bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-cell analysis reveals urothelial cell heterogeneity and regenerative cues following cyclophosphamide-induced bladder injury
Authors: Cheng Xiaomu , Lai Huadong , Luo Wenqin , Zhang Man , Miao Juju , Song Weichen , Xing Shunpeng , Wang Jia , Gao Wei-Qiang
Published: May 2021

Cyclophosphamide is a commonly used chemotherapeutic drug to treat cancer with side effects that trigger bladder injury and hemorrhagic cystitis. Although previous studies have demonstrated that certain cell subsets and communications are activated to drive the repair and regeneration of bladder, it is not well understood how distinct bladder cell subsets function synergistically in this process. Here, we used droplet-based single-cell RNA sequencing (scRNA-seq) to profile the cell types within the murine bladder mucous layer under normal and injured conditions. Our analysis showed that superficial cells are directly repaired by cycling intermediate cells. We further identified two resident mesenchymal lineages (Acta2+ myofibroblasts and Cd34+ fibroblasts). The delineation of cell-cell communications revealed that Acta2+ myofibroblasts upregulated Fgf7 expression during acute injury, which activated Fgfr signaling in progenitor cells within the basal/intermediate layers to promote urothelial cell growth and repair. Overall, our study contributes to a more comprehensive understanding of the cellular dynamics during cyclophosphamide-induced bladder injury and may help identify important niche factors contributing to the regeneration of injured bladders.
Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation
Authors: Yin Yun-Nian , Ding Rui-Qi , Ouyang Dong-Chen , Zhang Qing , Zhu Rong
Published: May 2021

α-Tertiary amides are of great importance for medicinal chemistry. However, they are often challenging to access through conventional methods due to reactivity and chemoselectivity issues. Here, we report a single-step approach towards such amides via cobalt-catalyzed intermolecular oxidative hydroamidation of unactivated alkenes, using nitriles of either solvent- or reagent-quantities. This protocol is selective for terminal alkenes over groups that rapidly react under known carbocation amidation conditions such as tertiary alcohols, electron-rich alkenes, ketals, weak C−H bonds, and carboxylic acids. Straightforward access to a diverse array of hindered amides is demonstrated, including a rapid synthesis of an aminoadamantane-derived pharmaceutical intermediate.
Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease
Authors: Youlten Scott E. , Kemp John P. , Logan John G. , Ghirardello Elena J. , Sergio Claudio M. , Dack Michael R. G. , Guilfoyle Siobhan E. , Leitch Victoria D. , Butterfield Natalie C. , Komla-Ebri Davide , Chai Ryan C. , Corr Alexander P. , Smith James T. , Mohanty Sindhu T. , Morris John A. , McDonald Michelle M. , Quinn Julian M. W. , McGlade Amelia R. , Bartonicek Nenad , Jansson Matt , Hatzikotoulas Konstantinos , Irving Melita D. , Beleza-Meireles Ana , Rivadeneira Fernando , Duncan Emma , Richards J. Brent , Adams David J. , Lelliott Christopher J. , Brink Robert , Phan Tri Giang , Eisman John A. , Evans David M. , Zeggini Eleftheria , Baldock Paul A. , Bassett J. H. Duncan , Williams Graham R. , Croucher Peter I.
Published: May 2021

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease.
A data-independent acquisition-based global phosphoproteomics system enables deep profiling
Authors: Kitata Reta Birhanu , Choong Wai-Kok , Tsai Chia-Feng , Lin Pei-Yi , Chen Bo-Shiun , Chang Yun-Chien , Nesvizhskii Alexey I. , Sung Ting-Yi , Chen Yu-Ju
Published: May 2021

Phosphoproteomics can provide insights into cellular signaling dynamics. To achieve deep and robust quantitative phosphoproteomics profiling for minute amounts of sample, we here develop a global phosphoproteomics strategy based on data-independent acquisition (DIA) mass spectrometry and hybrid spectral libraries derived from data-dependent acquisition (DDA) and DIA data. Benchmarking the method using 166 synthetic phosphopeptides shows high sensitivity (<0.1 ng), accurate site localization and reproducible quantification (~5% median coefficient of variation). As a proof-of-concept, we use lung cancer cell lines and patient-derived tissue to construct a hybrid phosphoproteome spectral library covering 159,524 phosphopeptides (88,107 phosphosites). Based on this library, our single-shot streamlined DIA workflow quantifies 36,350 phosphosites (19,755 class 1) in cell line samples within two hours. Application to drug-resistant cells and patient-derived lung cancer tissues delineates site-specific phosphorylation events associated with resistance and tumor progression, showing that our workflow enables the characterization of phosphorylation signaling with deep coverage, high sensitivity and low between-run missing values.
PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions
Authors: Ercolano Giuseppe , Gomez-Cadena Alejandra , Dumauthioz Nina , Vanoni Giulia , Kreutzfeldt Mario , Wyss Tania , Michalik Liliane , Loyon Romain , Ianaro Angela , Ho Ping-Chih , Borg Christophe , Kopf Manfred , Merkler Doron , Krebs Philippe , Romero Pedro , Trabanelli Sara , Jandus Camilla
Published: May 2021

Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.
Tunneling current modulation in atomically precise graphene nanoribbon heterojunctions
Authors: Senkovskiy Boris V. , Nenashev Alexey V. , Alavi Seyed K. , Falke Yannic , Hell Martin , Bampoulis Pantelis , Rybkovskiy Dmitry V. , Usachov Dmitry Yu. , Fedorov Alexander V. , Chernov Alexander I. , Gebhard Florian , Meerholz Klaus , Hertel Dirk , Arita Masashi , Okuda Taichi , Miyamoto Koji , Shimada Kenya , Fischer Felix R. , Michely Thomas , Baranovskii Sergei D. , Lindfors Klas , Szkopek Thomas , Grüneis Alexander
Published: May 2021

Lateral heterojunctions of atomically precise graphene nanoribbons (GNRs) hold promise for applications in nanotechnology, yet their charge transport and most of the spectroscopic properties have not been investigated. Here, we synthesize a monolayer of multiple aligned heterojunctions consisting of quasi-metallic and wide-bandgap GNRs, and report characterization by scanning tunneling microscopy, angle-resolved photoemission, Raman spectroscopy, and charge transport. Comprehensive transport measurements as a function of bias and gate voltages, channel length, and temperature reveal that charge transport is dictated by tunneling through the potential barriers formed by wide-bandgap GNR segments. The current-voltage characteristics are in agreement with calculations of tunneling conductance through asymmetric barriers. We fabricate a GNR heterojunctions based sensor and demonstrate greatly improved sensitivity to adsorbates compared to graphene based sensors. This is achieved via modulation of the GNR heterojunction tunneling barriers by adsorbates.
Co-occupancy identifies transcription factor co-operation for axon growth
Authors: Venkatesh Ishwariya , Mehra Vatsal , Wang Zimei , Simpson Matthew T. , Eastwood Erik , Chakraborty Advaita , Beine Zac , Gross Derek , Cabahug Michael , Olson Greta , Blackmore Murray G.
Published: May 2021

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.
Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling
Authors: Lee Wei Ting C. , Yin Yandong , Morten Michael J. , Tonzi Peter , Gwo Pam Pam , Odermatt Diana C. , Modesti Mauro , Cantor Sharon B. , Gari Kerstin , Huang Tony T. , Rothenberg Eli
Published: May 2021

Guanine-rich DNA sequences occur throughout the human genome and can transiently form G-quadruplex (G4) structures that may obstruct DNA replication, leading to genomic instability. Here, we apply multi-color single-molecule localization microscopy (SMLM) coupled with robust data-mining algorithms to quantitatively visualize replication fork (RF)-coupled formation and spatial-association of endogenous G4s. Using this data, we investigate the effects of G4s on replisome dynamics and organization. We show that a small fraction of active replication forks spontaneously form G4s at newly unwound DNA immediately behind the MCM helicase and before nascent DNA synthesis. These G4s locally perturb replisome dynamics and organization by reducing DNA synthesis and limiting the binding of the single-strand DNA-binding protein RPA. We find that the resolution of RF-coupled G4s is mediated by an interplay between RPA and the FANCJ helicase. FANCJ deficiency leads to G4 accumulation, DNA damage at G4-associated replication forks, and silencing of the RPA-mediated replication stress response. Our study provides first-hand evidence of the intrinsic, RF-coupled formation of G4 structures, offering unique mechanistic insights into the interference and regulation of stable G4s at replication forks and their effect on RPA-associated fork signaling and genomic instability.
Structures of flavivirus RNA promoters suggest two binding modes with NS5 polymerase
Authors: Lee Eunhye , Bujalowski Paul J. , Teramoto Tadahisa , Gottipati Keerthi , Scott Seth D. , Padmanabhan Radhakrishnan , Choi Kyung H.
Published: May 2021

