bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global Observations and CMIP6 Simulations of Compound Extremes of Monthly Temperature and Precipitation
Authors: Wu Yi , Miao Chiyuan , Sun Ying , AghaKouchak Amir , Shen Chenwei , Fan Xuewei 
Published: May 2021

AbstractCompound climate extremes, such as events with concurrent temperature and precipitation extremes, have significant impacts on the health of humans and ecosystems. This paper aims to analyze temporal and spatial characteristics of compound extremes of monthly temperature and precipitation, evaluate the performance of the sixth phase of the Coupled Model Intercomparison Project (CMIP6) models in simulating compound extremes, and investigate their future changes under Shared Socioeconomic Pathways (SSPs). The results show a significant increase in the frequency of compound warm extremes (warm/dry and warm/wet) but a decrease in compound cold extremes (cold/dry and cold/wet) during 1985–2014 relative to 1955–1984. The observed upward trends of compound warm extremes over China are much higher than those worldwide during the period of interest. A multi‐model ensemble (MME) of CMIP6 models performs well in simulating temporal changes of warm/wet extremes, and temporal correlation coefficients between MME and observations are above 0.86. Under future scenarios, CMIP6 simulations show substantial rises in compound warm extremes and declines in compound cold extremes. Globally, the average frequency of warm/wet extremes over a 30‐yr period is projected to increase for 2070–2099 relative to 1985–2014 by 18.53, 34.15, 48.79, and 59.60 under SSP1‐2.6, SSP2‐4.5, SSP3‐7.0, and SSP5‐8.5, respectively. Inter‐model uncertainties for the frequencies of compound warm extremes are considerably higher than those of compound cold extremes. The projected uncertainties in the global occurrences of warm/wet extremes are 3.82 times those of warm/dry extremes during 2070–2099 and especially high for the Amazon and the Tibetan Plateau.
A Multi‐Instrument Study of a Dipolarization Event in the Inner Magnetosphere
Authors: Matsui H. , Torbert R. B. , Spence H. E. , Argall M. R. , Cohen I. J. , Cooper M. B. , Ergun R. E. , Farrugia C. J. , Fennell J. F. , Fuselier S. A. , Gkioulidou M. , Khotyaintsev Yu. V. , Lindqvist P.‐A. , Matsuoka A. , Russell C. T. , Shoji M. , Strangeway R. J. , Turner D. L. , Vaith H. , Wygant J. R. 
Published: May 2021

AbstractA dipolarization of the background magnetic field was observed during a conjunction of the Magnetospheric Multiscale (MMS) spacecraft and Van Allen Probe B on September 22, 2018. The spacecraft were located in the inner magnetosphere at L ∼ 6–7 just before midnight magnetic local time (MLT). The radial separation between MMS and Probe B was ∼1RE. Gradual dipolarization or an increase of the northward component BZ of the background field occurred on a timescale of minutes. Exploration of energization and Radiation in Geospace located 0.5 MLT eastward at a similar L shell also measured a gradual increase. The spatial scale was of the order of 1 RE. On top of that, MMS and Probe B measured BZ increases, and a decrease in one case, on a timescale of seconds, accompanied by large electric fields with amplitudes > several tens of mV/m. Spatial scale lengths were of the order of the ion inertial length and the ion gyroradius. The inertial term in the momentum equation and the Hall term in the generalized Ohm's law were sometimes non‐negligible. These small‐scale variations are discussed in terms of the ballooning/interchange instability and kinetic Alfvén waves among others. It is inferred that physics of multiple scales was involved in the dynamics of this dipolarization event.
Plain Language Summary Required for Submission to Journal of Geophysical Research: Solid Earth
Authors: Manighetti Isabelle , Abercrombie Rachel E. , Ben‐Zion Yehuda , Bernabé Yves , Bostock Michael , Dekkers Mark J. , Parman Stephen W. , Schmitt Doug , Tregoning Paul 
Published: May 2021

