bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychiatric comorbidities in Asperger syndrome are related with polygenic overlap and differ from other Autism subtypes
Authors: González-Peñas Javier , Costas Javier Costas , García-Alcón Alicia , Penzol María José , Rodríguez Julio , Rodríguez-Fontenla Cristina , Alonso-González Aitana , Fernández-Prieto Montse , Carracedo Ángel , Arango Celso , Parellada Mara
Published: July 2020

There is great phenotypic heterogeneity within autism spectrum disorders (ASD), which has led to question their classification into a single diagnostic category. The study of the common genetic variation in ASD has suggested a greater contribution of other psychiatric conditions in Asperger syndrome (AS) than in the rest of the DSM-IV ASD subtypes (Non_AS). Here, using available genetic data from previously performed genome-wide association studies (GWAS), we aimed to study the genetic overlap between five of the most related disorders (schizophrenia (SCZ), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorders (OCD) and anxiety (ANX)), and AS, comparing it with the overlap in Non_AS subtypes. A Spanish cohort of autism trios (N = 371) was exome sequenced as part of the Autism Sequencing Consortium (ASC) and 241 trios were extensively characterized to be diagnosed with AS following DSM-IV and Gillberg’s criteria (N = 39) or not (N = 202). Following exome imputation, polygenic risk scores (PRS) were calculated for ASD, SCZ, ADHD, MDD, ANX, and OCD (from available summary data from Psychiatric Genomic Consortium (PGC) repository) in the Spanish trios’ cohort. By using polygenic transmission disequilibrium test (pTDT), we reported that risk for SCZ (Pscz = 0.008, corrected-PSCZ = 0.0409), ADHD (PADHD = 0.021, corrected-PADHD = 0.0301), and MDD (PMDD = 0.039, corrected-PMDD = 0.0501) is over-transmitted to children with AS but not to Non_AS. Indeed, agnostic clustering procedure with deviation values from pTDT tests suggested two differentiated clusters of subjects, one of which is significantly enriched in AS (P = 0.025). Subsequent analysis with S-Predixcan, a recently developed software to predict gene expression from genotype data, revealed a clear pattern of correlation between cortical gene expression in ADHD and AS (P < 0.001) and a similar strong correlation pattern between MDD and AS, but also extendable to another non-brain tissue such as lung (P < 0.001). Altogether, these results support the idea of AS being qualitatively distinct from Non_AS autism and consistently evidence the genetic overlap between AS and ADHD, MDD, or SCZ.
Patterns of autism symptoms: hidden structure in the ADOS and ADI-R instruments
Authors: Lefort-Besnard Jérémy , Vogeley Kai , Schilbach Leonhard , Varoquaux Gaël , Thirion Bertrand , Dumas Guillaume , Bzdok Danilo
Published: July 2020

We simultaneously revisited the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) with a comprehensive data-analytics strategy. Here, the combination of pattern-analysis algorithms and extensive data resources (n = 266 patients aged 7–49 years) allowed identifying coherent clinical constellations in and across ADI-R and ADOS assessments widespread in clinical practice. Our clustering approach revealed low- and high-severity patient groups, as well as a group scoring high only in the ADI-R domains, providing quantitative contours for the widely assumed autism subtypes. Sparse regression approaches uncovered the most clinically predictive questionnaire domains. The social and communication domains of the ADI-R showed convincing performance to predict the patients’ symptom severity. Finally, we explored the relative importance of each of the ADI-R and ADOS domains conditioning on age, sex, and fluid IQ in our sample. The collective results suggest that (i) identifying autism subtypes and severity for a given individual may be most manifested in the ADI-R social and communication domains, (ii) the ADI-R might be a more appropriate tool to accurately capture symptom severity, and (iii) the ADOS domains were more relevant than the ADI-R domains to capture sex differences.
Level and timing of physical activity during normal daily life in depressed and non-depressed individuals
Authors: Minaeva Olga , Booij Sanne H. , Lamers Femke , Antypa Niki , Schoevers Robert A. , Wichers Marieke , Riese Harriëtte
Published: July 2020

