bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila
Authors: Andreazza Simonetta , Samstag Colby L. , Sanchez-Martinez Alvaro , Fernandez-Vizarra Erika , Gomez-Duran Aurora , Lee Juliette J. , Tufi Roberta , Hipp Michael J. , Schmidt Elizabeth K. , Nicholls Thomas J. , Gammage Payam A. , Chinnery Patrick F. , Minczuk Michal , Pallanck Leo J. , Kennedy Scott R. , Whitworth Alexander J.
Published: July 2019

Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. mito-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and mito-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make mito-APOBEC1 an excellent mtDNA mutator model for ageing research.
The cascade of global trade to large climate forcing over the Tibetan Plateau glaciers
Authors: Yi Kan , Meng Jing , Yang Haozhe , He Cenlin , Henze Daven K. , Liu Junfeng , Guan Dabo , Liu Zhu , Zhang Lin , Zhu Xi , Cheng Yanli , Tao Shu
Published: July 2019

Black carbon (BC) aerosols constitute unique and important anthropogenic climate forcers that potentially accelerate the retreat of glaciers over the Himalayas and Tibetan Plateau (HTP). Here we show that a large amount of BC emissions produced in India and China—a region of BC emissions  to which the HTP is more vulnerable compared with other regions—are related to the consumption of goods and services in the USA and Europe through international trade. These processes lead to a virtual transport pathway of BC from distant regions to the HTP glaciers. From a consumption perspective, the contribution from India to the HTP glaciers shows a rapid increasing trend while the contributions from the USA, Europe, and China decreased over the last decade. International trade aggravates the BC pollution over the HTP glaciers and may cause significant climate change there. Global efforts toward reducing the cascading of BC emissions to Asia, especially the Indian subcontinent, are urgently needed.
Adaptive responses of animals to climate change are most likely insufficient
Authors: Radchuk Viktoriia , Reed Thomas , Teplitsky Céline , van de Pol Martijn , Charmantier Anne , Hassall Christopher , Adamík Peter , Adriaensen Frank , Ahola Markus P. , Arcese Peter , Miguel Avilés Jesús , Balbontin Javier , Berg Karl S. , Borras Antoni , Burthe Sarah , Clobert Jean , Dehnhard Nina , de Lope Florentino , Dhondt André A. , Dingemanse Niels J. , Doi Hideyuki , Eeva Tapio , Fickel Joerns , Filella Iolanda , Fossøy Frode , Goodenough Anne E. , Hall Stephen J. G. , Hansson Bengt , Harris Michael , Hasselquist Dennis , Hickler Thomas , Joshi Jasmin , Kharouba Heather , Martínez Juan Gabriel , Mihoub Jean-Baptiste , Mills James A. , Molina-Morales Mercedes , Moksnes Arne , Ozgul Arpat , Parejo Deseada , Pilard Philippe , Poisbleau Maud , Rousset Francois , Rödel Mark-Oliver , Scott David , Senar Juan Carlos , Stefanescu Constanti , Stokke Bård G. , Kusano Tamotsu , Tarka Maja , Tarwater Corey E. , Thonicke Kirsten , Thorley Jack , Wilting Andreas , Tryjanowski Piotr , Merilä Juha , Sheldon Ben C. , Pape Møller Anders , Matthysen Erik , Janzen Fredric , Dobson F. Stephen , Visser Marcel E. , Beissinger Steven R. , Courtiol Alexandre , Kramer-Schadt Stephanie
Published: July 2019

Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species.
Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism
Authors: Robert-Paganin Julien , Robblee James P. , Auguin Daniel , Blake Thomas C. A. , Bookwalter Carol S. , Krementsova Elena B. , Moussaoui Dihia , Previs Michael J. , Jousset Guillaume , Baum Jake , Trybus Kathleen M. , Houdusse Anne
Published: July 2019

Plasmodium parasites are obligate intracellular protozoa and causative agents of malaria, responsible for half a million deaths each year. The lifecycle progression of the parasite is reliant on cell motility, a process driven by myosin A, an unconventional single-headed class XIV molecular motor. Here we demonstrate that myosin A from Plasmodium falciparum (PfMyoA) is critical for red blood cell invasion. Further, using a combination of X-ray crystallography, kinetics, and in vitro motility assays, we elucidate the non-canonical interactions that drive this motor’s function. We show that PfMyoA motor properties are tuned by heavy chain phosphorylation (Ser19), with unphosphorylated PfMyoA exhibiting enhanced ensemble force generation at the expense of speed. Regulated phosphorylation may therefore optimize PfMyoA for enhanced force generation during parasite invasion or for fast motility during dissemination. The three PfMyoA crystallographic structures presented here provide a blueprint for discovery of specific inhibitors designed to prevent parasite infection.
The generation and use of recombinant extracellular vesicles as biological reference material
Authors: Geeurickx Edward , Tulkens Joeri , Dhondt Bert , Van Deun Jan , Lippens Lien , Vergauwen Glenn , Heyrman Elisa , De Sutter Delphine , Gevaert Kris , Impens Francis , Miinalainen Ilkka , Van Bockstal Pieter-Jan , De Beer Thomas , Wauben Marca H. M. , Nolte-‘t-Hoen Esther N. M. , Bloch Katarzyna , Swinnen Johannes V. , van der Pol Edwin , Nieuwland Rienk , Braems Geert , Callewaert Nico , Mestdagh Pieter , Vandesompele Jo , Denys Hannelore , Eyckerman Sven , De Wever Olivier , Hendrix An
Published: July 2019

