bluuebunny/crossref_metadata_2025 huggingface dataset:
The Time Evolution of Optical Lightning Flashes
Authors: Peterson Michael , Rudlosky Scott
Published: December 2018

The composition and time evolution of lightning are examined using the Lighting Imaging Sensor (LIS). Frame‐by‐frame optical lightning measurements are clustered into features whose radiant energy, horizontal footprint, and timing may be analyzed statistically. A LIS series feature is used to describe distinct periods of near continuous illumination that persists over multiple LIS frames. Series are integrated into the LIS clustering hierarchy between the group and flash level. An average series illuminates 40% of the flash footprint while accounting for 20% of the flash radiance, and just 1% of the flash duration. LIS flashes typically contain optical emissions that are exceptionally radiant and may persist over multiple frames. Series features cluster these bright optical pulses, allowing their number and time separation to be quantified in each flash. This optical multiplicity averages 1.7 for flashes with at least one particularly radiant group. Multigroup series most often occur early in the flash duration with 13% to 18% at first light. Series are typically separated by 100 ms or more in multiseries flashes. Bright series, by contrast, typically occur in rapid succession, with at most a few dozen milliseconds between them. Because series are optical features, they may result from any physical process that produces strong optical emissions. The statistics presented herein support the idea that series may originate from multiple physical processes.
Observations of Lower Tropospheric Water Vapor Structures in GOES‐16 ABI Imagery
Authors: Grasso Lewis , Bikos Dan , Miller Steven
Published: December 2018

During the afternoon of 16 April 2017 over Durango, Mexico, Geostationary Operational Environmental Satellite (GOES)‐16 Advanced Baseline Imager (ABI) imagery near 1.38 and 7.34 μm exhibited nonstationary banded features. Alternating patterns of bright (dry) and dark (moist) bands were evident in images of 1.38‐μm reflectance, while corresponding warm (dry) and cool (moist) bands were evident in images of 7.34‐μm brightness temperatures. Based on observations, ambient southwesterly flow across the region is hypothesized to have channeled water vapor through major valleys over western Durango, followed by terrain lifting of water vapor over the plateau of central Durango. Due to lifting, moist bands appeared relatively cool in imagery near 7.34 μm. Similar bright and dark banded patterns were also evident in ABI imagery over Chihuahua, Mexico, on 8 May 2017. During the afternoon over Chihuahua, broken linear segments of cumulus formed within moist portions of the bands. Imagery from the 12.3‐ to 10.3‐μm split window difference also supported the presence of moist bands. In the 8 May 2017 case, the banded features are hypothesized to be the result of horizontal convective rolls. Observations suggested that dark (moist) bands in imagery near 1.38 μm corresponded to the rising branch of horizontal rolls. Due to vertical motion, broken linear segments of cloud streets formed within the rolls. One consequence of newly identified features of the clear‐sky water vapor field indicated the importance of new ABI measurements to aid forecasters in their interpretation of complex mesoscale dynamics.
Results of First-Round of Surveillance in Individuals at High-Risk of Pancreatic Cancer from the AISP (Italian Association for the Study of the Pancreas) Registry
Authors: Paiella Salvatore , Capurso Gabriele , Cavestro Giulia Martina , Butturini Giovanni , Pezzilli Raffaele , Salvia Roberto , Signoretti Marianna , Crippa Stefano , Carrara Silvia , Frigerio Isabella , Bassi Claudio , Falconi Massimo , Iannicelli Elsa , Giardino Alessandro , Mannucci Alessandro , Laghi Andrea , Laghi Luigi , Frulloni Luca , Zerbi Alessandro ,   on behalf of the Italian Association for the Study of the Pancreas (AISP)
Published: December 2018

INTRODUCTION:

Surveillance programs on high-risk individuals (HRIs) can detect pre-malignant lesions or early pancreatic cancer (PC). We report the results of the first screening round of the Italian multicenter program supported by the Italian Association for the study of the Pancreas (AISP).

METHODS:

The multicenter surveillance program included asymptomatic HRIs with familial (FPC) or genetic frailty (GS: BRCA1/2, p16/CDKN2A, STK11/LKB1or PRSS1, mutated genes) predisposition to PC. The surveillance program included at least an annual magnetic resonance cholangio pancreatography (MRCP). Endoscopic ultrasound (EUS) was proposed to patients who refused or could not be submitted to MRCP.

RESULTS:

One-hundreds eighty-seven HRIs underwent a first-round screening examination with MRCP (174; 93.1%) or EUS (13; 6.9%) from September 2015 to March 2018.The mean age was 51 years (range 21–80).One-hundreds sixty-five (88.2%) FPC and 22 (11.8%) GF HRIs were included. MRCP detected 28 (14.9%) presumed branch-duct intraductal papillary mucinous neoplasms (IPMN), 1 invasive carcinoma/IPMN and one low-grade mixed-type IPMN, respectively. EUS detected 4 PC (2.1%): 1 was resected, 1 was found locally advanced intraoperatively, and 2 were metastatic. Age > 50 (OR 3.3, 95%CI 1.4–8), smoking habit (OR 2.8, 95%CI 1.1–7.5), and having > 2 relatives with PC (OR 2.7, 95%CI 1.1–6.4) were independently associated with detection of pre-malignant and malignant lesions. The diagnostic yield for MRCP/EUS was 24% for cystic lesions. The overall rate of surgery was 2.6% with nil mortality.

