bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF1R signaling is a regulator of pathogenesis in progressive MS
Authors: Hagan Nellwyn , Kane John L. , Grover Deepak , Woodworth Lisa , Madore Charlotte , Saleh Jacqueline , Sancho Jose , Liu Jinyu , Li Yi , Proto Jonathan , Zelic Matija , Mahan Amy , Kothe Michael , Scholte Andrew A. , Fitzgerald Maria , Gisevius Barbara , Haghikia Aiden , Butovsky Oleg , Ofengeim Dimitry 
Published: October 2020

AbstractMicroglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1Rinh) for preclinical testing. sCSF1Rinh blocked receptor phosphorylation and downstream signaling in both microglia and macrophages and altered cellular functions including proliferation, survival, and cytokine production. In vivo, CSF1R inhibition with sCSF1Rinh attenuated neuroinflammation and reduced microglial proliferation in a murine acute LPS model. Furthermore, the sCSF1Rinh attenuated a disease-associated microglial phenotype and blocked both axonal damage and neurological impairments in an experimental autoimmune encephalomyelitis (EAE) model of MS. While previous studies have focused on microglial depletion following CSF1R inhibition, our data clearly show that signaling downstream of this receptor can be beneficially modulated in the context of CNS injury. Together, these data suggest that CSF1R inhibition can reduce deleterious microglial proliferation and modulate microglial phenotypes during neuroinflammatory pathogenesis, particularly in progressive MS.
Epigenetic silencing of ZIC4 contributes to cancer progression in hepatocellular carcinoma
Authors: Chen Wenbiao , Tang Donge , Tang Dongxin , Dai Yong 
Published: October 2020

AbstractInactivation of tumor suppressor gene played critical roles in the development and progression of human hepatocellular carcinoma (HCC). Zic family member 4 (ZIC4) is transcription factor and plays an important role in the developmental process. However, the expression and biological role of ZIC4 in HCC is poorly understood. Here, bioinformatics analysis based on The Cancer Genome Atlas (TCGA) database revealed an aberrant hypermethylation of ZIC4 in HCC. ZIC4 is frequently hypermethylated in promoter region and down expressed in HCC cells and tissues. Functionally, ZIC4 inhibition facilitated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, ZIC4 overexpression reduced proliferation and invasiveness of HCC cells. In addition, ZIC4 inhibition rescued the antitumor effect induced by enhancer of zeste homolog 2 (EZH2) knockdown or EZH2 inhibitor. Mechanistically, EZH2 knockdown or EZH2 inhibitor reduced the enrichment of EZH2 and H3K27me3 in ZIC4 promoter region and leading to the upregulation of ZIC4. Altogether, these data indicate that epigenetic silencing of ZIC4 by EZH2 mediated H3K27me3 is an important mechanism in HCC and provide a new therapeutic target for the treatment of hepatocellular carcinoma disease.
Prime editing for functional repair in patient-derived disease models
Authors: Schene Imre F. , Joore Indi P. , Oka Rurika , Mokry Michal , van Vugt Anke H. M. , van Boxtel Ruben , van der Doef Hubert P. J. , van der Laan Luc J. W. , Verstegen Monique M. A. , van Hasselt Peter M. , Nieuwenhuis Edward E. S. , Fuchs Sabine A. 
Published: October 2020

AbstractPrime editing is a recent genome editing technology using fusion proteins of Cas9-nickase and reverse transcriptase, that holds promise to correct the vast majority of genetic defects. Here, we develop prime editing for primary adult stem cells grown in organoid culture models. First, we generate precise in-frame deletions in the gene encoding β‐catenin (CTNNB1) that result in proliferation independent of Wnt-stimuli, mimicking a mechanism of the development of liver cancer. Moreover, prime editing functionally recovers disease-causing mutations in intestinal organoids from patients with DGAT1-deficiency and liver organoids from a patient with Wilson disease (ATP7B). Prime editing is as efficient in 3D grown organoids as in 2D grown cell lines and offers greater precision than Cas9-mediated homology directed repair (HDR). Base editing remains more reliable than prime editing but is restricted to a subgroup of pathogenic mutations. Whole-genome sequencing of four prime-edited clonal organoid lines reveals absence of genome-wide off-target effects underscoring therapeutic potential of this versatile and precise gene editing strategy.
Pattern recognition based on machine learning identifies oil adulteration and edible oil mixtures
Authors: Lim Kevin , Pan Kun , Yu Zhe , Xiao Rong Hui 
Published: October 2020

