bluuebunny/crossref_metadata_2025 huggingface dataset:
Uncovering and quantifying the subduction zone sulfur cycle from the slab perspective
Authors: Li Ji-Lei , Schwarzenbach Esther M. , John Timm , Ague Jay J. , Huang Fang , Gao Jun , Klemd Reiner , Whitehouse Martin J. , Wang Xin-Shui
Published: January 2020

Sulfur belongs among H2O, CO2, and Cl as one of the key volatiles in Earth’s chemical cycles. High oxygen fugacity, sulfur concentration, and δ34S values in volcanic arc rocks have been attributed to significant sulfate addition by slab fluids. However, sulfur speciation, flux, and isotope composition in slab-dehydrated fluids remain unclear. Here, we use high-pressure rocks and enclosed veins to provide direct constraints on subduction zone sulfur recycling for a typical oceanic lithosphere. Textural and thermodynamic evidence indicates the predominance of reduced sulfur species in slab fluids; those derived from metasediments, altered oceanic crust, and serpentinite have δ34S values of approximately −8‰, −1‰, and +8‰, respectively. Mass-balance calculations demonstrate that 6.4% (up to 20% maximum) of total subducted sulfur is released between 30–230 km depth, and the predominant sulfur loss takes place at 70–100 km with a net δ34S composition of −2.5 ± 3‰. We conclude that modest slab-to-wedge sulfur transport occurs, but that slab-derived fluids provide negligible sulfate to oxidize the sub-arc mantle and cannot deliver34S-enriched sulfur to produce the positive δ34S signature in arc settings. Most sulfur has negative δ34S and is subducted into the deep mantle, which could cause a long-term increase in the δ34S of Earth surface reservoirs.
African-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin
Authors: Singh Kumar Sachin , Leu Julia I-Ju , Barnoud Thibaut , Vonteddu Prashanthi , Gnanapradeepan Keerthana , Lin Cindy , Liu Qin , Barton James C. , Kossenkov Andrew V. , George Donna L. , Murphy Maureen E. , Dotiwala Farokh
Published: January 2020

A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07–2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.
Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling
Authors: Kumar Manish , Leon Coria Aralia , Cornick Steve , Petri Björn , Mayengbam Shyamchand , Jijon Humberto B. , Moreau France , Shearer Jane , Chadee Kris
Published: January 2020

Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2−/−) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2−/− mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.
Single-cell analysis reveals new evolutionary complexity in uveal melanoma
Authors: Durante Michael A. , Rodriguez Daniel A. , Kurtenbach Stefan , Kuznetsov Jeffim N. , Sanchez Margaret I. , Decatur Christina L. , Snyder Helen , Feun Lynn G. , Livingstone Alan S. , Harbour J. William
Published: January 2020

Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and non-neoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8+ T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.
Erythroid differentiation regulator-1 induced by microbiota in early life drives intestinal stem cell proliferation and regeneration
Authors: Abo Hirohito , Chassaing Benoit , Harusato Akihito , Quiros Miguel , Brazil Jennifer C. , Ngo Vu L. , Viennois Emilie , Merlin Didier , Gewirtz Andrew T. , Nusrat Asma , Denning Timothy L.
Published: January 2020

Gut microbiota and their metabolites are instrumental in regulating intestinal homeostasis. However, early-life microbiota associated influences on intestinal development remain incompletely understood. Here we demonstrate that co-housing of germ-free (GF) mice with specific-pathogen free (SPF) mice at weaning (exGF) results in altered intestinal gene expression. Our results reveal that one highly differentially expressed gene, erythroid differentiation regulator-1 (Erdr1), is induced during development in SPF but not GF or exGF mice and localizes to Lgr5+ stem cells and transit amplifying (TA) cells. Erdr1 functions to induce Wnt signaling in epithelial cells, increase Lgr5+ stem cell expansion, and promote intestinal organoid growth. Additionally, Erdr1 accelerates scratch-wound closure in vitro, increases Lgr5+ intestinal stem cell regeneration following radiation-induced injury in vivo, and enhances recovery from dextran sodium sulfate (DSS)-induced colonic damage. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.
Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin
Authors: Mitra Sreyoshi , Bodor Dani L. , David Ana F. , Abdul-Zani Izma , Mata João F. , Neumann Beate , Reither Sabine , Tischer Christian , Jansen Lars E. T.
Published: January 2020