DISCUSSION:

The rate of malignancies found in this cohort was high (2.6%). According to the International Cancer of the Pancreas Screening Consortium the screening goal achievement was high (1%).
Overall survival of transplant eligible patients with newly diagnosed multiple myeloma: comparative effectiveness analysis of modern induction regimens on outcome
Authors: Paquin Ashley R. , Kumar Shaji K. , Buadi Francis K. , Gertz Morie A. , Lacy Martha Q. , Dispenzieri Angela , Dingli David , Hwa Lisa , Fonder Amie , Hobbs Miriam , Hayman Suzanne R. , Zeldenrust Steven R. , Lust John A. , Russell Stephen J. , Leung Nelson , Kapoor Prashant , Go Ronald S. , Lin Yi , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma , Kyle Robert A. , Rajkumar S. Vincent
Published: December 2018

Overall survival (OS) of multiple myeloma has improved remarkably over time, with the recent Intergroupe Francophone du Myelome (IFM) 2009 randomized trial reporting a 4-year OS rate of approximately 82% in patients receiving modern therapy. However, survival estimates from clinical trials may overestimate outcomes seen in clinical practice even with the adjustment for age and other key characteristics. The purpose of this study was to determine the OS of myeloma patients seen in routine clinical practice who resembled the cohort studied in the IFM 2009 trial. A second goal was to conduct a brief comparative effectiveness analysis of bortezomib, lenalidomide, dexamethasone, and other major induction regimens used during the study period. We studied all patients with myeloma 65 years of age and younger, seen at the Mayo Clinic between January 1, 2010 and August 31, 2015, who had a stem cell harvest performed within 12 months of initial diagnosis. Patients with baseline serum creatinine >2 mg/dL were excluded. Five hundred and eighteen patients were studied. The 4-year OS rate was 82.3%, comparable to results achieved in the contemporaneous IFM randomized trial. The 4-year OS rates for standard and high-risk myeloma were 86.3% and 68.2%, respectively.
CCN3 and DLL1 co-regulate osteogenic differentiation of mouse embryonic fibroblasts in a Hey1-dependent manner
Authors: Su Xin , Wei Yalin , Cao Junjie , Wu Xiulin , Mou Daiyong , Luo Jinyong , Li Aifang , Zuo Guo-Wei , Tang Min
Published: December 2018

Notch signaling pathway is one of the most important pathways to regulate intercellular signal transduction and is crucial in the regulation of bone regeneration. Nephroblastoma overexpressed (NOV or CCN3) serves as a non-canonical secreted ligand of Notch signaling pathway and its role in the process of osteogenic differentiation of mesenchymal stem cells (MSCs) was undefined. Here we conducted a comprehensive study on this issue. In vivo and in vitro studies have shown that CCN3 significantly inhibited the early and late osteogenic differentiation of mouse embryonic fibroblasts (MEFs), the expression of osteogenesis-related factors, and the subcutaneous ectopic osteogenesis of MEFs in nude mice. In mechanism studies, we found that CCN3 significantly inhibited the expression of BMP9 and the activation of BMP/Smad and BMP/MAPK signaling pathways. There was also a mutual inhibition between CCN3 and DLL1, one of the classic membrane protein ligands of Notch signaling pathway. Additionally, we further found that Hey1, the target gene shared by BMP and Notch signaling pathways, partially reversed the inhibitory effect of CCN3 on osteoblastic differentiation of MEFs. In summary, our findings suggested that CCN3 significantly inhibited the osteogenic differentiation of MEFs. The inhibitory effect of CCN3 was mainly through the inhibition of BMP signaling and the mutual inhibition with DLL1, so as to inhibit the expression of Hey1, the target gene shared by BMP and Notch signaling pathways.
Therapeutic effect of hepatocyte growth factor-overexpressing bone marrow-derived mesenchymal stem cells on CCl4-induced hepatocirrhosis.
Authors: Zhang Yichi , Li Ruini , Rong Weiwei , Han Mingzi , Cui Chenghu , Feng Zhenning , Sun Xiaoli , Jin Shizhu
Published: December 2018