Engaging in physical activity is known to reduce depressive symptoms. However, little is known which behavioral factors are relevant, and how patterns of activity change during depressive episodes. We expected that compared to controls, in depressed individuals the level of activity would be lower, the amplitude of 24-h-actigraphy profiles more dampened and daytime activities would start later. We used 14-day continuous-actigraphy data from participants in the Netherlands Study of Depression and Anxiety (NESDA) who participated in an ambulatory assessment study. Participants with a depression diagnosis in the past 6 months (n = 58) or its subsample with acute depression (DSM diagnosis in the past 1 month, n = 43) were compared to controls without diagnoses (n = 63). Depression was diagnosed with a diagnostic interview. Actigraphy-derived variables were activity mean levels (MESOR), the difference between peak and mean level (amplitude) and the timing of the activity peak (acrophase), which were estimated with cosinor analysis. Compared to the control group, both depression groups (total: B = −0.003, p = 0.033; acute: B = −0.004, p = 0.005) had lower levels of physical activity. Amplitude was also dampened, but in the acute depression group only (total: B = −0.002, p = 0.065; acute: B = −0.003, p = 0.011). Similarly, the timing of activity was marginally significant towards a later timing of activity in the acute, but not total depression group (total: B = 0.206, p = 0.398; acute: B = 0.405, p = 0.084). In conclusion, our findings may be relevant for understanding how different aspects of activity (level and timing) contribute to depression. Further prospective research is needed to disentangle the direction of the association between depression and daily rest-activity rhythms.
Deciphering the response and resistance to immune-checkpoint inhibitors in lung cancer with artificial intelligence-based analysis: when PIONeeR meets QUANTIC
Authors: Ciccolini Joseph , Benzekry Sébastien , Barlesi Fabrice
Published: July 2020

This project aims to generate dense longitudinal data in lung cancer patients undergoing anti-PD1/PDL1 therapy. Mathematical modelling with mechanistic learning algorithms will help decipher the mechanisms underlying the response or resistance to immunotherapy. A better understanding of these mechanisms should help identifying actionable items to increase the efficacy of immune-checkpoint inhibitors.
ω-6 Polyunsaturated fatty acids (linoleic acid) activate both autophagy and antioxidation in a synergistic feedback loop via TOR-dependent and TOR-independent signaling pathways
Authors: Yang Bo , Zhou Yan , Wu Mengjiao , Li Xueshan , Mai Kangsen , Ai Qinghui
Published: July 2020

ω-6 Polyunsaturated fatty acids (PUFAs) are essential fatty acids that participate in macroautophagy (hereafter referred to as autophagy) and the Kelch ECH-associating protein 1 (Keap1)—nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant system in organisms. However, the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and Keap1–Nrf2 antioxidant system are not completely understood. Therefore, the purposes of this study were to explore the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and antioxidant system and to investigate the potential relationship between autophagy and antioxidant system through transcriptomic analysis, quantitative real-time polymerase chain reaction (RT-qPCR), western blot analysis, coimmunoprecipitation (Co-IP) and electrophoretic mobility shift assays (EMSAs) in vivo and in vitro. The results of the present study indicated that ω-6 PUFAs in diets induced autophagy but decrease antioxidant ability in vivo. However, the results also provided evidence, for the first time, that ω-6 PUFAs (linoleic acid) induced autophagy and increased antioxidant ability through the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and the AMPK-target of rapamycin (TOR) signaling pathway in hepatocytes in vitro. Interestingly, the findings revealed a ω-6 PUFA-induced synergistic feedback loop between autophagy and antioxidant system, which are connected with each other through the P62 and Keap1 complex. These results suggested that ω-6 PUFAs (linoleic acid) could be useful for activating a synergistic feedback loop between autophagy and antioxidant system and could greatly aid in the prevention and treatment of multiple pathologies.
The miR-1224-5p/TNS4/EGFR axis inhibits tumour progression in oesophageal squamous cell carcinoma
Authors: Shi Zhi-Zhou , Wang Wen-Jun , Chen Yun-Xia , Fan Ze-Wen , Xie Xiu-Feng , Yang Li-Yan , Chang Chen , Cai Yan , Hao Jia-Jie , Wang Ming-Rong , Bai Jie
Published: July 2020

Oesophageal squamous cell carcinoma (ESCC) is a common and aggressive malignancy. Although many molecular alterations have been observed in ESCC, the mechanisms underlying the development and progression of this disease remain unclear. In the present study, miR-1224-5p was identified to be downregulated in ESCC tissues compared to normal tissues, and its low expression was correlated with shorter survival time in patients. In vitro experiments showed that miR-1224-5p inhibited the proliferation, colony formation, migration and invasion of ESCC cells. Mechanistic investigation revealed that miR-1224-5p directly targeted TNS4 and inhibited its expression, which led to the inactivation of EGFR-EFNA1/EPHA2-VEGFA (vascular endothelial growth factor A) signalling. Experiments in vivo confirmed the suppressive effect of miR-1224-5p on oesophageal cancer cells. By immunohistochemistry analysis of ESCC specimens, we found that TNS4 expression was positively correlated with that of VEGFA, and was significantly associated with lymph node metastasis and shorter survival time in patients. Together, our data suggest that miR-1224-5p downregulation is a frequent alteration in ESCC that promotes cell proliferation, migration, invasion and tumour growth by activating the EGFR-EFNA1/EPHA2-VEGFA signalling pathway via inhibition of TNS4 expression. Decreased miR-1224-5p and elevated TNS4 are unfavourable prognostic factors for ESCC patients.
Maf1 regulates dendritic morphogenesis and influences learning and memory
Authors: Chen Kui , Zhu Liang , Guo Lin , Pan Yuan-Bo , Feng Dong-Fu
Published: July 2020