Centromeres are defined by a self-propagating chromatin structure based on stable inheritance of CENP-A containing nucleosomes. Here, we present a genetic screen coupled to pulse-chase labeling that allow us to identify proteins selectively involved in deposition of nascent CENP-A or in long-term transmission of chromatin-bound CENP-A. These include factors with known roles in DNA replication, repair, chromatin modification, and transcription, revealing a broad set of chromatin regulators that impact on CENP-A dynamics. We further identify the SUMO-protease SENP6 as a key factor, not only controlling CENP-A stability but virtually the entire centromere and kinetochore. Loss of SENP6 results in hyper-SUMOylation of CENP-C and CENP-I but not CENP-A itself. SENP6 activity is required throughout the cell cycle, suggesting that a dynamic SUMO cycle underlies a continuous surveillance of the centromere complex that in turn ensures stable transmission of CENP-A chromatin.
YAP/TAZ direct commitment and maturation of lymph node fibroblastic reticular cells
Authors: Choi Sung Yong , Bae Hosung , Jeong Sun-Hye , Park Intae , Cho Hyunsoo , Hong Seon Pyo , Lee Da-Hye , Lee Choong-kun , Park Jin-Sung , Suh Sang Heon , Choi Jeongwoon , Yang Myung Jin , Jang Jeon Yeob , Onder Lucas , Moon Jeong Hwan , Jeong Han-Sin , Adams Ralf H. , Kim Jin-Man , Ludewig Burkhard , Song Joo-Hye , Lim Dae-Sik , Koh Gou Young
Published: January 2020

Fibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis. Mechanistically, the interaction between YAP/TAZ and p52 promotes chemokine expression that is required for commitment of FRC lineage prior to lymphotoxin-β receptor (LTβR) engagement, whereas LTβR activation suppresses YAP/TAZ activity for FRC maturation. Our findings thus present YAP/TAZ as critical regulators of commitment and maturation of FRCs, and hold promise for better understanding of FRC-mediated pathophysiologic processes.
The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing
Authors: Hu Xiaohui , Harvey Samuel E. , Zheng Rong , Lyu Jingyi , Grzeskowiak Caitlin L. , Powell Emily , Piwnica-Worms Helen , Scott Kenneth L. , Cheng Chonghui
Published: January 2020

Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein–protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.
Isolation of Angola-like Marburg virus from Egyptian rousette bats from West Africa
Authors: Amman Brian R. , Bird Brian H. , Bakarr Ibrahim A. , Bangura James , Schuh Amy J. , Johnny Jonathan , Sealy Tara K. , Conteh Immah , Koroma Alusine H. , Foday Ibrahim , Amara Emmanuel , Bangura Abdulai A. , Gbakima Aiah A. , Tremeau-Bravard Alexandre , Belaganahalli Manjunatha , Dhanota Jasjeet , Chow Andrew , Ontiveros Victoria , Gibson Alexandra , Turay Joseph , Patel Ketan , Graziano James , Bangura Camilla , Kamanda Emmanuel S. , Osborne Augustus , Saidu Emmanuel , Musa Jonathan , Bangura Doris , Williams Samuel Maxwell Tom , Wadsworth Richard , Turay Mohamed , Edwin Lavalie , Mereweather-Thompson Vanessa , Kargbo Dickson , Bairoh Fatmata V. , Kanu Marilyn , Robert Willie , Lungai Victor , Guetiya Wadoum Raoul Emeric , Coomber Moinya , Kanu Osman , Jambai Amara , Kamara Sorie M. , Taboy Celine H. , Singh Tushar , Mazet Jonna A. K. , Nichol Stuart T. , Goldstein Tracey , Towner Jonathan S. , Lebbie Aiah
Published: January 2020

Marburg virus (MARV) causes sporadic outbreaks of severe Marburg virus disease (MVD). Most MVD outbreaks originated in East Africa and field studies in East Africa, South Africa, Zambia, and Gabon identified the Egyptian rousette bat (ERB; Rousettus aegyptiacus) as a natural reservoir. However, the largest recorded MVD outbreak with the highest case–fatality ratio happened in 2005 in Angola, where direct spillover from bats was not  shown. Here, collaborative studies by the Centers for Disease Control and Prevention, Njala University, University of California, Davis USAID-PREDICT, and the University of Makeni identify MARV circulating in ERBs in Sierra Leone. PCR, antibody and virus isolation data from 1755 bats of 42 species shows active MARV infection in approximately 2.5% of ERBs. Phylogenetic analysis identifies MARVs that are similar to the Angola strain. These results provide evidence of MARV circulation in West Africa and demonstrate the value of pathogen surveillance to identify previously undetected threats.
Redox-coupled proton pumping drives carbon concentration in the photosynthetic complex I
Authors: Schuller Jan M. , Saura Patricia , Thiemann Jacqueline , Schuller Sandra K. , Gamiz-Hernandez Ana P. , Kurisu Genji , Nowaczyk Marc M. , Kaila Ville R. I.
Published: January 2020

