bluuebunny/crossref_metadata_2025 huggingface dataset:
A rectal gastrointestinal stromal tumor—a plea for neoadjuvant imatinib and TAMIS
Authors: Balu Jagan , Subramanian Sankar , Suresh P , Shankar Narayanan AP , Sandhu Amamndeep Sing
Published: September 2019

Here we describe an infrequent case of gastrointestinal stromal tumor of the rectum in a 57 year-old man with spindle cell neoplasm probably gastrointestinal stromal tumor and CT scan showed tumor from the anterior rectal wall and offered abdominoperineal resection for the same. The patient was started on imatinib and had a significant reduction in symptoms. The patient was reassessed with the CT scan, which showed a reduction in tumor size and Transanal minimally invasive surgery was planned for the patient. Use of imatinib prior to surgical resection to attain the reduced size of the tumor within the limit of resection is an attractive approach. Since tumor development can happen rapidly again after substantial tumor shrinkage, the best time to operate depending on resectability and the maximum therapeutic outcome remains divisive.
Big Data and Personalized Pricing
Authors: Steinberg Etye
Published: September 2019

Technological advances introduce the possibility that, in the future, firms will be able to use big-data analysis to discover and offer consumers their individual reservation price (i.e., the highest price each consumer would be willing to pay, given their preferences and available income). This can generate some interesting benefits, such as a better state of affairs in terms of equality of both welfare and resources, as well as increased social welfare. However, these benefits are countered by considerations of relational equality. This article takes up the market-failures approach as its basis to demonstrate what is wrong with using big data to personalize prices. The article offers an improvement to the market-failures approach and argues that what is wrong with using big data to personalize prices is that it unfairly undermines consumers’ ability to benefit from the market, which is the very point of having a market.
Advancing regulatory science and assessment of FDA REMS programs: A mixed-methods evaluation examining physician survey response
Authors: Brewer Sarah E. , Campagna Elizabeth J. , Morrato Elaine H.
Published: September 2019

Purpose:

Food and Drug Administration’s (FDA) Draft Guidance for Industry on pharmaceutical REMS (Risk Evaluation and Mitigation Strategies) assessment and survey methodology highlights physician knowledge–attitudes–behaviors (KAB) surveys as regulatory science tools. This mixed-methods evaluation advances regulatory science and the assessment of FDA REMS programs when using physician surveys. We: (1) reviewed published physician survey response rates; and (2) assessed response bias in a simulation study of secondary survey data using different accrual cut-off strategies.

Methods:

A systematic literature review was conducted of US physician surveys (2000–2014) on pharmaceutical use (n = 75). Kruskal–Wallis tests were used to examine the relationships between response rates and survey design characteristics. The simulation was conducted using secondary data from a population-based physician KAB survey on diabetes risk management with antipsychotic use in Missouri Medicaid (n = 973 accrued over 30 weeks). Survey item responses were compared using Pearson’s chi-square tests for two faster completion simulations: Fixed Sample (n = 300) and Fixed Time (8 weeks).

Results:

Survey response rates ranged from 7% to 100% (median = 48%, IQR = 34%–68%). Surveys of targeted populations and surveys using member lists were associated with higher response rates (p = 0.02). In the simulation, 9 of 20 (45%) KAB items, including diabetes screening advocacy, differed significantly using the smaller Fixed Sample strategy (achieved in 12 days) versus full accrual. Fewer response differences were found using the Fixed Time strategy (2 of 20 [10%] items).

Conclusions:

Published data on physician surveys report low response rates with most associated with the sample source selected. FDA REMS assessments should include formal evaluation of survey accrual and response bias.
Types of iconicity and combinatorial strategies distinguish semantic categories in silent gesture across cultures
Authors: ORTEGA GERARDO , ÖZYÜREK ASLI
Published: September 2019

abstract

In this study we explore whether different types of iconic gestures (i.e., acting, drawing, representing) and their combinations are used systematically to distinguish between different semantic categories in production and comprehension. In Study 1, we elicited silent gestures from Mexican and Dutch participants to represent concepts from three semantic categories: actions, manipulable objects, and non-manipulable objects. Both groups favoured the acting strategy to represent actions and manipulable objects; while non-manipulable objects were represented through the drawing strategy. Actions elicited primarily single gestures whereas objects elicited combinations of different types of iconic gestures as well as pointing. In Study 2, a different group of participants were shown gestures from Study 1 and were asked to guess their meaning. Single-gesture depictions for actions were more accurately guessed than for objects. Objects represented through two-gesture combinations (e.g., acting + drawing) were more accurately guessed than objects represented with a single gesture. We suggest iconicity is exploited to make direct links with a referent, but when it lends itself to ambiguity, individuals resort to combinatorial structures to clarify the intended referent. Iconicity and the need to communicate a clear signal shape the structure of silent gestures and this in turn supports comprehension.
Ni muy lejos ni muy cerca: Patrón de asentamiento de los periodos alfareros en la microrregión de Angostura, Chile central
Authors: Sanhueza Lorena , Ardiles Flavio , Miranda Cesar , Correa Itaci , Falabella Fernanda , Cornejo Luis
Published: September 2019

