bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel sunflower MIMO fractal antenna with low mutual coupling and dual wide operating bands
Authors: Abed Amer T.
Published: October 2019

A novel multiple-input and multiple-output (MIMO) fractal antenna excited by a coplanar waveguide was investigated in this study. A novel technique was used to improve the isolation of 20 dB between the dual radiating elements by inserting a strip line into the outer edges of the ground plane. A sunflower structure was used to configure the antenna in three steps. At each step, an additional sunflower structure was added with half the size of that used in the previous step to enhance the impedance bandwidth. The measured values of envelop correlation coefficient and total active reflection coefficient indicated that the proposed MIMO antenna has high-diversity performance between radiating elements. Wide dual operating bands of 2–2.9 and 5–10 GHz were obtained, which can support different wireless communications, such as 3G, LTE (2.6 GHz), WLAN (2.4 GHz/5 GHz), WiMAX (2.4 GHz/5GHz), ISM (2.4 GHz/5 GHz), 5G (5–6 GHz), and satellite communications (6–8 GHz). The MIMO fractal antenna with a small size achieved a maximum efficiency of 85% and a peak value gain of 6 dBi, low-channel capacity loss of 0.15–0.4 b/s/Hz, and high isolation between radiating elements is suitable for portable communication devices.
Floodplain Land Cover and Flow Hydrodynamic Control of Overbank Sedimentation in Compound Channel Flows
Authors: Juez Carmelo , Schärer C. , Jenny H. , Schleiss A. J. , Franca M. J.
Published: October 2019

Overbank sedimentation is predominantly due to fine sediments transported under suspension that become trapped and settle in floodplains when high‐flow conditions occur in rivers. In a compound channel, the processes of exchanging water and fine sediments between the main channel and floodplains regulate the geomorphological evolution and are crucial for the maintenance of the ecosystem functions of the floodplains. These hydrodynamic and morphodynamic processes depend on variables such as the flow‐depth ratio between the water depth in the main channel and the water depth in the floodplain, the width ratio between the width of the main channel and the width of the floodplain, and the floodplain land cover characterized by the type of roughness. This paper examines, by means of laboratory experiments, how these variables are interlinked and how the deposition of sediments in the compound channel is jointly determined by them. The combination of these compound channel characteristics modulates the production of vertically axised large turbulent vortical structures in the mixing interface. Such vortical structures determine the water mass exchange between the main channel and the floodplain, conditioning in turn the transport of sediment particles conveyed in the water, and, therefore, the resulting overbank sedimentation. The existence and pattern of sedimentation are conditioned by both the hydrodynamic variables (the flow‐depth ratio and the width ratio) and the floodplain land cover simulated in terms of smooth walls, meadow‐type roughness, sparse‐wood‐type roughness, and dense‐wood‐type roughness.
Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation
Authors: Su Xiuhua , Wang Qianqian , Guo Wei , Pei Xiaolei , Niu Qing , Liu Maolan , Liu Yuanyuan , Chen Song , Feng Sizhou , He Yi , Yang Donglin , Zhang Rongli , Ma Qiaoling , Zhai Weihua , Pang Aiming , Wei Jialin , Huang Yong , Luo Yuechen , Han Mingzhe , Feng Xiaoming , Jiang Erlie
Published: October 2019

Accumulating evidence suggests that a reduction in the number of Foxp3+ regulatory T cells (Tregs) contributes to the pathogenesis of acute graft-versus-host disease (aGVHD), which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the precise features and mechanism underlying the defects in Tregs remain largely unknown. In this study, we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution. Tregs from aGVHD patients exhibited multiple defects, including the instability of Foxp3 expression, especially in response to IL-12, impaired suppressor function, decreased migratory capacity, and increased apoptosis. Transcriptional profiling revealed the downregulation of Lkb1, a previously identified critical regulator of murine Treg identity and metabolism, and murine Lkb1-regulated genes in Tregs from aGVHD patients. Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene, respectively. Furthermore, a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity. These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.
Unique structure and function of viral rhodopsins
Authors: Bratanov Dmitry , Kovalev Kirill , Machtens Jan-Philipp , Astashkin Roman , Chizhov Igor , Soloviov Dmytro , Volkov Dmytro , Polovinkin Vitaly , Zabelskii Dmitrii , Mager Thomas , Gushchin Ivan , Rokitskaya Tatyana , Antonenko Yuri , Alekseev Alexey , Shevchenko Vitaly , Yutin Natalya , Rosselli Riccardo , Baeken Christian , Borshchevskiy Valentin , Bourenkov Gleb , Popov Alexander , Balandin Taras , Büldt Georg , Manstein Dietmar J. , Rodriguez-Valera Francisco , Fahlke Christoph , Bamberg Ernst , Koonin Eugene , Gordeliy Valentin
Published: October 2019

