bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cryo-EM structures of lipopolysaccharide transporter LptB2FGC in lipopolysaccharide or AMP-PNP-bound states reveal its transport mechanism
Authors: Tang Xiaodi , Chang Shenghai , Luo Qinghua , Zhang Zhengyu , Qiao Wen , Xu Caihuang , Zhang Changbin , Niu Yang , Yang Wenxian , Wang Ting , Zhang Zhibo , Zhu Xiaofeng , Wei Xiawei , Dong Changjiang , Zhang Xing , Dong Haohao 
Published: September 2019

AbstractLipopolysaccharides (LPS) of Gram-negative bacteria are critical for the defence against cytotoxic substances and must be transported from the inner membrane (IM) to the outer membrane (OM) through a bridge formed by seven membrane proteins (LptBFGCADE). The IM component LptB2FG powers the process through a yet unclarified mechanism. Here we report three high-resolution cryo-EM structures of LptB2FG alone and complexed with LptC (LptB2FGC), trapped in either the LPS- or AMP-PNP-bound state. The structures reveal conformational changes between these states and substrate binding with or without LptC. We identify two functional transmembrane arginine-containing loops interacting with the bound AMP-PNP and elucidate allosteric communications between the domains. AMP-PNP binding induces an inward rotation and shift of the transmembrane helices of LptFG and LptC to tighten the cavity, with the closure of two lateral gates, to eventually expel LPS into the bridge. Functional assays reveal the functionality of the LptF and LptG periplasmic domains. Our findings shed light on the LPS transport mechanism.
Potent antibody lineage against malaria transmission elicited by human vaccination with Pfs25
Authors: McLeod Brandon , Miura Kazutoyo , Scally Stephen W. , Bosch Alexandre , Nguyen Ngan , Shin Hanjun , Kim Dongkyoon , Volkmuth Wayne , Rämisch Sebastian , Chichester Jessica A. , Streatfield Stephen , Woods Colleen , Schief William R. , Emerling Daniel , King C. Richter , Julien Jean-Philippe 
Published: September 2019

AbstractTransmission-blocking vaccines have the potential to be key contributors to malaria elimination. Such vaccines elicit antibodies that inhibit parasites during their development in Anopheles mosquitoes, thus breaking the cycle of transmission. To date, characterization of humoral responses to Plasmodium falciparum transmission-blocking vaccine candidate Pfs25 has largely been conducted in pre-clinical models. Here, we present molecular analyses of human antibody responses generated in a clinical trial evaluating Pfs25 vaccination. From a collection of monoclonal antibodies with transmission-blocking activity, we identify the most potent transmission-blocking antibody yet described against Pfs25; 2544. The interactions of 2544 and three other antibodies with Pfs25 are analyzed by crystallography to understand structural requirements for elicitation of human transmission-blocking responses. Our analyses provide insights into Pfs25 immunogenicity and epitope potency, and detail an affinity maturation pathway for a potent transmission-blocking antibody in humans. Our findings can be employed to guide the design of improved malaria transmission-blocking vaccines.
Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas
Authors: Scala Federico , Kobak Dmitry , Shan Shen , Bernaerts Yves , Laturnus Sophie , Cadwell Cathryn Rene , Hartmanis Leonard , Froudarakis Emmanouil , Castro Jesus Ramon , Tan Zheng Huan , Papadopoulos Stelios , Patel Saumil Surendra , Sandberg Rickard , Berens Philipp , Jiang Xiaolong , Tolias Andreas Savas 
Published: September 2019

AbstractLayer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking interneurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ interneurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are used across the cortex as building blocks to assemble cortical circuits.
Ultrafast isomerization-induced cooperative motions to higher molecular orientation in smectic liquid-crystalline azobenzene molecules
Authors: Hada Masaki , Yamaguchi Daisuke , Ishikawa Tadahiko , Sawa Takayoshi , Tsuruta Kenji , Ishikawa Ken , Koshihara Shin-ya , Hayashi Yasuhiko , Kato Takashi 
Published: September 2019