El análisis del patrón de asentamiento en sociedades no jerárquicas tiene un gran potencial para abordar su variabilidad, en la medida que sus niveles de integración tienen una expresión física en los espacios corresidenciales y en la distancia entre ellos. A partir de una prospección intensiva en la microrregión de Angostura, Chile central, se compara la organización espacial de los asentamientos habitacionales de los periodos alfareros del área. Se trabajó con el tamaño y densidad de los 19 sitios detectados en el área, así como su distribución espacial. Se los delimitó por medio de redes de pozos de sondeo, a partir de cuya densidad se estimó la extensión y estructura de los sitios. La asignación cronocultural se realizó a partir de la clasificación del material alfarero y por 150 fechados por termoluminiscencia. La comparación indica que los periodos Alfarero temprano e Intermedio tardío presentan tanto similitudes como diferencias. En ambos momentos el patrón de asentamiento es disperso y la principal diferencia radica en la estructura interna de los sitios. Los asentamientos del Intermedio tardío tienen una menor cantidad de concentraciones y la densidad tiende a ser mayor, lo que sugiere que la composición de las unidades residenciales es distinta, estando compuestas por un mayor número de personas en el momento más tardío.
The Residential Segregation of Immigrants in the United States from 1850 to 1940
Authors: Eriksson Katherine , Ward Zachary
Published: September 2019

We provide the first estimates of immigrant residential segregation between 1850 and 1940 that cover the entire United States and are consistent across time and space. To do so, we adapt the Logan–Parman method to immigrants by measuring segregation based on the nativity of the next-door neighbor. In addition to providing a consistent measure of segregation, we also document new patterns such as high levels of segregation in rural areas, in small factory towns and for non-European sources. Early twentieth-century immigrants spatially assimilated at a slow rate, leaving immigrants’ lived experience distinct from natives for decades after arrival.
Stress Drop, Apparent Stress, and Radiation Efficiency of Clustered Earthquakes in the Nucleation Volume of the 6 April 2009, Mw 6.1 L'Aquila Earthquake
Authors: Calderoni Giovanna , Rovelli Antonio , Di Giovambattista Rita
Published: September 2019

We investigate the variability of Brune stress drop (∆σ) and apparent stress (τa) of 23 earthquakes occurred in a small crustal volume adjacent to the hypocenter of the destructive Mw 6.1 L'Aquila earthquake. Their magnitude range is 2.7 ≤ Mw ≤ 4.1. Interevent variability of stress drop and apparent stress results in a factor of 10, well beyond the individual‐event uncertainty. Radiation efficiency ηsw = τa/∆σ varies mostly between 0.1 and 0.2, but in the days immediately before and after the main shock, ηsw tends to be smaller decreasing to values as low as 0.06. This may be the consequence of ruptures migrating in those days into a focal volume with higher dynamic strength. The temporal change of ηsw is tentatively interpreted as a spatial variation due to the earthquake migration into the locked portion of the fault that originated the main shock. Consistently, no variation in stress drop and apparent stress is observed between foreshocks and aftershocks but the smallest and largest ∆σ result in a good correlation with the largest and smallest b‐values, respectively, imaged by other authors in the rupture nucleation volume.
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

Lipopolysaccharides (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

Transmission-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

Layer 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

The 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

Myoepithelial 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

Axin 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

PTEN 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

An 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

Although 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

In 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

Nonlinear 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

Human 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

R. 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

The 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

Pregnancy-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

Renal 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.
Atomic-scale thermal manipulation with adsorbed atoms on a solid surface at a liquid-solid interface
Authors: Fujiwara Kunio , Shibahara Masahiko
Published: September 2019