AbstractThe editors of JGR: Solid Earth announce that Plain Language Summaries will be required for all manuscripts.
Type I and III interferon responses in SARS-CoV-2 infection
Authors: Kim You-Me , Shin Eui-Cheol 
Published: May 2021

AbstractCoronavirus disease 2019 (COVID-19), the current pandemic disease, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Type I and III interferons (IFNs) are innate cytokines that are important in the first-line defense against viruses. Similar to many other viruses, SARS-CoV-2 has evolved mechanisms for evading the antiviral effects of type I and III IFNs at multiple levels, including the induction of IFN expression and cellular responses to IFNs. In this review, we describe the innate sensing mechanisms of SARS-CoV-2 and the mechanisms used by SARS-CoV-2 to evade type I and III IFN responses. We also discuss contradictory reports regarding impaired and robust type I IFN responses in patients with severe COVID-19. Finally, we discuss how delayed but exaggerated type I IFN responses can exacerbate inflammation and contribute to the severe progression of COVID-19.
Freeform imaging systems: Fermat’s principle unlocks “first time right” design
Authors: Duerr Fabian , Thienpont Hugo 
Published: May 2021

AbstractFor more than 150 years, scientists have advanced aberration theory to describe, analyze and eliminate imperfections that disturb the imaging quality of optical components and systems. Simultaneously, they have developed optical design methods for and manufacturing techniques of imaging systems with ever-increasing complexity and performance up to the point where they are now including optical elements that are unrestricted in their surface shape. These so-called optical freeform elements offer degrees of freedom that can greatly extend the functionalities and further boost the specifications of state-of-the-art imaging systems. However, the drastically increased number of surface coefficients of these freeform surfaces poses severe challenges for the optical design process, such that the deployment of freeform optics remained limited until today. In this paper, we present a deterministic direct optical design method for freeform imaging systems based on differential equations derived from Fermat’s principle and solved using power series. The method allows calculating the optical surface coefficients that ensure minimal image blurring for each individual order of aberrations. We demonstrate the systematic, deterministic, scalable, and holistic character of our method with catoptric and catadioptric design examples. As such we introduce a disruptive methodology to design optical imaging systems from scratch, we largely reduce the “trial-and-error” approach in present-day optical design, and we pave the way to a fast-track uptake of freeform elements to create the next-generation high-end optics. We include a user application that allows users to experience this unique design method hands-on.
C/EBPβ is a MYB- and p300-cooperating pro-leukemogenic factor and promising drug target in acute myeloid leukemia
Authors: Yusenko Maria V. , Trentmann Amke , Casolari Debora A. , Abdel Ghani Luca , Lenz Mairin , Horn Melanie , Dörner Wolfgang , Klempnauer Stefan , Mootz Henning D. , Arteaga Maria Francisca , Mikesch Jan-Henrik , D’Andrea Richard J. , Gonda Thomas J. , Müller-Tidow Carsten , Schmidt Thomas J. , Klempnauer Karl-Heinz 
Published: May 2021

AbstractTranscription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ. C/EBPβ-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPβ broadly shapes the transcriptional program of AML cells. We show that expression of GFI1, a direct MYB target gene, is controlled cooperatively by MYB, C/EBPβ, and co-activator p300, and is down-regulated by C/EBPβ-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPβ-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPβ-inhibitory STLs. Overall, our data identify C/EBPβ as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPβ may have therapeutic potential against AML.
Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia
Authors: Parellada Eduard , Gassó Patricia 
Published: May 2021

AbstractSchizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.
Radiomics and radiogenomics in gliomas: a contemporary update
Authors: Singh Gagandeep , Manjila Sunil , Sakla Nicole , True Alan , Wardeh Amr H. , Beig Niha , Vaysberg Anatoliy , Matthews John , Prasanna Prateek , Spektor Vadim 
Published: May 2021