Flaviviruses use a ~70 nucleotide stem-loop structure called stem-loop A (SLA) at the 5′ end of the RNA genome as a promoter for RNA synthesis. Flaviviral polymerase NS5 specifically recognizes SLA to initiate RNA synthesis and methylate the 5′ guanosine cap. We report the crystal structures of dengue (DENV) and Zika virus (ZIKV) SLAs. DENV and ZIKV SLAs differ in the relative orientations of their top stem-loop helices to bottom stems, but both form an intermolecular three-way junction with a neighboring SLA molecule. To understand how NS5 engages SLA, we determined the SLA-binding site on NS5 and modeled the NS5-SLA complex of DENV and ZIKV. Our results show that the gross conformational differences seen in DENV and ZIKV SLAs can be compensated by the differences in the domain arrangements in DENV and ZIKV NS5s. We describe two binding modes of SLA and NS5 and propose an SLA-mediated RNA synthesis mechanism.
Deep generative model embedding of single-cell RNA-Seq profiles on hyperspheres and hyperbolic spaces
Authors: Ding Jiarui , Regev Aviv
Published: May 2021

Single-cell RNA-Seq (scRNA-seq) is invaluable for studying biological systems. Dimensionality reduction is a crucial step in interpreting the relation between cells in scRNA-seq data. However, current dimensionality reduction methods are often confounded by multiple simultaneous technical and biological variability, result in “crowding” of cells in the center of the latent space, or inadequately capture temporal relationships. Here, we introduce scPhere, a scalable deep generative model to embed cells into low-dimensional hyperspherical or hyperbolic spaces to accurately represent scRNA-seq data. ScPhere addresses multi-level, complex batch factors, facilitates the interactive visualization of large datasets, resolves cell crowding, and uncovers temporal trajectories. We demonstrate scPhere on nine large datasets in complex tissue from human patients or animal development. Our results show how scPhere facilitates the interpretation of scRNA-seq data by generating batch-invariant embeddings to map data from new individuals, identifies cell types affected by biological variables, infers cells’ spatial positions in pre-defined biological specimens, and highlights complex cellular relations.
Experimental vulnerability analysis of QKD based on attack ratings
Authors: Kumar Rupesh , Mazzoncini Francesco , Qin Hao , Alléaume Romain
Published: May 2021

Inspired by the methodology used for classical cryptographic hardware, we consider the use of attack ratings in the context of QKD security evaluation. To illustrate the relevance of this approach, we conduct an experimental vulnerability assessment of CV-QKD against saturation attacks, for two different attack strategies. The first strategy relies on inducing detector saturation by performing a large coherent displacement. This strategy is experimentally challenging and therefore translates into a high attack rating. We also propose and experimentally demonstrate a second attack strategy that simply consists in saturating the detector with an external laser. The low rating we obtain indicates that this attack constitutes a primary threat for practical CV-QKD systems. These results highlight the benefits of combining theoretical security considerations with vulnerability analysis based on attack ratings, in order to guide the design and engineering of practical QKD systems towards the highest possible security standards.
Characteristics of chronic obstructive pulmonary disease patients with robust progression of emphysematous change
Authors: Tsutsumi Akihiro , Chubachi Shotaro , Irie Hidehiro , Sasaki Mamoru , Yamada Yoshitake , Sugiura Hiroaki , Jinzaki Masahiro , Nakamura Hidetoshi , Asano Koichiro , Betsuyaku Tomoko , Fukunaga Koichi
Published: May 2021

Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P = 0.04) and having osteoporosis (OR, 2.13; P = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.
Author Correction: Centrifugation does not remove bacteria from the fat fraction of human milk
Authors: Stinson Lisa F. , Ma Jie , Rea Alethea , Dymock Michael , Geddes Donna T.
Published: May 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Prognostic histologic subtyping of dominant tumor in resected synchronous multiple adenocarcinomas of lung
Authors: Tsai Ping-Chung , Liu Chia , Yeh Yi-Chen , Chen Chun-Ku , Hsu Po-Kuei , Chen Hui-Shan , Huang Chien-Sheng , Hsieh Chih-Cheng , Hsu Han-Shui , Huang Biing-Shiun
Published: May 2021

The prognostic role of histological patterns of dominant tumor (DT) and second dominant tumor (sDT) in synchronous multiple adenocarcinoma (SMADC) of lung remains unclear. SMADC patients diagnosed between 2003 and 2015 were retrospectively reviewed. DT and sDT were defined as two maximum diameters of consolidation among multiple tumors. Histological pattern was determined using IASLC/ATS/ERS classification system. DTs were divided into low- (lepidic), intermediate- (acinar, papillary) and high-grade (micropapillary, solid) subtypes, and sDTs into non-invasive predominant (lepidic) and invasive predominant (acinar, papillary, micropapillary, solid) subtypes. During mean 74-month follow-up among 149 nodal-negative patients having SMADC resected, recurrence was noted in 44 (29.5%), with significantly higher percentage in high-grade DT (p < 0.001). Five-year overall (OS) and disease-free (DFS) survivals in low-, intermediate- and high-grade DT were 96.9%, 94.3%, 63.3% (p < 0.001) and 100%, 87.2%, 30.0%, respectively (p < 0.001). Cox-regression multivariate analysis demonstrated high-grade DT as a significant predictor for DFS (Hazard ratio [HR] 5.324; 95% CI 2.570–11.462, p < 0.001) and OS (HR 3.287; 95% CI 1.323–8.168, p = 0.010). Analyzing DT and sDT together, we found no significant differences in DFS, either in intermediate- or high-grade DT plus invasive or non-invasive sDT. DT was histologically an independent risk factor of DFS and OS in completely resected nodal-negative SMADCs.
Network pharmacology approach to decipher signaling pathways associated with target proteins of NSAIDs against COVID-19
Authors: Oh Ki Kwang , Adnan Md. , Cho Dong Ha
Published: May 2021

