam radiotherapy or brachytherapy). Each treatment option comes with side effects and in the case of radiotherapy one potential complication is bowel toxicity from radiation exposure. New technologies are being developed to try and mitigate the side effects and long term morbidity of this treatment, and to expand access to radiotherapy for patients who may previously have been excluded (i.e those with inflammatory bowel disease). Rectal Spacers are absorbable polyethylene glycol hydrogels injected into the perirectal space. These position the anterior rectal wall away from the prostate, subsequently minimising radiation dose to the rectum. Rectal Spacers have been introduced to National Healthcare Service (NHS) practice as part of the Innovation and Technology Payment (ITP) programme, however, their use is now under review.

Methodology and Results:

In this editorial we conduct a narrative review of some of the available evidence for Rectal Spacers, discuss their utilization within the NHS and the barriers to their wider use. We also explore preliminary dosimetry and quality of life data for use of Rectal Spacers in our centre where we have been part of the NHS ITP programme. Dosimetry data and Quality of life questionnaires were gathered from 22 treated patients and 11 matched controls. This indicated lower radiation doses to the prostate in those treated with Rectal Spacers.

Conclusion:

Rectal Spacers are an effective method to reduce radiation dose to the prostate in men treated for localised prostate cancer, however, their use remains under review in the NHS and there are a variety of barriers to upscaling their use.
“A Colony of Alien Capital”: French Investments, Polish Identity, and a Story of Murder in 1930s Warsaw
Authors: Łazor Jerzy
Published: July 2022

This article explores public reactions to a murder of a foreign managing director running a French-owned textile factory in interwar Poland. The 1932 killing provoked an intense discussion in the press, which sheds light on Polish identity and narrative strategies used by the elites to rationalize the consequences of Poland's peripheral economic status. The study is based on discourse analysis of over 200 press articles. I argue that commentators saw the killing as the result of French policies in the factory, and interpreted these in turn as the result of either the Polish government's negligence, influenced by Paris's diplomats, or of global capitalism. The most dramatic arguments framed French policies in Żyrardów as a form of colonialism or slavery. This framing was based on the journalists’ perception of French actions as transgressions of two imagined hierarchies: a geo-racial division of the world, and the local hierarchy of labor.
Response of hairy galinsoga (Galinsoga quadriradiata) to nitrogen, phosphorus, and competition from lettuce
Authors: DiTommaso Antonio , Mohler Charles L. , Westbrook Anna S.
Published: July 2022

Hairy galinsoga (Galinsoga quadriradiata Cav.) is a troublesome weed in lettuce (Lactuca sativa L.) and other low-growing crops. Many troublesome weed species are more responsive to fertilizer than major crops, and hence potentially more competitive under fertile conditions. This study examined the responses of G. quadriradiata and lettuce, in monoculture or competition with each other, to nitrogen and phosphorus. A greenhouse experiment assessed the biomass and flower production of G. quadriradiata grown in 16 nutrient treatments. The nutrient treatments were arranged in a phosphorus series, in which phosphorus varied, while nitrogen was either low or high, and a nitrogen series, in which nitrogen varied, while phosphorus was either low or high. A field experiment examined G. quadriradiata biomass, flower production, and competition with lettuce using the same nutrient treatments as the greenhouse experiment. Galinsoga quadriradiata dry biomass increased with phosphorus addition, especially when nitrogen was abundant. In the phosphorus series at high nitrogen, G. quadriradiata produced more biomass when competing with lettuce than in monoculture. Nutrient addition generally increased flower production per unit mass. Lettuce fresh biomass increased with phosphorus, but lettuce dry biomass was largely unaffected by fertility. Lettuce fresh and dry biomass were sometimes decreased by competition from G. quadriradiata, relative to intraspecific competition. We conclude that high phosphorus rates increase the productivity of G. quadriradiata and may increase its competitiveness. Therefore, high phosphorus rates should be avoided unless good weed control can be assured.
Fähigkeitsbeeinträchtigungen bei psychischen Erkrankungen
Authors: Linden Michael , Baron Dr. Stefanie , Muschalla Dr. Beate , Ostholt-Corsten Dr. Margarete
Published: July 2022