Recent years have seen an increase of extracellular vesicle (EV) research geared towards biological understanding, diagnostics and therapy. However, EV data interpretation remains challenging owing to complexity of biofluids and technical variation introduced during sample preparation and analysis. To understand and mitigate these limitations, we generated trackable recombinant EV (rEV) as a biological reference material. Employing complementary characterization methods, we demonstrate that rEV are stable and bear physical and biochemical traits characteristic of sample EV. Furthermore, rEV can be quantified using fluorescence-, RNA- and protein-based technologies available in routine laboratories. Spiking rEV in biofluids allows recovery efficiencies of commonly implemented EV separation methods to be identified, intra-method and inter-user variability induced by sample handling to be defined, and to normalize and improve sensitivity of EV enumerations. We anticipate that rEV will aid EV-based sample preparation and analysis, data normalization, method development and instrument calibration in various research and biomedical applications.
Diagonal nematicity in the pseudogap phase of HgBa2CuO4+δ
Authors: Murayama H. , Sato Y. , Kurihara R. , Kasahara S. , Mizukami Y. , Kasahara Y. , Uchiyama H. , Yamamoto A. , Moon E.-G. , Cai J. , Freyermuth J. , Greven M. , Shibauchi T. , Matsuda Y.
Published: July 2019

The pseudogap phenomenon in the cuprates is arguably the most mysterious puzzle in the field of high-temperature superconductivity. The tetragonal cuprate HgBa2CuO4+δ, with only one CuO2 layer per primitive cell, is an ideal system to tackle this puzzle. Here, we measure the magnetic susceptibility anisotropy within the CuO2 plane with exceptionally high-precision magnetic torque experiments. Our key finding is that a distinct two-fold in-plane anisotropy sets in below the pseudogap temperature T*, which provides thermodynamic evidence for a nematic phase transition with broken four-fold symmetry. Surprisingly, the nematic director orients along the diagonal direction of the CuO2 square lattice, in sharp contrast to the bond nematicity along the Cu-O-Cu direction. Another remarkable feature is that the enhancement of the diagonal nematicity with decreasing temperature is suppressed around the temperature at which short-range charge-density-wave formation occurs. Our result suggests a competing relationship between diagonal nematic and charge-density-wave order in HgBa2CuO4+δ.
RIF1 promotes replication fork protection and efficient restart to maintain genome stability
Authors: Mukherjee Chirantani , Tripathi Vivek , Manolika Eleni Maria , Heijink Anne Margriet , Ricci Giulia , Merzouk Sarra , de Boer H. Rudolf , Demmers Jeroen , van Vugt Marcel A. T. M. , Ray Chaudhuri Arnab
Published: July 2019

Homologous recombination (HR) and Fanconi Anemia (FA) pathway proteins in addition to their DNA repair functions, limit nuclease-mediated processing of stalled replication forks. However, the mechanism by which replication fork degradation results in genome instability is poorly understood. Here, we identify RIF1, a non-homologous end joining (NHEJ) factor, to be enriched at stalled replication forks. Rif1 knockout cells are proficient for recombination, but displayed degradation of reversed forks, which depends on DNA2 nuclease activity. Notably, RIF1-mediated protection of replication forks is independent of its function in NHEJ, but depends on its interaction with Protein Phosphatase 1. RIF1 deficiency delays fork restart and results in exposure of under-replicated DNA, which is the precursor of subsequent genomic instability. Our data implicate RIF1 to be an essential factor for replication fork protection, and uncover the mechanisms by which unprotected DNA replication forks can lead to genome instability in recombination-proficient conditions.
Nanoscale mapping of quasiparticle band alignment
Authors: Ulstrup Søren , Giusca Cristina E. , Miwa Jill A. , Sanders Charlotte E. , Browning Alex , Dudin Pavel , Cacho Cephise , Kazakova Olga , Gaskill D. Kurt , Myers-Ward Rachael L. , Zhang Tianyi , Terrones Mauricio , Hofmann Philip
Published: July 2019

Control of atomic-scale interfaces between materials with distinct electronic structures is crucial for the design and fabrication of most electronic devices. In the case of two-dimensional materials, disparate electronic structures can be realized even within a single uniform sheet, merely by locally applying different vertical gate voltages. Here, we utilize the inherently nano-structured single layer and bilayer graphene on silicon carbide to investigate lateral electronic structure variations in an adjacent single layer of tungsten disulfide (WS2). The electronic band alignments are mapped in energy and momentum space using angle-resolved photoemission with a spatial resolution on the order of 500 nm (nanoARPES). We find that the WS2 band offsets track the work function of the underlying single layer and bilayer graphene, and we relate such changes to observed lateral patterns of exciton and trion luminescence from WS2.
Author Correction: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9
Authors: Croft Brittany , Ohnesorg Thomas , Hewitt Jacqueline , Bowles Josephine , Quinn Alexander , Tan Jacqueline , Corbin Vincent , Pelosi Emanuele , van den Bergen Jocelyn , Sreenivasan Rajini , Knarston Ingrid , Robevska Gorjana , Vu Dung Chi , Hutson John , Harley Vincent , Ayers Katie , Koopman Peter , Sinclair Andrew
Published: July 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Trace-free counterfactual communication with a nanophotonic processor
Authors: Alonso Calafell I. , Strömberg T. , Arvidsson-Shukur D. R. M. , Rozema L. A. , Saggio V. , Greganti C. , Harris N. C. , Prabhu M. , Carolan J. , Hochberg M. , Baehr-Jones T. , Englund D. , Barnes C. H. W. , Walther P.
Published: July 2019