Hepatocirrhosis is one of the most severe complications of chronic hepatic disease in terms of medical intervention, and the available therapies are limited and not very successful. In this study, bone marrow-derived mesenchymal stem cells (BM-MSCs) from host rats were transduced with an adenoviral vector labelled with green fluorescent protein (EGFP) to overexpress hepatocyte growth factor (HGF). The therapeutic effect of these modified stem cells (HGF-BM-MSC group) transplanted intravenously into hepatocirrhosis model rats treated with CCl4 was evaluated using serological, biochemical and histological approaches. We compared the rats in the HGF-BM-MSC group with those in the other groups (rats treated with BM-MSCs, rats treated with HGF and untreated rats (Controls)) in detail. The localisation of EGFP-tagged BM-MSCs in the injured liver was evaluated using a microscope, and the cells co-expressed hepatocyte nuclear factor 4α, albumin and cytokeratin 18. After treatment for 4 weeks, the HGF-BM-MSC, BM-MSC and HGF groups exhibited increased protein and mRNA levels of hepatocyte nuclear factor 4α, albumin and cytokeratin 18, but decreased levels of aspartate aminotransferase, alanine aminotransferase and total bilirubin. These findings indicate that BM-MSC transplantation and HGF application have great potential for the treatment of hepatocirrhosis.
Polymer morphology and interfacial charge transfer dominate over energy-dependent scattering in organic-inorganic thermoelectrics
Authors: Kumar Pawan , Zaia Edmond W. , Yildirim Erol , Repaka D. V. Maheswar , Yang Shuo-Wang , Urban Jeffrey J. , Hippalgaonkar Kedar
Published: December 2018

Hybrid (organic-inorganic) materials have emerged as a promising class of thermoelectric materials, achieving power factors (S2σ) exceeding those of either constituent. The mechanism of this enhancement is still under debate, and pinpointing the underlying physics has proven difficult. In this work, we combine transport measurements with theoretical simulations and first principles calculations on a prototypical PEDOT:PSS-Te(Cux) nanowire hybrid material system to understand the effect of templating and charge redistribution on the thermoelectric performance. Further, we apply the recently developed Kang-Snyder charge transport model to show that scattering of holes in the hybrid system, defined by the energy-dependent scattering parameter, remains the same as in the host polymer matrix; performance is instead dictated by polymer morphology manifested in an energy-independent transport coefficient. We build upon this language to explain thermoelectric behavior in a variety of PEDOT and P3HT based hybrids acting as a guide for future work in multiphase materials.
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia
Authors: Tron Adriana E. , Belmonte Matthew A. , Adam Ammar , Aquila Brian M. , Boise Lawrence H. , Chiarparin Elisabetta , Cidado Justin , Embrey Kevin J. , Gangl Eric , Gibbons Francis D. , Gregory Gareth P. , Hargreaves David , Hendricks J. Adam , Johannes Jeffrey W. , Johnstone Ricky W. , Kazmirski Steven L. , Kettle Jason G. , Lamb Michelle L. , Matulis Shannon M. , Nooka Ajay K. , Packer Martin J. , Peng Bo , Rawlins Philip B. , Robbins Daniel W. , Schuller Alwin G. , Su Nancy , Yang Wenzhan , Ye Qing , Zheng Xiaolan , Secrist J. Paul , Clark Edwin A. , Wilson David M. , Fawell Stephen E. , Hird Alexander W.
Published: December 2018

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
Escherichia coli can survive stress by noisy growth modulation
Authors: Patange Om , Schwall Christian , Jones Matt , Villava Casandra , Griffith Douglas A. , Phillips Andrew , Locke James C. W.
Published: December 2018

Gene expression can be noisy, as can the growth of single cells. Such cell-to-cell variation has been implicated in survival strategies for bacterial populations. However, it remains unclear how single cells couple gene expression with growth to implement these strategies. Here, we show how noisy expression of a key stress-response regulator, RpoS, allows E. coli to modulate its growth dynamics to survive future adverse environments. We reveal a dynamic positive feedback loop between RpoS and growth rate that produces multi-generation RpoS pulses. We do so experimentally using single-cell, time-lapse microscopy and microfluidics and theoretically with a stochastic model. Next, we demonstrate that E. coli prepares for sudden stress by entering prolonged periods of slow growth mediated by RpoS. This dynamic phenotype is captured by the RpoS-growth feedback model. Our synthesis of noisy gene expression, growth, and survival paves the way for further exploration of functional phenotypic variability.
JunB regulates homeostasis and suppressive functions of effector regulatory T cells
Authors: Koizumi Shin-ichi , Sasaki Daiki , Hsieh Tsung-Han , Taira Naoyuki , Arakaki Nana , Yamasaki Shinichi , Wang Ke , Sarkar Shukla , Shirahata Hiroki , Miyagi Mio , Ishikawa Hiroki
Published: December 2018

Foxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.
Differentiation of primate primordial germ cell-like cells following transplantation into the adult gonadal niche
Authors: Sosa Enrique , Chen Di , Rojas Ernesto J. , Hennebold Jon D. , Peters Karen A. , Wu Zhuang , Lam Truong N. , Mitchell Jennifer M. , Sukhwani Meena , Tailor Ramesh C. , Meistrich Marvin L. , Orwig Kyle E. , Shetty Gunapala , Clark Amander T.
Published: December 2018