Photosynthetic organisms capture light energy to drive their energy metabolism, and employ the chemical reducing power to convert carbon dioxide (CO2) into organic molecules. Photorespiration, however, significantly reduces the photosynthetic yields. To survive under low CO2 concentrations, cyanobacteria evolved unique carbon-concentration mechanisms that enhance the efficiency of photosynthetic CO2 fixation, for which the molecular principles have remained unknown. We show here how modular adaptations enabled the cyanobacterial photosynthetic complex I to concentrate CO2 using a redox-driven proton-pumping machinery. Our cryo-electron microscopy structure at 3.2 Å resolution shows a catalytic carbonic anhydrase module that harbours a Zn2+ active site, with connectivity to proton-pumping subunits that are activated by electron transfer from photosystem I. Our findings illustrate molecular principles in the photosynthetic complex I machinery that enabled cyanobacteria to survive in drastically changing CO2 conditions.
YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
Authors: Tanaka Hikari , Homma Hidenori , Fujita Kyota , Kondo Kanoh , Yamada Shingo , Jin Xiaocen , Waragai Masaaki , Ohtomo Gaku , Iwata Atsushi , Tagawa Kazuhiko , Atsuta Naoki , Katsuno Masahisa , Tomita Naoki , Furukawa Katsutoshi , Saito Yuko , Saito Takashi , Ichise Ayaka , Shibata Shinsuke , Arai Hiroyuki , Saido Takaomi , Sudol Marius , Muramatsu Shin-ichi , Okano Hideyuki , Mufson Elliott J. , Sobue Gen , Murayama Shigeo , Okazawa Hitoshi
Published: January 2020

The timing and characteristics of neuronal death in Alzheimer’s disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.
Programmable meroterpene synthesis
Authors: Shen Xingyu , Ting Chi P. , Xu Gong , Maimone Thomas J.
Published: January 2020

The bicyclo[3.3.1]nonane architecture is a privileged structural motif found in over 1000 natural products with relevance to neurodegenerative disease, bacterial and parasitic infection, and cancer among others. Despite disparate biosynthetic machinery, alkaloid, terpene, and polyketide-producing organisms have all evolved pathways to incorporate this carbocyclic ring system. Natural products of mixed polyketide/terpenoid origins (meroterpenes) are a particularly rich and important source of biologically active bicyclo[3.3.1]nonane-containing molecules. Herein we detail a fully synthetic strategy toward this broad family of targets based on an abiotic annulation/rearrangement strategy resulting in a 10-step total synthesis of garsubellin A, an enhancer of choline acetyltransferase and member of the large family of polycyclic polyprenylated acylphloroglucinols. This work solidifies a strategy for making multiple, diverse meroterpene chemotypes in a programmable assembly process involving a minimal number of chemical transformations.
Spatial attention enhances network, cellular and subthreshold responses in mouse visual cortex
Authors: Speed Anderson , Del Rosario Joseph , Mikail Navid , Haider Bilal
Published: January 2020

Internal brain states strongly modulate sensory processing during behaviour. Studies of visual processing in primates show that attention to space selectively improves behavioural and neural responses to stimuli at the attended locations. Here we develop a visual spatial task for mice that elicits behavioural improvements consistent with the effects of spatial attention, and simultaneously measure network, cellular, and subthreshold activity in primary visual cortex. During trial-by-trial behavioural improvements, local field potential (LFP) responses to stimuli detected inside the receptive field (RF) strengthen. Moreover, detection inside the RF selectively enhances excitatory and inhibitory neuron responses to task-irrelevant stimuli and suppresses noise correlations and low frequency LFP fluctuations. Whole-cell patch-clamp recordings reveal that detection inside the RF increases synaptic activity that depolarizes membrane potential responses at the behaviorally relevant location. Our study establishes that mice display fundamental signatures of visual spatial attention spanning behavioral, network, cellular, and synaptic levels, providing new insight into rapid cognitive enhancement of sensory signals in visual cortex.
Vacuum Rabi splitting of a dark plasmonic cavity mode revealed by fast electrons
Authors: Bitton Ora , Gupta Satyendra Nath , Houben Lothar , Kvapil Michal , Křápek Vlastimil , Šikola Tomáš , Haran Gilad
Published: January 2020

Recent years have seen a growing interest in strong coupling between plasmons and excitons, as a way to generate new quantum optical testbeds and influence chemical dynamics and reactivity. Strong coupling to bright plasmonic modes has been achieved even with single quantum emitters. Dark plasmonic modes fare better in some applications due to longer lifetimes, but are difficult to probe as they are subradiant. Here, we apply electron energy loss (EEL) spectroscopy to demonstrate that a dark mode of an individual plasmonic bowtie can interact with a small number of quantum emitters, as evidenced by Rabi-split spectra. Coupling strengths of up to 85 meV place the bowtie-emitter devices at the onset of the strong coupling regime. Remarkably, the coupling occurs at the periphery of the bowtie gaps, even while the electron beam probes their center. Our findings pave the way for using EEL spectroscopy to study exciton-plasmon interactions involving non-emissive photonic modes.
Identifying Eigen-like hydrated protons at negatively charged interfaces
Authors: Tyrode Eric , Sengupta Sanghamitra , Sthoer Adrien
Published: January 2020

