bluuebunny/crossref_metadata_2025 huggingface dataset:
Mistargeted retinal axons form synaptically segregated subcircuits in the visual thalamus of albino mice
Authors: McCracken Sean , McCoy Liam , Hu Ziyi , Hodges Julie , Valkova Katia , Williams Philip R , Morgan Josh
Published: November 2024

A Hebbian model of circuit remodeling predicts that two sets of inputs with sufficiently distinct activity patterns will synaptically capture separate sets of target cells. Mice in which a subset of retinal ganglion cells (RGCs) target the wrong region of the dorsal lateral geniculate nucleus (dLGN) provide the conditions for testing this prediction. In albino mice, mistargeted RGC axons form an island of terminals that is distinct from the surrounding neuropil. Blocking retinal activity during development prevents the formation of this island. However, the synaptic connectivity of the island was unknown. Here, we combine light and electron microscopy to determine if this activity-dependent island of axon terminals represent a synaptically segregated subcircuit. We reconstructed the microcircuitry of the boundary between the island and non-island RGCs and found a remarkably strong segregation within retinogeniculate connectivity. We conclude that, when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit from the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and for our understanding of the implementation of activity dependent development.
Outer hair cells stir cochlear fluids
Authors: Lee Choongheon , Shokrian Mohammad , Henry Kenneth S , Carney Laurel H , Holt Joseph C , Nam Jong-Hoon
Published: November 2024

We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid-structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently indicate that the outer-hair-cell action in the tail region of cochlear traveling waves is for cochlear fluid circulation.
Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury
Authors: Somasundaram Preethi , Farley Madeline M , Rudy Melissa A , Sigal Katya , Asencor Andoni I , Stefanoff David G , Shah Malay , Goli Puneetha , Heo Jenny , Wang Shufang , Tran Nicholas M , Watkins Trent A
Published: November 2024

Stress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.
Identification of ERAD-dependent degrons for the endoplasmic reticulum lumen
Authors: Sharninghausen Rachel , Hwang Jiwon , Dennison Devon D , Baldridge Ryan D
Published: November 2024

Degrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol. Using Saccharomyces cerevisiae, we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate proteasomal degradation through the endoplasmic reticulum associated degradation (ERAD) system. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation in budding yeast and mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and builds toward therapeutic approaches that exploit the highly conserved ERAD system.
Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function
Authors: Ono Kazuya , Jarysta Amandine , Hughes Natasha C , Jukic Alma , Chang Hui Ho Vanessa , Deans Michael R , Eatock Ruth Anne , Cullen Kathleen E , Kindt Katie S , Tarchini Basile
Published: November 2024

Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered – swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.
CPT1A Mediates Radiation Sensitivity in Colorectal Cancer
Authors: Chen Zhenhui , Yu Lu , Zheng Zhihao , Wang Xusheng , Guo Qiqing , Chen Yuchuan , Zhang Yaowei , Zhang Yuqin , Xiao Jianbiao , Chen Keli , Fan Hongying , Ding Yi
Published: November 2024

The prevalence and mortality rates of colorectal cancer (CRC) are increasing worldwide. Radiation resistance hinders radiotherapy, a standard treatment for advanced CRC, leading to local recurrence and metastasis. Elucidating the molecular mechanisms underlying radioresistance in CRC is critical to enhance therapeutic efficacy and patient outcomes. Bioinformatic analysis and tumour tissue examination were conducted to investigate the
CPT1A
mRNA and protein levels in CRC and their correlation with radiotherapy efficacy. Furthermore, lentiviral overexpression and CRISPR/Cas9 lentiviral vectors, along with
in vitro
and
in vivo
radiation experiments, were used to explore the effect of CPT1A on radiosensitivity. Additionally, transcriptomic sequencing, molecular biology experiments, and bioinformatic analyses were employed to elucidate the molecular mechanisms by which CPT1A regulates radiosensitivity. CPT1A was significantly downregulated in CRC and negatively correlated with responsiveness to neoadjuvant radiotherapy. Functional studies suggested that CPT1A mediates radiosensitivity, influencing reactive oxygen species (ROS) scavenging and DNA damage response. Transcriptomic and molecular analyses highlighted the involvement of the peroxisomal pathway. Mechanistic exploration revealed that CPT1A downregulates the FOXM1-SOD1/SOD2/CAT axis, moderating cellular ROS levels after irradiation and enhancing radiosensitivity. CPT1A downregulation contributes to radioresistance in CRC by augmenting the FOXM1-mediated antioxidant response. Thus, CPT1A is a potential biomarker of radiosensitivity and a novel target for overcoming radioresistance, offering a future direction to enhance CRC radiotherapy.
Systematic genetic characterization of the human PKR kinase domain highlights its functional malleability to escape a poxvirus substrate mimic
Authors: Chambers Michael James , Scobell Sophia B , Sadhu Meru J
Published: November 2024