Maf1, a general transcriptional regulator and mTOR downstream effector, is highly expressed in the hippocampus and cortex, but the function of Maf1 in neurons is not well elucidated. Here, we first demonstrate that Maf1 plays a central role in the inhibition of dendritic morphogenesis and the growth of dendritic spines both in vitro and in vivo. Furthermore, Maf1 downregulation paradoxically leads to activation of AKT-mTOR signaling, which is mediated by decreased PTEN expression. Moreover, we confirmed that Maf1 could regulate the activity of PTEN promoter by luciferase reporter assay, and proved that Maf1 could bind to the promoter of PTEN by ChIP-PCR experiment. We also demonstrate that expression of Maf1 in the hippocampus affects learning and memory in mice. Taken together, we show for the first time that Maf1 inhibits dendritic morphogenesis and the growth of dendritic spines through AKT-mTOR signaling by increasing PTEN expression.
Purine metabolism regulates DNA repair and therapy resistance in glioblastoma
Authors: Zhou Weihua , Yao Yangyang , Scott Andrew J. , Wilder-Romans Kari , Dresser Joseph J. , Werner Christian K. , Sun Hanshi , Pratt Drew , Sajjakulnukit Peter , Zhao Shuang G. , Davis Mary , Nelson Barbara S. , Halbrook Christopher J. , Zhang Li , Gatto Francesco , Umemura Yoshie , Walker Angela K. , Kachman Maureen , Sarkaria Jann N. , Xiong Jianping , Morgan Meredith A. , Rehemtualla Alnawaz , Castro Maria G. , Lowenstein Pedro , Chandrasekaran Sriram , Lawrence Theodore S. , Lyssiotis Costas A. , Wahl Daniel R.
Published: July 2020

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.
The electron affinity of astatine
Authors: Leimbach David , Karls Julia , Guo Yangyang , Ahmed Rizwan , Ballof Jochen , Bengtsson Lars , Boix Pamies Ferran , Borschevsky Anastasia , Chrysalidis Katerina , Eliav Ephraim , Fedorov Dmitry , Fedosseev Valentin , Forstner Oliver , Galland Nicolas , Garcia Ruiz Ronald Fernando , Granados Camilo , Heinke Reinhard , Johnston Karl , Koszorus Agota , Köster Ulli , Kristiansson Moa K. , Liu Yuan , Marsh Bruce , Molkanov Pavel , Pašteka Lukáš F. , Ramos João Pedro , Renault Eric , Reponen Mikael , Ringvall-Moberg Annie , Rossel Ralf Erik , Studer Dominik , Vernon Adam , Warbinek Jessica , Welander Jakob , Wendt Klaus , Wilkins Shane , Hanstorp Dag , Rothe Sebastian
Published: July 2020

One of the most important properties influencing the chemical behavior of an element is the electron affinity (EA). Among the remaining elements with unknown EA is astatine, where one of its isotopes, 211At, is remarkably well suited for targeted radionuclide therapy of cancer. With the At− anion being involved in many aspects of current astatine labeling protocols, the knowledge of the electron affinity of this element is of prime importance. Here we report the measured value of the EA of astatine to be 2.41578(7) eV. This result is compared to state-of-the-art relativistic quantum mechanical calculations that incorporate both the Breit and the quantum electrodynamics (QED) corrections and the electron–electron correlation effects on the highest level that can be currently achieved for many-electron systems. The developed technique of laser-photodetachment spectroscopy of radioisotopes opens the path for future EA measurements of other radioelements such as polonium, and eventually super-heavy elements.
Synthetic microbial communities of heterotrophs and phototrophs facilitate sustainable growth
Authors: Zuñiga Cristal , Li Tingting , Guarnieri Michael T. , Jenkins Jackson P. , Li Chien-Ting , Bingol Kerem , Kim Young-Mo , Betenbaugh Michael J. , Zengler Karsten
Published: July 2020