Recently, two groups of rhodopsin genes were identified in large double-stranded DNA viruses. The structure and function of viral rhodopsins are unknown. We present functional characterization and high-resolution structure of an Organic Lake Phycodnavirus rhodopsin II (OLPVRII) of group 2. It forms a pentamer, with a symmetrical, bottle-like central channel with the narrow vestibule in the cytoplasmic part covered by a ring of 5 arginines, whereas 5 phenylalanines form a hydrophobic barrier in its exit. The proton donor E42 is placed in the helix B. The structure is unique among the known rhodopsins. Structural and functional data and molecular dynamics suggest that OLPVRII might be a light-gated pentameric ion channel analogous to pentameric ligand-gated ion channels, however, future patch clamp experiments should prove this directly. The data shed light on a fundamentally distinct branch of rhodopsins and may contribute to the understanding of virus-host interactions in ecologically important marine protists.
New elevation data triple estimates of global vulnerability to sea-level rise and coastal flooding
Authors: Kulp Scott A. , Strauss Benjamin H.
Published: October 2019

Most estimates of global mean sea-level rise this century fall below 2 m. This quantity is comparable to the positive vertical bias of the principle digital elevation model (DEM) used to assess global and national population exposures to extreme coastal water levels, NASA’s SRTM. CoastalDEM is a new DEM utilizing neural networks to reduce SRTM error. Here we show – employing CoastalDEM—that 190 M people (150–250 M, 90% CI) currently occupy global land below projected high tide lines for 2100 under low carbon emissions, up from 110 M today, for a median increase of 80 M. These figures triple SRTM-based values. Under high emissions, CoastalDEM indicates up to 630 M people live on land below projected annual flood levels for 2100, and up to 340 M for mid-century, versus roughly 250 M at present. We estimate one billion people now occupy land less than 10 m above current high tide lines, including 230 M below 1 m.
Redox-governed charge doping dictated by interfacial diffusion in two-dimensional materials
Authors: Park Kwanghee , Kang Haneul , Koo Seonghyun , Lee DaeEung , Ryu Sunmin
Published: October 2019

Controlling extra charge carriers is pivotal in manipulating electronic, optical, and magnetic properties of various two-dimensional materials. Nonetheless, the ubiquitous hole doping of two-dimensional materials in the air and acids has been controversial in its mechanistic details. Here we show their common origin is an electrochemical reaction driven by redox couples of oxygen and water molecules. Using real-time photoluminescence imaging of WS2 and Raman spectroscopy of graphene, we capture molecular diffusion through the two-dimensional nanoscopic space between two-dimensional materials and hydrophilic substrates, and show that the latter accommodate water molecules also serving as a hydrating solvent. We also demonstrate that HCl-induced doping is governed by dissolved O2 and pH in accordance with the Nernst equation. The nanoscopic electrochemistry anatomized in this work sets an ambient limit to material properties, which is universal to not only 2D but also other forms of materials.
Foxg specifies sensory neurons in the anterior neural plate border of the ascidian embryo
Authors: Liu Boqi , Satou Yutaka
Published: October 2019

Foxg constitutes a regulatory loop with Fgf8 and plays an important role in the development of anterior placodes and the telencephalon in vertebrate embryos. Ascidians, which belong to Tunicata, the sister group of vertebrates, develop a primitive placode-like structure at the anterior boundary of the neural plate, but lack a clear counterpart of the telencephalon. In this animal, Foxg is expressed in larval palps, which are adhesive organs with sensory neurons. Here, we show that Foxg begins to be expressed in two separate rows of cells within the neural plate boundary region under the control of the MAPK pathway to pattern this region. However, Foxg is not expressed in the brain, and we find no evidence that knockdown of Foxg affects brain formation. Our data suggest that recruitment of Fgf to the downstream of Foxg might have been a critical evolutionary event for the telencephalon in the vertebrate lineage.
Collective excitation of plasmon-coupled Au-nanochain boosts photocatalytic hydrogen evolution of semiconductor
Authors: Yu Guiyang , Qian Jun , Zhang Peng , Zhang Bo , Zhang Wenxiang , Yan Wenfu , Liu Gang
Published: October 2019

Localized surface plasmon resonance (LSPR) offers a valuable opportunity to improve the efficiency of photocatalysts. However, plasmonic enhancement of photoconversion is still limited, as most of metal-semiconductor building blocks depend on LSPR contribution of isolated metal nanoparticles. In this contribution, the concept of collective excitation of embedded metal nanoparticles is demonstrated as an effective strategy to enhance the utilization of plasmonic energy. The contribution of Au-nanochain to the enhancement of photoconversion is 3.5 times increase in comparison with that of conventional isolated Au nanoparticles. Experimental characterization and theoretical simulation show that strongly coupled plasmonic nanostructure of Au-nanochain give rise to highly intensive electromagnetic field. The enhanced strength of electromagnetic field essentially boosts the formation rate of electron-hole pair in semiconductor, and ultimately improves photocatalytic hydrogen evolution activity of semiconductor photocatalysts. The concept of embedded coupled-metal nanostructure represents a promising strategy for the rational design of high-performance photocatalysts.
Conductive 2D metal-organic framework for high-performance cathodes in aqueous rechargeable zinc batteries
Authors: Nam Kwan Woo , Park Sarah S. , dos Reis Roberto , Dravid Vinayak P. , Kim Heejin , Mirkin Chad A. , Stoddart J. Fraser
Published: October 2019