Evolutionary arms races can arise at the contact surfaces between host and viral proteins, producing dynamic spaces in which genetic variants are continually pursued.  However, the sampling of genetic variation must be balanced with the need to maintain protein function. A striking case is given by protein kinase R (PKR), a member of the mammalian innate immune system. PKR detects viral replication within the host cell and halts protein synthesis to prevent viral replication by phosphorylating eIF2α, a component of the translation initiation machinery. PKR is targeted by many viral antagonists, including poxvirus pseudosubstrate antagonists that mimic the natural substrate, eIF2α, and inhibit PKR activity. Remarkably, PKR has several rapidly evolving residues at this interface, suggesting it is engaging in an evolutionary arms race, despite the surface’s critical role in phosphorylating eIF2α. To systematically explore the evolutionary opportunities available at this dynamic interface, we generated and characterized a library of 426 SNP-accessible nonsynonymous variants of human PKR for their ability to escape inhibition by the model pseudosubstrate inhibitor K3, encoded by the vaccinia virus gene K3L. We identified key sites in the PKR kinase domain that harbor K3-resistant variants, as well as critical sites where variation leads to loss of function. We find K3-resistant variants are readily available throughout the interface and are enriched at sites under positive selection. Moreover, variants beneficial against K3 were also beneficial against an enhanced variant of K3, indicating resilience to viral adaptation. Overall, we find that the eIF2α-binding surface of PKR is highly malleable, potentiating its evolutionary ability to combat viral inhibition.
Importance of feature selection stability in the classifier evaluation on high-dimensional genetic data
Authors: Łukaszuk Tomasz , Krawczuk Jerzy
Published: November 2024

Classifiers trained on high-dimensional data, such as genetic datasets, often encounter situations where the number of features exceeds the number of objects. In these cases, classifiers typically rely on a small subset of features. For a robust algorithm, this subset should remain relatively stable with minor changes in the training data, such as the replacement of a few samples. While the stability of feature selection is a common focus in studies of feature selection algorithms, it is less emphasized in classifier evaluation, where only metrics such as accuracy are commonly used. We investigate the importance of feature selection stability through an empirical study of four classifiers (logistic regression, support vector machine, convex and piecewise Linear, and Random Forest) on seven high dimensional, publicly available, gene datasets. We measure the stability of feature selection using Lustgarten, Nogueira and Jaccard Index measures. We employed our own cross-validation procedure that guarantees a difference of exactly p objects between any two training sets which allows us to control the level of disturbance in the data. Our results show the existence of a drop in feature selection stability when we increase disturbance in the data in all 28 experiment configurations (seven datasets and four classifiers). The relationship is not linear, but resembles more of a hyperbolic pattern. In the evaluation of the tested classifiers, logistic regression demonstrated the highest stability. It was followed in order by support vector machine, convex and piecewise linear, with Random Forest exhibiting the lowest stability among them. This work provides evidence that all tested classifiers are very sensitive to even small changes in learning data in terms of features used by the model, while showing almost no sensitivity in terms of accuracy. The data and codes to reproduce the results in the article are available publicly on GitHub: https://github.com/tlukaszuk/feature-selection-stability-in-classifier-evaluation.
Essence and Economic Impacts of Food: A Thematic Analysis
Authors: C Uche, , E. N Ajie,
Published: November 2024

The number of food insecure people may not have changed much despite the global campaigns especially in Africa where for centuries people dined and lived on natural, wild and organic food sources which supported their health and vitality although adjudged crude and inadequate.  The West may have attained significant mile stones in food security for a price. Modern (western) food condiments and feeding patterns which the elites in Africa are subscribing to seem to be programmed to impoverish human health and in the process enriching the pharmaceutical industries. The emergence and adoption of western food culture and feeding regimen has heralded the emergence of diseases and sicknesses hitherto little known to most Africans. The basic essence of food is to ensure body growth, repair of and maintenance of body tissues and regulation of vital processes. Any food form that ensures you visit a doctor is poisoning no matter the taste and packaging hence the need for not only food security but also adequacy. Food security is also an important component of economic development and germane to global economic agenda.  Food adequacy supports economic and Sustainable Development Goals (SDGs) of any government by enhancing the citizens’ health thus broadening productivity and economic opportunities. This is important because food presently is a big industry globally and can earn big profits and make a difference in the economy because it can impact economic development in many different forms. It can affect health and education and because it plays important roles in health and education, it can plausibly impact economic growth and development especially human capital formation and is a necessary tool to spur economic growth.
Characterization and Classification of Soils of Chamba Block of Tehri Garhwal District of Uttarakhand, India: A Case Study from Lesser Himalayas
Authors: Joon Vikas , Meena Rajesh Kumar , Nagdev Ritu , Surya Jaya N.
Published: November 2024