Despite the importance of the hydrogen ion in a wide range of biological, chemical, and physical processes, its molecular structure in solution remains lively debated. Progress has been primarily hampered by the extreme diffuse nature of the vibrational signatures of hydrated protons in bulk solution. Using the inherently surface-specific vibrational sum frequency spectroscopy technique, we show that at selected negatively charged interfaces, a resolved spectral feature directly linked to the H3O+ core in an Eigen-like species can be readily identified in a biologically compatible pH range. Centered at ~2540 cm−1, the band is seen to shift to ~1875 cm−1 when forming D3O+ upon isotopic substitution. The results offer the possibility of tracking and understanding from a molecular perspective the behavior of hydrated protons at charged interfaces.
A helitron-induced RabGDIα variant causes quantitative recessive resistance to maize rough dwarf disease
Authors: Liu Qingcai , Deng Suining , Liu Baoshen , Tao Yongfu , Ai Haiyue , Liu Jianju , Zhang Yongzhong , Zhao Yan , Xu Mingliang
Published: January 2020

Maize rough dwarf disease (MRDD), caused by various species of the genus Fijivirus, threatens maize production worldwide. We previously identified a quantitative locus qMrdd1 conferring recessive resistance to one causal species, rice black-streaked dwarf virus (RBSDV). Here, we show that Rab GDP dissociation inhibitor alpha (RabGDIα) is the host susceptibility factor for RBSDV. The viral P7-1 protein binds tightly to the exon-10 and C-terminal regions of RabGDIα to recruit it for viral infection. Insertion of a helitron transposon into RabGDIα intron 10 creates alternative splicing to replace the wild-type exon 10 with a helitron-derived exon 10. The resultant splicing variant RabGDIα-hel has difficulty being recruited by P7-1, thus leading to quantitative recessive resistance to MRDD. All naturally occurring resistance alleles may have arisen from a recent single helitron insertion event. These resistance alleles are valuable to improve maize resistance to MRDD and potentially to engineer RBSDV resistance in other crops.
Targeting glutamine metabolism slows soft tissue sarcoma growth
Authors: Lee Pearl , Malik Dania , Perkons Nicholas , Huangyang Peiwei , Khare Sanika , Rhoades Seth , Gong Yao-Yu , Burrows Michelle , Finan Jennifer M. , Nissim Itzhak , Gade Terence P. F. , Weljie Aalim M. , Simon M. Celeste
Published: January 2020

Tumour cells frequently utilize glutamine to meet bioenergetic and biosynthetic demands of rapid cell growth. However, glutamine dependence can be highly variable between in vitro and in vivo settings, based on surrounding microenvironments and complex adaptive responses to glutamine deprivation. Soft tissue sarcomas (STSs) are mesenchymal tumours where cytotoxic chemotherapy remains the primary approach for metastatic or unresectable disease. Therefore, it is critical to identify alternate therapies to improve patient outcomes. Using autochthonous STS murine models and unbiased metabolomics, we demonstrate that glutamine metabolism supports sarcomagenesis. STS subtypes expressing elevated glutaminase (GLS) levels are highly sensitive to glutamine starvation. In contrast to previous studies, treatment of autochthonous tumour-bearing animals with Telaglenastat (CB-839), an orally bioavailable GLS inhibitor, successfully inhibits undifferentiated pleomorphic sarcoma (UPS) tumour growth. We reveal glutamine metabolism as critical for sarcomagenesis, with CB-839 exhibiting potent therapeutic potential.
Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance
Authors: Oe Yuki , Wang Xiaowen , Patriarchi Tommaso , Konno Ayumu , Ozawa Katsuya , Yahagi Kazuko , Hirai Hirokazu , Tsuboi Takashi , Kitaguchi Tetsuya , Tian Lin , McHugh Thomas J. , Hirase Hajime
Published: January 2020

Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca2+ elevation and facilitates synaptic plasticity, while activation of β-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca2+ and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca2+ elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory.
An optochemical tool for light-induced dissociation of adherens junctions to control mechanical coupling between cells
Authors: Ollech Dirk , Pflästerer Tim , Shellard Adam , Zambarda Chiara , Spatz Joachim Pius , Marcq Philippe , Mayor Roberto , Wombacher Richard , Cavalcanti-Adam Elisabetta Ada
Published: January 2020