Currently, there is considerable interest in developing advanced rechargeable batteries that boast efficient distribution of electricity and economic feasibility for use in large-scale energy storage systems. Rechargeable aqueous zinc batteries are promising alternatives to lithium-ion batteries in terms of rate performance, cost, and safety. In this investigation, we employ Cu3(HHTP)2, a two-dimensional (2D) conductive metal-organic framework (MOF) with large one-dimensional channels, as a zinc battery cathode. Owing to its unique structure, hydrated Zn2+ ions which are inserted directly into the host structure, Cu3(HHTP)2, allow high diffusion rate and low interfacial resistance which enable the Cu3(HHTP)2 cathode to follow the intercalation pseudocapacitance mechanism. Cu3(HHTP)2 exhibits a high reversible capacity of 228 mAh g−1 at 50 mA g−1. At a high current density of 4000 mA g−1 (~18 C), 75.0% of the initial capacity is maintained after 500 cycles. These results provide key insights into high-performance, 2D conductive MOF designs for battery electrodes.
Carbon and health implications of trade restrictions
Authors: Lin Jintai , Du Mingxi , Chen Lulu , Feng Kuishuang , Liu Yu , V. Martin Randall , Wang Jingxu , Ni Ruijing , Zhao Yu , Kong Hao , Weng Hongjian , Liu Mengyao , van Donkelaar Aaron , Liu Qiuyu , Hubacek Klaus
Published: October 2019

In a globalized economy, production of goods can be disrupted by trade disputes. Yet the resulting impacts on carbon dioxide emissions and ambient particulate matter (PM2.5) related premature mortality are unclear. Here we show that in contrast to a free trade world, with the emission intensity in each sector unchanged, an extremely anti-trade scenario with current tariffs plus an additional 25% tariff on each traded product would reduce the global export volume by 32.5%, gross domestic product by 9.0%, carbon dioxide by 6.3%, and PM2.5-related mortality by 4.1%. The respective impacts would be substantial for the United States, Western Europe and China. A freer trade scenario would increase global carbon dioxide emission and air pollution due to higher levels of production, especially in developing regions with relatively high emission intensities. Global collaborative actions to reduce emission intensities in developing regions could help achieve an economic-environmental win-win state through globalization.
Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone
Authors: Noble Emily E. , Wang Zhuo , Liu Clarissa M. , Davis Elizabeth A. , Suarez Andrea N. , Stein Lauren M. , Tsan Linda , Terrill Sarah J. , Hsu Ted M. , Jung A-Hyun , Raycraft Lauren M. , Hahn Joel D. , Darvas Martin , Cortella Alyssa M. , Schier Lindsey A. , Johnson Alexander W. , Hayes Matthew R. , Holschneider Daniel P. , Kanoski Scott E.
Published: October 2019

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.
Increased yields and biological potency of knob-into-hole-based soluble MHC class II molecules
Authors: Serra Pau , Garabatos Nahir , Singha Santiswarup , Fandos César , Garnica Josep , Solé Patricia , Parras Daniel , Yamanouchi Jun , Blanco Jesús , Tort Meritxell , Ortega Mireia , Yang Yang , Ellestad Kristofor K. , Santamaria Pere
Published: October 2019

Assembly of soluble peptide-major histocompatibility complex class II (pMHCII) monomers into multimeric structures enables the detection of antigen-specific CD4+ T cells in biological samples and, in some configurations, their reprogramming in vivo. Unfortunately, current MHCII-αβ chain heterodimerization strategies are typically associated with low production yields and require the use of foreign affinity tags for purification, precluding therapeutic applications in humans. Here, we show that fusion of peptide-tethered or empty MHCII-αβ chains to the IgG1-Fc mutated to form knob-into-hole structures results in the assembly of highly stable pMHCII monomers. This design enables the expression and rapid purification of challenging pMHCII types at high yields without the need for leucine zippers and purification affinity tags. Importantly, this design increases the antigen-receptor signaling potency of multimerized derivatives useful for therapeutic applications and facilitates the detection and amplification of low-avidity T cell specificities in biological samples using flow cytometry.
Cryo-EM structure of the complete E. coli DNA gyrase nucleoprotein complex
Authors: Vanden Broeck Arnaud , Lotz Christophe , Ortiz Julio , Lamour Valérie
Published: October 2019