In the present study, an attempt was made to characterize and classify the soils occurring on different topography in the Chamba block of Tehri Garhwal district of Uttarakhand. A detailed soil survey was carried out by simple random sampling and studying master profiles using Landscape Ecological Unit’s map on 1:10000 scale to study the soils. The high-resolution remote sensing data product derived from the IRS-R2, specifically the LISS-IV data and GIS approaches were used. Nine representative pedons (covering all the soil types) were studied for their morphological, physical and chemical properties. These soils were very shallow to deep, dark grayish brown to dark brown/dark yellowish brown, brown to dark yellowish brown, dark grayish brown to olive brown and very dark grayish brown to dark yellowish brown in colour. Structure of the surface soils varied from sub-angular blocky to disturbed to single grain.Soil texture varied fromsandy loam to sandy loam, sandy loam to loam, loamy sand to sand and loam to clay loam in texture, strongly acidic to acidic (<5.5-6.5) and neutral (6.5-7.5) in reaction. The electric conductivity exhibited a range from 0.17 to 1.83 dS m-1 within surface horizons and from 0.02 to 0.80 dS m-1 within the sub-surface horizons, accompanied by organic carbon content categorized as medium (0.50-0.75%) to high (>0.75%). The exchangeable cations, specifically Ca2+, Mg2+, Na+, and K+, demonstrated variability ranging from 4.90 to 10.40, 1.30 to 4.00, 0.39 to 1.01, and 0.44 to 1.27 cmol p+kg-1, respectively, in surface horizons. Base saturation (BS) varied from 80 to 92% in surface horizons and from 68 to 91% in the sub-surface horizons. The cation exchange capacity (CEC) varied between 8.6 to 19.9 cmol p+kg-1 in surface horizons and from 2.7 to 17.2 cmol p+kg-1 in the sub-surface horizons. The soils were classified within the Entisols and Inceptisols orders. To ensure sustainable agricultural production within these soils, it is imperative to implement appropriate management strategies to mitigate the impacts of soil degradation.
Impact of Soil Amendments and Improved Alkaline Water on the Physico-chemical Characteristics of the Soil, the Distribution of Salt in the Soil, the Growth, and the Yield of Hybrid Cotton Grown in Sodic Soil with Drip Irrigation
Authors: Suresh T. , Selvamurugan M. , Baskar M. , Santhy P. , Balasubramaniam P.
Published: November 2024

The effects of ameliorated alkali water and soil amendments on the soil properties, growth, and yield of hybrid cotton in sodic soil under drip irrigation were investigated in this field experiment at Anbil Dharmalingam Agricultural College and Research Institute, Trichy, using cotton (RCH-20) as a test crop. The main-plot treatments included drip irrigation with gypsum treatment water and drip irrigation with spent wash treatment water; the sub-plot treatments included soil application of gypsum @ 50% GR (5.2 t ha-1) and a one-time soil application of distillery spent wash at 5 lakh liters ha-1. The treatment without amendments under main plot and sub-plots was used as a control. The experiment was designed in a strip-plot design with four replications. The application of additives through irrigation water or soil dramatically lowered the post-harvest soil's pH. Plots applied with wasted wash had the greatest pH reduction (M1S1) 7.81, followed by those applied with gypsum (M2S2) 7.90 and control (M3S3) 8.15. Because there was more soluble salt present in the spent wash treated plots, there was a little rise in EC. Drip irrigation with distillery spent wash (DSW) treated water and drip irrigation with gypsum treated water, respectively, resulted in ESP decreases of (M2S2) 0.97 and (M1S1) 0.61 over control. Similarly, ESP decreased by 2.63 and 1.31 when gypsum and DSW were applied to the soil, respectively, compared to the control. The organic carbon values ranged from (M3S3) 0.47 to (M2S2) 0.92 percent. In general, an increase in organic carbon content was observed in all the treatments that received amendments (Gypsum& DSW) compared to control. Salt distribution pattern conducted in treatment of distillery spent wash @ 5.0 lakh liters ha-1 significantly increased vertical depth of soil pH ranges (7.56,7.68,7.80,8.30) and decreased EC ranges (1.05,1.02,1.00,0.95) followed by horizontal line soil pH ranges (7.54,7.51,7.49,7.50) and EC ranges (1.04,1.02,1.00,1.02) at 120 DAS after application. In the experimental field recorded vertical depth of soil increased pH and decreased electrical conductivity compared to horizontal distances of soil pH and EC. The physico- chemical properties reduced in treatment one time application of DSW @ 5 lakh liters ha-1 recorded the highest physico-chemical properties followed by the treatment receiving irrigation with gypsum bed treated alkali water and lowest was recorded in the untreated alkali water irrigated through drip system in non- amended soil.
Optimization of Crystallographic Texture for Sheet-forming Applications Using Taylor-based Models
Authors: Galán-López Jesús , Kestens Leo A. I.
Published: August 2018