In standard communication information is carried by particles or waves. Counterintuitively, in counterfactual communication particles and information can travel in opposite directions. The quantum Zeno effect allows Bob to transmit a message to Alice by encoding information in particles he never interacts with. A first remarkable protocol for counterfactual communication relied on thousands of ideal optical operations for high success rate performance. Experimental realizations of that protocol have thus employed post-selection to demonstrate counterfactuality. This post-selection, together with arguments concerning a so-called “weak trace” of the particles traveling from Bob to Alice, have led to a discussion regarding the counterfactual nature of the protocol. Here we circumvent these controversies, implementing a new, and fundamentally different, protocol in a programmable nanophotonic processor, based on reconfigurable silicon-on-insulator waveguides that operate at telecom wavelengths. This, together with our telecom single-photon source and highly efficient superconducting nanowire single-photon detectors, provides a versatile and stable platform for a high-fidelity implementation of counterfactual communication with single photons, allowing us to actively tune the number of steps in the Zeno measurement, and achieve a bit error probability below 1%, without post-selection and with a vanishing weak trace. Our demonstration shows how our programmable nanophotonic processor could be applied to more complex counterfactual tasks and quantum information protocols.
Comprehensive review on virtual reality for the treatment of violence: implications for youth with schizophrenia
Authors: Dellazizzo Laura , Potvin Stéphane , Bahig Sami , Dumais Alexandre
Published: July 2019

Youth violence is a complex and multifactorial issue that has severe health and social consequences. While treatment options exist to treat/reduce violence in at-risk populations such as schizophrenia, there remains limitations in the efficacy of current interventions. Virtual reality (VR) appears to be a unique possibility to expose offenders and to train coping skills in virtual situations that are capable of eliciting aggression‐relevant behavior without threatening others. The focus of this paper is to provide a comprehensive review of studies using VR to manage violence across several at-risk populations, with a particular emphasis on youth with schizophrenia. Despite the encouraging success of VR applications for the treatment of different mental health problems, no studies have explored the usability of VR to specifically treat violence in patients with schizophrenia. A limited number of studies have focused on violence risk factors in other mental health problems (i.e., emotion regulation in individual suffering from post-traumatic disorders) that may be targeted in treatments to reduce the risk of violence. The preliminary studies using VR as a therapeutic element have shown reductions in anger, improvements in conflict-resolution skills as well as in empathy levels, and decreases in aggression. Possible applications of these interventions in youth with schizophrenia will be discussed.
Author Correction: Superconducting Diamond on Silicon Nitride for Device Applications
Authors: Bland Henry A. , Thomas Evan L. H. , Klemencic Georgina M. , Mandal Soumen , Morgan David J. , Papageorgiou Andreas , Jones Tyrone G. , Williams Oliver A.
Published: July 2019

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.
Honeybee pupal length assessed by CT-scan technique: effects of Varroa infestation, developmental stage and spatial position within the brood comb
Authors: Facchini Elena , Nalon Laura , Andreis Maria Elena , Di Giancamillo Mauro , Rizzi Rita , Mortarino Michele
Published: July 2019

Honeybee pupae morphology can be affected by a number of stressor, but in vivo investigation is difficult. A computed tomography (CT) technique was applied to visualize a comb’s inner structure without damaging the brood. The CT scan was performed on a brood comb containing pupae developed from eggs laid by the queen during a time window of 48 hours. From the CT images, the position of each pupa was determined by recording coordinates to a common reference point. Afterwards, every brood cell was inspected in order to assess the developmental stage of the pupa, the presence of Varroa destructor, the number and progeny of foundress mites. Using data on 651 pupae, the relationships between varroa infestation status, developmental stage and spatial position of the pupa within the brood comb, and its length were investigated. Pupae at 8 post-capping days were shorter than pupae at 7 post-capping days. Pupae in infected cells were significantly shorter than those in varroa-free cells and this effect was linked both to mite number and stage and to the position in the comb. Overall, the results suggest that the CT-scan may represent a suitable non-invasive tool to investigate the morphology and developing status of honeybee brood.
Coupled feedback regulation of nuclear factor of activated T-cells (NFAT) modulates activation-induced cell death of T cells
Authors: Shin Sung-Young , Kim Min-Wook , Cho Kwang-Hyun , Nguyen Lan K.
Published: July 2019