DNA gyrase is an essential enzyme involved in the homeostatic control of DNA supercoiling and the target of successful antibacterial compounds. Despite extensive studies, a detailed architecture of the full-length DNA gyrase from the model organism E. coli is still missing. Herein, we report the complete structure of the E. coli DNA gyrase nucleoprotein complex trapped by the antibiotic gepotidacin, using phase-plate single-particle cryo-electron microscopy. Our data unveil the structural and spatial organization of the functional domains, their connections and the position of the conserved GyrA-box motif. The deconvolution of two states of the DNA-binding/cleavage domain provides a better understanding of the allosteric movements of the enzyme complex. The local atomic resolution in the DNA-bound area reaching up to 3.0 Å enables the identification of the antibiotic density. Altogether, this study paves the way for the cryo-EM determination of gyrase complexes with antibiotics and opens perspectives for targeting conformational intermediates.
Computing by modulating spontaneous cortical activity patterns as a mechanism of active visual processing
Authors: Chen Guozhang , Gong Pulin
Published: October 2019

Cortical populations produce complex spatiotemporal activity spontaneously without sensory inputs. However, the fundamental computational roles of such spontaneous activity remain unclear. Here, we propose a new neural computation mechanism for understanding how spontaneous activity is actively involved in cortical processing: Computing by Modulating Spontaneous Activity (CMSA). Using biophysically plausible circuit models, we demonstrate that spontaneous activity patterns with dynamical properties, as found in empirical observations, are modulated or redistributed by external stimuli to give rise to neural responses. We find that this CMSA mechanism of generating neural responses provides profound computational advantages, such as actively speeding up cortical processing. We further reveal that the CMSA mechanism provides a unifying explanation for many experimental findings at both the single-neuron and circuit levels, and that CMSA in response to natural stimuli such as face images is the underlying neurophysiological mechanism of perceptual “bubbles” as found in psychophysical studies.
Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
Authors: Frega Monica , Linda Katrin , Keller Jason M. , Gümüş-Akay Güvem , Mossink Britt , van Rhijn Jon-Ruben , Negwer Moritz , Klein Gunnewiek Teun , Foreman Katharina , Kompier Nine , Schoenmaker Chantal , van den Akker Willem , van der Werf Ilse , Oudakker Astrid , Zhou Huiqing , Kleefstra Tjitske , Schubert Dirk , van Bokhoven Hans , Nadif Kasri Nael
Published: October 2019

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS.
If we build it they will come: targeting the immune response to breast cancer
Authors: Gatti-Mays Margaret E. , Balko Justin M. , Gameiro Sofia R. , Bear Harry D. , Prabhakaran Sangeetha , Fukui Jami , Disis Mary L. , Nanda Rita , Gulley James L. , Kalinsky Kevin , Abdul Sater Houssein , Sparano Joseph A. , Cescon David , Page David B. , McArthur Heather , Adams Sylvia , Mittendorf Elizabeth A.
Published: October 2019

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.
Spatial high-resolution socio-energetic data for municipal energy system analyses
Authors: Weinand Jann M. , McKenna Russell , Mainzer Kai
Published: October 2019

In the context of the energy transition, municipalities are increasingly attempting to exploit renewable energies. Socio-energetic data are required as input for municipal energy system analyses. This Data Descriptor provides a compilation of 40 indicators for all 11,131 German municipalities. In addition to census data such as population density, mobility data such as the number of vehicles and data on the potential of renewables such as wind energy are included. Most of the data set also contains public data, the allocation of which to municipalities was an extensive task. The data set can support in addressing a wide range of energy-related research challenges. A municipality typology has already been developed with the data, and the resulting municipality grouping is also included in the data set.
Author Correction: Preparation from a revisited wet chemical route of phase-pure, monocrystalline and SHG-efficient BiFeO3 nanoparticles for harmonic bio-imaging
Authors: Clarke Gareth , Rogov Andrii , McCarthy Sarah , Bonacina Luigi , Gun’ko Yurii , Galez Christine , Le Dantec Ronan , Volkov Yuri , Mugnier Yannick , Prina-Mello Adriele
Published: October 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Author Correction: Effects of sampling effort on biodiversity patterns estimated from environmental DNA metabarcoding surveys
Authors: Grey Erin K. , Bernatchez Louis , Cassey Phillip , Deiner Kristy , Deveney Marty , Howland Kimberly L. , Lacoursière-Roussel Anaïs , Leong Sandric Chee Yew , Li Yiyuan , Olds Brett , Pfrender Michael E. , Prowse Thomas A. A. , Renshaw Mark A. , Lodge David M.
Published: October 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Diabetes status affects long-term changes in coronal caries - The SHIP Study
Authors: Schmolinsky Julia , Kocher Thomas , Rathmann Wolfgang , Völzke Henry , Pink Christiane , Holtfreter Birte
Published: October 2019