AbstractThe natural history and treatment landscape of primary brain tumours are complicated by the varied tumour behaviour of primary or secondary gliomas (high-grade transformation of low-grade lesions), as well as the dilemmas with identification of radiation necrosis, tumour progression, and pseudoprogression on MRI. Radiomics and radiogenomics promise to offer precise diagnosis, predict prognosis, and assess tumour response to modern chemotherapy/immunotherapy and radiation therapy. This is achieved by a triumvirate of morphological, textural, and functional signatures, derived from a high-throughput extraction of quantitative voxel-level MR image metrics. However, the lack of standardisation of acquisition parameters and inconsistent methodology between working groups have made validations unreliable, hence multi-centre studies involving heterogenous study populations are warranted. We elucidate novel radiomic and radiogenomic workflow concepts and state-of-the-art descriptors in sub-visual MR image processing, with relevant literature on applications of such machine learning techniques in glioma management.
Single cell transcriptional zonation of human psoriasis skin identifies an alternative immunoregulatory axis conducted by skin resident cells
Authors: Gao Yuge , Yao Xinyu , Zhai Yumeng , Li Li , Li Huini , Sun Xianqi , Yu Pei , Xue Tiankuo , Li Yuzhen , Hu Yizhou 
Published: May 2021

AbstractPsoriasis is the most common skin disease in adults. Current experimental and clinical evidences suggested the infiltrating immune cells could target local skin cells and thus induce psoriatic phenotype. However, recent studies indicated the existence of a potential feedback signaling loop from local resident skin cells to infiltrating immune cells. Here, we deconstructed the full-thickness human skins of both healthy donors and patients with psoriasis vulgaris at single cell transcriptional level, and further built a neural-network classifier to evaluate the evolutional conservation of skin cell types between mouse and human. Last, we systematically evaluated the intrinsic and intercellular molecular alterations of each cell type between healthy and psoriatic skin. Cross-checking with psoriasis susceptibility gene loci, cell-type based differential expression, and ligand-receptor communication revealed that the resident psoriatic skin cells including mesenchymal and epidermis cell types, which specifically harbored the target genes of psoriasis susceptibility loci, intensively evoked the expression of major histocompatibility complex (MHC) genes, upregulated interferon (INF), tumor necrosis factor (TNF) signalling and increased cytokine gene expression for primarily aiming the neighboring dendritic cells in psoriasis. The comprehensive exploration and pathological observation of psoriasis patient biopsies proposed an uncovered immunoregulatory axis from skin local resident cells to immune cells, thus provided a novel insight for psoriasis treatment. In addition, we published a user-friendly website to exhibit the transcriptional change of each cell type between healthy and psoriatic human skin.
Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy
Authors: Mansilla M. J. , Presas-Rodríguez S. , Teniente-Serra A. , González-Larreategui I. , Quirant-Sánchez B. , Fondelli F. , Djedovic N. , Iwaszkiewicz-Grześ D. , Chwojnicki K. , Miljković Đ. , Trzonkowski P. , Ramo-Tello C. , Martínez-Cáceres E. M. 
Published: May 2021

AbstractMultiple sclerosis (MS) is a leading cause of chronic neurological disability in young to middle-aged adults, affecting ~2.5 million people worldwide. Currently, most therapeutics for MS are systemic immunosuppressive or immunomodulatory drugs, but these drugs are unable to halt or reverse the disease and have the potential to cause serious adverse events. Hence, there is an urgent need for the development of next-generation treatments that, alone or in combination, stop the undesired autoimmune response and contribute to the restoration of homeostasis. This review analyzes current MS treatments as well as different cell-based therapies that have been proposed to restore homeostasis in MS patients (tolerogenic dendritic cells, regulatory T cells, mesenchymal stem cells, and vaccination with T cells). Data collected from preclinical studies performed in the experimental autoimmune encephalomyelitis (EAE) model of MS in animals, in vitro cultures of cells from MS patients and the initial results of phase I/II clinical trials are analyzed to better understand which parameters are relevant for obtaining an efficient cell-based therapy for MS.
A recurrent de novo ZSWIM6 variant in a Japanese patient with severe neurodevelopmental delay and frequent vomiting
Authors: Yanagishita Tomoe , Eto Kaoru , Yamamoto-Shimojima Keiko , Segawa Osamu , Nagata Miho , Ishihara Yasuki , Miyashita Yohei , Asano Yoshihiro , Sakata Yasushi , Nagata Satoru , Yamamoto Toshiyuki 
Published: May 2021