Microbial communities comprised of phototrophs and heterotrophs hold great promise for sustainable biotechnology. Successful application of these communities relies on the selection of appropriate partners. Here we construct four community metabolic models to guide strain selection, pairing phototrophic, sucrose-secreting Synechococcus elongatus with heterotrophic Escherichia coli K-12, Escherichia coli W, Yarrowia lipolytica, or Bacillus subtilis. Model simulations reveae metabolic exchanges that sustain the heterotrophs in minimal media devoid of any organic carbon source, pointing to S. elongatus-E. coli K-12 as the most active community. Experimental validation of flux predictions for this pair confirms metabolic interactions and potential production capabilities. Synthetic communities bypass member-specific metabolic bottlenecks (e.g. histidine- and transport-related reactions) and compensate for lethal genetic traits, achieving up to 27% recovery from lethal knockouts. The study provides a robust modelling framework for the rational design of synthetic communities with optimized growth sustainability using phototrophic partners.
Strategies to enable large-scale proteomics for reproducible research
Authors: Poulos Rebecca C. , Hains Peter G. , Shah Rohan , Lucas Natasha , Xavier Dylan , Manda Srikanth S. , Anees Asim , Koh Jennifer M. S. , Mahboob Sadia , Wittman Max , Williams Steven G. , Sykes Erin K. , Hecker Michael , Dausmann Michael , Wouters Merridee A. , Ashman Keith , Yang Jean , Wild Peter J. , deFazio Anna , Balleine Rosemary L. , Tully Brett , Aebersold Ruedi , Speed Terence P. , Liu Yansheng , Reddel Roger R. , Robinson Phillip J. , Zhong Qing
Published: July 2020

Reproducible research is the bedrock of experimental science. To enable the deployment of large-scale proteomics, we assess the reproducibility of mass spectrometry (MS) over time and across instruments and develop computational methods for improving quantitative accuracy. We perform 1560 data independent acquisition (DIA)-MS runs of eight samples containing known proportions of ovarian and prostate cancer tissue and yeast, or control HEK293T cells. Replicates are run on six mass spectrometers operating continuously with varying maintenance schedules over four months, interspersed with ~5000 other runs. We utilise negative controls and replicates to remove unwanted variation and enhance biological signal, outperforming existing methods. We also design a method for reducing missing values. Integrating these computational modules into a pipeline (ProNorM), we mitigate variation among instruments over time and accurately predict tissue proportions. We demonstrate how to improve the quantitative analysis of large-scale DIA-MS data, providing a pathway toward clinical proteomics.
Structure and mechanism of potent bifunctional β-lactam- and homoserine lactone-degrading enzymes from marine microorganisms
Authors: Selleck Christopher , Pedroso Marcelo Monteiro , Wilson Liam , Krco Stefan , Knaven Esmée Gianna , Miraula Manfredi , Mitić Nataša , Larrabee James A. , Brück Thomas , Clark Alice , Guddat Luke W. , Schenk Gerhard
Published: July 2020

Genes that confer antibiotic resistance can rapidly be disseminated from one microorganism to another by mobile genetic elements, thus transferring resistance to previously susceptible bacterial strains. The misuse of antibiotics in health care and agriculture has provided a powerful evolutionary pressure to accelerate the spread of resistance genes, including those encoding β-lactamases. These are enzymes that are highly efficient in inactivating most of the commonly used β-lactam antibiotics. However, genes that confer antibiotic resistance are not only associated with pathogenic microorganisms, but are also found in non-pathogenic (i.e. environmental) microorganisms. Two recent examples are metal-dependent β-lactamases (MBLs) from the marine organisms Novosphingobium pentaromativorans and Simiduia agarivorans. Previous studies have demonstrated that their β-lactamase activity is comparable to those of well-known MBLs from pathogenic sources (e.g. NDM-1, AIM-1) but that they also possess efficient lactonase activity, an activity associated with quorum sensing. Here, we probed the structure and mechanism of these two enzymes using crystallographic, spectroscopic and fast kinetics techniques. Despite highly conserved active sites both enzymes demonstrate significant variations in their reaction mechanisms, highlighting both the extraordinary ability of MBLs to adapt to changing environmental conditions and the rather promiscuous acceptance of diverse substrates by these enzymes.
Mini-canaloplasty as a modified technique for the surgical treatment of open-angle glaucoma
Authors: Rękas Marek , Konopińska Joanna , Byszewska Anna , Mariak Zofia
Published: July 2020