We estimated effects of diabetes mellitus and metabolic control on long-term change in coronal caries and restorative status using 11-year-follow-up data from the population-based Study of Health in Pomerania. Data of 3731 participants with baseline and 5- and 11-year follow-up information were included. Diabetes was defined via self-reported physician´s diagnosis or intake of glucose-lowering drugs or hemoglobin A1c (HbA1c) ≥6.5% or fasting blood glucose levels ≥11.1 mmol/l. The diabetes status was defined as no diabetes (HbA1c < 6.5% or non-fasting blood glucose <11.1 mmol/l), subjects with known or undetected diabetes mellitus and HbA1c ≤ 7% (well-controlled diabetes), and subjects with known or undetected diabetes mellitus and HbA1c > 7% (poorly-controlled diabetes). The caries status was clinically assessed using the half-mouth method and the Decayed Missing Filled Surfaces (DMFS) index and its component scores were determined. Covariate-adjusted linear mixed models were evaluated. Rates in change in DMFS were significantly higher in subjects with poorly-controlled diabetes compared to subjects without diabetes. Subjects with poorly- and well-controlled diabetes had significantly higher rates in change in Missing Surfaces (MS) compared to subjects without diabetes. For the DFS, rates in change were significantly lower for subjects with well-controlled diabetes and higher for subjects with poorly-controlled diabetes as compared to subjects without diabetes. Concordantly, all rates in change increased proportional to HbA1c levels. Effects were even more pronounced in subjects with diabetes duration of ≥5 years. Subjects with poorly-controlled diabetes are at higher risk for caries progression compared to subjects without diabetes, especially in case of longer disease duration.
Low Intensity Focused Ultrasound (LOFU)-mediated Acoustic Immune Priming and Ablative Radiation Therapy for in situ Tumor Vaccines
Authors: Skalina Karin A. , Singh Saurabh , Chavez Claudia Gutierrez , Macian Fernando , Guha Chandan
Published: October 2019

Focal ablative therapies have been primarily used for local tumor ablation. However, they often fail to impact systemic disease. Here we propose the use of low intensity focused ultrasound (LOFU), a noninvasive, nontoxic, conformal therapy, to deliver acoustic stress to the tumor for immune priming. We demonstrate that LOFU significantly induces expression and cell surface localization of heat shock proteins in murine breast (4T1) and prostate adenocarcinoma (TPSA23) cancer cell lines. In vivo LOFU followed by ablative radiation therapy (RT) results in primary tumor cure, upregulation of a cytotoxic immune response and induction of immunological memory by inhibiting secondary tumor growth upon re-challenge with tumor cells. We, therefore, describe a regimen of a combination therapy with noninvasive, acoustic immune priming and ablative radiation therapy to generate an in situ tumor vaccine, induce CD8+ T cells against tumor-associated antigens and provide a viable oncologic treatment option for solid tumors.
The Tibetan Plateau Uplift is Crucial for Eastward Propagation of Madden-Julian Oscillation
Authors: Yang Young-Min , Lee June-Yi , Wang Bin
Published: October 2019

The Tibetan Plateau (TP) and Himalayas have been treated as an essential external factor in shaping Asian monsoon and mid-latitude atmospheric circulation. In this study we perform numerical experiments with different uplift altitudes using the Nanjing University of Information Science and Technology Earth System Model to examine potential impacts of uplift of the TP and Himalayas on eastward propagation of the MJO and the associated mechanisms. Analysis of experimental results with dynamics-based MJO diagnostics indicates two potential mechanisms. First, the uplift considerably enhances low-level mean westerlies in the Indian Ocean and convection in the Maritime Continent, which in turn strengthens boundary layer moisture convergence (BLMC) to the east of the MJO convective center. The increased BLMC reinforces upward transport of moisture and heat from BL to free atmosphere and increases lower tropospheric diabatic heating by shallow and congestus clouds ahead of the MJO center, enhancing the Kelvin-Rossby wave feedback. Second, the uplift increases upper tropospheric mean easterlies and stratiform heating at the west of the MJO center, which contributes to eastward propagation of MJO by generating positive moist static energy at the east of MJO center. This study will contribute to a better understanding of the origin of the MJO and improvement in simulation of MJO propagation.
Colorimetric Assay Reports on Acyl Carrier Protein Interactions
Authors: Acheampong Kofi K. , Kokona Bashkim , Braun Gabriel A. , Jacobsen Danielle R. , Johnson Karl A. , Charkoudian Louise K.
Published: October 2019