AbstractPrevious studies have shown that each edible oil type has its own characteristic fatty acid profile; however, no method has yet been described allowing the identification of oil types simply based on this characteristic. Moreover, the fatty acid profile of a specific oil type can be mimicked by a mixture of 2 or more oil types. This has led to fraudulent oil adulteration and intentional mislabeling of edible oils threatening food safety and endangering public health. Here, we present a machine learning method to uncover fatty acid patterns discriminative for ten different plant oil types and their intra-variability. We also describe a supervised end-to-end learning method that can be generalized to oil composition of any given mixtures. Trained on a large number of simulated oil mixtures, independent test dataset validation demonstrates that the model has a 50th percentile absolute error between 1.4–1.8% and a 90th percentile error of 4–5.4% for any 3-way mixtures of the ten oil types. The deep learning model can also be further refined with on-line training. Because oil-producing plants have diverse geographical origins and hence slightly varying fatty acid profiles, an online-training method provides also a way to capture useful knowledge presently unavailable. Our method allows the ability to control product quality, determining the fair price of purchased oils and in-turn allowing health-conscious consumers the future of accurate labeling.
Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains
Authors: Kim Jinuk , Han Wonhee , Park Taeyong , Kim Eun Jin , Bang Injin , Lee Hyun Sik , Jeong Yejin , Roh Kyeonghwan , Kim Jeesoo , Kim Jong-Seo , Kang Chanhee , Seok Chaok , Han Jin-Kwan , Choi Hee-Jung 
Published: October 2020

AbstractLow-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2–SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.
Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path
Authors: Dodd Thomas , Botto Margherita , Paul Fabian , Fernandez-Leiro Rafael , Lamers Meindert H. , Ivanov Ivaylo 
Published: October 2020

AbstractProofreading by replicative DNA polymerases is a fundamental mechanism ensuring DNA replication fidelity. In proofreading, mis-incorporated nucleotides are excised through the 3′-5′ exonuclease activity of the DNA polymerase holoenzyme. The exonuclease site is distal from the polymerization site, imposing stringent structural and kinetic requirements for efficient primer strand transfer. Yet, the molecular mechanism of this transfer is not known. Here we employ molecular simulations using recent cryo-EM structures and biochemical analyses to delineate an optimal free energy path connecting the polymerization and exonuclease states of E. coli replicative DNA polymerase Pol III. We identify structures for all intermediates, in which the transitioning primer strand is stabilized by conserved Pol III residues along the fingers, thumb and exonuclease domains. We demonstrate switching kinetics on a tens of milliseconds timescale and unveil a complete pol-to-exo switching mechanism, validated by targeted mutational experiments.
The nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp
Authors: Yang Jin , Anderson Brent W. , Turdiev Asan , Turdiev Husan , Stevenson David M. , Amador-Noguez Daniel , Lee Vincent T. , Wang Jue D. 
Published: October 2020

AbstractThe alarmone nucleotides guanosine tetraphosphate and pentaphosphate, commonly referred to as (p)ppGpp, regulate bacterial responses to nutritional and other stresses. There is evidence for potential existence of a third alarmone, guanosine-5′-monophosphate-3′-diphosphate (pGpp), with less-clear functions. Here, we demonstrate the presence of pGpp in bacterial cells, and perform a comprehensive screening to identify proteins that interact respectively with pGpp, ppGpp and pppGpp inBacillusspecies. Both ppGpp and pppGpp interact with proteins involved in inhibition of purine nucleotide biosynthesis and with GTPases that control ribosome assembly or activity. By contrast, pGpp interacts with purine biosynthesis proteins but not with the GTPases. In addition, we show that hydrolase NahA (also known as YvcI) efficiently produces pGpp by hydrolyzing (p)ppGpp, thus modulating alarmone composition and function. Deletion ofnahAleads to reduction of pGpp levels, increased (p)ppGpp levels, slower growth recovery from nutrient downshift, and loss of competitive fitness. Our results support the existence and physiological relevance of pGpp as a third alarmone, with functions that can be distinct from those of (p)ppGpp.
Unravelling the room-temperature atomic structure and growth kinetics of lithium metal
Authors: Liang Chao , Zhang Xun , Xia Shuixin , Wang Zeyu , Wu Jiayi , Yuan Biao , Luo Xin , Liu Weiyan , Liu Wei , Yu Yi 
Published: October 2020

AbstractAlkali metals are widely studied in various fields such as medicine and battery. However, limited by the chemical reactivity and electron/ion beam sensitivity, the intrinsic atomic structure of alkali metals and its fundamental properties are difficult to be revealed. Here, a simple and versatile method is proposed to form the alkali metals in situ inside the transmission electron microscope. Taking alkali salts as the starting materials and electron beam as the trigger, alkali metals can be obtained directly. With this method, atomic resolution imaging of lithium and sodium metal is achieved at room temperature, and the growth of alkali metals is visualized at atomic-scale with millisecond temporal resolution. Furthermore, our observations unravel the ambiguities in lithium metal growth on garnet-type solid electrolytes for lithium-metal batteries. Finally, our method enables a direct study of physical contact property of lithium metal as well as its surface passivation oxide layer, which may contribute to better understanding of lithium dendrite and solid electrolyte interphase issues in lithium ion batteries.
The desensitization pathway of GABAA receptors, one subunit at a time
Authors: Gielen Marc , Barilone Nathalie , Corringer Pierre-Jean 
Published: October 2020

AbstractGABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.
Chemical trends of deep levels in van der Waals semiconductors
Authors: Ci Penghong , Tian Xuezeng , Kang Jun , Salazar Anthony , Eriguchi Kazutaka , Warkander Sorren , Tang Kechao , Liu Jiaman , Chen Yabin , Tongay Sefaattin , Walukiewicz Wladek , Miao Jianwei , Dubon Oscar , Wu Junqiao 
Published: October 2020

AbstractProperties of semiconductors are largely defined by crystal imperfections including native defects. Van der Waals (vdW) semiconductors, a newly emerged class of materials, are no exception: defects exist even in the purest materials and strongly affect their electrical, optical, magnetic, catalytic and sensing properties. However, unlike conventional semiconductors where energy levels of defects are well documented, they are experimentally unknown in even the best studied vdW semiconductors, impeding the understanding and utilization of these materials. Here, we directly evaluate deep levels and their chemical trends in the bandgap of MoS2, WS2 and their alloys by transient spectroscopic study. One of the deep levels is found to follow the conduction band minimum of each host, attributed to the native sulfur vacancy. A switchable, DX center - like deep level has also been identified, whose energy lines up instead on a fixed level across different hosts, explaining a persistent photoconductivity above 400 K.
Immediate and transgenerational effects of thymol supplementation, inactivated Salmonella and chronic heat stress on representative immune variables of Japanese quail
Authors: Videla E. A. , Giayetto O. , Fernández M. E. , Chacana P. A. , Marín R. H. , Nazar F. N. 
Published: October 2020

AbstractEnvironmental challenges are integrated in the inmunoneuroendocrine interplay, impacting the immune system of the challenged individuals, and potentially implying transgenerational effects on their offspring. This study addressed whether dietary supplementation with thymol can modulate the immune response of adult Japanese quail when simultaneously exposed to an inoculum of inactivated Salmonella Enteritidis and a chronic heat stress (CHS). We also evaluated whether the experienced situations by adults can affect the immune response of their undisturbed offspring. In the parental generation, supplemented quail exposed to CHS had a higher inflammatory response and similar values of the heterophil/lymphocyte (H/L) ratio than those that were not supplemented. In their offspring, those chicks whose parents were exposed to CHS showed higher inflammatory response and lower antibody production. Regarding the H/L ratio, chicks whose parents were supplemented showed lower H/L ratio values. Dietary supplementation with thymol partially and positively modulated the inflammatory response and avoided H/L ratio alteration in the parental generation exposed to high environmental temperatures, suggesting these adults were better at dealing with the challenge. The lower H/L ratio values in the offspring suggests that chicks are more capable to deal with potential stressful situations associated with conventional breeding conditions.
A platform incorporating trimeric antigens into self-assembling nanoparticles reveals SARS-CoV-2-spike nanoparticles to elicit substantially higher neutralizing responses than spike alone
Authors: Zhang Baoshan , Chao Cara W. , Tsybovsky Yaroslav , Abiona Olubukola M. , Hutchinson Geoffrey B. , Moliva Juan I. , Olia Adam S. , Pegu Amarendra , Phung Emily , Stewart-Jones Guillaume B. E. , Verardi Raffaello , Wang Lingshu , Wang Shuishu , Werner Anne , Yang Eun Sung , Yap Christina , Zhou Tongqing , Mascola John R. , Sullivan Nancy J. , Graham Barney S. , Corbett Kizzmekia S. , Kwong Peter D. 
Published: October 2020