Non-steroidal anti-inflammatory drugs (NSAIDs) showed promising clinical efficacy toward COVID-19 (Coronavirus disease 2019) patients as potent painkillers and anti-inflammatory agents. However, the prospective anti-COVID-19 mechanisms of NSAIDs are not evidently exposed. Therefore, we intended to decipher the most influential NSAIDs candidate(s) and its novel mechanism(s) against COVID-19 by network pharmacology. FDA (U.S. Food & Drug Administration) approved NSAIDs (19 active drugs and one prodrug) were used for this study. Target proteins related to selected NSAIDs and COVID-19 related target proteins were identified by the Similarity Ensemble Approach, Swiss Target Prediction, and PubChem databases, respectively. Venn diagram identified overlapping target proteins between NSAIDs and COVID-19 related target proteins. The interactive networking between NSAIDs and overlapping target proteins was analyzed by STRING. RStudio plotted the bubble chart of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis of overlapping target proteins. Finally, the binding affinity of NSAIDs against target proteins was determined through molecular docking test (MDT). Geneset enrichment analysis exhibited 26 signaling pathways against COVID-19. Inhibition of proinflammatory stimuli of tissues and/or cells by inactivating the RAS signaling pathway was identified as the key anti-COVID-19 mechanism of NSAIDs. Besides, MAPK8, MAPK10, and BAD target proteins were explored as the associated target proteins of the RAS. Among twenty NSAIDs, 6MNA, Rofecoxib, and Indomethacin revealed promising binding affinity with the highest docking score against three identified target proteins, respectively. Overall, our proposed three NSAIDs (6MNA, Rofecoxib, and Indomethacin) might block the RAS by inactivating its associated target proteins, thus may alleviate excessive inflammation induced by SARS-CoV-2.
Determinants of loss to care and risk of clinical progression in PLWH who are re-engaged in care after a temporary loss
Authors: Mussini Cristina , Lorenzini Patrizia , Cozzi-Lepri Alessandro , Mammone Alessia , Guaraldi Giovanni , Marchetti Giulia , Lichtner Miriam , Lapadula Giuseppe , Lo Caputo Sergio , Antinori Andrea , d’Arminio Monforte Antonella , Girardi Enrico
Published: May 2021

The risk of developing AIDS is elevated not only among those with a late HIV diagnosis but also among those lost to care (LTC). The aims were to address the risk of becoming LTC and of clinical progression in LTC patients who re-enter care. Patients were defined as LTC if they had no visit for ≥ 18 months. Of these, persons with subsequent visits were defined as re-engaged in care (RIC). Factors associated with becoming LTC and RIC were investigated. The risk of disease progression was estimated by comparing RIC with patients continuously followed. Over 11,285 individuals included, 3962 became LTC, and of these, 1062 were RIC. Older age, presentation with AIDS and with higher HIV-RNA were associated with a reduced risk of LTC. In contrast, lower education level, irregular job, being an immigrant and injecting-drug user were associated with an increased LTC probability. Moreover, RIC with HIV-RNA > 200 copies/mL at the re-entry had a higher risk of clinical progression, while those with HIV-RNA ≤ 200 copies/mL had a higher risk of only non-AIDS progression. Patients re-entering care after being LTC appeared to be at higher risk of clinical progression than those continuously in care. Active strategies for re-engagement in care should be promoted.
Realization and training of an inverter-based printed neuromorphic computing system
Authors: Weller Dennis D. , Hefenbrock Michael , Beigl Michael , Aghassi-Hagmann Jasmin , Tahoori Mehdi B.
Published: May 2021