Fähigkeitsorientierte Beurteilung In diesem Buch wird dargestellt, was unter Fähigkeiten zu verstehen ist, wie sie zu erfassen und zu quantifizieren sind, welche Bedeutung ihnen bei psychischen Erkrankungen zukommt und welche therapeutischen und sozialmedizinischen Folgen daraus erwachsen. Krankheit geht nicht nur mit Beschwerden und Symptomen einher, sondern auch mit Fähigkeitseinschränkungen. Diese dienen nicht nur als Diagnosekriterien, sie bestimmen vor allem über das Ausmaß der Krankheitsfolgen und damit die Schwere und sozialmedizinische Wertigkeit von Krankheiten. Auf Fähigkeitsbeeinträchtigungen basieren Urteile über Arbeitsfähigkeit, Erwerbsminderung, Leistungen zur Teilhabe oder Pflegebedürftigkeit. Die detaillierte Beschreibung von Fähigkeiten hat unmittelbare Bedeutung für die Patientenversorgung. Es gibt speziell fähigkeitsorientierte Behandlungsansätze wie Selbstsicherheitstraining oder ein Training beruflicher Fähigkeiten im Rahmen von Leistungen zur Teilhabe am Arbeitsleben. Die zweite Auflage wurde ergänzend zum passenden Testverfahren „Mini-ICF-APP“ aktualisiert und erweitert. Das „Mini-ICF-APP“ (Mini-ICF-Rating für Aktivitäts- und Partizipationsstörungen bei psychischen Erkrankungen) ist ein Fremdratinginstrument, welches eine Erfassung und Quantifizierung von psychopathologiesensitiven Fähigkeitsbeeinträchtigungen ermöglicht. Das Buch enthält darüber hinaus eine Reihe weiterer Skalen und Instrumente, die in der Fähigkeitsdiagnostik ergänzend eingesetzt werden können.
Increased Water Content in the Active Layer Revealed by Regional‐Scale InSAR and Independent Component Analysis on the Central Qinghai‐Tibet Plateau
Authors: Chen Jie , Wu Tonghua , Liu Lin , Gong Wenyu , Zwieback Simon , Zou Defu , Zhu Xiaofan , Hu Guojie , Du Erji , Wu Xiaodong , Li Ren , Yang Sizhong
Published: July 2022

Isolating seasonal deformation from Interferometric Synthetic Aperture Radar (InSAR) time‐series is critical to quantitative understanding the freeze‐thaw processes in permafrost regions. Physics‐ or statistics‐based approaches have been developed to extract seasonal deformation, yet both constraining their evolution in time domain, and thus impeded the quantification of their amplitude variability especially over large scales. By applying Independent Component Analysis (ICA) on Sentinel‐1 InSAR measurements during 2015–2019 on the central Qinghai‐Tibet Plateau, we reveal that the averaged seasonal deformation is increasing with a linear trend of around 0.17 cm/year. The growing seasonal amplitude is attributed to an 8 cm increase of the Equivalent Water Thickness in the active layer. The results demonstrate the capability of ICA‐based decomposition on isolating freeze‐thaw‐related deformation from other components. The large‐scale spatial distribution of varied seasonal deformation can provide new insight into quantifying the water mass balance in vast permafrost regions.
Mooring Measurements of Anadyr Current Nitrate, Phosphate, and Silicate Enable Updated Bering Strait Nutrient Flux Estimates
Authors: Hennon Tyler D. , Danielson Seth L. , Woodgate Rebecca A. , Irving Brita , Stockwell Dean A. , Mordy Calvin W.
Published: July 2022

In situ nutrient concentration data and salinity‐nutrient parameterizations established at Anadyr Strait from June 2017 to June 2018 are used to estimate monthly Pacific‐to‐Arctic fluxes of nitrate, phosphate, and silicate through Bering Strait over 1997–2019. In most months our estimates rely on measurements made from mooring‐based sensors and whole water samples, while over May–August the basis is shipboard hydrography. We find annually averaged Bering Strait fluxes of 16 ± 6, 1.5 ± 0.5, and 30 ± 11 kmol/s for nitrate, phosphate, and silicate, respectively, with inter‐annual variability ±30% of the mean. Maximum fluxes occur in April, exceeding the annual average by ∼50%, while minimum fluxes occur in December. Annually averaged fluxes estimated here are ∼50% higher than previous estimates. Significant (p < 0.05) increasing trends in phosphate and silicate fluxes are found over 1998–2018, but not nitrate. However, it is unclear if these trend results are due to differences in draw‐down or limitations of the salinity‐nutrient parameterizations.
Ambient Noise Attenuation Tomography Reveals an Asymmetric Damage Zone Across San Jacinto Fault Near Anza, California
Authors: Liu Xin , Beroza Gregory C. , Ben‐Zion Yehuda
Published: July 2022