A major challenge in stem cell differentiation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo. In the mouse, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and to the birth of offspring. Here we report the use of xenotransplantation (monkey to mouse) and homologous transplantation (monkey to monkey) to validate our in vitro protocol for differentiating male rhesus (r) macaque PGCLCs (rPGCLCs) from induced pluripotent stem cells (riPSCs). Specifically, transplantation of aggregates containing rPGCLCs into mouse and nonhuman primate testicles overcomes a major bottleneck in rPGCLC differentiation. These findings suggest that immature rPGCLCs once transplanted into an adult gonadal niche commit to differentiate towards late rPGCs that initiate epigenetic reprogramming but do not complete the conversion into ENO2-positive spermatogonia.
Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis
Authors: Martínez-Fábregas Jonathan , Prescott Alan , van Kasteren Sander , Pedrioli Deena Leslie , McLean Irwin , Moles Anna , Reinheckel Thomas , Poli Valeria , Watts Colin
Published: December 2018

Diverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under ‘fed’ rather than ‘starved’ conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.
Stabilization of cytokine mRNAs in iNKT cells requires the serine-threonine kinase IRE1alpha
Authors: Govindarajan Srinath , Gaublomme Djoere , Van der Cruyssen Renée , Verheugen Eveline , Van Gassen Sofie , Saeys Yvan , Tavernier Simon , Iwawaki Takao , Bloch Yehudi , Savvides Savvas. N. , Lambrecht Bart N. , Janssens Sophie , Elewaut Dirk , Drennan Michael B.
Published: December 2018

Activated invariant natural killer T (iNKT) cells rapidly produce large amounts of cytokines, but how cytokine mRNAs are induced, stabilized and mobilized following iNKT activation is still unclear. Here we show that an endoplasmic reticulum stress sensor, inositol-requiring enzyme 1α (IRE1α), links key cellular processes required for iNKT cell effector functions in specific iNKT subsets, in which TCR-dependent activation of IRE1α is associated with downstream activation of p38 MAPK and the stabilization of preformed cytokine mRNAs. Importantly, genetic deletion of IRE1α in iNKT cells reduces cytokine production and protects mice from oxazolone colitis. We therefore propose that an IRE1α-dependent signaling cascade couples constitutive cytokine mRNA expression to the rapid induction of cytokine secretion and effector functions in activated iNKT cells.
Local and global chromatin interactions are altered by large genomic deletions associated with human brain development
Authors: Zhang Xianglong , Zhang Ying , Zhu Xiaowei , Purmann Carolin , Haney Michael S. , Ward Thomas , Khechaduri Arineh , Yao Jie , Weissman Sherman M. , Urban Alexander E.
Published: December 2018

Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.
A rapid and robust method for single cell chromatin accessibility profiling
Authors: Chen Xi , Miragaia Ricardo J. , Natarajan Kedar Nath , Teichmann Sarah A.
Published: December 2018

The assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk Tn5 tagging with single-nuclei sorting. We demonstrate that our method works robustly across various systems, including fresh and cryopreserved cells from primary tissues. By profiling over 3000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors.
Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species
Authors: Muñoz José F. , Gade Lalitha , Chow Nancy A. , Loparev Vladimir N. , Juieng Phalasy , Berkow Elizabeth L. , Farrer Rhys A. , Litvintseva Anastasia P. , Cuomo Christina A.
Published: December 2018

Candida auris is an emergent multidrug-resistant fungal pathogen causing increasing reports of outbreaks. While distantly related to C. albicans and C. glabrata, C. auris is closely related to rarely observed and often multidrug-resistant species from the C. haemulonii clade. Here, we analyze near complete genome assemblies for the four C. auris clades and three related species, and map intra- and inter-species rearrangements across the seven chromosomes. Using RNA-Seq-guided gene predictions, we find that most mating and meiosis genes are conserved and that clades contain either the MTLa or MTLα mating loci. Comparing the genomes of these emerging species to those of other Candida species identifies genes linked to drug resistance and virulence, including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11. Gene expression analysis identifies transporters and metabolic regulators specific to C. auris and those conserved with related species which may contribute to differences in drug response in this emerging fungal clade.
Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis
Authors: Ponath Gerald , Lincoln Matthew R. , Levine-Ritterman Maya , Park Calvin , Dahlawi Somiah , Mubarak Mayyan , Sumida Tomokazu , Airas Laura , Zhang Shun , Isitan Cigdem , Nguyen Thanh D. , Raine Cedric S. , Hafler David A. , Pitt David
Published: December 2018

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.
Structural basis of meiotic telomere attachment to the nuclear envelope by MAJIN-TERB2-TERB1
Authors: Dunce James M. , Milburn Amy E. , Gurusaran Manickam , da Cruz Irene , Sen Lee T. , Benavente Ricardo , Davies Owen R.
Published: December 2018