Plastic deformation of metallic materials is an inherently anisotropic process as a result of the presence of preferential orientations in their crystallographic texture. Crystal plasticity modeling, which allows simulating the response of polycrystal aggregates taking into account their texture and other microstructural parameters, has been extensively used to predict this behavior. In this work, crystal
plasticity models are used to deal with the opposite problem: given a desired behavior, determine how to modify a texture to approximate this behavior in the most efficient way. This goal can be expressed as an optimization problem, in which the objective is to find the texture with the best formability properties among all the possible ones. An incremental optimization method, based on the gradient descent algorithm, has been developed and applied to different initial textures corresponding to typical steel and aluminum sheet products. According to expectations, the textures found present a stronger

$$\gamma $$

γ

fiber component. Moreover, the method sets the basis for the development of more complicated optimization schemes directed toward optimizing specific materials and forming processes.
Avoid the Goose! Paramedic Identification of Esophageal Intubation by Ultrasound
Authors: Lema Penelope C. , O’Brien Michael , Wilson Juliana , James Erika St. , Lindstrom Heather , DeAngelis John , Caldwell Jennifer , May Paul , Clemency Brian
Published: August 2018

Objectives

Rapid identification of esophageal intubations is critical to avoid patient morbidity and mortality. Continuous waveform capnography remains the gold standard for endotracheal tube (ETT) confirmation, but it has limitations. Point-of-care ultrasound (POCUS) may be a useful alternative for confirming ETT placement. The objective of this study was to determine the accuracy of paramedic-performed POCUS identification of esophageal intubations with and without ETT manipulation.

Methods

A prospective, observational study using a cadaver model was conducted. Local paramedics were recruited as subjects and each completed a survey of their demographics, employment history, intubation experience, and prior POCUS training. Subjects participated in a didactic session in which they learned POCUS identification of ETT location. During each study session, investigators randomly placed an ETT in either the trachea or esophagus of four cadavers, confirmed with direct laryngoscopy. Subjects then attempted to determine position using POCUS both without and with manipulation of the ETT. Manipulation of the tube was performed by twisting the tube. Descriptive statistics and logistic regression were used to assess the results and the effects of previous paramedic experience.

Results

During 12 study sessions, from March 2014 through December 2015, 57 subjects participated, evaluating a total of 228 intubations: 113 tracheal and 115 esophageal. Subjects were 84.0% male, mean age of 39 years (range: 22 - 62 years), with median experience of seven years (range: 0.6 - 39 years). Paramedics correctly identified ETT location in 158 (69.3%) cases without and 194 (85.1%) with ETT manipulation. The sensitivity and specificity of identifying esophageal location without ETT manipulation increased from 52.2% (95% confidence interval [CI], 43.0-61.0) and 86.7% (95% CI, 81.0-93.0) to 87.0% (95% CI, 81.0-93.0) and 83.2% (95% CI, 0.76-0.90) after manipulation (P<.0001), without affecting specificity (P=.45). Subjects correctly identified 41 previously incorrectly identified esophageal intubations. Paramedic experience, previous intubations, and POCUS experience did not correlate with ability to identify tube location.

Conclusion:

Paramedics can accurately identify esophageal intubations with POCUS, and manipulation improves identification. Further studies of paramedic use of dynamic POCUS to identify inadvertent esophageal intubations are needed.