A properly functioning immune system is vital for an organism’s wellbeing. Immune tolerance is a critical feature of the immune system that allows immune cells to mount effective responses against exogenous pathogens such as viruses and bacteria, while preventing attack to self-tissues. Activation-induced cell death (AICD) in T lymphocytes, in which repeated stimulations of the T-cell receptor (TCR) lead to activation and then apoptosis of T cells, is a major mechanism for T cell homeostasis and helps maintain peripheral immune tolerance. Defects in AICD can lead to development of autoimmune diseases. Despite its importance, the regulatory mechanisms that underlie AICD remain poorly understood, particularly at an integrative network level. Here, we develop a dynamic multi-pathway model of the integrated TCR signalling network and perform model-based analysis to characterize the network-level properties of AICD. Model simulation and analysis show that amplified activation of the transcriptional factor NFAT in response to repeated TCR stimulations, a phenomenon central to AICD, is tightly modulated by a coupled positive-negative feedback mechanism. NFAT amplification is predominantly enabled by a positive feedback self-regulated by NFAT, while opposed by a NFAT-induced negative feedback via Carabin. Furthermore, model analysis predicts an optimal therapeutic window for drugs that help minimize proliferation while maximize AICD of T cells. Overall, our study provides a comprehensive mathematical model of TCR signalling and model-based analysis offers new network-level insights into the regulation of activation-induced cell death in T cells.
The effects of valve leaflet mechanics on lymphatic pumping assessed using numerical simulations
Authors: Li Huabing , Mei Yumeng , Maimon Nir , Padera Timothy P. , Baish James W. , Munn Lance L.
Published: July 2019

The lymphatic system contains intraluminal leaflet valves that function to bias lymph flow back towards the heart. These valves are present in the collecting lymphatic vessels, which generally have lymphatic muscle cells and can spontaneously pump fluid. Recent studies have shown that the valves are open at rest, can allow some backflow, and are a source of nitric oxide (NO). To investigate how these valves function as a mechanical valve and source of vasoactive species to optimize throughput, we developed a mathematical model that explicitly includes Ca2+ -modulated contractions, NO production and valve structures. The 2D lattice Boltzmann model includes an initial lymphatic vessel and a collecting lymphangion embedded in a porous tissue. The lymphangion segment has mechanically-active vessel walls and is flanked by deformable valves. Vessel wall motion is passively affected by fluid pressure, while active contractions are driven by intracellular Ca2+ fluxes. The model reproduces NO and Ca2+ dynamics, valve motion and fluid drainage from tissue. We find that valve structural properties have dramatic effects on performance, and that valves with a stiffer base and flexible tips produce more stable cycling. In agreement with experimental observations, the valves are a major source of NO. Once initiated, the contractions are spontaneous and self-sustained, and the system exhibits interesting non-linear dynamics. For example, increased fluid pressure in the tissue or decreased lymph pressure at the outlet of the system produces high shear stress and high levels of NO, which inhibits contractions. On the other hand, a high outlet pressure opposes the flow, increasing the luminal pressure and the radius of the vessel, which results in strong contractions in response to mechanical stretch of the wall. We also find that the location of contraction initiation is affected by the extent of backflow through the valves.
A critical role of autophagy in regulating the mesenchymal transition of ductular cells in liver cirrhosis
Authors: Hung Tzu-Min , Huang Yu-Jen , Lin Yu-Chun , Chen Yu-Hsuan , Wu Yao-Ming , Lee Po-Huang
Published: July 2019

Our previous studies have shown that autophagy mediates the link between ductular reaction (DR) and liver cirrhosis. Whether the subsequent fibrogenic response is regulated by increased autophagy in DR remains unclear. Here, using both human liver specimens and a rat model of liver cirrhosis induced by 2-acetylaminofluorene (AAF) and carbon tetrachloride (CCL4), we explored the involvement of autophagy in regulating mesenchymal transition of ductular cells. Ductular cells from AAF/CCL4 livers exhibited increased autophagy compared to those of normal livers. These cells showed morphological and functional characteristics of mesenchymal cells. Blocking autophagy using bafilomycin A1 or siRNA targeting ATG7 reduced the expression of mesenchymal markers in these ductular cells from AAF/CCL4 livers, indicating a role for autophagy in regulating the mesenchymal phenotype of ductular cells. Furthermore, we show that the mesenchymal transition in DR requires the activation of transforming growth factor-β (TGF-β) signaling in an autophagy-dependent manner. Importantly, in cirrhotic human livers, ductular cells that are positive for LC3B also showed increased expression of TGF-β and fibroblast-specific protein-1. Our data suggest activation of autophagy in ductular cells, and also demonstrate that it is required for the mesenchymal transition during the DR, processes that are critically involved in the pathogenesis of cirrhosis.
Author Correction: Rice intermediate filament, OsIF, stabilizes photosynthetic machinery and yield under salinity and heat stress
Authors: Soda Neelam , Gupta Brijesh K. , Anwar Khalid , Sharan Ashutosh , Govindjee  , Singla-Pareek Sneh L. , Pareek Ashwani
Published: July 2019

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.
Author Correction: Temperature Chaos, Memory Effect, and Domain Fluctuations in the Spiral Antiferromagnet Dy
Authors: Kustov Sergey , Liubimova Iuliia , Corró Miguel , Torrens-Serra Joan , Wang Xiebin , Haines Charles R. S. , Salje Ekhard K. H.
Published: July 2019