Meiotic chromosomes undergo rapid prophase movements, which are thought to facilitate the formation of inter-homologue recombination intermediates that underlie synapsis, crossing over and segregation. The meiotic telomere complex (MAJIN, TERB1, TERB2) tethers telomere ends to the nuclear envelope and transmits cytoskeletal forces via the LINC complex to drive these rapid movements. Here, we report the molecular architecture of the meiotic telomere complex through the crystal structure of MAJIN-TERB2, together with light and X-ray scattering studies of wider complexes. The MAJIN-TERB2 2:2 hetero-tetramer binds strongly to DNA and is tethered through long flexible linkers to the inner nuclear membrane and two TRF1-binding 1:1 TERB2-TERB1 complexes. Our complementary structured illumination microscopy studies and biochemical findings reveal a telomere attachment mechanism in which MAJIN-TERB2-TERB1 recruits telomere-bound TRF1, which is then displaced during pachytene, allowing MAJIN-TERB2-TERB1 to bind telomeric DNA and form a mature attachment plate.
Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA
Authors: Menolfi Demis , Jiang Wenxia , Lee Brian J. , Moiseeva Tatiana , Shao Zhengping , Estes Verna , Frattini Mark G. , Bakkenist Christopher J. , Zha Shan
Published: December 2018

ATR kinase is activated by RPA-coated single-stranded DNA (ssDNA) to orchestrate DNA damage responses. Here we show that ATR inhibition differs from ATR loss. Mouse model expressing kinase-dead ATR (Atr+/KD), but not loss of ATR (Atr+/−), displays ssDNA-dependent defects at the non-homologous region of X-Y chromosomes during male meiosis leading to sterility, and at telomeres, rDNA, and fragile sites during mitosis leading to lymphocytopenia. Mechanistically, we find that ATR kinase activity is necessary for the rapid exchange of ATR at DNA-damage-sites, which in turn promotes CHK1-phosphorylation. ATR-KD, but not loss of ATR, traps a subset of ATR and RPA on chromatin, where RPA is hyper-phosphorylated by ATM/DNA-PKcs and prevents downstream repair. Consequently, Atr+/KD cells have shorter inter-origin distances and are vulnerable to induced fork collapses, genome instability and mitotic catastrophe. These results reveal mechanistic differences between ATR inhibition and ATR loss, with implications for ATR signaling and cancer therapy.
Overcoming efficiency and stability limits in water-processing nanoparticular organic photovoltaics by minimizing microstructure defects
Authors: Xie Chen , Heumüller Thomas , Gruber Wolfgang , Tang Xiaofeng , Classen Andrej , Schuldes Isabel , Bidwell Matthew , Späth Andreas , Fink Rainer H. , Unruh Tobias , McCulloch Iain , Li Ning , Brabec Christoph J.
Published: December 2018

There is a strong market driven need for processing organic photovoltaics from eco-friendly solvents. Water-dispersed organic semiconducting nanoparticles (NPs) satisfy these premises convincingly. However, the necessity of surfactants, which are inevitable for stabilizing NPs, is a major obstacle towards realizing competitive power conversion efficiencies for water-processed devices. Here, we report on a concept for minimizing the adverse impact of surfactants on solar cell performance. A poloxamer facilitates the purification of organic semiconducting NPs through stripping excess surfactants from aqueous dispersion. The use of surfactant-stripped NPs based on poly(3-hexylthiophene) / non-fullerene acceptor leads to a device efficiency and stability comparable to the one from devices processed by halogenated solvents. A record efficiency of 7.5% is achieved for NP devices based on a low-band gap polymer system. This elegant approach opens an avenue that future organic photovoltaics processing may be indeed based on non-toxic water-based nanoparticle inks.
Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy
Authors: Di Leo Angelo , O’Shaughnessy Joyce , Sledge George W. , Martin Miguel , Lin Yong , Frenzel Martin , Hardebeck Molly C. , Smith Ian C. , Llombart-Cussac Antonio , Goetz Matthew P. , Johnston Stephen
Published: December 2018

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (<36 months). Benefit (PFS hazard ratio, ORR increase) from abemaciclib was observed in all patient subgroups. Patients with indicators of poor prognosis had the largest benefit from the addition of abemaciclib. However, in MONARCH 3, for patients with certain good prognostic factors (TFI ≥ 36 months, bone-only disease) ET achieved a median PFS of >20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib.
Costs and benefits of Papacarie in pediatric dentistry: a randomized clinical trial
Authors: Bottega Fernanda , Bussadori Sandra Kalil , Battisti Iara Denise Endruweit , Vieira Eusélia Paveglio , Pompeo Tiago Szambelan , Winkelmann Eliane Roseli
Published: December 2018

