bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy
Authors: Ma Zhao , Li Jin , Lin Kai , Ramachandran Mythili , Zhang Dalin , Showalter Megan , De Souza Cristabelle , Lindstrom Aaron , Solano Lucas N. , Jia Bei , Urayama Shiro , Duan Yuyou , Fiehn Oliver , Lin Tzu-yin , Li Minyong , Li Yuanpei 
Published: September 2020

AbstractIntegration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.
Light microscopy based approach for mapping connectivity with molecular specificity
Authors: Shen Fred Y. , Harrington Margaret M. , Walker Logan A. , Cheng Hon Pong Jimmy , Boyden Edward S. , Cai Dawen 
Published: September 2020

AbstractMapping neuroanatomy is a foundational goal towards understanding brain function. Electron microscopy (EM) has been the gold standard for connectivity analysis because nanoscale resolution is necessary to unambiguously resolve synapses. However, molecular information that specifies cell types is often lost in EM reconstructions. To address this, we devise a light microscopy approach for connectivity analysis of defined cell types called spectral connectomics. We combine multicolor labeling (Brainbow) of neurons with multi-round immunostaining Expansion Microscopy (miriEx) to simultaneously interrogate morphology, molecular markers, and connectivity in the same brain section. We apply this strategy to directly link inhibitory neuron cell types with their morphologies. Furthermore, we show that correlative Brainbow and endogenous synaptic machinery immunostaining can define putative synaptic connections between neurons, as well as map putative inhibitory and excitatory inputs. We envision that spectral connectomics can be applied routinely in neurobiology labs to gain insights into normal and pathophysiological neuroanatomy.
Two-photon excited deep-red and near-infrared emissive organic co-crystals
Authors: Wang Yu , Wu Huang , Li Penghao , Chen Su , Jones Leighton O. , Mosquera Martín A. , Zhang Long , Cai Kang , Chen Hongliang , Chen Xiao-Yang , Stern Charlotte L. , Wasielewski Michael R. , Ratner Mark A. , Schatz George C. , Stoddart J. Fraser 
Published: September 2020

AbstractTwo-photon excited near-infrared fluorescence materials have garnered considerable attention because of their superior optical penetration, higher spatial resolution, and lower optical scattering compared with other optical materials. Herein, a convenient and efficient supramolecular approach is used to synthesize a two-photon excited near-infrared emissive co-crystalline material. A naphthalenediimide-based triangular macrocycle and coronene form selectively two co-crystals. The triangle-shaped co-crystal emits deep-red fluorescence, while the quadrangle-shaped co-crystal displays deep-red and near-infrared emission centered on 668 nm, which represents a 162 nm red-shift compared with its precursors. Benefiting from intermolecular charge transfer interactions, the two co-crystals possess higher calculated two-photon absorption cross-sections than those of their individual constituents. Their two-photon absorption bands reach into the NIR-II region of the electromagnetic spectrum. The quadrangle-shaped co-crystal constitutes a unique material that exhibits two-photon absorption and near-infrared emission simultaneously. This co-crystallization strategy holds considerable promise for the future design and synthesis of more advanced optical materials.
Age and life expectancy clocks based on machine learning analysis of mouse frailty
Authors: Schultz Michael B. , Kane Alice E. , Mitchell Sarah J. , MacArthur Michael R. , Warner Elisa , Vogel David S. , Mitchell James R. , Howlett Susan E. , Bonkowski Michael S. , Sinclair David A. 
Published: September 2020

AbstractThe identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (FrailtyInferredGeriatricHealthTimeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis ofFrailty andDeath) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
Giant magneto-optical responses in magnetic Weyl semimetal Co3Sn2S2
Authors: Okamura Y. , Minami S. , Kato Y. , Fujishiro Y. , Kaneko Y. , Ikeda J. , Muramoto J. , Kaneko R. , Ueda K. , Kocsis V. , Kanazawa N. , Taguchi Y. , Koretsune T. , Fujiwara K. , Tsukazaki A. , Arita R. , Tokura Y. , Takahashi Y. 
Published: September 2020