Authors present a modified surgical technique for canaloplasty without preparing the classical trabeculo-Descemet’s membrane (TDM) and having to close sutures. Twelve patients with open-angle glaucoma (OAG) (aged 58–77 years) received the modified technique, which does not require the deep scleral flap to be excised, an intrascleral lake to be created, or TDM dissection. After accessing the Schlemm’s canal (SC), cannulation and placement of the sutures are made similar to those in the classical canaloplasty. The conjunctiva is closed via bipolar diathermy. The mean intraocular pressure (IOP) before surgery was 18.0 ± 8 mmHg, and the mean number of anti-glaucoma medications taken was 3 ± 1. Mean IOP at the end of the observation period (18.0 ± 6.0 months) was reduced by 23% (15.5 ± 4.1 mmHg), while the mean number of medications taken was reduced to 0.25 ± 1.0. In all eyes, the SC was successively opened, with no cheese-wiring. Adverse events included microhyphaema, mild corneal oedema, and folds in the TDM. The eyes recovered spontaneously within a few days after the procedure. The mini-canaloplasty technique may reduce the risk of complications associated with classical canaloplasty while effectively lowering the IOP in patients with OAG.
Enhanced mechanical and wear properties of Al6061 alloy nanocomposite reinforced by CNT-template-grown core–shell CNT/SiC nanotubes
Authors: Yoo Sung Chan , Kang Byungchul , Van Trinh Pham , Phuong Doan Dinh , Hong Soon Hyung
Published: July 2020

Novel one-dimensional template-grown coaxial SiC@carbon nanotubes (SiC@CNTs) were fabricated using a chemical vapor deposition method. To facilitate the formation of SiC on CNT template, a molecular-level mixing process was used to coat the surface of commercial multiwalled carbon nanotubes (MWCNTs) by Fe2O3. These Fe-CNTs were transformed into SiC@CNT nanotubes, which were then mixed with Al6061 alloy and consolidated by spark plasma sintering to obtain Al6061-SiC@CNT nanocomposites. The addition of 5 vol% SiC@CNT resulted in 58% enhancement in Young’s modulus and 46% enhancement in yield strength. Furthermore, the friction coefficient was reduced by 31% and the specific wear rate was reduced by 45%. The enhancement effect of Al6061-SiC@CNT on the mechanical and tribological properties was much greater than those of traditional nanoparticles, nanowires, and whiskers of SiCs. The extraordinary strengthening behavior of SiC@CNT, when compared with that of other SiC analogues, is attributed to the coaxial structure consisting of a SiC shell and CNT core. This coaxial structure enhanced the mechanical and tribological properties beyond that attainable with traditional SiC-derived reinforcements.
Automated application of low energy electron irradiation enables inactivation of pathogen- and cell-containing liquids in biomedical research and production facilities
Authors: Fertey Jasmin , Thoma Martin , Beckmann Jana , Bayer Lea , Finkensieper Julia , Reißhauer Susann , Berneck Beatrice Sarah , Issmail Leila , Schönfelder Jessy , Casado Javier Portillo , Poremba Andre , Rögner Frank-Holm , Standfest Bastian , Makert Gustavo R. , Walcher Lia , Kistenmacher Ann-Kathrin , Fricke Stephan , Grunwald Thomas , Ulbert Sebastian
Published: July 2020

Ionizing radiation is widely used to inactivate pathogens. It mainly acts by destroying nucleic acids but causes less damage to structural components like proteins. It is therefore highly suited for the sterilization of biological samples or the generation of inactivated vaccines. However, inactivation of viruses or bacteria requires relatively high doses and substantial amounts of radiation energy. Consequently, irradiation is restricted to shielded facilities—protecting personnel and the environment. We have previously shown that low energy electron irradiation (LEEI) has the same capacity to inactivate pathogens in liquids as current irradiation methods, but generates much less secondary X-ray radiation, which enables the use in normal laboratories by self-shielded irradiation equipment. Here, we present concepts for automated LEEI of liquids, in disposable bags or as a continuous process. As the electrons have a limited penetration depth, the liquid is transformed into a thin film. High concentrations of viruses (Influenza, Zika virus and Respiratory Syncytial Virus), bacteria (E. coli, B. cereus) and eukaryotic cells (NK-92 cell line) are efficiently inactivated by LEEI in a throughput suitable for various applications such as sterilization, vaccine manufacturing or cell therapy. Our results validate the premise that for pathogen and cell inactivation in liquids, LEEI represents a suitable and versatile irradiation method for standard biological research and production laboratories.
The role of ADC values within the normal-appearing brain in the prognosis of multiple sclerosis activity during interferon-β therapy in the 3-year follow-up: a preliminary report
Authors: Zacharzewska-Gondek Anna , Pokryszko-Dragan Anna , Budrewicz Sławomir , Sąsiadek Marek , Trybek Grzegorz , Bladowska Joanna
Published: July 2020