Modulating thermal transport through interfaces is one of the central issues in nanoscience and nanotechnology. This study examined thermal transport between atoms adsorbed on a solid surface and a liquid phase based on non-equilibrium molecular dynamics. The heat flux was detected at sub-atomic spatial resolution, yielding a two-dimensional map of local heat flux in the vicinity of the adsorbed atoms on the surface. Based on the detected heat flux, the possibility of atomic-scale thermal manipulation with the adsorbed atoms was examined by varying the interaction strengths between the liquid molecules and atoms adsorbed on the surface. The results of the local heat flux at the single-atom scale clearly showed effects of the adsorbed atoms on the thermal transport through the liquid-solid interface; they can significantly enhance the heat flux at the single-atom scale using degrees of freedom normal to the macroscopic temperature gradient. The effect was especially evident for a low wettability surface, which provides key information on local enhancement at the single-atom scale of the thermal transport through a liquid-solid interface.
Unsupervised machine learning using an imaging mass spectrometry dataset automatically reassembles grey and white matter
Authors: Nampei Makoto , Horikawa Makoto , Ishizu Keisuke , Yamazaki Fumiyoshi , Yamada Hidemoto , Kahyo Tomoaki , Setou Mitsutoshi
Published: September 2019

Current histological and anatomical analysis techniques, including fluorescence in situ hybridisation, immunohistochemistry, immunofluorescence, immunoelectron microscopy and fluorescent fusion protein, have revealed great distribution diversity of mRNA and proteins in the brain. However, the distributional pattern of small biomolecules, such as lipids, remains unclear. To this end, we have developed and optimised imaging mass spectrometry (IMS), a combined technique incorporating mass spectrometry and microscopy, which is capable of comprehensively visualising biomolecule distribution. We demonstrated the differential distribution of phospholipids throughout the cell body and axon of neuronal cells using IMS analysis. In this study, we used solarix XR, a high mass resolution and highly sensitive MALDI-FT-ICR-MS capable of detecting higher number of molecules than conventional MALDI-TOF-MS instruments, to create a molecular distribution dataset. We examined the diversity of biomolecule distribution in rat brains using IMS and hypothesised that unsupervised machine learning reconstructs brain structures such as the grey and white matters. We have demonstrated that principal component analysis (PCA) can reassemble the grey and white matters without assigning brain anatomical regions. Hierarchical clustering allowed us to classify the 10 groups of observed molecules according to their distributions. Furthermore, the group of molecules specifically localised in the cerebellar cortex was estimated to be composed of phospholipids.
A causal study of the phenomenon of ultrasound neurostimulation applied to an in vivo invertebrate nervous model
Authors: Vion-Bailly Jérémy , N’Djin W. Apoutou , Suarez Castellanos Ivan Mauricio , Mestas Jean-Louis , Carpentier Alexandre , Chapelon Jean-Yves
Published: September 2019

Focused ultrasound are considered to be a promising tool for the treatment of neurological conditions, overcoming the limitations of current neurostimulation techniques in terms of spatial resolution and invasiveness. Much evidence to support the feasibility of ultrasound activation of neurons at the systemic level has already been provided, but to this day, the biophysical mechanisms underlying ultrasound neurostimulation are still widely unknown. In order to be able to establish a clear and robust causality between acoustic parameters of the excitation and neurobiological characteristics of the response, it is necessary to work at the cellular level, or alternatively on very simple animal models. The study reported here responds to three objectives. Firstly, to propose a simple nervous model for the study of the ultrasound neurostimulation phenomenon, associated with a clear and simple experimental protocol. Secondly, to compare the characteristics of this model’s nervous response to ultrasound neurostimulation with its nervous response to mechanical and electrical stimulation. Thirdly, to study the role played by certain acoustic parameters in the success rate of the phenomenon of ultrasound stimulation. The feasibility of generating action potentials (APs) in the giant axons of an earthworm’s ventral nerve cord, using pulsed ultrasound stimuli (f = 1.1 MHz, Ncycles = 175–1150, PRF = 25–125 Hz, Npulses = 20, PA = 2.5–7.3 MPa), was demonstrated. The time of generation (TOG) of APs associated with ultrasound stimulation was found to be significantly shorter and more stable than the TOG associated with mechanical stimulation (p < 0.001). By applying a causal approach to interpret the results of this study, it was concluded that, in this model, the nervous response to focused ultrasound is initiated along the afferent neurons, in between the mechanosensors and the synaptic connections with the giant axons. Additionally, early results are provided, highlighting a trend for the success rate of ultrasound neurostimulation and number of APs triggered per response to increase with increasing pulse repetition frequency (p < 0.05 and p < 0.001, respectively), increasing pulse duration and increasing pulse amplitude.
A new ecology-on-a-chip microfluidic platform to study interactions of microbes with a rising oil droplet
Authors: White Andrew R. , Jalali Maryam , Sheng Jian
Published: September 2019