LemaPC, O’BrienM, WilsonJ, St. JamesE, LindstromH, DeAngelisJ, CaldwellJ, MayP, ClemencyB.Avoid the goose! Paramedic identification of esophageal intubation by ultrasound. Prehosp Disaster Med.2018;33(4):406–410
‘Real Grounds’ in Matter and Things in Themselves
Authors: Langton Rae
Published: August 2018

Matter’s real essence is a ground for certain features of phenomena. Things in themselves are likewise a ground for certain features of phenomena. How do these claims relate? The former is a causal essentialism about physics, Stang argues; and the features so grounded are phenomenally nomically necessary. The latter involves a distinctive ontology of things in themselves, I argue; but the features so grounded are not noumenally nomically necessary. Stang’s version of Kant’s modal metaphysics is admirable, but does not go far enough. Kant’s causal essentialism involves the essences of fundamental properties, as well as of matter. And things in themselves are grounds, because they are substances, the ‘substrate’ of phenomena.
Nicholas Stang’s Kant’s Modal Metaphysics
Authors: McDaniel Kris
Published: August 2018

In this critical review, I focus on two things. First, I respond to Stang’s interpretation of Descartes, according to which Descartes’ endorsement of his ontological argument commits him to possibilism, the doctrine that there are, or at least could be, non-existent individuals. My response consists in presenting a version of Descartes’ argument the acceptance of which does not require the acceptance of possibilism. The second thing I focus on is Stang’s claim that Kant distinguishes several kinds of real possibility. I raise worries about Stang’s formulations of various doctrines of real possibility, and I preliminarily explore how real essence and ground are connected with the various kinds of real necessity Stang’s Kant recognizes.
Democratic Waves in Historical Perspective
Authors: Gunitsky Seva
Published: August 2018

For over two centuries, the evolution of democracy has been marked by repeated democratic waves. Yet these cross-border bursts of revolution and reform have varied widely in their origins, intensity, and success rates. How do we compare cascades of regime change, and what lessons do they offer about the spread of democracy? I lay out a historical framework of democratic waves that focuses on recurring causal mechanisms across time. Thirteen democratic waves are categorized according to two dimensions: 1) the origins of external influence, located in eitherverticalhegemonic transformations or inhorizontalcross-border linkages; 2) the strength of external influence, taking the form ofcontagionwhen outside forces dominate andemulationwhen domestic focal points shape the timing of contention. This approach allows for more meaningful comparisons between these important, recurring, yet seemingly incomparable democratic waves. More generally, it suggests that the global history of democracy cannot be reduced to the sum of its national trajectories.
A Discussion of Claire L. Adida, David D. Laitin, and Marie-Anne Valfort’s Why Muslim Integration Fails in Christian-Heritage Societies
Authors: Norton Anne
Published: August 2018

The title of the book needs no explanation: Why Muslim Integration Fails in Christian-Heritage Societies. It marks an issue of widespread and obvious current relevance, especially in Europe and in the United States in the age of Donald Trump. It registers a claim that is surely controversial and that also perhaps blends empirical and normative judgments. The book is thus a perfect candidate for a Perspectives symposium because it opens itself to so many different perspectives.
Experimental implementation of fully controlled dephasing dynamics and synthetic spectral densities
Authors: Liu Zhao-Di , Lyyra Henri , Sun Yong-Nan , Liu Bi-Heng , Li Chuan-Feng , Guo Guang-Can , Maniscalco Sabrina , Piilo Jyrki
Published: August 2018

Engineering, controlling, and simulating quantum dynamics is a strenuous task. However, these techniques are crucial to develop quantum technologies, preserve quantum properties, and engineer decoherence. Earlier results have demonstrated reservoir engineering, construction of a quantum simulator for Markovian open systems, and controlled transition from Markovian to non-Markovian regime. Dephasing is an ubiquitous mechanism to degrade the performance of quantum computers. However, all-purpose quantum simulator for generic dephasing is still missing. Here, we demonstrate full experimental control of dephasing allowing us to implement arbitrary decoherence dynamics of a qubit. As examples, we use a photon to simulate the dynamics of a qubit coupled to an Ising chain in a transverse field and also demonstrate a simulation of nonpositive dynamical map. Our platform opens the possibility to simulate dephasing of any physical system and study fundamental questions on open quantum systems.
Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens
Authors: Lin Zihua , Xu Xiaobo , Zhao Sheng , Yang Xiaohong , Guo Jian , Zhang Qun , Jing Chunmei , Chen Shawn , He Yun
Published: August 2018

Development of effective antimicrobial agents continues to be a great challenge, particularly due to the increasing resistance of superbugs and frequent hospital breakouts. There is an urgent need for more potent and safer antibiotics with novel scaffolds. As historically many commercial drugs were derived from natural products, discovery of antimicrobial agents from complex natural product structures still holds a great promise. Herein, we report the total synthesis of natural albomycins δ1 (1a), δ2 (1b), and ε (1c), which validates the structures of these peptidylnucleoside compounds and allows for synthetic access to bioactive albomycin analogs. The efficient synthesis of albomycins enables extensive evaluations of these natural products against model bacteria and clinical pathogens. Albomycin δ2 has the potential to be developed into an antibacterial drug to treat Streptococcus pneumoniae and Staphylococcus aureus infections.
Nanophotonic Pockels modulators on a silicon nitride platform
Authors: Alexander Koen , George John P. , Verbist Jochem , Neyts Kristiaan , Kuyken Bart , Van Thourhout Dries , Beeckman Jeroen
Published: August 2018