AbstractThe photoisomerization of molecules is widely used to control the structure of soft matter in both natural and synthetic systems. However, the structural dynamics of the molecules during isomerization and their subsequent response are difficult to elucidate due to their complex and ultrafast nature. Herein, we describe the ultrafast formation of higher-orientation of liquid-crystalline (LC) azobenzene molecules via linearly polarized ultraviolet light (UV) using ultrafast time-resolved electron diffraction. The ultrafast orientation is caused by the trans-to-cis isomerization of the azobenzene molecules. Our observations are consistent with simplified molecular dynamics calculations that revealed that the molecules are aligned with the laser polarization axis by their cooperative motion after photoisomerization. This insight advances the fundamental chemistry of photoresponsive molecules in soft matter as well as their ultrafast photomechanical applications.
Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ
Authors: Ding Lina , Su Ying , Fassl Anne , Hinohara Kunihiko , Qiu Xintao , Harper Nicholas W. , Huh Sung Jin , Bloushtain-Qimron Noga , Jovanović Bojana , Ekram Muhammad , Zi Xiaoyuan , Hines William C. , Alečković Maša , Gil del Alcazar Carlos , Caulfield Ryan J. , Bonal Dennis M. , Nguyen Quang-De , Merino Vanessa F. , Choudhury Sibgat , Ethington Gabrielle , Panos Laura , Grant Michael , Herlihy William , Au Alfred , Rosson Gedge D. , Argani Pedram , Richardson Andrea L. , Dillon Deborah , Allred D. Craig , Babski Kirsten , Kim Elizabeth Min Hui , McDonnell Charles H. , Wagner Jon , Rowberry Ron , Bobolis Kristie , Kleer Celina G. , Hwang E. Shelley , Blum Joanne L. , Cristea Simona , Sicinski Piotr , Fan Rong , Long Henry W. , Sukumar Saraswati , Park So Yeon , Garber Judy E. , Bissell Mina , Yao Jun , Polyak Kornelia 
Published: September 2019

AbstractMyoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues ofBRCA1andBRCA2germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues ofBRCA1mutation carriers the frequency of p63+TCF7+myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues ofBRCA1germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin
Authors: Ji Lei , Lu Bo , Zamponi Raffaella , Charlat Olga , Aversa Robert , Yang Zinger , Sigoillot Frederic , Zhu Xiaoping , Hu Tiancen , Reece-Hoyes John S. , Russ Carsten , Michaud Gregory , Tchorz Jan S. , Jiang Xiaomo , Cong Feng 
Published: September 2019

AbstractAxin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.
Identification of the PTEN-ARID4B-PI3K pathway reveals the dependency on ARID4B by PTEN-deficient prostate cancer
Authors: Wu Ray-Chang , Young In-Chi , Chen Yu-Fang , Chuang Sung-Ting , Toubaji Antoun , Wu Mei-Yi 
Published: September 2019

AbstractPTEN is frequently mutated in prostate cancer. The tumor suppressor function of PTEN is attributed to its lipid phosphatase activity that counters PI3K action. Here, we report a PTEN-ARID4B-PI3K axis in which PTEN inhibits expression of ARID4B, while ARID4B is a transcriptional activator of the PI3K subunit genes PIK3CA and PIK3R2 that are crucial for activation of the PI3K/AKT pathway. Reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, suggesting a mechanism by which ARID4B activates these promoters. Functional analyses reveals that ARID4B is required for prostate tumorigenesis when PTEN is deficient. The biological significance is further substantiated by the existence of a PTEN/ARID4B/PIK3CA three-gene signature that improves the predictive power for prostate cancer recurrence in patients. In summary, we identify ARID4B as a master regulator in the PTEN-PI3K pathway, thus providing a potential therapeutic target for prostate cancer carrying PTEN mutations.
Longitudinal EEG power in the first postnatal year differentiates autism outcomes
Authors: Gabard-Durnam Laurel J. , Wilkinson Carol , Kapur Kush , Tager-Flusberg Helen , Levin April R. , Nelson Charles A. 
Published: September 2019

AbstractAn aim of autism spectrum disorder (ASD) research is to identify early biomarkers that inform ASD pathophysiology and expedite detection. Brain oscillations captured in electroencephalography (EEG) are thought to be disrupted as core ASD pathophysiology. We leverage longitudinal EEG power measurements from 3 to 36 months of age in infants at low- and high-risk for ASD to test how and when power distinguishes ASD risk and diagnosis by age 3-years. Power trajectories across the first year, second year, or first three years postnatally were submitted to data-driven modeling to differentiate ASD outcomes. Power dynamics during the first postnatal year best differentiate ASD diagnoses. Delta and gamma frequency power trajectories consistently distinguish infants with ASD diagnoses from others. There is also a developmental shift across timescales towards including higher-frequency power to differentiate outcomes. These findings reveal the importance of developmental timing and trajectory in understanding pathophysiology and classifying ASD outcomes.
Thorium-nitrogen multiple bonds provide evidence for pushing-from-below for early actinides
Authors: Du Jingzhen , Alvarez-Lamsfus Carlos , Wildman Elizabeth P. , Wooles Ashley J. , Maron Laurent , Liddle Stephen T. 
Published: September 2019