Advances in microfluidics technology has enabled many discoveries on microbial mechanisms and phenotypes owing to its exquisite controls over biological and chemical environments. However, emulating accurate ecologically relevant flow environments (e.g. microbes around a rising oil droplet) in microfluidics remains challenging. Here, we present a microfluidic platform, i.e. ecology-on-a-chip (eChip), that simulates environmental conditions around an oil droplet rising through ocean water as commonly occurred during a deep-sea oil spill or a natural seep, and enables detailed observations of microbe-oil interactions at scales relevant to marine ecology (i.e. spatial scales of individual bacterium in a dense suspension and temporal scales from milliseconds to weeks or months). Owing to the unique capabilities, we present unprecedented observations of polymeric microbial aggregates formed on rising oil droplets and their associated hydrodynamic impacts including flow fields and momentum budgets. Using the platform with Pseudomonas, Marinobacter, and Alcarnivorax, we have shown that polymeric aggregates formed by them present significant differences in morphology, growth rates, and hydrodynamic impacts. This platform enables us to investigate unexplored array of microbial interactions with oil drops.
Impaired neurocognitive and psychomotor performance in patients with inflammatory bowel disease
Authors: Tadin Hadjina Ivana , Zivkovic Piero Marin , Matetic Andrija , Rusic Doris , Vilovic Marino , Bajo Diana , Puljiz Zeljko , Tonkic Ante , Bozic Josko
Published: September 2019

Limited evidence exists regarding cognitive and psychomotor function in patients with inflammatory bowel disease (IBD). Therefore, we aimed to compare the neurocognitive and psychomotor function of 60 IBD patients with 60 age/sex-matched controls. Computer-based instrument Complex Reactinometer Drenovac (CRD) was used for assessment of cognitive domains: convergent thinking (simple mathematical tasks; CRD-11), perceptive abilities (light signal position discrimination; CRD-311) and sophisticated operative thinking (complex psychomotor coordination; CRD-411). The most important analyzed parameters were total test solving time (TTTS); minimal time of particular test solving (TMIN) and total number of wrong reactions (NER). Performance in all three cognitive tests showed statistically significantly longer TTTS and TMIN in IBD patients (P < 0.05), while there was no significant difference in NER. Aforementioned findings were adjusted for BMI, age and duration of education. Our study has shown impaired neurocognitive and psychomotor function in IBD patients compared to controls, especially in mental processing speed and mental endurance of perceptive abilities, convergent thinking and complex operative thinking.
Quantitative screening of the effects of hyper-osmotic stress on cancer cells cultured in 2- or 3-dimensional settings
Authors: Miermont Agnes , Lee Sharon Wei Ling , Adriani Giulia , Kamm Roger D.
Published: September 2019

The maintenance of precise cell volume is critical for cell survival. Changes in extracellular osmolarity affect cell volume and may impact various cellular processes such as mitosis, mitochondrial functions, DNA repair as well as cell migration and proliferation. Much of what we know about the mechanisms of cell osmoregulation comes from in vitro two-dimensional (2D) assays that are less physiologically relevant than three-dimensional (3D) in vitro or in vivo settings. Here, we developed a microfluidic model to study the impact of hyper-osmotic stress on the migration, proliferation and ion channel/transporter expression changes of three metastatic cell lines (MDA-MB-231, A549, T24) in 2D versus 3D environments. We observed a global decrease in cell migration and proliferation upon hyper-osmotic stress treatment, with similar responses between 2D and 3D conditions. Specific ion channels/aquaporins are over-expressed in metastatic cells and play a central role during osmo-regulation. Therefore, the effects of hyper-osmotic stress on two transporters, aquaporin 5 (AQP5) and the transient receptor potential cation channel (TRPV4), was investigated. While hyper-osmotic stress had no major impact on the transporters of cells cultured in 2D, cells embedded in collagen gel (3D) decreased their AQP5 expression and exhibited a reduction in intra-cellular translocation of TRPV4. Furthermore, cell dispersion from T24 aggregates embedded in 3D collagen gel decreased with higher levels of hyper-osmotic stress. In conclusion, this study provides evidence on the impact of hyper-osmotic stress on various aspects of metastatic cell progression and highlights the importance of having a 3D cell culture platform in investigating molecular players involved in cancer cell migration.
Whole Genome Sequencing of the Mutamouse Model Reveals Strain- and Colony-Level Variation, and Genomic Features of the Transgene Integration Site
Authors: Meier Matthew J. , Beal Marc A. , Schoenrock Andrew , Yauk Carole L. , Marchetti Francesco
Published: September 2019