Predictors of multiple sclerosis (MS) activity during disease-modifying treatment are being extensively investigated. The aim of this study was to assess the prognosis of NEDA (no evidence of disease activity) status during IFN-β (interferon-β) treatment, using apparent diffusion coefficient (ADC) measurements obtained at initial MRI (magnetic resonance imaging). In 87 MS patients treated with IFN-β, ADC values were calculated for 13 regions of normal-appearing white and grey matter (NAWM, NAGM) based on MRI performed with a 1.5 T magnet before (MS0, n = 45) or after one year of therapy (MS1, n = 42). Associations were evaluated between ADC, conventional MRI findings, demographic and clinical factors and NEDA status within the following 3 years using logistic, Cox and multinomial logistic regression models. NEDA rates in the MS0 group were 64.4%, 46.5% and 33.3% after the 1st, 2nd and 3rd year of treatment, respectively and in MS1 patients 71.4% and 48.7% for the periods 1st–2nd and 1st–3rd years of treatment, respectively. ADC values in the NAWM regions contributed to loss of NEDA and its clinical and radiological components, with a 1–3% increase in the risk of NEDA loss (p = 0.0001–0.0489) in both groups. ADC measurements may have an additional prognostic value with regard to NEDA status.
Precision-based exercise as a new therapeutic option for children and adolescents with haematological malignancies
Authors: Lanfranconi Francesca , Zardo W. , Moriggi T. , Villa E. , Radaelli G. , Radaelli S. , Paoletti F. , Bottes E. , Miraglia T. , Pollastri L. , Vago P. , Nichelli F. , Jankovic M. , Biondi A. , Balduzzi A.
Published: July 2020

Children and adolescents with haematological malignancies (PedHM) are characterized by a severe loss of exercise ability during cancer treatment, lasting throughout their lives once healed and impacting their social inclusion prospects. The investigation of the effect of a precision-based exercise program on the connections between systems of the body in PedHM patients is the new frontier in clinical exercise physiology. This study is aimed at evaluating the effects of 11 weeks (3 times weekly) of combined training (cardiorespiratory, resistance, balance and flexibility) on the exercise intolerance in PedHM patients. Two-hundred twenty-six PedHM patients were recruited (47% F). High or medium frequency participation (HAd and MAd) was considered when a participant joined; > 65% or between 30% and < 64% of training sessions, respectively. The “up and down stairs'' test (TUDS), “6 min walking” test (6MWT), the “5 Repetition Maximum strength” leg extension and arm lateral raise test (5RM-LE and 5RM-ALR), flexibility (stand and reach), and balance (stabilometry), were performed and evaluated before and after training. The TUDS, the 5RM-LE and 5RM-ALR, and the flexibility exercises showed an increase in HAd and MAd groups (P < 0.05), while the 6MWT and balance tests showed improvement only in HAd group (P < 0.0001). These results support the ever-growing theory that, in the case of the treatment of PedHM, ‘exercise is medicine’ and it has the potential to increase the patient’s chances of social inclusion.
Variations in storm-induced bed level dynamics across intertidal flats
Authors: de Vet P. L. M. , van Prooijen B. C. , Colosimo I. , Steiner N. , Ysebaert T. , Herman P. M. J. , Wang Z. B.
Published: July 2020

Hydrodynamic forces on intertidal flats vary over a range of temporal and spatial scales. These spatiotemporal inhomogeneities have implications for intertidal flat morphodynamics and ecology. We determine whether storm events are capable of altering the long-term morphological evolution of intertidal flats, and unravel the contributions of tidal flow, wind-driven flow, waves, and water depth on inhomogeneities in bed level dynamics (bed level changes over ~days) across these areas. We complement decades of bed level measurements on eight intertidal flats in two estuaries in the Netherlands with an extensive 1-month field campaign on one of those flats. Across this intertidal flat, the hydrodynamics and morphodynamics of a storm event were captured, including the post-storm recovery. We show that individual events can persistently alter the morphological evolution of intertidal flats; magnitudes of some bed level changes are even comparable to years of continuous evolution. The morphological impacts of events are largely controlled by the relative timing of the forcing processes, and not solely by their magnitudes. Spatiotemporal variations in bed level dynamics of intertidal flats are driven by a combination of: (1) the inhomogeneous distributions of the hydrodynamic forcing processes (including the under-explored role of the wind); and (2) the linear proportionality between bed level dynamics and the local bed slope.
A glycomics and proteomics study of aging and Parkinson’s disease in human brain
Authors: Raghunathan Rekha , Hogan John D. , Labadorf Adam , Myers Richard H. , Zaia Joseph
Published: July 2020

Previous studies on Parkinson’s disease mechanisms have shown dysregulated extracellular transport of α-synuclein and growth factors in the extracellular space. In the human brain these consist of perineuronal nets, interstitial matrices, and basement membranes, each composed of a set of collagens, non-collagenous glycoproteins, proteoglycans, and hyaluronan. The manner by which amyloidogenic proteins spread extracellularly, become seeded, oligomerize, and are taken up by cells, depends on intricate interactions with extracellular matrix molecules. We sought to assess the alterations to structure of glycosaminoglycans and proteins that occur in PD brain relative to controls of similar age. We found that PD differs markedly from normal brain in upregulation of extracellular matrix structural components including collagens, proteoglycans and glycosaminoglycan binding molecules. We also observed that levels of hemoglobin chains, possibly related to defects in iron metabolism, were enriched in PD brains. These findings shed important new light on disease processes that occur in association with PD.
Distribution patterns, carbon sources and niche partitioning in cave shrimps (Atyidae: Typhlatya)
Authors: Chávez-Solís E. M. , Solís C. , Simões N. , Mascaró M.
Published: July 2020