The cadherin-catenin complex at adherens junctions (AJs) is essential for the formation of cell-cell adhesion and epithelium integrity; however, studying the dynamic regulation of AJs at high spatio-temporal resolution remains challenging. Here we present an optochemical tool which allows reconstitution of AJs by chemical dimerization of the force bearing structures and their precise light-induced dissociation. For the dimerization, we reconstitute acto-myosin connection of a tailless E-cadherin by two ways: direct recruitment of α-catenin, and linking its cytosolic tail to the transmembrane domain. Our approach enables a specific ON-OFF switch for mechanical coupling between cells that can be controlled spatially on subcellular or tissue scale via photocleavage. The combination with cell migration analysis and traction force microscopy shows a wide-range of applicability and confirms the mechanical contribution of the reconstituted AJs. Remarkably, in vivo our tool is able to control structural and functional integrity of the epidermal layer in developing Xenopus embryos.
Evolutionary diversity in tropical tree communities peaks at intermediate precipitation
Authors: Neves Danilo M. , Dexter Kyle G. , Baker Timothy R. , Coelho de Souza Fernanda , Oliveira-Filho Ary T. , Queiroz Luciano P. , Lima Haroldo C. , Simon Marcelo F. , Lewis Gwilym P. , Segovia Ricardo A. , Arroyo Luzmila , Reynel Carlos , Marcelo-Peña José L. , Huamantupa-Chuquimaco Isau , Villarroel Daniel , Parada G. Alexander , Daza Aniceto , Linares-Palomino Reynaldo , Ferreira Leandro V. , Salomão Rafael P. , Siqueira Geovane S. , Nascimento Marcelo T. , Fraga Claudio N. , Pennington R. Toby
Published: January 2020

Global patterns of species and evolutionary diversity in plants are primarily determined by a temperature gradient, but precipitation gradients may be more important within the tropics, where plant species richness is positively associated with the amount of rainfall. The impact of precipitation on the distribution of evolutionary diversity, however, is largely unexplored. Here we detail how evolutionary diversity varies along precipitation gradients by bringing together a comprehensive database on the composition of angiosperm tree communities across lowland tropical South America (2,025 inventories from wet to arid biomes), and a new, large-scale phylogenetic hypothesis for the genera that occur in these ecosystems. We find a marked reduction in the evolutionary diversity of communities at low precipitation. However, unlike species richness, evolutionary diversity does not continually increase with rainfall. Rather, our results show that the greatest evolutionary diversity is found in intermediate precipitation regimes, and that there is a decline in evolutionary diversity above 1,490 mm of mean annual rainfall. If conservation is to prioritise evolutionary diversity, areas of intermediate precipitation that are found in the South American ‘arc of deforestation’, but which have been neglected in the design of protected area networks in the tropics, merit increased conservation attention.
Theoretical analyses and experimental validation of the effects caused by the fluorinated substituent modification of DNA
Authors: Koseki Jun , Konno Masamitsu , Asai Ayumu , Horie Naohiro , Tsunekuni Kenta , Kawamoto Koichi , Obika Satoshi , Doki Yuichiro , Mori Masaki , Ishii Hideshi
Published: January 2020

Halogen-modified nucleic acid molecules, such as trifluorothymidine (FTD) and 5-fluorouracil, are widely used in medical science and clinical site. These compounds have a very similar nucleobase structure. It is reported that both of these compounds could be incorporated into DNA. The incorporation of FTD produces highly anti-tumor effect. However, it is not known whether to occur a significant effect by the incorporation of 5-fluorouracil. Nobody knows why such a difference will occur. To understand the reason why there is large differences between trifluorothymidine and 5-fluorouracil, we have performed the molecular dynamics simulations and molecular orbital calculations. Although the active interaction energy between Halogen-modified nucleic acids or and complementary adenine was increased, in only FTD incorporated DNA, more strongly dispersion force interactions with an adjacent base were detected in many thermodynamic DNA conformations. As the results, the conformational changes occur even if it is in internal body temperature. Then the break of hydrogen bonding between FTD and complementary adenine base occur more frequently. The double helix structural destabilization of DNA with FTD is resulted from autoagglutination caused by the bonding via halogen orbitals such as halogen bonding and the general van der Waals interactions such as CH–$${\rm{\pi }}$$π, lone pair (LP)–$${\rm{\pi }}$$π, and $${\rm{\pi }}$$π–$${\rm{\pi }}$$π interactions. Therefore, it is strongly speculated that such structural changes caused by trifluoromethyl group is important for the anti-tumor effect of FTD alone.
Adaptive Landscape Shaped by Core Endogenous Network Coordinates Complex Early Progenitor Fate Commitments in Embryonic Pancreas
Authors: Wang Junqiang , Yuan Ruoshi , Zhu Xiaomei , Ao Ping
Published: January 2020