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.
Energy-flux control of the steady-state, creep, and dynamic slip modes of faults
Authors: Reches Ze’ev , Zu Ximeng , Carpenter Brett M.
Published: July 2019

Faults exhibit a gamut of slip styles from stable sliding and creep events to earthquakes. These slip styles are affected by the fault properties, e.g., weakening or strengthening, and the properties of the loading system. Here, we investigate the poorly understood effect of energy-flux to the fault that should equal or exceed the energy-dissipation-rate along the slipping fault. We explore the relationship between energy-flux and slip style in shear experiments along granite and diorite laboratory faults, during which the faults were subjected to controlled energy-flux, and responded spontaneously to it. The monitored evolution of slip-velocity, shear stress, and slip-distance revealed three slip styles that depend on the applied energy-flux: (1) steady-state slip; (2) spontaneous creep events of small displacement with negligible weakening; and (3) spontaneous, unstable events with slip-velocities up to 0.8 m/s, slip-distances up to 0.5 m, and stress-drops up to 1 MPa, which are comparable to observed values of moderate earthquakes. These slip styles are similar in character to those observed along natural faults. We further propose that the rate of energy flow from crustal blocks can control the slip velocity during earthquakes.
Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy
Authors: Vedvyas Yogindra , McCloskey Jaclyn E. , Yang Yanping , Min Irene M. , Fahey Thomas J. , Zarnegar Rasa , Hsu Yen-Michael S. , Hsu Jing-Mei , Van Besien Koen , Gaudet Ian , Law Ping , Kim Nak Joon , Hofe Eric von , Jin Moonsoo M.
Published: July 2019

While the majority of thyroid cancer patients are easily treatable, those with anaplastic or poorly differentiated recurrent thyroid carcinomas have a very poor prognosis with a median survival of less than a year. Previously, we have shown a significant correlation between ICAM-1 overexpression and malignancy in thyroid cancer, and have pioneered the use of ICAM-1 targeted CAR T cells as a novel treatment modality. For clinical translation of this novel modality, we designed CAR T cells possessing micromolar rather than nanomolar affinity to ICAM-1 to avoid cytotoxicity in normal cells with basal levels of ICAM-1 expression. Herein, we report the automated process of CAR T cell manufacturing with CliniMACS Prodigy (Miltenyi Biotec) using cryopreserved peripheral blood leukocytes from apheresis collections. Using Prodigy, thawed leukopak cells were enriched for CD4+and CD8+T cells, subjected to double transduction using lentiviral vector, and expanded in culture for a total of 10 days with a final yield of 2–4 × 109cells. The resulting CAR T cells were formulated for cryopreservation to be used directly for infusion into patients after thawing with no further processing. We examined cross-reactivity of CAR T cells toward both human and murine ICAM-1 and ICAM-1 expression in human and mouse tissues to demonstrate that both efficacy and on-target, off-tumor toxicity can be studied in our preclinical model. Selective anti-tumor activity in the absence of toxicity provides proof-of-concept that micromolar affinity tuned CAR T cells can be used to target tumors expressing high levels of antigen while avoiding normal tissues expressing basal levels of the same antigen. These studies support the initiation of a phase I study to evaluate the safety and potential efficacy of micromolar affinity tuned CAR T cells against newly diagnosed anaplastic and refractory or recurrent thyroid cancers.
MTP18 is a Novel Regulator of Mitochondrial Fission in CNS Neuron Development, Axonal Growth, and Injury Responses
Authors: Kreymerman Alexander , Buickians David N. , Nahmou Michael M. , Tran Tammy , Galvao Joana , Wang Yan , Sun Nicholas , Bazik Leah , Huynh Star K. , Cho In-Jae , Boczek Tomasz , Chang Kun-Che , Kunzevitzky Noelia J. , Goldberg Jeffrey L.
Published: July 2019

The process of mitochondrial fission-fusion has been implicated in diverse neuronal roles including neuronal survival, axon degeneration, and axon regeneration. However, whether increased fission or fusion is beneficial for neuronal health and/or axonal growth is not entirely clear, and is likely situational and cell type-dependent. In searching for mitochondrial fission-fusion regulating proteins for improving axonal growth within the visual system, we uncover that mitochondrial fission process 1,18 kDa (MTP18/MTFP1), a pro-fission protein within the CNS, is critical to maintaining mitochondrial size and volume under normal and injury conditions, in retinal ganglion cells (RGCs). We demonstrate that MTP18’s expression is regulated by transcription factors involved in axonal growth, Kruppel-like factor (KLF) transcription factors-7 and -9, and that knockdown of MTP18 promotes axon growth. This investigation exposes MTP18’s previously unexplored role in regulating mitochondrial fission, implicates MTP18 as a downstream component of axon regenerative signaling, and ultimately lays the groundwork for investigations on the therapeutic efficacy of MTP18 expression suppression during CNS axon degenerative events.
Achieving excellent microformability in aluminum by engineering a unique ultrafine-grained microstructure
Authors: Dhal A. , Panigrahi S. K. , Shunmugam M. S.
Published: July 2019