Silicon nitride (SiN) is emerging as a competitive platform for CMOS-compatible integrated photonics. However, active devices such as modulators are scarce and still lack in performance. Ideally, such a modulator should have a high bandwidth, good modulation efficiency, low loss, and cover a wide wavelength range. Here, we demonstrate the first electro-optic modulators based on ferroelectric lead zirconate titanate (PZT) films on SiN, in both the O-band and C-band. Bias-free operation, bandwidths beyond 33 GHz and data rates of 40 Gbps are shown, as well as low propagation losses (α ≈ 1 dB cm−1). A half-wave voltage-length product of 3.2 V cm is measured. Simulations indicate that further improvement is possible. This approach offers a much-anticipated route towards high-performance phase modulators on SiN.
FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation
Authors: Shanmughapriya Santhanam , Tomar Dhanendra , Dong Zhiwei , Slovik Katherine J. , Nemani Neeharika , Natarajaseenivasan Kalimuthusamy , Carvalho Edmund , Lu Christy , Corrigan Kaitlyn , Garikipati Venkata Naga Srikanth , Ibetti Jessica , Rajan Sudarsan , Barrero Carlos , Chuprun Kurt , Kishore Raj , Merali Salim , Tian Ying , Yang Wenli , Madesh Muniswamy
Published: August 2018

Although many factors contribute to cellular differentiation, the role of mitochondria Ca2+ dynamics during development remains unexplored. Because mammalian embryonic epiblasts reside in a hypoxic environment, we intended to understand whether mCa2+ and its transport machineries are regulated during hypoxia. Tissues from multiple organs of developing mouse embryo evidenced a suppression of MICU1 expression with nominal changes on other MCU complex components. As surrogate models, we here utilized human embryonic stem cells (hESCs)/induced pluripotent stem cells (hiPSCs) and primary neonatal myocytes to delineate the mechanisms that control mCa2+ and bioenergetics during development. Analysis of MICU1 expression in hESCs/hiPSCs showed low abundance of MICU1 due to its direct repression by Foxd1. Experimentally, restoration of MICU1 established the periodic cCa2+ oscillations and promoted cellular differentiation and maturation. These findings establish a role of mCa2+ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1.
HIV-1 intron-containing RNA expression induces innate immune activation and T cell dysfunction
Authors: Akiyama Hisashi , Miller Caitlin M. , Ettinger Chelsea R. , Belkina Anna C. , Snyder-Cappione Jennifer E. , Gummuluru Suryaram
Published: August 2018

Low levels of type I interferon (IFN-I) are thought to be a driving force for immune activation and T-cell exhaustion in HIV-1 infected individuals on combination antiretroviral therapy (cART), though the causative mechanisms for persistent IFN-I signaling have remained unclear. Here, we show Rev–CRM1-dependent nuclear export and peripheral membrane association of intron-containing HIV-1 RNA, independent of primary viral sequence or viral protein expression, is subject to sensing and signaling via MAVS, resulting in IFN-I-dependent pro-inflammatory responses in macrophages. Additionally, HIV-1 intron-containing-RNA-induced innate immune activation of macrophages leads to upregulation of inhibitory receptor expression and functional immune exhaustion of co-cultured T cells. Our findings suggest that persistent expression of HIV-1 intron-containing RNA in macrophages contributes to chronic immune activation and T-cell dysfunction and that use of HIV RNA expression inhibitors as adjunct therapy might abrogate aberrant inflammation and restore immune function in HIV-infected individuals on cART.
High-resolution in situ transcriptomics of Pseudomonas aeruginosa unveils genotype independent patho-phenotypes in cystic fibrosis lungs
Authors: Rossi Elio , Falcone Marilena , Molin Søren , Johansen Helle Krogh
Published: August 2018

Life-long bacterial infections in cystic fibrosis (CF) airways constitute an excellent model both for persistent infections and for microbial adaptive evolution in complex dynamic environments. Using high-resolution transcriptomics applied on CF sputum, we profile transcriptional phenotypes of Pseudomonas aeruginosa populations in patho-physiological conditions. Here we show that the soft-core genome of genetically distinct populations, while maintaining transcriptional flexibility, shares a common expression program tied to the lungs environment. We identify genetically independent traits defining P. aeruginosa physiology in vivo, documenting the connection between several previously identified mutations in CF isolates and some of the convergent phenotypes known to develop in later stages of the infection. In addition, our data highlight to what extent this organism can exploit its extensive repertoire of physiological pathways to acclimate to a new niche and suggest how alternative nutrients produced in the lungs may be utilized in unexpected metabolic contexts.
Modeling the impact of drug interactions on therapeutic selectivity
Authors: Weinstein Zohar B. , Kuru Nurdan , Kiriakov Szilvia , Palmer Adam C. , Khalil Ahmad S. , Clemons Paul A. , Zaman Muhammad H. , Roth Frederick P. , Cokol Murat
Published: August 2018