AbstractA recurrent ZSWIM6 variant, NM_020928.2:c.2737C>T [p.Arg913*], was identified in a Japanese male patient with severe neurodevelopmental delay, epilepsy, distinctive facial features, microcephaly, growth deficiency, abnormal behavior, and frequent vomiting but without frontonasal or limb malformations. In this patient, distinctive facial features gradually became apparent with age, and severe vomiting caused by gastroesophageal reflux continued even after percutaneous endoscopic gastrostomy.
Structural coordination between active sites of a CRISPR reverse transcriptase-integrase complex
Authors: Wang Joy Y. , Hoel Christopher M. , Al-Shayeb Basem , Banfield Jillian F. , Brohawn Stephen G. , Doudna Jennifer A. 
Published: May 2021

AbstractCRISPR-Cas systems provide adaptive immunity in bacteria and archaea, beginning with integration of foreign sequences into the host CRISPR genomic locus and followed by transcription and maturation of CRISPR RNAs (crRNAs). In some CRISPR systems, a reverse transcriptase (RT) fusion to the Cas1 integrase and Cas6 maturase creates a single protein that enables concerted sequence integration and crRNA production. To elucidate how the RT-integrase organizes distinct enzymatic activities, we present the cryo-EM structure of a Cas6-RT-Cas1—Cas2 CRISPR integrase complex. The structure reveals a heterohexamer in which the RT directly contacts the integrase and maturase domains, suggesting functional coordination between all three active sites. Together with biochemical experiments, our data support a model of sequential enzymatic activities that enable CRISPR sequence acquisition from RNA and DNA substrates. These findings highlight an expanded capacity of some CRISPR systems to acquire diverse sequences that direct CRISPR-mediated interference.
Intrinsic coupling between spatially-separated surface Fermi-arcs in Weyl orbit quantum Hall states
Authors: Nishihaya Shinichi , Uchida Masaki , Nakazawa Yusuke , Kriener Markus , Taguchi Yasujiro , Kawasaki Masashi 
Published: May 2021

AbstractTopological semimetals hosting bulk Weyl points and surface Fermi-arc states are expected to realize unconventional Weyl orbits, which interconnect two surface Fermi-arc states on opposite sample surfaces under magnetic fields. While the presence of Weyl orbits has been proposed to play a vital role in recent observations of the quantum Hall effect even in three-dimensional topological semimetals, actual spatial distribution of the quantized surface transport has been experimentally elusive. Here, we demonstrate intrinsic coupling between two spatially-separated surface states in the Weyl orbits by measuring a dual-gate device of a Dirac semimetal film. Independent scans of top- and back-gate voltages reveal concomitant modulation of doubly-degenerate quantum Hall states, which is not possible in conventional surface orbits as in topological insulators. Our results evidencing the unique spatial distribution of Weyl orbits provide new opportunities for controlling the novel quantized transport by various means such as external fields and interface engineering.
On-demand synthesis of phosphoramidites
Authors: Sandahl Alexander F. , Nguyen Thuy J. D. , Hansen Rikke A. , Johansen Martin B. , Skrydstrup Troels , Gothelf Kurt V. 
Published: May 2021

AbstractAutomated chemical synthesis of oligonucleotides is of fundamental importance for the production of primers for the polymerase chain reaction (PCR), for oligonucleotide-based drugs, and for numerous other medical and biotechnological applications. The highly optimised automised chemical oligonucleotide synthesis relies upon phosphoramidites as the phosphate precursors and one of the drawbacks of this technology is the poor bench stability of phosphoramidites. Here, we report on the development of an on-demand flow synthesis of phosphoramidites from their corresponding alcohols, which is accomplished with short reaction times, near-quantitative yields and without the need of purification before being submitted directly to automated oligonucleotide synthesis. Sterically hindered as well as redox unstable phosphoramidites are synthesised using this methodology and the subsequent couplings are near-quantitative for all substrates. The vision for this technology is direct integration into DNA synthesisers thereby omitting manual synthesis and storage of phosphoramidites.
Histological and transcriptomic analysis of adipose and muscle of dairy calves supplemented with 5-hydroxytryptophan
Authors: Field Sena L. , Marrero Marcela G. , Liu Lihe , Peñagaricano Francisco , Laporta Jimena 
Published: May 2021