Emerging applications in soft robotics, wearables, smart consumer products or IoT-devices benefit from soft materials, flexible substrates in conjunction with electronic functionality. Due to high production costs and conformity restrictions, rigid silicon technologies do not meet application requirements in these new domains. However, whenever signal processing becomes too comprehensive, silicon technology must be used for the high-performance computing unit. At the same time, designing everything in flexible or printed electronics using conventional digital logic is not feasible yet due to the limitations of printed technologies in terms of performance, power and integration density. We propose to rather use the strengths of neuromorphic computing architectures consisting in their homogeneous topologies, few building blocks and analog signal processing to be mapped to an inkjet-printed hardware architecture. It has remained a challenge to demonstrate non-linear elements besides weighted aggregation. We demonstrate in this work printed hardware building blocks such as inverter-based comprehensive weight representation and resistive crossbars as well as printed transistor-based activation functions. In addition, we present a learning algorithm developed to train the proposed printed NCS architecture based on specific requirements and constraints of the technology.
Deep hierarchical embedding for simultaneous modeling of GPCR proteins in a unified metric space
Authors: Lee Taeheon , Lee Sangseon , Kang Minji , Kim Sun
Published: May 2021

GPCR proteins belong to diverse families of proteins that are defined at multiple hierarchical levels. Inspecting relationships between GPCR proteins on the hierarchical structure is important, since characteristics of the protein can be inferred from proteins in similar hierarchical information. However, modeling of GPCR families has been performed separately for each of the family, subfamily, and sub-subfamily level. Relationships between GPCR proteins are ignored in these approaches as they process the information in the proteins with several disconnected models. In this study, we propose DeepHier, a deep learning model to simultaneously learn representations of GPCR family hierarchy from the protein sequences with a unified single model. Novel loss term based on metric learning is introduced to incorporate hierarchical relations between proteins. We tested our approach using a public GPCR sequence dataset. Metric distances in the deep feature space corresponded to the hierarchical family relation between GPCR proteins. Furthermore, we demonstrated that further downstream tasks, like phylogenetic reconstruction and motif discovery, are feasible in the constructed embedding space. These results show that hierarchical relations between sequences were successfully captured in both of technical and biological aspects.
Cross-sectional analysis of the Parkinson’s disease Non-motor International Longitudinal Study baseline non-motor characteristics, geographical distribution and impact on quality of life
Authors: van Wamelen Daniel J. , Sauerbier Anna , Leta Valentina , Rodriguez-Blazquez Carmen , Falup-Pecurariu Cristian , Rodriguez‐Violante Mayela , Rizos Alexandra , Tsuboi Y. , Metta Vinod , Bhidayasiri Roongroj , Bhattacharya Kalyan , Borgohain Rupam , Prashanth L. K. , Rosales Raymond , Lewis Simon , Fung Victor , Behari Madhuri , Goyal Vinay , Kishore Asha , Lloret Santiago Perez , Martinez-Martin Pablo , Chaudhuri K. Ray
Published: May 2021

Growing evidence suggests that non-motor symptoms (NMS) in Parkinson’s disease (PD) have differential progression patterns that have a different natural history from motor progression and may be geographically influenced. We conducted a cross-sectional analysis of 1607 PD patients of whom 1327 were from Europe, 208 from the Americas, and 72 from Asia. The primary objective was to assess baseline non-motor burden, defined by Non-Motor Symptoms Scale (NMSS) total scores. Other aims included identifying the factors predicting quality of life, differences in non-motor burden between drug-naïve and non-drug-naïve treated patients, and non-motor phenotypes across different geographical locations. Mean age was 65.9 ± 10.8 years, mean disease duration 6.3 ± 5.6 years, median Hoehn and Yahr stage was 2 (2–3), and 64.2% were male. In this cohort, mean NMSS scores were 46.7 ± 37.2. Differences in non-motor burden and patterns differed significantly between drug-naïve participants, those with a disease duration of less than five years, and those with a duration of five years or over (p ≤ 0.018). Significant differences were observed in geographical distribution (NMSS Europe: 46.4 ± 36.3; Americas: 55.3 ± 42.8; Asia: 26.6 ± 25.1; p < 0.001), with differences in sleep/fatigue, urinary, sexual, and miscellaneous domains (p ≤ 0.020). The best predictor of quality of life was the mood/apathy domain (β = 0.308, p < 0.001). This global study reveals that while non-motor symptoms are globally present with severe NMS burden impacting quality of life in PD, there appear to be differences depending on disease duration and geographical distribution.
Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models
Authors: Bragazzi Cunha Juliana , Elenbaas Jared S. , Maitra Dhiman , Kuo Ning , Azuero-Dajud Rodrigo , Ferguson Allison C. , Griffin Megan S. , Lentz Stephen I. , Shavit Jordan A. , Omary M. Bishr
Published: May 2021