The classical development hierarchy of pancreatic cell fate commitments describes that multipotent progenitors (MPs) first bifurcate into tip cells and trunk cells, and then these cells give rise to acinar cells and endocrine/ductal cells separately. However, lineage tracings reveal that pancreatic progenitors are highly heterogeneous in tip and trunk domains in embryonic pancreas. The progenitor fate commitments from multipotency to unipotency during early pancreas development is insufficiently characterized. In pursuing a mechanistic understanding of the complexity in progenitor fate commitments, we construct a core endogenous network for pancreatic lineage decisions based on genetic regulations and quantified its intrinsic dynamic properties using dynamic modeling. The dynamics reveal a developmental landscape with high complexity that has not been clarified. Not only well-characterized pancreatic cells are reproduced, but also previously unrecognized progenitors—tip progenitor (TiP), trunk progenitor (TrP), later endocrine progenitor (LEP), and acinar progenitors (AciP/AciP2) are predicted. Further analyses show that TrP and LEP mediate endocrine lineage maturation, while TiP, AciP, AciP2 and TrP mediate acinar and ductal lineage maturation. The predicted cell fate commitments are validated by analyzing single-cell RNA sequencing (scRNA-seq) data. Significantly, this is the first time that a redefined hierarchy with detailed early pancreatic progenitor fate commitment is obtained.
Conversion of partial restorer Swarna into restorer by transferring fertility restorer Rf gene(s) through marker assisted back cross breeding (MABB) in rice
Authors: Ponnuswamy Revathi , Singh Arun Kumar , Raman Meenakshi Sundaram , Subbarao Lella venkata , C.N. Neeraja
Published: January 2020

The major constraints in hybrid rice breeding are availability of limited number of parental lines with specific desirable traits and lower frequency of restorers among elite breeding lines. The popular, high-yielding mega-rice variety Swarna, has been identified to be a partial restorer (as it has only one of major fertility restorer genes, Rf4) and hence cannot be utilized directly in the hybrid rice breeding. To convert the partial restorer to complete restorer, a cross was made between Swarna and a stable restorer KMR3R possessing Rf3 and Rf4 genes and developed BC1F5 and BC2F4 populations by marker-assisted back cross breeding (MABB). The SSR marker DRRM-RF3-10 linked to Rf3 gene located on chromosome 1, clearly distinguished restorers from partial restorers. All the improved lines of Swarna possessing Rf3 and Rf4 genes showed complete fertility restoration in test crosses with higher grain yield heterosis. Few rice hybrids developed by using converted restorers were evaluated in multi location testing under the All India Co-ordinated Rice Improvement Project (AICRIP). The results indicated that new rice hybrids expressed higher heterosis with matching grain quality attributes like Swarna. This study provides significantly novel and relevant restorers to enhance and economize future hybrid rice breeding programs.
Benchmarking Deep Learning Architectures for Predicting Readmission to the ICU and Describing Patients-at-Risk
Authors: Barbieri Sebastiano , Kemp James , Perez-Concha Oscar , Kotwal Sradha , Gallagher Martin , Ritchie Angus , Jorm Louisa
Published: January 2020

To compare different deep learning architectures for predicting the risk of readmission within 30 days of discharge from the intensive care unit (ICU). The interpretability of attention-based models is leveraged to describe patients-at-risk. Several deep learning architectures making use of attention mechanisms, recurrent layers, neural ordinary differential equations (ODEs), and medical concept embeddings with time-aware attention were trained using publicly available electronic medical record data (MIMIC-III) associated with 45,298 ICU stays for 33,150 patients. Bayesian inference was used to compute the posterior over weights of an attention-based model. Odds ratios associated with an increased risk of readmission were computed for static variables. Diagnoses, procedures, medications, and vital signs were ranked according to the associated risk of readmission. A recurrent neural network, with time dynamics of code embeddings computed by neural ODEs, achieved the highest average precision of 0.331 (AUROC: 0.739, F1-Score: 0.372). Predictive accuracy was comparable across neural network architectures. Groups of patients at risk included those suffering from infectious complications, with chronic or progressive conditions, and for whom standard medical care was not suitable. Attention-based networks may be preferable to recurrent networks if an interpretable model is required, at only marginal cost in predictive accuracy.
Beneficial bile acid metabolism from Lactobacillus plantarum of food origin
Authors: Prete Roberta , Long Sarah Louise , Gallardo Alvaro Lopez , Gahan Cormac G. , Corsetti Aldo , Joyce Susan A.
Published: January 2020

Bile acid (BA) signatures are altered in many disease states. BA metabolism is an important microbial function to assist gut colonization and persistence, as well as microbial survival during gastro intestinal (GI) transit and it is an important criteria for potential probiotic bacteria. Microbes that express bile salt hydrolase (BSH), gateway BA modifying enzymes, are considered to have an advantage in the gut. This property is reported as selectively limited to gut-associated microbes. Food-associated microbes have the potential to confer health benefits to the human consumer. Here, we report that food associated Lactobacillus plantarum strains are capable of BA metabolism, they can withstand BA associated stress and propagate, a recognised important characteristic for GIT survival. Furthermore, we report that these food associated Lactobacillus plantarum strains have the selective ability to alter BA signatures in favour of receptor activation that would be beneficial to humans. Indeed, all of the strains examined showed a clear preference to alter human glycol-conjugated BAs, although clear strain-dependent modifications were also evident. This study demonstrates that BA metabolism by food-borne non-pathogenic bacteria is beneficial to both microbe and man and it identifies an evolutionary-conserved characteristic, previously considered unique to gut residents, among food-associated non-pathogenic isolates.
Evaluation of capsular contracture following immediate prepectoral versus subpectoral direct-to-implant breast reconstruction
Authors: Sobti Nikhil , Weitzman Rachel E. , Nealon Kassandra P. , Jimenez Rachel B. , Gfrerer Lisa , Mattos David , Ehrlichman Richard J. , Gadd Michele , Specht Michelle , Austen William G. , Liao Eric C.
Published: January 2020