AbstractAntigens displayed on self-assembling nanoparticles can stimulate strong immune responses and have been playing an increasingly prominent role in structure-based vaccines. However, the development of such immunogens is often complicated by inefficiencies in their production. To alleviate this issue, we developed a plug-and-play platform using the spontaneous isopeptide-bond formation of the SpyTag:SpyCatcher system to display trimeric antigens on self-assembling nanoparticles, including the 60-subunit Aquifex aeolicus lumazine synthase (LuS) and the 24-subunit Helicobacter pylori ferritin. LuS and ferritin coupled to SpyTag expressed well in a mammalian expression system when an N-linked glycan was added to the nanoparticle surface. The respiratory syncytial virus fusion (F) glycoprotein trimer—stabilized in the prefusion conformation and fused with SpyCatcher—could be efficiently conjugated to LuS-SpyTag or ferritin-SpyTag, enabling multivalent display of F trimers with prefusion antigenicity. Similarly, F-glycoprotein trimers from human parainfluenza virus-type 3 and spike-glycoprotein trimers from SARS-CoV-2 could be displayed on LuS nanoparticles with decent yield and antigenicity. Notably, murine vaccination with 0.08 µg of SARS-CoV-2 spike-LuS nanoparticle elicited similar neutralizing responses as 2.0 µg of spike, which was ~ 25-fold higher on a weight-per-weight basis. The versatile platform described here thus allows for multivalent plug-and-play presentation on self-assembling nanoparticles of trimeric viral antigens, with SARS-CoV-2 spike-LuS nanoparticles inducing particularly potent neutralizing responses.
Improving ultrasound images with elevational angular compounding based on acoustic refraction
Authors: Afshari Parastoo , Zakian Christian , Ntziachristos Vasilis 
Published: October 2020

AbstractUltrasound imaging is affected by coherent noise or speckle, which reduces contrast and overall image quality and degrades the diagnostic precision of the collected images. Elevational angular compounding (EAC) is an attractive means of addressing this limitation, since it reduces speckle noise while operating in real-time. However, current EAC implementations rely on mechanically rotating a one-dimensional (1D) transducer array or electronically beam steering of two-dimensional (2D) arrays to provide different elevational imaging angles, which increases the size and cost of the systems. Here we present a novel EAC implementation based on a 1D array, which does not necessitate mechanically rotating the transducer. The proposed refraction-based elevational angular compounding technique (REACT) instead utilizes a translating cylindrical acoustic lens that steers the ultrasound beam along the elevational direction. Applying REACT to investigate phantoms and excised tissue samples demonstrated superior suppression of ultrasound speckle noise compared to previous EAC methods, with up to a two-fold improvement in signal- and contrast-to-noise ratios. The effects of elevational angular width on speckle reduction was further investigated to determine the appropriate conditions for applying EAC. This study introduces acoustic refractive elements as potential low cost solutions to noise reduction, which could be integrated into current medical ultrasound devices.
Comparison of transoral robotic surgery with other surgeries for obstructive sleep apnea
Authors: Tsou Yung-An , Chang Wen-Dien 
Published: October 2020

AbstractThis study compared the characteristic surgical parameters and clinical effects of transoral robotic surgery (TORS) and other available methods used to alleviate obstructive sleep apnea. Articles on TORS and other surgeries for obstructive sleep apnea were identified in the PubMed and EMBASE databases. Two investigators independently reviewed the articles and classified the data for meta-analysis. The pooled effect sizes of TORS (standardized mean difference; SMD = − 2.38), coblation tongue base resection (CTBR; SMD = − 2.00) and upper airway stimulation (UAS; SMD = − 0.94) revealed significant improvement in the apnea–hypopnea index (AHI; p < 0.05). The lowest O2 saturation reported was significantly increased following TORS (SMD = 1.43), CTBR (SMD = 0.86) and UAS (SMD = 1.24, p < 0.05). Furthermore, TORS (SMD = − 2.91) and CTBR (SMD = − 1.51, p < 0.05) significantly reduced the Epworth Sleepiness Scale (ESS) score. No significant difference in operation time, success rate, or instances of complication were observed between TORS and the other compared interventions. The use of TORS in obstructive sleep apnea has the same rate of success and failure as other methods of surgical intervention for obstructive sleep apnea with no statistical difference in operation times. The reported clinical effects on the AHI, lowest O2 saturation, and ESS scores of TORS were similar to those of other surgeries.
Colour matters more than shape for chimpanzees’ recognition of developmental face changes
Authors: Kawaguchi Yuri , Nakamura Koyo , Tomonaga Masaki 
Published: October 2020

AbstractSocial primates must recognise developmental stages of other conspecifics in order to behave appropriately. Infant faces have peculiar morphological characteristics—relatively large eyes, a small nose, and small mouth—known as baby schema. In addition, the infant faces of many primate species have unique skin coloration. However, it is unclear which features serve as critical cues for chimpanzees to recognise developmental changes in their faces. The present study aimed to investigate the relative contributions of facial shape and colour to age categorisation in chimpanzees. We used a symbolic matching-to-sample task in which chimpanzees were trained to discriminate between adult and infant faces. Then, we tested how their age category judgments transferred to a series of morphed faces which systematically differed in facial shape and colour. Statistical image quantification analysis revealed significant differences both in shape and colour between adult and infant faces. However, we found that facial coloration contributed to age categorisation in chimpanzees more than facial shape. Our results showed that chimpanzees use unique infantile facial coloration as a salient cue when discriminating between adult and infant faces. The display of their developmental stages through facial colour may help chimpanzees to induce appropriate behaviour from other individuals.