Cave shrimps of the Typhlatya genus are common and widespread in fresh, brackish and marine groundwater throughout the Yucatan Peninsula (Mexico). These species are ideal models to test niche partitioning within sympatric species in oligotrophic systems. Nevertheless, their food sources remain unidentified, and despite their frequency and functional importance, distribution and abundance patterns of these species within caves have not been fully recognized. Here, we describe the abundance of three Typhlatya species in different temporal and spatial scales, investigate changes in water conditions, and potential sources of carbon as an indication of food origin. Species composition and abundance varied markedly in space and time revealing patterns that differed from one system to another and in relation to environmental parameters. Isotope analysis showed that each species reflects a particular δ13C and Δ14C fingerprint, suggesting they feed in different proportions from the available carbon sources. Overall, our findings suggest a niche partitioning of habitat and feeding sources amongst the three Typhlatya species investigated, where environmental characteristics and physiological differences could play an important role governing their distribution patterns.
Early evidence of sheep lambing de-seasoning in the Western Mediterranean in the sixth millennium BCE
Authors: Tornero Carlos , Balasse Marie , Bréhard Stéphanie , Carrère Isabelle , Fiorillo Denis , Guilaine Jean , Vigne Jean-Denis , Manen Claire
Published: July 2020

Today, sheep farmers in the Western Mediterranean de-season their ewes to achieve autumnal births. This strategy contrasts sharply with spring lambing further north, and provides benefits in terms of out-of-season availability of animal products. These competences are closely linked to specific sheep physiology and favorable Western Mediterranean climatic conditions. It is not known exactly how far back in the past the ability to de-season Mediterranean sheep breeds extends. This study shows that this practice existed seven millennia ago in Southern France, at an early stage of the major agricultural expansion of the Neolithic into the Western Mediterranean. To achieve this reproductive management regime, three prerequisites were required: (i) the ability of sheep to give birth in autumn, constituting early evidence for the genetic selection of specimens with prolonged reproductive fertility; (ii) intentional management of female and male interactions within the herd, which would have required good knowledge of the timing of the fertility cycle in ewes, and; (iii) adequate pasture resources to support lactation in the autumn, possibly favored by autumnal rains, substantiating previous paleoclimatological data for the existence of a Mediterranean-type precipitation regime at that time. Moreover, we also show that winter foddering of sheep occurred, using forest resources, and that this maintained good body weights for spring mating. These findings add pivotal information about shepherding practices and the socio-economic abilities of Early Neolithic communities, which allowed for the extension of their areas of influence from the Eastern Mediterranean area to the West during the Early Neolithic agricultural expansion in Europe.
Plasma polymerized nanoparticles effectively deliver dual siRNA and drug therapy in vivo
Authors: Michael Praveesuda , Lam Yuen Ting , Filipe Elysse C. , Tan Richard P. , Chan Alex H. P. , Lee Bob S. L. , Feng Nicolas , Hung Juichien , Cox Thomas R. , Santos Miguel , Wise Steven G.
Published: July 2020

Multifunctional nanocarriers (MNCs) promise to improve therapeutic outcomes by combining multiple classes of molecules into a single nanostructure, enhancing active targeting of therapeutic agents and facilitating new combination therapies. However, nanocarrier platforms currently approved for clinical use can still only carry a single therapeutic agent. The complexity and escalating costs associated with the synthesis of more complex MNCs have been major technological roadblocks in the pathway for clinical translation. Here, we show that plasma polymerized nanoparticles (PPNs), synthesised in reactive gas discharges, can bind and effectively deliver multiple therapeutic cargo in a facile and cost-effective process compatible with up scaled commercial production. Delivery of siRNA against vascular endothelial growth factor (siVEGF) at extremely low concentrations (0.04 nM), significantly reduced VEGF expression in hard-to-transfect cells when compared with commercial platforms carrying higher siRNA doses (6.25 nM). PPNs carrying a combination of siVEGF and standard of care Paclitaxel (PPN-Dual) at reduced doses (< 100 µg/kg) synergistically modulated the microenvironment of orthotopic breast tumors in mice, and significantly reduced tumor growth. We propose PPNs as a new nanomaterial for delivery of therapeutics, which can be easily functionalised in any laboratory setting without the need for additional wet-chemistry and purification steps.
The role of biomass burning states in light absorption enhancement of carbonaceous aerosols
Authors: Wu Yu , Cheng Tianhai , Pan Xiaole , Zheng Lijuan , Shi Shuaiyi , Liu Hang
Published: July 2020