AbstractThe Weyl semimetal (WSM), which hosts pairs of Weyl points and accompanying Berry curvature in momentum space near Fermi level, is expected to exhibit novel electromagnetic phenomena. Although the large optical/electronic responses such as nonlinear optical effects and intrinsic anomalous Hall effect (AHE) have recently been demonstrated indeed, the conclusive evidence for their topological origins has remained elusive. Here, we report the gigantic magneto-optical (MO) response arising from the topological electronic structure with intense Berry curvature in magnetic WSM Co3Sn2S2. The low-energy MO spectroscopy and the first-principles calculation reveal that the interband transitions on the nodal rings connected to the Weyl points show the resonance of the optical Hall conductivity and give rise to the giant intrinsic AHE in dc limit. The terahertz Faraday and infrared Kerr rotations are found to be remarkably enhanced by these resonances with topological electronic structures, demonstrating the novel low-energy optical response inherent to the magnetic WSM.
A shared genetic contribution to breast cancer and schizophrenia
Authors: Lu Donghao , Song Jie , Lu Yi , Fall Katja , Chen Xu , Fang Fang , Landén Mikael , Hultman Christina M. , Czene Kamila , Sullivan Patrick , Tamimi Rulla M. , Valdimarsdóttir Unnur A. 
Published: September 2020

AbstractAn association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09–0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.
Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity
Authors: Shao Li-Wa , Peng Qi , Dong Mingyue , Gao Kaiyu , Li Yumei , Li Yi , Li Chuan-Yun , Liu Ying 
Published: September 2020

AbstractThe ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.
Predictive factors for prognosis after gastrostomy placement in routine non-invasive ventilation users ALS patients
Authors: Hesters Adèle , Amador Maria del Mar , Debs Rabab , Le Forestier Nadine , Lenglet Timothée , Pradat Pierre-François , Salachas François , Faure Morgane , Jimenez Maria-Alejandra Galarza , Gonzalez-Bermejo Jesus , Morelot Capucine , Bruneteau Gaëlle 
Published: September 2020

AbstractDue to the expanding use of non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS), the question of enteral nutrition is increasingly raised in NIV users ALS patients. Here, we aimed to determine the prognostic factors for survival after gastrostomy placement in routine NIV users, taking into consideration ventilator dependence. Ninety-two routine NIV users ALS patients, who underwent gastrostomy insertion for severe dysphagia and/or weight loss, were included. We used a Cox proportional hazards model to identify factors affecting survival and compared time from gastrostomy to death and 30-day mortality rate between dependent (daily use ≥ 16 h) and non-dependent NIV users. The hazard of death after gastrostomy was significantly affected by 3 factors: age at onset (HR 1.047, p = 0.006), body mass index < 20 kg/m2 at the time of gastrostomy placement (HR 2.012, p = 0.016) and recurrent accumulation of airway secretions (HR 2.614, p = 0.001). Mean time from gastrostomy to death was significantly shorter in the dependent than in the non-dependent NIV users group (133 vs. 250 days, p = 0.04). The 30-day mortality rate was significantly higher in dependent NIV users (21.4% vs. 2.8%, p = 0.03). Pre-operative ventilator dependence and airway secretion accumulation are associated with worse prognosis and should be key decision-making criteria when considering gastrostomy tube placement in NIV users ALS patients.
Defining diagnostic cutoffs in neurological patients for serum very long chain fatty acids (VLCFA) in genetically confirmed X-Adrenoleukodystrophy
Authors: Rattay Tim W. , Rautenberg Maren , Söhn Anne S. , Hengel Holger , Traschütz Andreas , Röben Benjamin , Hayer Stefanie N. , Schüle Rebecca , Wiethoff Sarah , Zeltner Lena , Haack Tobias B. , Cegan Alexander , Schöls Ludger , Schleicher Erwin , Peter Andreas 
Published: September 2020