We perform seismic attenuation tomography of the shallow structure for the San Jacinto Fault in the Ramona Reservation of southern California. The study uses ambient seismic noise recorded by a linear array of 65 3‐C sensors across the fault. We extract amplitude decay information, with uncertainty, from noise interferometry functions. To account for strong heterogeneities in the complex shallow fault zone structure, we apply a frequency‐dependent amplitude correction for focusing/defocusing effects using inverted phase velocity maps obtained by solving the transport equation. We then estimate the attenuation structure based on the linear station‐triplet method for both Love and Rayleigh waves. The attenuation tomography indicates strong attenuation correlated with known San Jacinto Fault surface traces. The Love wave attenuation tomography reveals an asymmetric damage zone that exists primarily on the fault side with faster seismic velocity, consistent with earthquake ruptures on a fault bimaterial interface with preferred propagation direction to the northwest.
Identification of heptapeptides targeting a lethal bacterial strain in septic mice through an integrative approach
Authors: Zhang Xiaoyan , Li Shan , Luo Haihua , He Shuyue , Yang Huangda , Li Lei , Tian Tian , Han Qizheng , Ye Jiacong , Huang Chenyang , Liu Aihua , Jiang Yong
Published: July 2022

Effectively killing pathogenic bacteria is key for the treatment of sepsis. Although various anti-infective drugs have been used for the treatment of sepsis, the therapeutic effect is largely limited by the lack of a specific bacterium-targeting delivery system. This study aimed to develop antibacterial peptides that specifically target pathogenic bacteria for the treatment of sepsis. The lethal bacterial strainEscherichia coli MSI001was isolated from mice of a cecal ligation and puncture (CLP) model and was used as a target to screen bacterial binding heptapeptides through an integrative bioinformatics approach based on phage display technology and high-throughput sequencing (HTS). Heptapeptides binding to E. coliMSI001with high affinity were acquired after normalization by the heptapeptide frequency of the library. A representative heptapeptide VTKLGSL (VTK) was selected for fusion with the antibacterial peptide LL-37 to construct the specific-targeting antibacterial peptide VTK-LL37. We found that, in comparison with LL37, VTK-LL37 showed prominent bacteriostatic activity and an inhibitive effect on biofilm formation in vitro. In vivo experiments demonstrated that VTK-LL37 significantly inhibited bacterial growth, reduced HMGB1 expression, alleviated lesions of vital organs and improved the survival of mice subjected to CLP modeling. Furthermore, membrane DEGP and DEGQ were identified as VTK-binding proteins by proteomic methods. This study provides a novel strategy for targeted pathogen killing, which is helpful for the treatment of sepsis in the era of precise medicine.
A novel nonsense variant in ARID1B causing simultaneous RNA decay and exon skipping is associated with Coffin-Siris syndrome
Authors: Sofronova Viktoriia , Fukushima Yu , Masuno Mitsuo , Naka Mami , Nagata Miho , Ishihara Yasuki , Miyashita Yohei , Asano Yoshihiro , Moriwaki Takahito , Iwata Rina , Terawaki Seigo , Yamanouchi Yasuko , Otomo Takanobu
Published: July 2022