AbstractIn mammals, peripheral serotonin is involved in regulating energy balance. Herein, we characterized the transcriptomic profile and microstructure of adipose and muscle in pre-weaned calves with increased circulating serotonin. Holstein bull calves (21 ± 2 days old) were fed milk replacer supplemented with saline (CON, 8 mL/day n = 4) or 5-hydroxytryptophan (5-HTP, 90 mg/day, n = 4) for 10 consecutive days. Calves were euthanized on d10 to harvest adipose and muscle for RNA-Sequencing and histological analyses. Twenty-two genes were differentially expressed in adipose, and 33 in muscle. Notably, Interferon gamma inducible protein-47 was highly expressed and upregulated in muscle and adipose (avg. log FC = 6.5). Enriched pathways in adipose tissue revealed serotonin’s participation in lipid metabolism and PPAR signaling. In muscle, enriched pathways were related to histone acetyltransferase binding, Jak-STAT signaling, PI3K-Akt signaling and cell proliferation. Supplementation of 5-HTP increased cell proliferation and total cell number in adipose and muscle. Adipocyte surface area was smaller and muscle fiber area was not different in the 5-HTP group. Manipulating the serotonin pathway, through oral supplementation of 5-HTP, influences signaling pathways and cellular processes in adipose and muscle related to endocrine and metabolic functions which might translate into improvements in calf growth and development.
Comparative analysis of liver involvement caused by two DENV-2 lineages using an immunocompetent murine model
Authors: Jácome Fernanda Cunha , Caldas Gabriela Cardoso , Rasinhas Arthur da Costa , de Almeida Ana Luisa Teixeira , de Souza Daniel Dias Coutinho , Paulino Amanda Carlos , Leonardo Raphael , Barth Ortrud Monika , dos Santos Flavia Barreto , Barreto-Vieira Débora Ferreira 
Published: May 2021

AbstractDengue (DEN) is the most prevalent arbovirus among humans, and four billion people live at risk of infection. The clinical manifestations of DEN are variable, and the disease may present subclinically or asymptomatically. A quarter of patients develop classical dengue (CD) or severe dengue (SD), which is potentially lethal and involves vascular permeability changes, severe hemorrhage and organ damage. The involvement of the liver is a fairly common feature in DEN, and alterations range from asymptomatic elevation of transaminases to acute liver failure. Since its introduction in Brazil in 1990, two strains of Dengue virus (DENV) serotype 2 (DENV-2) have been detected: Lineage I, which is responsible for an outbreak in 1991, and Lineage II, which caused an epidemic greater than the previous one and had a different epidemiological profile. To date, studies on different strains of the same serotype/genotype and their association with disease severity are scarce. In addition, one of the greatest challenges regarding the study of DEN pathogenesis and the development of drug and vaccine therapies is the absence of an animal model that reproduces the disease as it occurs in humans. The main goals of this study were to assess BALB/c mouse susceptibility experimentally infected by two distinct DENV-2 strains and characterize possible differences in the clinical signs and alterations induced in the liver resulting from those infections. Mice infected by the two DENV-2 lineages gained less weight than uninfected mice; however, their livers were slightly heavier. Increased AST and AST levels were observed in infected mice, and the number of platelets increased in the first 72 h of infection and subsequently decreased. Mice infected with both lineages presented leukocytosis but at different times of infection. The histopathological changes induced by both lineages were similar and comparable to the changes observed in DEN fatal cases. The viral genome was detected in two liver samples. The results demonstrate the susceptibility of BALB/c mice to both DENV-2 lineages and suggest that the changes induced by those strains are similar, although for some parameters, they are manifested at different times of infection.