Papacarie gel is an agent that eliminates the need for local anesthesia and reduces the need for using a drill. However, there is no information regarding the cost per procedure. Therefore we analyzed the cost, per procedure, of Papacarie gel compared to the traditional method (drilling), and performed a comparison between these methods of carious tissue removal. A randomized clinical trial was performed with 24 children with an average age of 5.9 years old. Of these children, 12 were boys and 12 were girls, which resulted in a total of 46 restorations. Patients were separated into: Papacarie group (caries removal with the chemical-mechanical method - Papacarie gel) and Drill group (caries removal with the traditional method - drilling). Values of the materials used in the procedures, heart rate (before, 5 minutes during, and after dental treatment), and the total consultation duration were recorded. A level of significance of 5% was adopted. Papacarie had a lower cost per procedure ($ 0.91) when compared to the traditional method ($ 1.58). Papacarie provided a cost reduction of 42% compared to the traditional method. Using local anesthesia ($ 2.17), the cost reduction increased to 58%. In the procedure using drill + Papacarie ($ 1.37), the cost reduction was 33%. Heart rate, consultation duration, and number of restorations were not statistically different. Papacarie shows an excellent cost benefit for minimally invasive removal of carious tissue and is a feasible alternative for public health care.
Health risk stratification based on computed tomography pulmonary artery obstruction index for acute pulmonary embolism
Authors: Guo Fei , Zhu Guanghui , Shen Junjie , Ma Yichuan
Published: December 2018

Early effective identification of high-risk patients for acute pulmonary embolism (APE) contributes to timely treatment. The pulmonary artery obstruction index (PAOI) in computed tomography angiography (CTA) is a semi-quantitative observation index, commonly used to evaluate the severity of a patient’s condition. This study explores the ability of PAOI to assess the risk stratification of APE. Thirty patients with APE were analysed. They were classified according to the guidelines, and the PAOI and cardiovascular parameters were measured in CTA. The difference of PAOI between different risk stratification patients was compared, and the predictive value of the PAOI for high-risk stratification was evaluated by the receiver operating characteristic curve. The correlation between PAOI and cardiovascular parameters was also analysed by Spearman correlation analysis. The PAOI in low- and high-risk patients was (33.2 ± 18.6)% and (68.1 ± 11.8)% respectively, and the difference was statistically significant. The PAOI was strongly predictive for high-risk patients. The cut-off value was 52.5%, with a sensitivity of 100% and specificity of 81.0%. The PAOI was correlated with the main cardiovascular parameters. We conclude that the PAOI in CTA is helpful for assessing risk stratification in patients with APE, which contributes to the selection of both the treatment plan and prognostic evaluation.
In vitro Chondrocyte Responses in Mg-doped Wollastonite/Hydrogel Composite Scaffolds for Osteochondral Interface Regeneration
Authors: Yu Xinning , Zhao Tengfei , Qi Yiying , Luo Jianyang , Fang Jinghua , Yang Xianyan , Liu Xiaonan , Xu Tengjing , Yang Quanming , Gou Zhongru , Dai Xuesong
Published: December 2018

The zone of calcified cartilage (ZCC) is the mineralized region between the hyaline cartilage and subchondral bone and is critical in cartilage repair. A new non-stoichiometric calcium silicate (10% Ca substituted by Mg; CSi-Mg10) has been demonstrated to be highly bioactive in an osteogenic environment in vivo. This study is aimed to systematically evaluate the potential to regenerate osteochondral interface with different amount of Ca-Mg silicate in hydrogel-based scaffolds, and to compare with the scaffolds containing conventional Ca-phosphate biomaterials. Hydrogel-based porous scaffolds combined with 0–6% CSi-Mg10, 6% β-tricalcium phosphate (β-TCP) or 6% nanohydroxyapatite (nHAp) were made with three-dimensional (3D) printing. An increase in CSi-Mg10 content is desirable for promoting the hypertrophy and mineralization of chondrocytes, as well as cell proliferation and matrix deposition. Osteogenic and chondrogenic induction were both up-regulated in a dose-dependent manner. In comparison with the scaffolds containing 6% β-TCP or nHAp, human deep zone chondrocytes (hDZCs) seeded on CSi-Mg10 scaffold of equivalent concentration exhibited higher mineralization. It is noteworthy that the hDZCs in the 6% CSi-Mg10 scaffolds maintained a higher expression of the calcified cartilage zone specific extracellular matrix marker and hypertrophic marker, collagen type X. Immunohistochemical and Alizarin Red staining reconfirmed these findings. The study demonstrated that hydrogel-based hybrid scaffolds containing 6% CSi-Mg10 are particularly desirable for inducing the formation of calcified cartilage.
Complete genome analysis of a Siphoviridae phage TSK1 showing biofilm removal potential against Klebsiella pneumoniae
Authors: Tabassum Rabia , Shafique Muafia , Khawaja Komal Amer , Alvi Iqbal Ahmed , Rehman Yasir , Sheik Cody S. , Abbas Zaigham , Rehman Shafiq ur
Published: December 2018