Coffin-Siris syndrome (CSS) is a congenital disorder that is characterized by an absent/hypoplastic fifth distal phalanx, psychomotor developmental delay, and coarse facial features. One of the causative genes, ARID1B (AT-rich interactive domain-containing protein 1B), encodes components of the BAF chromatin remodeling complexes. Here, we report a case of a 3-year 8-month-old male with a novel nonsense variant (NM_001374820.1:c.4282C > T, p.(Gln1428*)) in the ARID1B gene, which was identified with whole-exome sequencing. He showed clinical symptoms of cleft soft palate, distinctive facial features (flat nasal bridge, thick eyebrows, and long eyelashes), right cryptorchidism, and hypertrichosis that partially overlapped with CSS. One of the most characteristic features of CSS is absent/hypoplastic fifth distal phalanx. He showed no obvious clinical finding in the lengths of his fingers or in the formation of his fingernails. However, radiographic analyses of the metacarpophalangeal bones revealed shortening of all the distal phalanges and fifth middle phalanges, suggesting brachydactyly. We performed mRNA analyses and revealed that both nonsense-mediated decay and nonsense-associated altered splicing were simultaneously caused by the c.4282C > T nonsense variant. The proband’s clinical manifestations fit the previously reported criteria of disease for CSS or intellectual disability with ARID1B variant. Altogether, we suggest that c.4282C > T is a pathogenic variant that causes this clinical phenotype.
Noise correlations in neural ensemble activity limit the accuracy of hippocampal spatial representations
Authors: Hazon Omer , Minces Victor H. , Tomàs David P. , Ganguli Surya , Schnitzer Mark J. , Jercog Pablo E.
Published: July 2022

Neurons in the CA1 area of the mouse hippocampus encode the position of the animal in an environment. However, given the variability in individual neurons responses, the accuracy of this code is still poorly understood. It was proposed that downstream areas could achieve high spatial accuracy by integrating the activity of thousands of neurons, but theoretical studies point to shared fluctuations in the firing rate as a potential limitation. Using high-throughput calcium imaging in freely moving mice, we demonstrated the limiting factors in the accuracy of the CA1 spatial code. We found that noise correlations in the hippocampus bound the estimation error of spatial coding to ~10 cm (the size of a mouse). Maximal accuracy was obtained using approximately [300–1400] neurons, depending on the animal. These findings reveal intrinsic limits in the brain’s representations of space and suggest that single neurons downstream of the hippocampus can extract maximal spatial information from several hundred inputs.
Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression
Authors: Yan Shuting , Zhu Qiyao , Jain Swati , Schlick Tamar
Published: July 2022

The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE experiments, the FSE adopts a heterogeneous, length-dependent conformational landscape consisting of an assumed 3-stem H-type pseudoknot (graph motif 3_6), and two alternative motifs (3_3 and 3_5). Here, for the first time, we build and simulate, by microsecond molecular dynamics, 30 models for all three motifs plus motif-stabilizing mutants at different lengths. Our 3_6 pseudoknot systems, which agree with experimental structures, reveal interconvertible L and linear conformations likely related to ribosomal pausing and frameshifting. The 3_6 mutant inhibits this transformation and could hamper frameshifting. Our 3_3 systems exhibit length-dependent stem interactions that point to a potential transition pathway connecting the three motifs during ribosomal elongation. Together, our observations provide new insights into frameshifting mechanisms and anti-viral strategies.
Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis
Authors: Caporarello Nunzia , Lee Jisu , Pham Tho X. , Jones Dakota L. , Guan Jiazhen , Link Patrick A. , Meridew Jeffrey A. , Marden Grace , Yamashita Takashi , Osborne Collin A. , Bhagwate Aditya V. , Huang Steven K. , Nicosia Roberto F. , Tschumperlin Daniel J. , Trojanowska Maria , Ligresti Giovanni
Published: July 2022

Vascular dysfunction is a hallmark of chronic diseases in elderly. The contribution of the vasculature to lung repair and fibrosis is not fully understood. Here, we performed an epigenetic and transcriptional analysis of lung endothelial cells (ECs) from young and aged mice during the resolution or progression of bleomycin-induced lung fibrosis. We identified the transcription factor ETS-related gene (ERG) as putative orchestrator of lung capillary homeostasis and repair, and whose function is dysregulated in aging. ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury. Loss of endothelial ERG enhances paracrine fibroblast activation in vitro, and impairs lung fibrosis resolution in young mice in vivo. scRNA-seq of ERG deficient mouse lungs reveales transcriptional and fibrogenic abnormalities resembling those associated with aging and human lung fibrosis, including reduced number of general capillary (gCap) ECs. Our findings demonstrate that lung endothelial chromatin remodeling deteriorates with aging leading to abnormal transcription, vascular dysrepair, and persistent fibrosis following injury.
Limited influence of irrigation on pre-monsoon heat stress in the Indo-Gangetic Plain
Authors: Jha Roshan , Mondal Arpita , Devanand Anjana , Roxy M. K. , Ghosh Subimal
Published: July 2022