Combination therapies that produce synergistic growth inhibition are widely sought after for the pharmacotherapy of many pathological conditions. Therapeutic selectivity, however, depends on the difference between potency on disease-causing cells and potency on non-target cell types that cause toxic side effects. Here, we examine a model system of antimicrobial compound combinations applied to two highly diverged yeast species. We find that even though the drug interactions correlate between the two species, cell-type-specific differences in drug interactions are common and can dramatically alter the selectivity of compounds when applied in combination vs. single-drug activity—enhancing, diminishing, or inverting therapeutic windows. This study identifies drug combinations with enhanced cell-type-selectivity with a range of interaction types, which we experimentally validate using multiplexed drug-interaction assays for heterogeneous cell cultures. This analysis presents a model framework for evaluating drug combinations with increased efficacy and selectivity against pathogens or tumors.
Revealing the mechanisms of membrane protein export by virulence-associated bacterial secretion systems
Authors: Krampen Lea , Malmsheimer Silke , Grin Iwan , Trunk Thomas , Lührmann Anja , de Gier Jan-Willem , Wagner Samuel
Published: August 2018

Many bacteria export effector proteins fulfilling their function in membranes of a eukaryotic host. These effector membrane proteins appear to contain signals for two incompatible bacterial secretion pathways in the same protein: a specific export signal, as well as transmembrane segments that one would expect to mediate targeting to the bacterial inner membrane. Here, we show that the transmembrane segments of effector proteins of type III and type IV secretion systems indeed integrate in the membrane as required in the eukaryotic host, but that their hydrophobicity in most instances is just below the threshold required for mediating targeting to the bacterial inner membrane. Furthermore, we show that binding of type III secretion chaperones to both the effector’s chaperone-binding domain and adjacent hydrophobic transmembrane segments also prevents erroneous targeting. These results highlight the evolution of a fine discrimination between targeting pathways that is critical for the virulence of many bacterial pathogens.
Super-regional land-use change and effects on the grassland specialist flora
Authors: Auffret Alistair G. , Kimberley Adam , Plue Jan , Waldén Emelie
Published: August 2018

Habitat loss through land-use change is the most pressing threat to biodiversity worldwide. European semi-natural grasslands have suffered an ongoing decline since the early twentieth century, but we have limited knowledge of how grassland loss has affected biodiversity across large spatial scales. We quantify land-use change over 50–70 years across a 175,000 km2 super-region in southern Sweden, identifying a widespread loss of open cover and a homogenisation of landscape structure, although these patterns vary considerably depending on the historical composition of the landscape. Analysing species inventories from 46,796 semi-natural grasslands, our results indicate that habitat loss and degradation have resulted in a decline in grassland specialist plant species. Local factors are the best predictors of specialist richness, but the historical landscape predicts present-day richness better than the contemporary landscape. This supports the widespread existence of time-lagged biodiversity responses, indicating that further species losses could occur in the future.
Perrault syndrome type 3 caused by diverse molecular defects in CLPP
Authors: Brodie Erica J. , Zhan Hanmiao , Saiyed Tamanna , Truscott Kaye N. , Dougan David A.
Published: August 2018

The maintenance of mitochondrial protein homeostasis (proteostasis) is crucial for correct cellular function. Recently, several mutations in the mitochondrial protease CLPP have been identified in patients with Perrault syndrome 3 (PRLTS3). These mutations can be arranged into two groups, those that cluster near the docking site (hydrophobic pocket, Hp) for the cognate unfoldase CLPX (i.e. T145P and C147S) and those that are adjacent to the active site of the peptidase (i.e. Y229D). Here we report the biochemical consequence of mutations in both regions. The Y229D mutant not only inhibited CLPP-peptidase activity, but unexpectedly also prevented CLPX-docking, thereby blocking the turnover of both peptide and protein substrates. In contrast, Hp mutations cause a range of biochemical defects in CLPP, from no observable change to CLPP activity for the C147S mutant, to dramatic disruption of most activities for the “gain-of-function” mutant T145P - including loss of oligomeric assembly and enhanced peptidase activity.
The statistical shape of geometric reasoning
Authors: Hart Yuval , Dillon Moira R. , Marantan Andrew , Cardenas Anna L. , Spelke Elizabeth , Mahadevan L.
Published: August 2018