During microforming of conventional materials, specimen and microstructural length-scales are close to each other. This leads to an abnormal deformation behavior of the material and reduces microformability. Engineering ultrafine-grained (UFG) microstructure in the material is a possible solution. However, micro-scale deformation behavior of UFG material is not fully understood. Present work attempts to comprehensively investigate the micro-scale deformation of four distinctly engineered microstructures: UFG with residual dislocations and elongated grains, UFG free of residual dislocation with equiaxed grains, bimodal-grained and coarse-grained. The deformation behavior is captured via micro-scale uniaxial tensile test and micro-deep drawing operation. Micro-cups generated from UFG material with equiaxed grains show excellent surface quality, form-accuracy and minimal process scatter. Postmortem microscopy of the formed micro-cups attributes this improved microformability to the activation of grain boundary-mediated plasticity in the material which results in synergetic grain migration and rotation. Presence of residual dislocations and elongated grains hinders the grain migration and rotation leading to strain localization and thinning. In case of bimodal and coarse-grained material, cross-slip based deformation mode progressively dominates over grain migration and rotation, which results in a reduction in microformability due to the influence of size-effect.
A collagen-based microwell migration assay to study NK-target cell interactions
Authors: Olofsson Per E. , Brandt Ludwig , Magnusson Klas E. G. , Frisk Thomas , Jaldén Joakim , Önfelt Björn
Published: July 2019

Natural killer (NK) cell cytotoxicity in tissue is dependent on the ability of NK cells to migrate through the extracellular matrix (ECM) microenvironment. Traditional imaging studies of NK cell migration and cytotoxicity have utilized 2D surfaces, which do not properly reproduce the structural and mechanical cues that shape the migratory response of NK cells in vivo. Here, we have combined a microwell assay that allows long-term imaging and tracking of small, well-defined populations of NK cells with an interstitial ECM-like matrix. The assay allows for long-term imaging of NK–target cell interactions within a confined 3D volume. We found marked differences in motility between individual cells with a small fraction of the cells moving slowly and being confined to a small volume within the matrix, while other cells moved more freely. A majority of NK cells also exhibited transient variation in their motility, alternating between periods of migration arrest and movement. The assay could be used as a complement to in vivo imaging to study human NK cell heterogeneity in migration and cytotoxicity.
Impact of intrapartum and postnatal antibiotics on the gut microbiome and emergence of antimicrobial resistance in infants
Authors: Tapiainen Terhi , Koivusaari Pirjo , Brinkac Lauren , Lorenzi Hernan A. , Salo Jarmo , Renko Marjo , Pruikkonen Hannele , Pokka Tytti , Li Weizhong , Nelson Karen , Pirttilä Anna Maria , Tejesvi Mysore V.
Published: July 2019

Altogether, 20–30% of women receive intrapartum antibiotic prophylaxis (IAP) to prevent sepsis in infants and 2–5% of newborn infants receive antibiotics due to suspected sepsis. Caesarean section has a long-term impact on the intestinal microbiome but the effects of perinatal antibiotics on gut microbiome in vaginally delivered infants are not well known. We compared the impact of IAP, postnatal antibiotics, or their combination on the gut microbiome and emergence of antimicrobial resistance in a controlled study of 149 newborn infants recruited within 24 hours after birth. We collected 659 fecal samples, including 426 daily samples from infants before discharge from the hospital and 111 follow-up samples at six months. Penicillin was mostly used for IAP and the combination of penicillin and aminoglycoside for postnatal treatment. Postnatal antibiotic groups received Lactobacillus reuteri probiotic. Newborn gut colonization differed in both IAP and postnatal antibiotics groups as compared to that in control group. The effect size of IAP was comparable to that caused by postnatal antibiotics. The observed differences were still present at six months and not prevented by lactobacilli consumption. Given the present clinical results, the impact of perinatal antibiotics on the subsequent health of newborn infants should be further evaluated.
Building carbon structures inside hollow carbon spheres
Authors: Gangatharan Prakash M. , Maubane-Nkadimeng Manoko S. , Coville Neil J.
Published: July 2019

The synthesis and characterization of helical carbon nanofibers (CNFs) contained within a fully confined nanoreactor is described. In particular, hollow carbon spheres (od = ca. 310 nm; wall thickness ca. 20 nm) were infiltrated with Cu ions (1%) to produce CuO particles (<10 nm) and the CuO was converted to Cu particles at temperature of 300 °C. Acetylene was then used as a carbon source to grow helical CNFs within the hollow carbon spheres. The diameter and helicity of the CNFs was influenced by the Cu content within a hollow carbon sphere, the limited Cu sintering inside a sphere as well as the dimensions of the sphere. The procedures employed suggest that the philosophy of building other structures (and molecules) with any elements within confined nanoreactors is possible.
Non-invasive evaluation of renal structure and function of healthy individuals with multiparametric MRI: Effects of sex and age
Authors: Li Xue-Ming , Yang Ling , Reng Jing , Xu Guo-Hui , Zhou Peng
Published: July 2019