Capsular contracture is a common adverse outcome following implant breast reconstruction, often associated with radiation treatment. The authors hypothesize that muscle fibrosis is the main contributor of breast reconstruction contracture after radiation. Retrospective chart review identified patients that underwent DTI reconstruction with pre-or post-operative breast irradiation. Signs of capsular contracture were assessed using clinic notes and independent graders reviewing two-dimensional images and anatomic landmarks. Capsular contracture rate was greater in the subpectoral vs. prepectoral group (n = 28, 51.8% vs. n = 12, 30.0%, p = 0.02). When compared to prepectoral DTI reconstruction in irradiated patients, subpectoral implant placement was nearly 4 times as likely to result in capsular contracture (p < 0.01). Rates of explantation, infection, tissue necrosis, and hematoma were comparable between groups. We also found that when subpectoral patients present with breast contracture, chemoparalysis of the muscle alone can resolve breast asymmetry, corroborating that muscle is a key contributor to breast contracture. As prepectoral breast reconstruction is gaining popularity, there have been questions regarding outcome following radiation treatment. This study suggest that prepectoral breast reconstruction is safe in an irradiated patient population, and in fact compares favorably with regard to breast contracture.
PDZRN3 protects against apoptosis in myoblasts by maintaining cyclin A2 expression
Authors: Honda Takeshi , Inui Makoto
Published: January 2020

PDZRN3 is a PDZ domain-containing RING-finger family protein that functions in various developmental processes. We previously showed that expression of PDZRN3 is induced together with that of MyoD during the early phase of skeletal muscle regeneration in vivo. We here show that PDZRN3 suppresses apoptosis and promotes proliferation in myoblasts in a manner dependent on cyclin A2. Depletion of PDZRN3 in mouse C2C12 myoblasts by RNA interference reduced the proportion of Ki-67-positive cells and the level of Akt phosphorylation, implicating PDZRN3 in regulation of both cell proliferation and apoptosis. Exposure of C2C12 cells as well as of C3H10T1/2 mesenchymal stem cells and NIH-3T3 fibroblasts to various inducers of apoptosis including serum deprivation resulted in a greater increase in the amount of cleaved caspase-3 in PDZRN3-depleted cells than in control cells. The abundance of cyclin A2 was reduced in PDZRN3-depleted C2C12 myoblasts, as was that of Mre11, which contributes to the repair of DNA damage. Overexpression of cyclin A2 restored the expression of Mre11 and Ki-67 as well as attenuated caspase-3 cleavage in PDZRN3-depleted cells deprived of serum. These results indicate that PDZRN3 suppresses apoptosis and promotes proliferation in myoblasts and other cell types by maintaining cyclin A2 expression.
Transcriptome analysis of potato shoots, roots and stolons under nitrogen stress
Authors: Tiwari Jagesh Kumar , Buckseth Tanuja , Zinta Rasna , Saraswati Aastha , Singh Rajesh Kumar , Rawat Shashi , Dua Vijay Kumar , Chakrabarti Swarup Kumar
Published: January 2020

Potato crop requires high dose of nitrogen (N) to produce high tuber yield. Excessive application of N causes environmental pollution and increases cost of production. Hence, knowledge about genes and regulatory elements is essential to strengthen research on N metabolism in this crop. In this study, we analysed transcriptomes (RNA-seq) in potato tissues (shoot, root and stolon) collected from plants grown in aeroponic culture under controlled conditions with varied N supplies i.e. low N (0.2 milli molar N) and high N (4 milli molar N). High quality data ranging between 3.25 to 4.93 Gb per sample were generated using Illumina NextSeq500 that resulted in 83.60–86.50% mapping of the reads to the reference potato genome. Differentially expressed genes (DEGs) were observed in the tissues based on statistically significance (p ≤ 0.05) and up-regulation with ≥ 2 log2 fold change (FC) and down-regulation with ≤ −2 log2 FC values. In shoots, of total 19730 DEGs, 761 up-regulated and 280 down-regulated significant DEGs were identified. Of total 20736 DEGs in roots, 572 (up-regulated) and 292 (down-regulated) were significant DEGs. In stolons, of total 21494 DEG, 688 and 230 DEGs were significantly up-regulated and down-regulated, respectively. Venn diagram analysis showed tissue specific and common genes. The DEGs were functionally assigned with the GO terms, in which molecular function domain was predominant in all the tissues. Further, DEGs were classified into 24 KEGG pathways, in which 5385, 5572 and 5594 DEGs were annotated in shoots, roots and stolons, respectively. The RT-qPCR analysis validated gene expression of RNA-seq data for selected genes. We identified a few potential DEGs responsive to N deficiency in potato such as glutaredoxin, Myb-like DNA-binding protein, WRKY transcription factor 16 and FLOWERING LOCUS T in shoots; high-affinity nitrate transporter, protein phosphatase-2c, glutaredoxin family protein, malate synthase, CLE7, 2-oxoglutarate-dependent dioxygenase and transcription factor in roots; and glucose-6-phosphate/phosphate translocator 2, BTB/POZ domain-containing protein, F-box family protein and aquaporin TIP1;3 in stolons, and many genes of unknown function. Our study highlights that these potential genes play very crucial roles in N stress tolerance, which could be useful in augmenting research on N metabolism in potato.
Discrimination of rosé wines using shotgun metabolomics with a genetic algorithm and MS ion intensity ratios
Authors: Gil Mélodie , Reynes Christelle , Cazals Guillaume , Enjalbal Christine , Sabatier Robert , Saucier Cédric
Published: January 2020