AbstractX-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene resulting in the accumulation of very long chain fatty acids (VLCFA). X-ALD is the most common peroxisomal disorder with adult patients (male and female) presenting with progressive spastic paraparesis with bladder disturbance, sensory ataxia with impaired vibration sense, and leg pain. 80% of male X-ALD patients have an adrenal failure, while adrenal dysfunction is rare in women with X-ALD. The objective of this study was to define optimal serum VLCFA cutoff values in patients with X-ALD-like phenotypes for the differentiation of genetically confirmed X-ALD and Non-X-ALD individuals. Three groups were included into this study: a) X-ALD cases with confirmed ABCD1 mutations (n = 34) and two Non-X-ALD cohorts: b) Patients with abnormal serum VCLFA levels despite negative testing for ABCD1 mutations (n = 15) resulting from a total of 1,953 VLCFA tests c) Phenotypically matching patients as Non-X-ALD controls (n = 104). Receiver operating curve analysis was used to optimize VLCFA cutoff values, which differentiate patients with genetically confirmed X-ALD and Non-X-ALD individuals. The serum concentration of C26:0 was superior to C24:0 for the detection of X-ALD. The best differentiation of Non-X-ALD and X-ALD individuals was obtained with a cutoff value of < 1.0 for the C24:0/C22:0 ratio resulting in a sensitivity of 97%, a specificity of 94.1% and a positive predictive value (PPV) of 83.8% for true X-ALD. Our findings further suggested a cutoff of < 0.02 for the ratio C26:0/C22:0 leading to a sensitivity of 90.9%, a specificity of 95.0%, and a PPV of 80.6%. Pearson correlation indicated a significant positive association between total blood cholesterol and VLCFA values. Usage of serum VLCFA are economical and established biomarkers suitable for the guidance of genetic testing matching the X-ALD phenotype. We suggest using our new optimized cutoff values, especially the two ratios (C24:0/C22:0 and C26:0/C22:0), in combination with standard lipid profiles.
Modelling the expected probability of correct assignment under uncertainty
Authors: Dvir Tom , Peres Renana , Rudnick Zeév 
Published: September 2020

AbstractWhen making important decisions such as choosing health insurance or a school, people are often uncertain what levels of attributes will suit their true preference. After choice, they might realize that their uncertainty resulted in a mismatch: choosing a sub-optimal alternative, while another available alternative better matches their needs. We study here the overall impact, from a central planner’s perspective, of decisions under such uncertainty. We use the representation of Voronoi tessellations to locate all individuals and alternatives in an attribute space. We provide an expression for the probability of correct match, and calculate, analytically and numerically, the average percentage of matches. We test dependence on the level of uncertainty and location. We find that the overall mismatch is considerable even for low uncertainty—a possible concern for policy makers. We further explore a commonly used practice—allocating service representatives to assist individuals’ decisions. We show that within a given budget and uncertainty level, the effective allocation is for individuals who are close to the boundary between several Voronoi cells, but are not right on the boundary.
NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium
Authors: Ward Alexander O. , Angelini Gianni D. , Caputo Massimo , Evans Paul C. , Johnson Jason L. , Suleiman M. Saadeh , Tulloh Robert M. , George Sarah J. , Zakkar Mustafa 
Published: September 2020