AbstractAlthough the chemistry of uranium-ligand multiple bonding is burgeoning, analogous complexes involving other actinides such as thorium remain rare and there are not yet any terminal thorium nitrides outside of cryogenic matrix isolation conditions. Here, we report evidence that reduction of a thorium-azide produces a transient Th≡N triple bond, but this activates C-H bonds to produce isolable parent imido derivatives or it can be trapped in an N-heterocycle amine. Computational studies on these thorium-nitrogen multiple bonds consistently evidences a σ > π energy ordering. This suggests pushing-from-below for thorium, where 6p-orbitals principally interact with filled f-orbitals raising the σ-bond energy. Previously this was dismissed for thorium, being the preserve of uranium-nitrides or the uranyl dication. Recognising that pushing-from-below perhaps occurs with thorium as well as uranium, and with imido ligands as well as nitrides, suggests this phenomenon may be more widespread than previously thought.
Hierarchical control of locomotion by distinct types of spinal V2a interneurons in zebrafish
Authors: Menelaou Evdokia , McLean David L. 
Published: September 2019

AbstractIn all vertebrates, excitatory spinal interneurons execute dynamic adjustments in the timing and amplitude of locomotor movements. Currently, it is unclear whether interneurons responsible for timing control are distinct from those involved in amplitude control. Here, we show that in larval zebrafish, molecularly, morphologically and electrophysiologically distinct types of V2a neurons exhibit complementary patterns of connectivity. Stronger higher-order connections from type I neurons to other excitatory V2a and inhibitory V0d interneurons provide timing control, while stronger last-order connections from type II neurons to motor neurons provide amplitude control. Thus, timing and amplitude are coordinated by distinct interneurons distinguished not by their occupation of hierarchically-arranged anatomical layers, but rather by differences in the reliability and probability of higher-order and last-order connections that ultimately form a single anatomical layer. These findings contribute to our understanding of the origins of timing and amplitude control in the spinal cord.
Efficient nonlinear beam shaping in three-dimensional lithium niobate nonlinear photonic crystals
Authors: Wei Dunzhao , Wang Chaowei , Xu Xiaoyi , Wang Huijun , Hu Yanlei , Chen Pengcheng , Li Jiawen , Zhu Yunzhi , Xin Chen , Hu Xiaopeng , Zhang Yong , Wu Dong , Chu Jiaru , Zhu Shining , Xiao Min 
Published: September 2019

AbstractNonlinear beam shaping refers to spatial reconfiguration of a light beam at a new frequency, which can be achieved by using nonlinear photonic crystals (NPCs). Direct nonlinear beam shaping has been achieved to convert second-harmonic waves into focusing spots, vortex beams, and diffraction-free beams. However, previous nonlinear beam shaping configurations in one-dimensional and two-dimensional (2D) NPCs generally suffer from low efficiency because of unfulfilled phase-matching condition. Here, we present efficient generations of second-harmonic vortex and Hermite-Gaussian beams in the recently-developed three-dimensional (3D) lithium niobate NPCs fabricated by using a femtosecond-laser-engineering technique. Since 3D χ(2) modulations can be designed to simultaneously fulfill the requirements of nonlinear wave-front shaping and quasi-phase-matching, the conversion efficiency is enhanced up to two orders of magnitude in a tens-of-microns-long 3D NPC in comparison to the 2D case. Efficient nonlinear beam shaping paves a way for its applications in optical communication, super-resolution imaging, high-dimensional entangled source, etc.
The effect of 2′-fucosyllactose on simulated infant gut microbiome and metabolites; a pilot study in comparison to GOS and lactose
Authors: Salli Krista , Anglenius Heli , Hirvonen Johanna , Hibberd Ashley A. , Ahonen Ilmari , Saarinen Markku T. , Tiihonen Kirsti , Maukonen Johanna , Ouwehand Arthur C. 
Published: September 2019

AbstractHuman milk oligosaccharides (HMOs) shape gut microbiota during infancy by acting as fermentable energy source. Using a semi-continuous colon simulator, effect of an HMO, 2′-fucosyllactose (2′-FL), on composition of the infant microbiota and microbial metabolites was evaluated in comparison to galacto-oligosaccharide (GOS) and lactose and control without additional carbon source. Data was analysed according to faecal sample donor feeding type: breast-fed (BF) or formula-fed (FF), and to rate of 2′-FL fermentation: fast or slow. Variation was found between the simulations in the ability to utilise 2′-FL. The predominant phyla regulated by 2′-FL, GOS and lactose were significant increase in Firmicutes, numerical in Actinobacteria, and numerical decrease in Proteobacteria compared to control. Verrucomicrobia increased in FF accounted forAkkermansia, whereas in fast-fermenting simulations Actinobacteria increased with trend for higherBifidobacterium, and Proteobacteria decrease accounted forEnterobacteriaceae. Short-chain fatty acids and lactic acid with 2′-FL were produced in intermediate levels being between ones generated by the control and GOS or lactose. In 2′-FL fast-fermenting group, acetic acid specifically increased with 2′-FL, whereas lactose and GOS also increased lactic acid. The results highlight specificity of 2′-FL as energy source for only certain microbes over GOS and lactose in the simulated gut model.
Riemerella anatipestifer infection in ducks induces IL-17A production, but not IL-23p19
Authors: Flores Rochelle A. , Fernandez-Colorado Cherry P. , Afrin Fahmida , Cammayo Paula Leona T. , Kim Suk , Kim Woo H. , Min Wongi 
Published: September 2019