A rapid Ultra Performance Liquid Chromatography coupled with Quadrupole/Time Of Flight Mass Spectrometry (UPLC-QTOF-MS) method was designed to quickly acquire high-resolution mass spectra metabolomics fingerprints for rosé wines. An original statistical analysis involving ion ratios, discriminant analysis, and genetic algorithm (GA) was then applied to study the discrimination of rosé wines according to their origins. After noise reduction and ion peak alignments on the mass spectra, about 14 000 different signals were detected. The use of an in-house mass spectrometry database allowed us to assign 72 molecules. Then, a genetic algorithm was applied on two series of samples (learning and validation sets), each composed of 30 commercial wines from three different wine producing regions of France. Excellent results were obtained with only four diagnostic peaks and two ion ratios. This new approach could be applied to other aspects of wine production but also to other metabolomics studies.
A misprocessed form of Apolipoprotein A-I is specifically associated with recurrent Focal Segmental Glomerulosclerosis
Authors: Jacobs-Cachá Conxita , Puig-Gay Natàlia , Helm Dominic , Rettel Mandy , Sellarès Joana , Meseguer Anna , Savitski Mikhail M. , Moreso Francesc J. , Soler Maria José , Seron Daniel , Lopez-Hellin Joan
Published: January 2020

Apolipoprotein A-Ib (ApoA-Ib) is a high molecular weight form of Apolipoprotein A-I (ApoA-I) found specifically in the urine of kidney-transplanted patients with recurrent idiopathic focal segmental glomerulosclerosis (FSGS). To determine the nature of the modification present in ApoA-Ib, we sequenced the whole APOA1 gene in ApoA-Ib positive and negative patients, and we also studied the protein primary structure using mass spectrometry. No genetic variations in the APOA1 gene were found in the ApoA-Ib positive patients that could explain the increase in its molecular mass. The mass spectrometry analysis revealed three extra amino acids at the N-Terminal end of ApoA-Ib that were not present in the standard plasmatic form of ApoA-I. These amino acids corresponded to half of the propeptide sequence of the immature form of ApoA-I (proApoA-I) indicating that ApoA-Ib is a misprocessed form of proApoA-I. The description of ApoA-Ib could be relevant not only because it can allow the automated analysis of this biomarker in the clinical practice but also because it has the potential to shed light into the molecular mechanisms that cause idiopathic FSGS, which is currently unknown.
Publisher Correction: Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C
Authors: Baiocchini Andrea , Del Nonno Franca , Taibi Chiara , Visco-Comandini Ubaldo , D’Offizi Gianpiero , Piacentini Mauro , Falasca Laura
Published: January 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Quality of life in people with ongoing symptoms of coeliac disease despite adherence to a strict gluten-free diet
Authors: Harnett Joanna E. , Myers Stephen P.
Published: January 2020

People with Coeliac disease who suffer persistent symptoms despite adherence to a gluten-free diet are at a greater risk of a reduced health related quality of life. The purpose of this paper is to report the quality of life experienced by this specific group of patients in Australia. A Coeliac Disease Specific Questionnaire (CDQ) was administered to 45 people who were enrolled in a clinical trial and reported persistent symptoms of Coeliac disease despite adherence to a strict gluten free diet. The clinical trial was based in New South Wales, Australia. The instrument used was a subscale and total scores of a CDQ measuring health related quality of life. At baseline the overall mean CDQ score was 147 ± 3.31 (optimum 196) consisting of 4 subscales; gastrointestinal 33 ± 0.88, emotional 32.9 ± 0.99, worries 39.8 ± 0.79 and social 41 ± 6.12 each with a potential score of 49. The health related quality of life of people reporting persistent symptoms of Coeliac disease despite adherence to a gluten free diet is sub-optimal with concerningly low scores for emotional quality.