Hot extremes are anticipated to be more frequent and more intense under climate change, making the Indo-Gangetic Plain of India, with a 400 million population, vulnerable to heat stress. Recent studies suggest that irrigation has significant cooling and moistening effects over this region. While large-scale irrigation is prevalent in the Indo-Gangetic Plain during the two major cropping seasons, Kharif (Jun-Sep) and Rabi (Nov-Feb), hot extremes are reported in the pre-monsoon months (Apr-May) when irrigation activities are minimal. Here, using observed irrigation data and regional climate model simulations, we show that irrigation effects on heat stress during pre-monsoon are 4.9 times overestimated with model-simulated irrigation as prescribed in previous studies. We find that irrigation increases relative humidity by only 2.5%, indicating that irrigation is a non-crucial factor enhancing the moist heat stress. On the other hand, we detect causal effects of aerosol abundance on the daytime land surface temperature. Our study highlights the need to consider actual irrigation data in testing model-driven hypotheses related to the land-atmosphere feedback driven by human water management.
Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts
Authors: Qiu Kangqiang , Zou Weiwei , Fang Hongbao , Hao Mingang , Mehta Kritika , Tian Zhiqi , Guan Jun-Lin , Zhang Kai , Huang Taosheng , Diao Jiajie
Published: July 2022

Mitochondria are highly dynamic organelles whose fragmentation by fission is critical to their functional integrity and cellular homeostasis. Here, we develop a method via optogenetic control of mitochondria–lysosome contacts (MLCs) to induce mitochondrial fission with spatiotemporal accuracy. MLCs can be achieved by blue-light-induced association of mitochondria and lysosomes through various photoactivatable dimerizers. Real-time optogenetic induction of mitochondrial fission is tracked in living cells to measure the fission rate. The optogenetic method partially restores the mitochondrial functions of SLC25A46−/− cells, which display defects in mitochondrial fission and hyperfused mitochondria. The optogenetic MLCs system thus provides a platform for studying mitochondrial fission and treating mitochondrial diseases.
A facile way to construct sensor array library via supramolecular chemistry for discriminating complex systems
Authors: Tian Jia-Hong , Hu Xin-Yue , Hu Zong-Ying , Tian Han-Wen , Li Juan-Juan , Pan Yu-Chen , Li Hua-Bin , Guo Dong-Sheng
Published: July 2022

Differential sensing, which discriminates analytes via pattern recognition by sensor arrays, plays an important role in our understanding of many chemical and biological systems. However, it remains challenging to develop new methods to build a sensor unit library without incurring a high workload of synthesis. Herein, we propose a supramolecular approach to construct a sensor unit library by taking full advantage of recognition and assembly. Ten sensor arrays are developed by replacing the building block combinations, adjusting the ratio between system components, and changing the environment. Using proteins as model analytes, we examine the discriminative abilities of these supramolecular sensor arrays. Then the practical applicability for discriminating complex analytes is further demonstrated using honey as an example. This sensor array construction strategy is simple, tunable, and capable of developing many sensor units with as few syntheses as possible.
The RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis
Authors: Zhu Sangsang , Quan Chao , Wang Ruizhen , Liang Derong , Su Shu , Rong Ping , Zhou Kun , Yang Xinyu , Chen Qiaoli , Li Min , Du Qian , Zhang Jingzi , Fang Lei , Wang Hong-Yu , Chen Shuai
Published: July 2022

Sarcoplasmic/endoplasmic reticulum calcium ATPase SERCA2 mediates calcium re-uptake from the cytosol into sarcoplasmic reticulum, and its dysfunction is a hallmark of heart failure. Multiple factors have been identified to modulate SERCA2 activity, however, its regulation is still not fully understood. Here we identify a Ral-GTPase activating protein RalGAPα1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAPα1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAPα1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAPα1 decreases SERCA2 activity and prolongs calcium re-uptake into sarcoplasmic reticulum. GDP-bound RalA, but not GTP-bound RalA, binds to SERCA2 and activates the pump for sarcoplasmic reticulum calcium re-uptake. Overexpression of a GDP-bound RalAS28N mutant in the heart preserves cardiac function in a mouse model of heart failure. Our findings have therapeutic implications for treatment of heart failure.
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

Lipid 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

Analysis 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

In 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

3-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

TREX1 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

Immunization 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

The 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

Previous 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

The 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

This 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

To 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

Grid-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

While 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

The 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

Neurons 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.