Clinically, when applying multiparametric magnetic resonance imaging (MRI) examinations in renal diseases, assessment of renal structure and function has to account for age- and sex-related effects. The aim of this study was to investigate the influence of age and sex on multiparametric MRI assessment of renal structure and function in healthy human beings. Studies on 33 healthy volunteers were performed using multiparametric MRI on a 3.0-Tesla MR scanner, including T1-weighted imaging, blood oxygen level-dependent MRI (BOLD MRI), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI). Our results revealed that the mean renal cortical thickness (RCT), ratio of cortex to parenchyma (CPR), and cortical R2* values were higher in males than in females. The cortical R2* value was higher in older group than in younger group (18.57 ± 0.99 vs 17.53 ± 0.58, p = 0.001); there was no significant difference in medullary R2* between the older and younger groups (38.18 ± 2.96 vs 36.45 ± 2.47, p = 0.077). The parenchymal thickness (PT) and medullary fractional anisotropy (FA) were lower in older group than in younger group (1.547 ± 0.06 vs 1.604 ± 0.05, p = 0.005 and 0.343 ± 0.03 vs 0.371 ± 0.03, p = 0.016, respectively). Pearson’s correlation analysis showed that PT and medullary FA were inversely related with age (r = −0.483, p = 0.004; r = −0.446, p = 0.009) while cortical R2* values was positively related (r = 0.511, p = 0.002, respectively). The medullary apparent diffusion coefficient (ADC) value had a significant association with PT (r = 0.359, p = 0.04). This study indicated that multiparametric renal MRI parameters are age and sex dependent.
Dissolution of a fibrous peptide by terahertz free electron laser
Authors: Kawasaki Takayasu , Tsukiyama Koichi , Irizawa Akinori
Published: July 2019

Fibrous peptides such as amyloid fibrils have various roles in biological system, e.g., as causal factor of serious amyloidosis in human and as functional regulator of cell formation in bacteria and eukaryotes. In addition, the fiber-type format is promising as biocompatible scaffold. Therefore, the dissolution method of peptide fibril is potentially useful at many scenes in medical and material fields: as reductive way of pathogenic amyloid, as modification technique of cell structure, and as fabrication tool of biomaterials. However, the fibril structure is generally difficult to be dissociated due to its rigid stacked conformation. Here, we propose a physical engineering technology using terahertz free electron laser (FEL) at far-infrared wavelengths from 70 to 80 μm. Infrared microscopy analysis of the irradiated fibril of calcitonin peptide as a model showed that β-sheet was decreased, and α-helix, turn, and others were increased, compared to those of the fibril before the FEL irradiation. Interestingly, the dissociative effect by the far-infrared laser was remarkable than that by the mid-infrared laser tuned to 6.1 μm that corresponds to amide I. In addition, simple heating at 363 K deformed the fibril state but increased the amount of β-sheet, which was contrast with the action by the FEL, and scanning-electron microscopy and Congo-red staining revealed that the fibril was collapsed power-dependently within a range from 25 to 900 mJ energies supplied with the FEL at 74 μm. It can be considered that irradiation of intense terahertz wave can dissociate fibrous conformation of peptide with little influence of thermal effect.
Tryptophan Oxidation in the UQCRC1 Subunit of Mitochondrial Complex III (Ubiquinol-Cytochrome C Reductase) in a Mouse Model of Myodegeneration Causes Large Structural Changes in the Complex: A Molecular Dynamics Simulation Study
Authors: Unni Sruthi , Thiyagarajan S. , Srinivas Bharath M. M. , Padmanabhan B.
Published: July 2019

Muscle diseases display mitochondrial dysfunction and oxidative damage. Our previous study in a cardiotoxin model of myodegeneration correlated muscle damage with mitochondrial dysfunction, which in turn entailed altered mitochondrial proteome and oxidative damage of mitochondrial proteins. Proteomic identification of oxidized proteins in muscle biopsies from muscular dystrophy patients and cardiotoxin model revealed specific mitochondrial proteins to be targeted for oxidation. These included respiratory complexes which displayed oxidative modification of Trp residues in different subunits. Among these, Ubiquinol-Cytochrome C Reductase Core protein 1 (UQCRC1), a subunit of Ubiquinol-Cytochrome C Reductase Complex or Cytochrome b-c1 Complex or Respiratory Complex III displayed oxidation of Trp395, which could be correlated with the lowered activity of Complex III. We hypothesized that Trp395 oxidation might contribute to altered local conformation and overall structure of Complex III, thereby potentially leading to altered protein activity. To address this, we performed molecular dynamics simulation of Complex III (oxidized at Trp395 of UQCRC1 vs. non-oxidized control). Molecular dynamic simulation analyses revealed local structural changes in the Trp395 site. Intriguingly, oxidized Trp395 contributed to decreased plasticity of Complex III due to significant cross-talk among the subunits in the matrix-facing region and subunits in the intermembrane space, thereby leading to impaired electron flow from cytochrome C.
Transcriptomics of a KDELR1 knockout cell line reveals modulated cell adhesion properties
Authors: Blum Andrea , Khalifa Saleem , Nordström Karl , Simon Martin , Schulz Marcel H. , Schmitt Manfred J.
Published: July 2019