The ability to produce new molecules of potential pharmaceutical relevance via combinatorial biosynthesis hinges on improving our understanding of acyl-carrier protein (ACP)-protein interactions. However, the weak and transient nature of these interactions makes them difficult to study using traditional spectroscopic approaches. Herein we report that converting the terminal thiol of the E. coli ACP 4′-phosphopantetheine arm into a mixed disulfide with 2-nitro-5-thiobenzoate ion (TNB−) activates this site to form a selective covalent cross-link with the active site cysteine of a cognate ketoacyl synthase (KS). The concomitant release of TNB2−, which absorbs at 412 nm, provides a visual and quantitative measure of mechanistically relevant ACP-KS interactions. The colorimetric assay can propel the engineering of biosynthetic routes to novel chemical diversity by providing a high-throughput screen for functional hybrid ACP-KS partnerships as well as the discovery of novel antimicrobial agents by enabling the rapid identification of small molecule inhibitors of ACP-KS interactions.
The neuronal ceroid lipofuscinosis protein Cln7 functions in the postsynaptic cell to regulate synapse development
Authors: Connolly Kyle J. , O’Hare Megan B. , Mohammed Alamin , Aitchison Katelyn M. , Anthoney Niki C. , Taylor Matthew J. , Stewart Bryan A. , Tuxworth Richard I. , Tear Guy
Published: October 2019

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Cln7 is conserved across species suggesting a common function. Here we demonstrate that Cln7 is required for the normal growth of synapses at the Drosophila larval neuromuscular junction. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication necessary for normal synapse development.
Low Power, CMOS-MoS2 Memtransistor based Neuromorphic Hybrid Architecture for Wake-Up Systems
Authors: Gupta Sarthak , Kumar Pratik , Paul Tathagata , van Schaik André , Ghosh Arindam , Thakur Chetan Singh
Published: October 2019

Neuromorphic architectures have become essential building blocks for next-generation computational systems, where intelligence is embedded directly onto low power, small area, and computationally efficient hardware devices. In such devices, realization of neural algorithms requires storage of weights in digital memories, which is a bottleneck in terms of power and area. We hereby propose a biologically inspired low power, hybrid architectural framework for wake-up systems. This architecture utilizes our novel high-performance, ultra-low power molybdenum disulphide (MoS2) based two-dimensional synaptic memtransistor as an analogue memory. Furthermore, it exploits random device mismatches to implement the population coding scheme. Power consumption per CMOS neuron block was found to be 3 nw in the 65 nm process technology, while the energy consumption per cycle was 0.3 pJ for potentiation and 20 pJ for depression cycles of the synaptic device. The proposed framework was demonstrated for classification and regression tasks, using both off-chip and simplified on-chip sign-based learning techniques.
Late-Onset Sepsis as a Risk Factor for Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants: A Nationwide Cohort Study
Authors: Jung Euiseok , Lee Byong Sop
Published: October 2019

This study aimed to determine the effect of late-onset sepsis (LOS) on the development of bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. A prospective cohort study was performed using data collected from 64 centres registered in the Korean national registry. LOS was defined as a positive blood culture and antibiotics treatment after 72 hours of life and prior to 36 weeks postmenstrual age (PMA). Data on the causative organisms were collected and analysed for respiratory outcomes. Among the 1,434 ELBW infants who survived to 36 weeks PMA, 481 (34%) developed LOS caused by bacteria (n = 405), fungi (n = 28), or both (n = 48). The incidence of BPD was significantly associated with LOS in both the entire cohort and the propensity score-matched cohort. Two or more LOS episodes were a risk factor for BPD. The impact of multiple episodes of LOS on BPD was prominent in infants who received mechanical ventilation for two weeks or less. The estimated odds ratios for BPD and severe BPD were greater with fungal LOS than with bacterial LOS. In conclusion, LOS, particularly complicated by multiple episodes and/or fungi, was a risk factor for BPD in ELBW infants.
Predictive validation of qualitative fibrosis staging in patients with chronic hepatitis B on antiviral therapy
Authors: Lee Hye Won , Na Kiyong , Kim Seung Up , Kim Beom Kyung , Park Jun Yong , Nahm Ji Hae , Lee Jung Il , Kim Do Young , Ahn Sang Hoon , Han Kwang-Hyub , Park Young Nyun
Published: October 2019