Multidrug-resistant Klebsiella pneumoniae is a nosocomial pathogen, produces septicemia, pneumonia and UTI. Excessive use of antibiotics contributes towards emergence of multidrug-resistance. Bacteriophage-therapy is a potential substitute of antibiotics with many advantages. In this investigation, microbiological and genome characterization of TSK1 bacteriophage and its biofilm elimination capability are presented. TSK1 showed narrow host range and highest stability at pH 7 and 37 °C. TSK1 reduced the growth of K. pneumoniae during the initial 14 hours of infection. Post-treatment with TSK1 against different age K. pneumoniae biofilms reduced 85–100% biomass. Pre-treatment of TSK1 bacteriophage against the biofilm of Klebsiella pneumoniae reduced > 99% biomass in initial 24 hr of incubation. The genome of TSK1 phage comprised 49,836 base pairs with GC composition of 50.44%. Total seventy-five open reading frames (ORFs) were predicted, 25 showed homology with known functional proteins, while 50 were called hypothetical, as no homologs with proved function exists in the genome databases. Blast and phylogenetic analysis put it in the Kp36 virus genus of family Siphoviridae. Proposed packaging strategy of TSK1 bacteriophage genome is headful packaging using the pac sites. The potential of TSK1 bacteriophage could be used to reduce the bacterial load and biofilm in clinical and non-clinical settings.
Free D-amino acids produced by commensal bacteria in the colonic lumen
Authors: Matsumoto Mitsuharu , Kunisawa Akihiro , Hattori Takanari , Kawana Shuichi , Kitada Yusuke , Tamada Hazuki , Kawano Shinichi , Hayakawa Yoshihiro , Iida Junko , Fukusaki Eiichiro
Published: December 2018

D-amino acids (D-AAs) have various biological activities, such as activation ofN-methyl-D-aspartic acid (NMDA) receptor as a co-agonist byD-Ser. Since several freeD-AAs are released in the broth monocultured with bacterium andD-AAs are probably utilized for bacterial communication, we presume that intestinal microbiota releases several kinds of freeD-AAs, which may be involved in the hosts’ health. However, presently, only four freeD-AAs have been found in the ceacal lumen, but not in the colonic lumen. Here, we showed, by simultaneous analysis of chiral AAs using high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS), that 12 freeD-AAs (D-Ala,D-Arg,D-Asp,D-Gln,D-Glu,D-allo-Ile,D-Leu,D-Lys,D-Met,D-Phe,D-Ser, andD-Trp) are produced by intestinal microbiota and identified bacterial groups belonging to Firmicutes as the relevant bacterial candidates.
Author Correction: Determination of critical cooling rates in metallic glass forming alloy libraries through laser spike annealing
Authors: Bordeenithikasem Punnathat , Liu Jingbei , Kube Sebastian A. , Li Yanglin , Ma Tianxing , Scanley B. Ellen , Broadbridge Christine C. , Vlassak Joost J. , Singer Jonathan P. , Schroers Jan
Published: December 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Fermi surface topology in a metallic phase of VO2 thin films grown on TiO2(001) substrates
Authors: Muraoka Yuji , Nagao Hiroki , Yao Yuichiro , Wakita Takanori , Terashima Kensei , Yokoya Takayoshi , Kumigashira Hiroshi , Oshima Masaharu
Published: December 2018

Since the first observation of the metal-to-insulator transition (MIT), VO2 has attracted substantial attention in terms of whether this transition is impelled by electron–phonon interaction (Peierls transition) or electron–electron interaction. Regarding Peierls transition, it has been theoretically predicted that the Fermi surface (FS) cross-section exhibits certain nesting features for a metallic phase of VO2. Various experimental studies related to the nesting feature have been reported. Nevertheless, there is no experimental result on FS topology. In this work, we determine the FS topology of the metallic phase of VO2 through studies of VO2 epitaxial thin films on TiO2(001) substrates, using synchrotron radiation angle-resolved photoemission spectroscopy (ARPES). Three electron pockets around Γ are observed in band structures along the Γ–X direction. These three bands form electron surfaces around Γ in the ΓXRZ plane. Furthermore, the lowest energy band FS exhibits the nesting feature corresponding to a nesting vector $$\overrightarrow{q}$$

q
→

 = ΓR, as predicted by the calculation. Our results strongly indicate the formation of the charge-density wave with $$\overrightarrow{q}$$

q
→

 = ΓR and thus, the importance of Peierls transition for the mechanism of the MIT in VO2.
Decomposer diversity increases biomass production and shifts aboveground-belowground biomass allocation of common wheat
Authors: Eisenhauer Nico , Vogel Anja , Jensen Britta , Scheu Stefan
Published: December 2018