Congenital erythropoietic porphyria (CEP) is a rare genetic disorder leading to accumulation of uro/coproporphyrin-I in tissues due to inhibition of uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity and photomutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation, and there is an unmet need for treating this orphan disease. Fluorescent porphyrins cause protein aggregation, which led us to hypothesize that uroporphyrin-I accumulation leads to protein aggregation and CEP-related bone phenotype. We developed a zebrafish model that phenocopies features of CEP. As in human patients, uroporphyrin-I accumulated in the bones of zebrafish, leading to impaired bone development. Furthermore, in an osteoblast-like cell line, uroporphyrin-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy. Using high-throughput drug screening, we identified acitretin, a second-generation retinoid, and showed that it reduced uroporphyrin-I accumulation and its deleterious effects on bones. Our findings provide a new CEP experimental model and a potential repurposed therapeutic.
A new method for facilitating ultrasound-guided in-plane cannulation of the subclavian vein: a randomized clinical trial
Authors: Mao Qingxiang , He Haitao , Lu Yuangang , Hu Yi , Wang Zhen , Gan Maoxiang , Chen Liyong , Yan Hong
Published: May 2021

The objective of this study was to propose a new method for facilitating needle-beam alignment ultrasound-guided in-plane catheterization of the subclavian vein (SCV). Three hundred patients were recruited, and ultrasound examination of the SCV was performed. Then, the patients were divided into two groups and SCV catheterization was performed: ultrasound-guided catheterization with the aiming method (group A) and ultrasound-guided catheterization with needle guide (group NG). The success rate, insertion time, number of skin breaks, number of needle redirections, needle visibility and rate of mechanical complications were documented and compared for each procedure. To depict the optimum long-axis view of the SCV, there was a 30° ± 7.3° angle (rotation) between the long axis of the ultrasound probe and the clavicle, while there was a 39° ± 7.4° angle (tilt) between the ultrasound beam plane and the right chest wall. The aiming method was associated with fewer skin breaks [(mean (IQR): 1 (1–1) times vs 1 (1–2) times, P = 0.009], a shorter time to cannulation [(mean (IQR): 39 (32–48.5) s vs 48 (44–54.8) s, P = 0.000] and more needle redirections [(mean (IQR): 0 (0–1) vs 0 (0–0), P = 0.000]. There were no differences between group A and group NG in the overall success rate, first puncture success rate, needle visibility or mechanical complication rate. In conclusion, during ultrasound-guided in-plane catheterization of the SCV, the aiming method provides comparable needle-beam alignment with a lower cannulation time than the needle guide technique.
Environmental conditions, diel period, and fish size influence the horizontal and vertical movements of red snapper
Authors: Bacheler Nathan M. , Shertzer Kyle W. , Runde Brendan J. , Rudershausen Paul J. , Buckel Jeffrey A.
Published: May 2021

Most demersal fishes are difficult to observe and track due to methodological and analytical constraints. We used an acoustic positioning system to elucidate the horizontal and vertical movements of 44 red snapper (Lutjanus campechanus) off North Carolina, USA, in 2019. Mean movement rate and distance off bottom varied by individual, with larger red snapper generally moving faster and spending more time farther off the bottom than smaller individuals. We used generalized additive mixed models that accounted for temporal autocorrelation in the data to show that mean hourly red snapper movement rate was lower during the day than at night and was negatively related to bottom water temperature. Moreover, red snapper spent more time off the bottom during the day than at night, and vertical movements were mostly related to bottom upwelling events that sporadically occurred in May–July. Our results and previous observations suggest that red snapper feed primarily on benthic organisms at night, and display diel vertical migration (i.e., thermotaxis) up to warmer waters (when present) during the day to aid digestive efficiency. Movement is a central organizing feature in ecology, and the sustainable management of fish will benefit from a better understanding of the timing and causes of fish movement.
A hierarchical clustering method of hydrogen bond networks in liquid water undergoing shear flow
Authors: Gao Yitian , Fang Hongwei , Ni Ke
Published: May 2021

Many properties of water, such as turbulent flow, are closely related to water clusters, whereas how water clusters form and transform in bulk water remains unclear. A hierarchical clustering method is introduced to search out water clusters in hydrogen bonded network based on modified Louvain algorithm of graph community. Hydrogen bonds, rings and fragments are considered as 1st-, 2nd-, and 3rd-level structures, respectively. The distribution, dynamics and structural characteristics of 4th- and 5th-level clusters undergoing non-shear- and shear-driven flow are also analyzed at various temperatures. At low temperatures, nearly 50% of water molecules are included in clusters. Over 60% of clusters remain unchanged between neighboring configurations. Obvious collective translational motion of clusters is observed. The topological difference for clusters is elucidated between the inner layer, which favors 6-membered rings, and the external surface layer, which contains more 5-membered rings. Temperature and shearing can not only accelerate the transformation or destruction of clusters at all levels but also change cluster structures. The assembly of large clusters can be used to discretize continuous liquid water to elucidate the properties of liquid water.
On Gaussian curvature and membrane fission
Authors: Rueda-Contreras Mara Denisse , Gallen Andreu F. , Romero-Arias J. Roberto , Hernandez-Machado Aurora , Barrio Rafael A.
Published: May 2021