AbstractR. anatipestifer (RA) is one of the most harmful bacterial pathogens affecting the duck industry, and infection is associated with the production of proinflammatory cytokines, including IL-17A. Another proinflammatory cytokine, IL-23, is critical for the development of Th17 cells, which produce IL-17. However, IL-23 roles have not been studied in this infection. Here, we describe the identification and mRNA expression analysis of duck IL-23p19 (duIL-23p19) in splenic lymphocytes and macrophages stimulated with killed RA and in spleens of RA-infected ducks. Expression of duIL-23p19 transcript identified in this study was relatively high in livers of healthy ducks and was upregulated in mitogen-activated splenic lymphocytes as well as in splenic lymphocytes and macrophages stimulated with killed RA. In spleens of RA-infected ducks, expression levels of duIL-23p19 transcript were unchanged at all time points except on days 4 and 7 post-infection; however, duIL-17A and IL-17F expression levels were upregulated in both spleens of RA-infected ducks and splenic lymphocytes and macrophages stimulated with killed RA. In sera collected at 24 h after this infection, duIL-23p19 expression levels were unchanged, whereas IL-17A significantly upregulated. These results suggest that IL-23p19 does not play a critical role in the IL-17A response in early stages of RA-infected ducks.
A Regularized Stochastic Block Model for the robust community detection in complex networks
Authors: Lu Xiaoyan , Szymanski Boleslaw K. 
Published: September 2019

AbstractThe stochastic block model is able to generate random graphs with different types of network partitions, ranging from the traditional assortative structures to the disassortative structures. Since the stochastic block model does not specify which mixing pattern is desired, the inference algorithms discover the locally most likely nodes’ partition, regardless of its type. Here we introduce a new model constraining nodes’ internal degree ratios in the objective function to guide the inference algorithms to converge to the desired type of structure in the observed network data. We show experimentally that given the regularized model, the inference algorithms, such as Markov chain Monte Carlo, reliably and quickly find the assortative or disassortative structure as directed by the value of a single parameter. In contrast, when the sought-after assortative community structure is not strong in the observed network, the traditional inference algorithms using the degree-corrected stochastic block model tend to converge to undesired disassortative partitions.
A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins
Authors: Bøtkjær Jane Alrø , Noer Pernille Rimmer , Oxvig Claus , Yding Andersen Claus 
Published: September 2019

AbstractPregnancy-associated plasma protein-A (PAPP-A) is a key regulator of insulin-like growth factor (IGF) bioactivity, by releasing the IGFs from their corresponding IGF-binding proteins (IGFBPs). The minor allele of the single nucleotide polymorphism (SNP), rs7020782 (serine < tyrosine), in PAPPA has previously been associated with recurrent pregnancy loss as well as with significant reduced levels of PAPP-A protein in human ovarian follicles. The aim of the present study was to reveal a possible functional effect of the rs7020782 SNP in PAPPA by comparing recombinant PAPP-A proteins from transfected human embryonic kidney 293 T cells. The proteolytic cleavage of IGFBP-4 was shown to be affected by the rs7020782 SNP in PAPPA, showing a significantly reduced cleavage rate for the serine variant compared to the tyrosine variant (p-value < 0.001). The serine variant also showed a trend towards reduced cleavage rates, that was not significant, towards IGFBP-2 and IGFBP-5 compared to the tyrosine variant. No differences were found when analysing cell surface binding, complex formation between PAPP-A and STC2 or proMBP, nor when analysing STC1 inhibition of PAPP-A-mediated IGFBP-4 cleavage. Regulation of IGF bioactivity in reproductive tissues is important and the rs7020782 SNP in PAPPA may disturb this regulation by altering the specific activity of PAPP-A.
Rrm2b deletion causes mitochondrial metabolic defects in renal tubules
Authors: Chen Yi-Fan , Lin I-Hsuan , Guo Yu-Ru , Chiu Wei-Jun , Wu Mai-Szu , Jia Wei , Yen Yun 
Published: September 2019

AbstractRenal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which Rrm2b has critical functions as reported. The Rrm2b kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. Rrm2b is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, Rrm2b deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.