The fibrosis in chronic hepatitis shows dynamic changes during antiviral therapy (AVT). We investigated whether P-I-R (progressive vs. indeterminate vs. regressive) staging is predictive of hepatocellular carcinoma (HCC) recurrence in patients with chronic hepatitis B (CHB) taking AVT who underwent resection. Patients with CHB-related HCC who underwent curative resection between 2004 and 2017 and had received ≥2 years AVT at the time of resection were eligible. Two pathologists performed P-I-R staging. In total, 104 patients with CHB-related HCC were enrolled. The mean age of the study population was 56.3 years. The mean duration of AVT at the time of resection was 62.6 months. During the follow-up period (mean, 45.5 months), 20 (19.2%) and 14 (13.5%) patients developed early and late recurrence of HCC, respectively. The cumulative incidence of late recurrence was significantly lower in patients with regressive patterns than in those with indeterminate and progressive patterns according to P-I-R staging (P = 0.015, log-rank test), although the cumulative incidence of overall recurrence according to P-I-R staging was similar. Hepatitis B virus DNA levels (hazard ratio [HR] = 3.200, P = 0.020) and the regressive P-I-R staging pattern (HR = 0.127, P = 0.047) independently predicted the risk of late recurrence. One-time assessment of the P-I-R staging at the time of curative resection in patients with CHB-related HCC receiving AVT independently predicted late HCC recurrence. Therefore, qualitative fibrosis assessment by P-I-R staging might be useful in predicting the outcomes of patients with CHB undergoing AVT.
Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells
Authors: Ozawa Shoichi , Tsujimoto Masayuki , Uchiyama Hitoshi , Ito Natsuko , Morishita Satoe , Yamamoto Mizuki , Irie Ryosuke , Sakashita Tohko , Tachiki Hidehisa , Furukubo Taku , Izumi Satoshi , Yamakawa Tomoyuki , Minegaki Tetsuya , Nishiguchi Kohshi
Published: October 2019

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.
Repeated buffered acidic saline infusion in the human masseter muscle as a putative experimental pain model
Authors: Louca Jounger Sofia , Eriksson Niklas , Lindskog Helena , Oscarsson Anna , Simonsson Vivian , Ernberg Malin , Christidis Nikolaos
Published: October 2019

This study investigated if repeated buffered acidic saline infusions into the masseter muscles induced muscle pain and mechanical sensitization. Fourteen healthy men participated in this double-blind, randomized, and placebo-controlled study. Two repeated infusions (day 1 and 3) were given in the masseter muscles with either a buffered acidic saline solution (pH 5.2) or an isotonic saline solution (pH 6) as control. After 10 days of wash-out, the experiment was repeated with the other substance. Pressure pain thresholds (PPT), pain intensity, maximum unassisted mouth opening (MUO), and pain drawings were assessed before, directly following, and after each infusion at 5, 15, and 30 min and on day 4 and 7. Fatigue and pain intensity were assessed after a one-minute chewing test 30 min after infusions and day 4 and 7. Acidic saline induced higher pain intensity than control day 3 up to 5 min after infusions, but did not affect PPT. The chewing test did not evoke higher fatigue during chewing or MUO or after acidic saline infusion compared to control. Repeated acidic saline infusions in the masseter muscles induced a short-lasting muscle pain without mechanical hyperalgesia or functional pain. Hence, this model might not be superior to already existing experimental muscle pain models.
Targeted deletion of NFAT-Interacting-Protein-(NIP) 45 resolves experimental asthma by inhibiting Innate Lymphoid Cells group 2 (ILC2)
Authors: Koch Sonja , Knipfer Lisa , Kölle Julia , Mirzakhani Hooman , Graser Anna , Zimmermann Theodor , Kiefer Alexander , Melichar Volker O. , Rascher Wolfgang , Papadopoulos Nikolaos G. , Rieker Ralf J. , Raby Benjamin A. , Weiss Scott T. , Wirtz Stefan , Finotto Susetta
Published: October 2019

Here we investigated the role of NFAT-interacting protein (NIP)-45, an Interleukin (IL)-4 inducing Transcription Factor, and its impact on the differentiation of Group 2 Innate -Lymphoid -Cells (ILC2s) in the pathogenesis of asthma. NIP45, a transcription factor regulating NFATc1 activity, mRNA was found to be induced in the Peripheral Blood mononuclear cells (PMBCs) of asthmatic pre-school children with allergies and in the peripheral blood CD4+ T cells from adult asthmatic patients. In PBMCs of asthmatic and control children, NIP45 mRNA directly correlated with NFATc1 but not with T-bet. Targeted deletion of NIP45 in mice resulted in a protective phenotype in experimental asthma with reduced airway mucus production, airway hyperresponsiveness and eosinophils. This phenotype was reversed by intranasal delivery of recombinant r-IL-33. Consistently, ILC2s and not GATA3+ CD4+ T-cells were decreased in the lungs of asthmatic NIP45−/− mice. Reduced cell number spleen ILC2s could be differentiated from NIP45−/− as compared to wild-type mice after in vivo injection of a microcircle-DNA vector expressing IL-25 and decreased cytokines and ILC2 markers in ILC2 differentiated from the bone marrow of NIP45−/− mice. NIP45 thus emerges as a new therapeutic target for the resolution of the airway pathology, down-regulation of ILC2s and mucus production in asthma.
Monotherapy versus combination therapy for multidrug-resistant Gram-negative infections: Systematic Review and Meta-Analysis
Authors: Schmid Adrian , Wolfensberger Aline , Nemeth Johannes , Schreiber Peter W. , Sax Hugo , Kuster Stefan P.
Published: October 2019