KDEL receptors (KDELRs) represent transmembrane proteins of the secretory pathway which regulate the retention of soluble ER-residents as well as retrograde and anterograde vesicle trafficking. In addition, KDELRs are involved in the regulation of cellular stress response and ECM degradation. For a deeper insight into KDELR1 specific functions, we characterised a KDELR1-KO cell line (HAP1) through whole transcriptome analysis by comparing KDELR1-KO cells with its respective HAP1 wild-type. Our data indicate more than 300 significantly and differentially expressed genes whose gene products are mainly involved in developmental processes such as cell adhesion and ECM composition, pointing out to severe cellular disorders due to a loss of KDELR1. Impaired adhesion capacity of KDELR1-KO cells was further demonstrated through in vitro adhesion assays, while collagen- and/or laminin-coating nearly doubled the adhesion property of KDELR1-KO cells compared to wild-type, confirming a transcriptional adaptation to improve or restore the cellular adhesion capability. Perturbations within the secretory pathway were verified by an increased secretion of ER-resident PDI and decreased cell viability under ER stress conditions, suggesting KDELR1-KO cells to be severely impaired in maintaining cellular homeostasis.
Evolutionary history of teleost intron-containing and intron-less rhodopsin genes
Authors: Fujiyabu Chihiro , Sato Keita , Utari Ni Made Laksmi , Ohuchi Hideyo , Shichida Yoshinori , Yamashita Takahiro
Published: July 2019

Recent progress in whole genome sequencing has revealed that animals have various kinds of opsin genes for photoreception. Among them, most opsin genes have introns in their coding regions. However, it has been known for a long time that teleost retinas express intron-less rhodopsin genes, which are presumed to have been formed by retroduplication from an ancestral intron-containing rhodopsin gene. In addition, teleosts have an intron-containing rhodopsin gene (exo-rhodopsin) exclusively for pineal photoreception. In this study, to unravel the evolutionary origin of the two teleost rhodopsin genes, we analyzed the rhodopsin genes of non-teleost fishes in the Actinopterygii. The phylogenetic analysis of full-length sequences of bichir, sturgeon and gar rhodopsins revealed that retroduplication of the rhodopsin gene occurred after branching of the bichir lineage. In addition, analysis of the tissue distribution and the molecular properties of bichir, sturgeon and gar rhodopsins showed that the abundant and exclusive expression of intron-containing rhodopsin in the pineal gland and the short lifetime of its meta II intermediate, which leads to optimization for pineal photoreception, were achieved after branching of the gar lineage. Based on these results, we propose a stepwise evolutionary model of teleost intron-containing and intron-less rhodopsin genes.
Douglas fir stimulates nitrification in French forest soils
Authors: Zeller Bernd , Legout Arnaud , Bienaimé Séverine , Gratia Bruno , Santenoise Philippe , Bonnaud Pascal , Ranger Jacques
Published: July 2019

Douglas fir trees presumable stimulate nitrification in the soil. We studied in 21 French Douglas fir forests if and how nitrification is modulated by soil properties, past land use and current forest management. Soil (0–10 cm depth) was collected and initial concentrations of N-NH4+ and N-NO3−, potential net nitrogen mineralization (PNM) and net nitrification (PNN) rates and microbial biomass were measured. At 11 of the 21 sites, annual nitrate fluxes in the soil were measured using anion exchange resin bags. Soils contained between 2.3 to 29.4 mg N-NO3− kg soil−1. About 86% (±14%) of mineral N was nitrate. The proportion of nitrate increased to almost 100% during incubation. PNN varied from 0.10 mg N kg soil−1 day−1 to 1.05 mg N kg soil−1 day−1 (21 sites). Neither the initial nitrate concentration nor PNN was related to soil chemistry (pH, % C, %N, P, CEC), microbial biomass, texture, past land use or thinning. In situ net nitrate accumulation (NNA) estimated with resins beds varied from 4 to 100 kg N-NO3− ha−1 yr−1 (11 sites). It was positively correlated with base saturation, clay content, ELLENBERG N, temperature and negatively with soil organic N, C/N ratio and precipitation.
Contrasting associations between breeding coloration and parasitism of male Arctic charr relate to parasite species and life cycle stage
Authors: Johansen I. B. , Henriksen E. H. , Shaw J. C. , Mayer I. , Amundsen P.-A. , Øverli Ø.
Published: July 2019

Conspicuous carotenoid ornamentation is considered a signal of individual “quality” and one of the most intensely studied traits found to co-vary with parasitism. Since it has been suggested that only “high quality” individuals have enough resources to express excessive sexual ornaments and resist parasites, current theory struggles to explain cases where the brightest individuals carry the most parasites. Surprisingly little emphasis has been put on the contrasting routes to fitness utilized by different parasite species inhabiting the same host. Using Arctic charr (Salvelinus alpinus) as model species, we hypothesized that skin redness and allocation of carotenoids between skin and muscle (redness ratio) will be positively and negatively associated with parasites using the fish as an intermediate and final host, respectively. Both pigment parameters were indeed positively associated with abundances of parasites awaiting trophic transmission (Diplostomum sp. and Diphyllobothrium spp.) and negatively associated with the abundance of adult Eubothrium salvelini tapeworms. These empirical data demonstrate that contrasting associations between carotenoid coloration and parasite intensities relates to the specific premises of different parasite species and life cycle stages.