AbstractThe long saphenous vein (LSV) is commonly used as a conduit in coronary artery bypass grafting. However, long term patency remains limited by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis. The impact of acute exposure of venous endothelial cells (ECs) to acute arterial wall shear stress (WSS) in the arterial circulation, and the subsequent activation of inflammatory pathways, remain poorly defined. Here, we tested the hypothesis that acute exposure of venous ECs to high shear stress is associated with inflammatory responses that are regulated by NF-κB both in-vitro and ex-vivo. Analysis of the LSV endothelium revealed that activation of NF-κB occurred within 30 min after exposure to arterial rates of shear stress. Activation of NF-κB was associated with increased levels of CCL2 production and enhanced binding of monocytes in LSVECs exposed to 6 h acute arterial WSS. Consistent with this, ex vivo exposure of LSVs to acute arterial WSS promoted monocyte interactions with the vessel lumen. Inhibition of the NF-κB pathway prevented acute arterial WSS-induced CCL2 production and reduced monocyte adhesion, both in vitro and in human LSV ex vivo, demonstrating that this pathway is necessary for the induction of the acute arterial WSS-induced pro-inflammatory response. We have identified NF-κB as a critical regulator of acute endothelial inflammation in saphenous vein in response to acute arterial WSS. Localised endothelial-specific inhibition of the NF-κB pathway may be beneficial to prevent vein graft inflammation and consequent failure.
Cells from discarded dressings differentiate chronic from acute wounds in patients with Epidermolysis Bullosa
Authors: Fuentes Ignacia , Guttmann-Gruber Christina , Tockner Birgit , Diem Anja , Klausegger Alfred , Cofré-Araneda Glenda , Figuera Olga , Hidalgo Yessia , Morandé Pilar , Palisson Francis , Rebolledo-Jaramillo Boris , Yubero María Joao , Cho Raymond J. , Rishel Heather I. , Marinkovich M. Peter , Teng Joyce M. C. , Webster Timothy G. , Prisco Marco , Eraso Luis H. , Piñon Hofbauer Josefina , South Andrew P. 
Published: September 2020

AbstractImpaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.
Solvent front position extraction with semi-automatic device as a powerful sample preparation procedure to quantitatitation of tryptophan in human plasma
Authors: Klimek-Turek Anna , Chomicki Adam , Fornal Emilia , Pradiuch Anna , Hys Michał , Dzido Tadeusz H. 
Published: September 2020

AbstractIn the paper the results of the tryptophan determination in human plasma samples prepared with the novel Solvent Front Position Extraction (SFPE) technique are presented. The SFPE procedure is used for preparation of real biological sample for the first time. The results obtained using SFPE are compared with those using the classical sample preparation procedure. Under the optimal conditions, tryptophan and its internal standard were separated from other plasma compounds (matrix) as a small common zone/spot on a chromatographic plate using semiautomatic device equipped with moving pipet, which distributed developing solvent on the adsorbent layer. Tryptophan and the internal standard were evenly distributed within the small common zone from that the both substances were extracted and the solution obtained was transferred to quantitation with LC–MS and MS techniques. The determination results are satisfactory, the percentage values of relative error and RSD relative standard deviation do not exceed 5%. The procedure is characterized by simplicity, high analysis throughput, very good sample purification and seems to be easy applicable to other biological samples with these advantages mentioned.
A multi-task, multi-stage deep transfer learning model for early prediction of neurodevelopment in very preterm infants
Authors: He Lili , Li Hailong , Wang Jinghua , Chen Ming , Gozdas Elveda , Dillman Jonathan R. , Parikh Nehal A. 
Published: September 2020

AbstractSurvivors following very premature birth (i.e., ≤ 32 weeks gestational age) remain at high risk for neurodevelopmental impairments. Recent advances in deep learning techniques have made it possible to aid the early diagnosis and prognosis of neurodevelopmental deficits. Deep learning models typically require training on large datasets, and unfortunately, large neuroimaging datasets with clinical outcome annotations are typically limited, especially in neonates. Transfer learning represents an important step to solve the fundamental problem of insufficient training data in deep learning. In this work, we developed a multi-task, multi-stage deep transfer learning framework using the fusion of brain connectome and clinical data for early joint prediction of multiple abnormal neurodevelopmental (cognitive, language and motor) outcomes at 2 years corrected age in very preterm infants. The proposed framework maximizes the value of both available annotated and non-annotated data in model training by performing both supervised and unsupervised learning. We first pre-trained a deep neural network prototype in a supervised fashion using 884 older children and adult subjects, and then re-trained this prototype using 291 neonatal subjects without supervision. Finally, we fine-tuned and validated the pre-trained model using 33 preterm infants. Our proposed model identified very preterm infants at high-risk for cognitive, language, and motor deficits at 2 years corrected age with an area under the receiver operating characteristic curve of 0.86, 0.66 and 0.84, respectively. Employing such a deep learning model, once externally validated, may facilitate risk stratification at term-equivalent age for early identification of long-term neurodevelopmental deficits and targeted early interventions to improve clinical outcomes in very preterm infants.