We propose a three-dimensional mathematical model to describe dynamical processes of membrane fission. The model is based on a phase field equation that includes the Gaussian curvature contribution to the bending energy. With the addition of the Gaussian curvature energy term numerical simulations agree with the predictions that tubular shapes can break down into multiple vesicles. A dispersion relation obtained with linear analysis predicts the wavelength of the instability and the number of formed vesicles. Finally, a membrane shape diagram is obtained for the different Gaussian and bending modulus, showing different shape regimes.
Nicotine suppresses Parkinson’s disease like phenotypes induced by Synphilin-1 overexpression in Drosophila melanogaster by increasing tyrosine hydroxylase and dopamine levels
Authors: Carvajal-Oliveros Angel , Domínguez-Baleón Carmen , Zárate Rafaella V. , Campusano Jorge M. , Narváez-Padilla Verónica , Reynaud Enrique
Published: May 2021

It has been observed that there is a lower Parkinson’s disease (PD) incidence in tobacco users. Nicotine is a cholinergic agonist and is the principal psychoactive compound in tobacco linked to cigarette addiction. Different studies have shown that nicotine has beneficial effects on sporadic and genetic models of PD. In this work we evaluate nicotine’s protective effect in a Drosophila melanogaster model for PD where Synphilin-1 (Sph-1) is expressed in dopaminergic neurons. Nicotine has a moderate effect on dopaminergic neuron survival that becomes more evident as flies age. Nicotine is beneficial on fly survival and motility increasing tyrosine hydroxylase and dopamine levels, suggesting that cholinergic agonists may promote survival and metabolic function of the dopaminergic neurons that express Sph-1. The Sph-1 expressing fly is a good model for the study of early-onset phenotypes such as olfaction loss one of the main non-motor symptom related to PD. Our data suggest that nicotine is an interesting therapeutic molecule whose properties should be explored in future research on the phenotypic modulators of the disease and for the development of new treatments.
Repeated exposure to dengue virus elicits robust cross neutralizing antibodies against Zika virus in residents of Northeastern Thailand
Authors: Hattakam Sararat , Elong Ngono Annie , McCauley Melanie , Shresta Sujan , Yamabhai Montarop
Published: May 2021

Zika virus (ZIKV) and dengue virus (DENV) are antigenically related mosquito-borne flaviviruses. ZIKV is becoming increasingly prevalent in DENV-endemic regions, raising the possibility that pre-existing immunity to one virus could modulate the response to a heterologous virus, although whether this would be beneficial or detrimental is unclear. Here, we analyzed sera from residents of a DENV-endemic region of Thailand to determine the prevalence of DENV-elicited antibodies capable of cross-neutralizing ZIKV. Sixty-one participants who were asymptomatic and unselected for viral serostatus were enrolled. Among them, 52 and 51 were seropositive for IgG antibody against DENV or ZIKV E proteins (ELISA assay), respectively. Notably, 44.23% (23/52) of DENV seropositive participants had serological evidence of multiple exposures to DENV, and these subjects had strikingly higher titers and broader reactivities of neutralizing antibodies (NAbs) against ZIKV and DENV heterotypes compared with participants with serological evidence of a single DENV infection (25/52, 48.1%). In total, 17 of the 61 participants (27.9%) had NAbs against ZIKV and all four DENV serotypes, and an additional 9 (14.8%) had NAbs against ZIKV and DENV1, 2, and 3. NAbs against DENV2 were the most prevalent (44/61, 72.1%) followed by DENV3 (38/61, 62.3%) and DENV1 (36/61, 59.0%). Of note, anti-ZIKV NAbs were more prevalent than anti-DENV4 NAbs (27/61, 44.3% and 21/61, 34.4%, respectively). Primary ZIKV infection was detected in two participants, confirming that ZIKV co-circulates in this region. Thus, residents of DENV-endemic regions with repeated exposure to DENV have higher titers of NAbs against ZIKV than individuals with only a single DENV exposure.
Association of meteorological factors with the frequency of primary rhegmatogenous retinal detachment in Japan
Authors: Iida Masanobu , Horiguchi Hiroshi , Katagiri Satoshi , Shirakashi Yuka , Yamada Yuki , Gunji Hisato , Nakano Tadashi
Published: May 2021