Infections caused by carbapenemase-producing, multidrug-resistant (MDR), or extensively drug-resistant (XDR) Gram-negative bacteria constitute a major therapeutic challenge. Whether combination antibiotic therapy is superior to monotherapy remains unknown. In this systematic review and meta-analysis OVID MEDLINE, EMBASE, PubMed, The Cochrane Library, and Scopus databases were searched for randomized controlled trials (RCTs) and observational studies published by December 2016 comparing mono- with combination antibiotic therapy for infections with carbapenemase-producing, MDR, or XDR Gram-negative bacteria. Mortality and clinical cure rates served as primary and secondary outcome measures, respectively. Of 8847 initially identified studies, 53 studies – covering pneumonia (n = 10 studies), blood stream (n = 15), osteoarticular (n = 1), and mixed infections (n = 27) - were included. 41% (n = 1848) of patients underwent monotherapy, and 59% (n = 2666) combination therapy. In case series/cohort studies (n = 45) mortality was lower with combination- vs. monotherapy (RR 0.83, CI 0.73–0.93, p = 0.002, I2 = 24%). Subgroup analysis revealed lower mortality with combination therapy with at least two in-vitro active antibiotics, in blood stream infections, and carbapenemase-producing Enterobacteriaceae. No mortality difference was seen in case-control studies (n = 6) and RCTs (n = 2). Cure rates did not differ regardless of study type. The two included RCTs had a high and unknown risk of bias, respectively. 16.7% (1/6) of case-control studies and 37.8% (17/45) of cases series/cohort studies were of good quality, whereas quality was poor in the remaining studies. In conclusion, combination antimicrobial therapy of multidrug-resistant Gram-negative bacteria appears to be superior to monotherapy with regard to mortality.
Diverging roles of the anterior insula in trauma-exposed individuals vulnerable or resilient to posttraumatic stress disorder
Authors: Jeong Hyeonseok , Chung Yong-An , Ma Jiyoung , Kim Jungyoon , Hong Gahae , Oh Jin Kyoung , Kim Myeongju , Ha Eunji , Hong Haejin , Yoon Sujung , Lyoo In Kyoon
Published: October 2019

Distinct brain alterations in response to traumatic events may render trauma-exposed individuals either resilient or vulnerable to posttraumatic stress disorder (PTSD). This study compared regional cerebral metabolic rate of glucose (rCMRglu) among trauma-exposed individuals with current PTSD (PTSD group, n = 61), those without current PTSD (Resilience/Recovery group, n = 26), and trauma-unexposed controls (Control group, n = 54). All participants underwent brain [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. Voxel-wise group differences in rCMRglu among the three groups were evaluated. Associations between rCMRglu and both PTSD severity and resilience were examined. The rCMRglu in the right anterior insula and adjacent prefrontal and striatal areas was lower in the PTSD group, while higher in the Resilience/Recovery group, compared to the Control group. In addition, the lower glucose metabolism of these areas was associated with higher severity and less improvement in PTSD symptoms in the PTSD group, while the higher levels of rCMRglu were correlated with stronger resilience in the Resilience/Recovery group. This study suggests distinct roles of the anterior insula in response to trauma between the PTSD and Resilience/Recovery groups. Heightened rCMRglu in the anterior insular regions may reflect an underlying mechanism of resilience against traumatic stress, while reduced rCMRglu may indicate vulnerability to PTSD.
Radiation-induced malignancies after intensity-modulated versus conventional mediastinal radiotherapy in a small animal model
Authors: Gomarteli Kaga , Fleckenstein Jens , Kirschner Stefanie , Bobu Vladimir , Brockmann Marc A. , Henzler Thomas , Meyer Mathias , Riffel Philipp , Schönberg Stefan O. , Veldwijk Marlon R. , Kränzlin Bettina , Hoerner Christian , Glatting Gerhard , Wenz Frederik , Herskind Carsten , Giordano Frank A.
Published: October 2019

A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3 × 5 or 3 × 8 Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n = 15/group, ntotal = 90). Tumors were assigned to volumes receiving 90–107%, 50–90%, 5–50%, and <5% of the target dose and characterized by histology and loss-of-heterozygosity (LOH). Irradiated rats predominantly developed lymphomas and sarcomas in areas receiving 50–107% (n = 26) rather than 5–50% (n = 7) of the target dose. Latency was significantly shortened only after 3 × 8 Gy vs. controls (p < 0.0001). The frequency (14/28 vs. 19/29; p = 0.29) and latency (218 vs. 189 days; p = 0.17) of radiation-associated tumors were similar after VMAT vs. AP/PA. LOH was strongly associated with sarcoma but not with treatment. The results do not support the hypothesis that IMRT increases the risk of second cancer. Thus the current practice of withholding dose-sparing IMRT from young patients may need to be re-evaluated.