Biodiversity is well known to enhance many ecosystem functions, but empirical evidence for the role of soil biodiversity for plant biomass production and allocation is scarce. Here we studied the effects of animal decomposer diversity (1, 2, and 4 species as well as a control without any decomposers) on the biomass production and aboveground-belowground biomass allocation of common wheat using two earthworm and two Collembola species using an additive design in two soil management types (organic and mineral fertilizer treatments) in a microcosm experiment. Shoot (+11%), spike (+7%), and root biomass (+56%), increased significantly with increasing decomposer diversity, and these effects were consistent across the two soil management types. Notably, decomposer diversity effects were stronger on root than on shoot biomass, significantly decreasing the shoot-to-root ratio (−27%). Increased plant biomass production was positively correlated with a decomposer richness-induced increase in soil water nitrate concentrations five weeks after the start of the experiment. However, elevated soil nitrate concentrations did not cause significantly higher plant tissue nitrogen concentrations and nitrogen amounts, suggesting that additional mechanisms might be at play. Consistent decomposer diversity effects across soil management types indicate that maintaining soil biodiversity is a robust and sustainable strategy to enhance crop yield.
Author Correction: Low dose of chlorine exposure exacerbates nasal and pulmonary allergic inflammation in mice
Authors: de Genaro Isabella Santos , de Almeida Francine Maria , Hizume-Kunzler Deborah Camargo , Moriya Henrique Takachi , Silva Ronaldo Aparecido , Cruz João Carlos Gonçalves , Lopes Renan Boeira , Righetti Renato Fraga , de Paula Vieira Rodolfo , Saiki Mitiko , Martins Milton Arruda , Tibério Iolanda de Fátima Lopes Calvo , Arantes-Costa Fernanda Magalhães , Saraiva-Romanholo Beatriz Mangueira
Published: December 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Transcriptome and protein interaction profiling in cancer cells with mutations in histone H3.3
Authors: Lim Jinyeong , Park Joo Hyun , Baude Annika , Fellenberg Jörg , Zustin Jozef , Haller Florian , Krücken Irene , Kang Hyun Guy , Park Yoon Jung , Plass Christoph , Lindroth Anders M.
Published: December 2018

Mutations of histone variant H3.3 are highly recurrent in childhood glioblastoma and in young adults with Giant Cell Tumor of the Bone (GCTB). The heterozygotic representation of the mutations in the tumors, and with potential histone H3 and H3.3 redundancy, suggest that the mutations are gain-of-function by nature. To address common H3.3 point mutations, we have generated data from GCTB patient samples with H3.3 G34W substitutions and engineered human GFP-tagged H3.3-mutated isogenic cell lines for high throughput data comparisons. First, a total of thirty-six patient samples and cell lines were used to acquire gene expression transcriptome data using microarray and RNA-sequencing. The expression data were validated with the orthogonal nCounter assay. Second, to uncover the H3.3-GFP interaction proteomes from the isogenic cell lines, immunoprecipitation of unmutated wild type, K27M, G34R, and G34W substitutions were performed. The RNA-sequencing data and the H3.3 interaction proteome enable potentially important functional insight into the tumorigenic process and should spur further detailed analysis.
The metabolic regimes of 356 rivers in the United States
Authors: Appling Alison P. , Read Jordan S. , Winslow Luke A. , Arroita Maite , Bernhardt Emily S. , Griffiths Natalie A. , Hall Robert O. , Harvey Judson W. , Heffernan James B. , Stanley Emily H. , Stets Edward G. , Yackulic Charles B.
Published: December 2018

A national-scale quantification of metabolic energy flow in streams and rivers can improve understanding of the temporal dynamics of in-stream activity, links between energy cycling and ecosystem services, and the effects of human activities on aquatic metabolism. The two dominant terms in aquatic metabolism, gross primary production (GPP) and aerobic respiration (ER), have recently become practical to estimate for many sites due to improved modeling approaches and the availability of requisite model inputs in public datasets. We assembled inputs from the U.S. Geological Survey and National Aeronautics and Space Administration for October 2007 to January 2017. We then ran models to estimate daily GPP, ER, and the gas exchange rate coefficient for 356 streams and rivers across the continental United States. We also gathered potential explanatory variables and spatial information for cross-referencing this dataset with other datasets of watershed characteristics. This dataset offers a first national assessment of many-day time series of metabolic rates for up to 9 years per site, with a total of 490,907 site-days of estimates.
Outlier analyses of the Protein Data Bank archive using a probability-density-ranking approach
Authors: Shao Chenghua , Liu Zonghong , Yang Huanwang , Wang Sijian , Burley Stephen K.
Published: December 2018

Outlier analyses are central to scientific data assessments. Conventional outlier identification methods do not work effectively for Protein Data Bank (PDB) data, which are characterized by heavy skewness and the presence of bounds and/or long tails. We have developed a data-driven nonparametric method to identify outliers in PDB data based on kernel probability density estimation. Unlike conventional outlier analyses based on location and scale, Probability Density Ranking can be used for robust assessments of distance from other observations. Analyzing PDB data from the vantage points of probability and frequency enables proper outlier identification, which is important for quality control during deposition-validation-biocuration of new three-dimensional structure data. Ranking of Probability Density also permits use of Most Probable Range as a robust measure of data dispersion that is more compact than Interquartile Range. The Probability-Density-Ranking approach can be employed to analyze outliers and data-spread on any large data set with continuous distribution.