This 5-year ecological study assessed the association between meteorological factors and rhegmatogenous retinal detachment (RRD) frequency in 571 eyes of 543 cases of primary RRD at the Jikei University Kashiwa Hospital, Japan. We examined the monthly and seasonal distributions of RRD frequency using one-way analysis of variance. We then evaluated the relationship between monthly RRD frequency and 36 meteorological parameters using Poisson regression analysis. Furthermore, we developed multivariate regression models to predict the frequency of RRD based on specific meteorological parameters. There were no significant differences in the monthly and seasonal distributions (monthly, P = 0.99; seasonal, P = 0.77). The following eight parameters were associated with a lower RRD frequency: average sea level barometric pressure and average daily variation of average temperature, maximum temperature, maximum wind speed, maximum instantaneous wind speed, humidity, average sea level barometric pressure, and minimum sea level barometric pressure (P < 0.05). The best model to predict RRD frequency showed sufficient validity (Akaike’s information criterion with correction for small sample size = 332.0) and predictive power (proportion of variance explained by cross-validation method = 84.82%, 95% CI 72.18–93.72). In conclusion, low atmospheric pressure and high meteorological stability are significantly associated with a higher frequency of RRD. In addition, the Poisson regression analysis showed sufficient validity and predictability for predicting RRD frequency.
Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model
Authors: Cáceres C. Joaquín , Cardenas-Garcia Stivalis , Carnaccini Silvia , Seibert Brittany , Rajao Daniela S. , Wang Jun , Perez Daniel R.
Published: May 2021

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the defining global health emergency of this century. GC-376 is a Mpro inhibitor with antiviral activity against SARS-CoV-2 in vitro. Using the K18-hACE2 mouse model, the in vivo antiviral efficacy of GC-376 against SARS-CoV-2 was evaluated. GC-376 treatment was not toxic in K18-hACE2 mice. Overall outcome of clinical symptoms and survival upon SARS-CoV-2 challenge were not improved in mice treated with GC-376 compared to controls. The treatment with GC-376 slightly improved survival from 0 to 20% in mice challenged with a high virus dose at 105 TCID50/mouse. Most notably, GC-376 treatment led to milder tissue lesions, reduced viral loads, fewer presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls in mice challenged with a low virus dose at 103 TCID50/mouse. This was particularly the case in the brain where a 5-log reduction in viral titers was observed in GC-376 treated mice compared to vehicle controls. This study supports the notion that GC-376 represents a promising lead candidate for further development to treat SARS-CoV-2 infection and that the K18-hACE2 mouse model is suitable to study antiviral therapies against SARS-CoV-2.
Identification of molecular signatures associated with early relapse after complete resection of lung adenocarcinomas
Authors: Pasternack Helen , Kuempers Christiane , Deng Mario , Watermann Iris , Olchers Till , Kuehnel Mark , Jonigk Danny , Kugler Christian , Stellmacher Florian , Goldmann Torsten , Kirfel Jutta , Ammerpohl Ole , Perner Sven , Reck Martin
Published: May 2021

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA–IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.
Functionally confirmed compound heterozygous ADAM17 missense loss-of-function variants cause neonatal inflammatory skin and bowel disease 1
Authors: Imoto Issei , Saito Masako , Suga Kenichi , Kohmoto Tomohiro , Otsu Masanobu , Horiuchi Keisuke , Nakayama Hironao , Higashiyama Shigeki , Sugimoto Mayumi , Sasaki Ayumi , Homma Yukako , Shono Miki , Nakagawa Ryuji , Hayabuchi Yasunobu , Tange Shoichiro , Kagami Shoji , Masuda Kiyoshi
Published: May 2021

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17, namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea. In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts (Adam10/17−/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.
Nitrogen supply and intercropping control of Fusarium wilt in faba bean depend on organic acids exuded from the roots
Authors: Lv Jiaxing , Xiao Jingxiu , Guo Zengpeng , Dong Kun , Dong Yan
Published: May 2021

Fusarium wilt in faba bean (Vicia faba L.) is caused by Fusarium oxysporum f. sp. fabae (FOF), which reduces the yield of crop. We used greenhouse, field and laboratory experiments to evaluate the role of organic acids in the occurrence of Fusarium wilt of faba bean to confirm the mechanism of rational application of nitrogen (N) and intercropping to alleviate Fusarium wilt. We investigated the response of organic acids exuded from the roots of faba bean to different N levels and cropping patterns (monocropping and intercropping with wheat). The results showed that the application of N and intercropping with wheat could control the Fusarium wilt of faba bean, which was closely related to the components and quantity of organic acids exuded from its roots. Among them, tartaric acid and malic acid are the most abundant and important, because they have a significant inhibitory effect on the growth and reproduction of FOF and substantially aid in the control of Fusarium wilt. The application of 90 kg ha−1 of N combined with wheat intercropping significantly controlled the Fusarium wilt and increased the grain yield of faba bean. Our results suggest that 90 kg ha−1 of N combined with intercropping is the most effective way to control Fusarium wilt and should be incorporated into agricultural management practices.