The MutaMouse transgenic rodent model is widely used for assessing in vivo mutagenicity. Here, we report the characterization of MutaMouse’s whole genome sequence and its genetic variants compared to the C57BL/6 reference genome. High coverage (>50X) next-generation sequencing (NGS) of whole genomes from multiple MutaMouse animals from the Health Canada (HC) colony showed ~5 million SNVs per genome, ~20% of which are putatively novel. Sequencing of two animals from a geographically separated colony at Covance indicated that, over the course of 23 years, each colony accumulated 47,847 (HC) and 17,677 (Covance) non-parental homozygous single nucleotide variants. We found no novel nonsense or missense mutations that impair the MutaMouse response to genotoxic agents. Pairing sequencing data with array comparative genomic hybridization (aCGH) improved the accuracy and resolution of copy number variants (CNVs) calls and identified 300 genomic regions with CNVs. We also used long-read sequence technology (PacBio) to show that the transgene integration site involved a large deletion event with multiple inversions and rearrangements near a retrotransposon. The MutaMouse genome gives important genetic context to studies using this model, offers insight on the mechanisms of structural variant formation, and contributes a framework to analyze aCGH results alongside NGS data.
Bone loss caused by dopaminergic degeneration and levodopa treatment in Parkinson’s disease model mice
Authors: Handa Kazuaki , Kiyohara Shuichi , Yamakawa Tomoyuki , Ishikawa Koji , Hosonuma Masahiro , Sakai Nobuhiro , Karakawa Akiko , Chatani Masahiro , Tsuji Mayumi , Inagaki Katsunori , Kiuchi Yuji , Takami Masamichi , Negishi-Koga Takako
Published: September 2019

Accumulating evidence have shown the association of Parkinson’s disease (PD) with osteoporosis. Bone loss in PD patients, considered to be multifactorial and a result of motor disfunction, is a hallmark symptom that causes immobility and decreased muscle strength, as well as malnutrition and medication. However, no known experimental evidence has been presented showing deleterious effects of anti-PD drugs on bone or involvement of dopaminergic degeneration in bone metabolism. Here, we show that osteoporosis associated with PD is caused by dopaminergic degeneration itself, with no deficit of motor activity, as well as treatment with levodopa, the current gold-standard medication for affected patients. Our findings show that neurotoxin-induced dopaminergic degeneration resulted in bone loss due to accelerated osteoclastogenesis and suppressed bone formation, which was associated with elevated prolactin. On the other hand, using an experimental model of postmenopausal osteoporosis, dopaminergic degeneration did not result in exacerbation of bone loss due to estrogen deficiency, but rather reduction of bone loss. Thus, this study provides evidence for the regulation of bone metabolism by the dopaminergic system through both gonadal steroid hormone-dependent and -independent functions, leading to possible early detection of osteoporosis development in individuals with PD.
A ribosomal protein S5 isoform is essential for oogenesis and interacts with distinct RNAs in Drosophila melanogaster
Authors: Kong Jian , Han Hong , Bergalet Julie , Bouvrette Louis Philip Benoit , Hernández Greco , Moon Nam-Sung , Vali Hojatollah , Lécuyer Éric , Lasko Paul
Published: September 2019

In Drosophila melanogaster there are two genes encoding ribosomal protein S5, RpS5a and RpS5b. Here, we demonstrate that RpS5b is required for oogenesis. Females lacking RpS5b produce ovaries with numerous developmental defects that undergo widespread apoptosis in mid-oogenesis. Females lacking germline RpS5a are fully fertile, but germline expression of interfering RNA targeting germline RpS5a in an RpS5b mutant background worsened the RpS5b phenotype and blocked oogenesis before egg chambers form. A broad spectrum of mRNAs co-purified in immunoprecipitations with RpS5a, while RpS5b-associated mRNAs were specifically enriched for GO terms related to mitochondrial electron transport and cellular metabolic processes. Consistent with this, RpS5b mitochondrial fractions are depleted for proteins linked to oxidative phosphorylation and mitochondrial respiration, and RpS5b mitochondria tended to form large clusters and had more heterogeneous morphology than those from controls. We conclude that RpS5b-containing ribosomes preferentially associate with particular mRNAs and serve an essential function in oogenesis.