Geometric reasoning has an inherent dissonance: its abstract axioms and propositions refer to perfect, idealized entities, whereas its use in the physical world relies on dynamic perception of objects. How do abstract Euclidean concepts, dynamics, and statistics come together to support our intuitive geometric reasoning? Here, we address this question using a simple geometric task – planar triangle completion. An analysis of the distribution of participants’ errors in localizing a fragmented triangle’s missing corner reveals scale-dependent deviations from a deterministic Euclidean representation of planar triangles. By considering the statistical physics of the process characterized via a correlated random walk with a natural length scale, we explain these results and further predict participants’ estimates of the missing angle, measured in a second task. Our model also predicts the results of a categorical reasoning task about changes in the triangle size and shape even when such completion strategies need not be invoked. Taken together, our findings suggest a critical role for noisy physical processes in our reasoning about elementary Euclidean geometry.
Systematic analysis reveals molecular characteristics of ERG-negative prostate cancer
Authors: Xiao Qingyu , Sun Yidi , Dobi Albert , Srivastava Shiv , Wang Wendy , Srivastava Sudhir , Ji Yuan , Hou Jun , Zhao Guo-Ping , Li Yixue , Li Hong
Published: August 2018

The TMPRSS2:ERG gene fusion is the most prevalent early driver gene activation in prostate cancers of European ancestry, while the fusion frequency is much lower in Africans and Asians. The genomic characteristics and mechanisms for patients lacking ERG fusion are still unclear. In this study, we systematically compared the characteristics of gene fusions, somatic mutations, copy number alterations and gene expression signatures between 201 ERG fusion positive and 296 ERG fusion negative prostate cancer samples. Both common and group-specific genomic alterations were observed, suggesting shared and different mechanisms of carcinogenesis in prostate cancer samples with or without ERG fusion. The genomic alteration patterns detected in ERG-negative group showed similarities with 77.5% of tumor samples of African American patients. These results emphasize that genomic and gene expression features of the ERG-negative group may provide a reference for populations with lower ERG fusion frequency. While the overall expression patterns were comparable between ERG-negative and ERG-positive tumors, we found that genomic alterations could affect the same pathway through distinct genes in the same pathway in both groups of tumor types. Altogether, the genomic and molecular characteristics revealed in our study may provide new opportunities for molecular stratification of ERG-negative prostate cancers.
Generalized Haldane models on laser-coupling optical lattices
Authors: Liu Wanli , Lin Zhi , Wang Z. D. , Chen Yan
Published: August 2018

We propose two generalized Haldane models on laser-coupling optical lattices. Laser-assisted nearest neighbour tunnelings generate artificial staggered magnetic flux, facilitating the realization of topological nontrivial band structures. As generalizations of Haldane model, these models support topological insulator and semimetal phases featuring high Chern numbers. We show simple rules for computing Chern numbers of our models and display the phase diagrams. Moreover, numerical calculations of energy spectra are in perfect agreement with our theoretical expectations. Our models may serve as two new family members for generalizing Haldane model on optical lattices.
Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome
Authors: Taki T. , Takeichi T. , Sugiura K. , Akiyama M.
Published: August 2018

Germline missense mutations inGJB2encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions ofIL15,CCL5,IL1A,IL23RandTLR5are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.
SiNWs Biophysically Regulate the Fates of Human Mesenchymal Stem Cells
Authors: Lin Hsin-I , Kuo Shu-Wen , Yen Ta-Jen , Lee Oscar K.
Published: August 2018

While biophysical stimuli from polymeric matrices are known to significantly affect the fates of human mesenchymal stem cells (hMSCs), the stimulatory effects of nano-sized silicon-based matrices on hMSCs have not been thoroughly investigated. We previously demonstrated that vertically aligned, single-crystalline silicon nanowires (SiNWs) can control the osteogenicity of hMSCs via controllable spring constants from SiNWs matrix. However, other possible differentiation fates of hMSCs on SiNWs have not been explored. We hypothesize that tunable spring constant from artificial SiNWs matrices can direct different types of hMSC differentiations. The spring constants of tunable SiNW matrices can be consistently controlled by tuning the SiNW length. The results of gene expression and cell stiffness suggest that hMSCs differentiations are sensitive to our distinguishable spring constants from the SiNWs groups, and simultaneously conduct osteogenicity and adipogenicity. These findings suggest that SiNW matrices can regulate the fates of hMSCs when the SiNW characteristics are carefully tuned.