Carbonaceous aerosols, which are emitted from biomass burning, significantly contribute to the Earth’s radiation balance. Radiative forcing caused by biomass burning has been poorly qualified, which is largely attributed to uncertain absorption enhancement values (Eabs) of black carbon (BC) aerosols. Laboratory measurements and theoretical modelling indicate a significant value of Eabs; but this enhancement is observed to be negligible in the ambient environment, implying that models may overestimate global warming due to BC. Here, we present an aggregate model integrating BC aerosol ensembles with different morphologies and mixing states and report a quantitative analysis of the BC Eabs from different combustion states during biomass burning. We show that the BC Eabs produced by flaming combustion may be up to two times more than those produced by smouldering combustion, suggesting that the particle morphology and mixing state of freshly emitted BC aerosols is an important source of the contrasting values of Eabs. The particle morphology of freshly emitted BC aerosols is widely assumed to be bare in models, which is rare in the ambient environment and leads to small estimates of Eabs by field observations. We conclude that the exact description of freshly emitted carbonaceous aerosols plays an important role in constraining aerosol radiative forcing.
Coronatine is more potent than jasmonates in regulating Arabidopsis circadian clock
Authors: Gao Min , Zhang Chong , Lu Hua
Published: July 2020

Recent studies establish a crucial role of the circadian clock in regulating plant defense against pathogens. Whether pathogens modulate host circadian clock as a potential strategy to suppress host innate immunity is not well understood. Coronatine is a toxin produced by the bacterial pathogen Pseudomonas syringae that is known to counteract Arabidopsis defense through mimicking defense signaling molecules, jasmonates (JAs). We report here that COR preferentially suppresses expression of clock-related genes in high throughput gene expression studies, compared with the plant-derived JA molecule methyl jasmonate (MJ). COR treatment dampens the amplitude and lengthens the period of all four reporters tested while MJ and another JA agonist JA-isoleucine (JA-Ile) only affect some reporters. COR, MJ, and JA-Ile act through the canonical JA receptor COI1 in clock regulation. These data support a stronger role of the pathogen-derived molecule COR than plant-derived JA molecules in regulating Arabidopsis clock. Further study shall reveal mechanisms underlying COR regulation of host circadian clock.
Parallel residual projection: a new paradigm for solving linear inverse problems
Authors: Miao Wei , Narayanan Vignesh , Li Jr-Shin
Published: July 2020

A grand challenge to solve a large-scale linear inverse problem (LIP) is to retain computational efficiency and accuracy regardless of the growth of the problem size. Despite the plenitude of methods available for solving LIPs, various challenges have emerged in recent times due to the sheer volume of data, inadequate computational resources to handle an oversized problem, security and privacy concerns, and the interest in the associated incremental or decremental problems. Removing these barriers requires a holistic upgrade of the existing methods to be computationally efficient, tractable, and equipped with scalable features. We, therefore, develop the parallel residual projection (PRP), a parallel computational framework involving the decomposition of a large-scale LIP into sub-problems of low complexity and the fusion of the sub-problem solutions to form the solution to the original LIP. We analyze the convergence properties of the PRP and accentuate its benefits through its application to complex problems of network inference and gravimetric survey. We show that any existing algorithm for solving an LIP can be integrated into the PRP framework and used to solve the sub-problems while handling the prevailing challenges.
In vitro selection for adhesion of Plasmodium falciparum-infected erythrocytes to ABO antigens does not affect PfEMP1 and RIFIN expression
Authors: van der Puije William , Wang Christian W. , Sudharson Srinidhi , Hempel Casper , Olsen Rebecca W. , Dalgaard Nanna , Ofori Michael F. , Hviid Lars , Kurtzhals Jørgen A. L. , Staalsoe Trine
Published: July 2020

Plasmodium falciparum causes the most severe form of malaria in humans. The adhesion of the infected erythrocytes (IEs) to endothelial receptors (sequestration) and to uninfected erythrocytes (rosetting) are considered major elements in the pathogenesis of the disease. Both sequestration and rosetting appear to involve particular members of several IE variant surface antigens (VSAs) as ligands, interacting with multiple vascular host receptors, including the ABO blood group antigens. In this study, we subjected genetically distinct P. falciparum parasites to in vitro selection for increased IE adhesion to ABO antigens in the absence of potentially confounding receptors. The selection resulted in IEs that adhered stronger to pure ABO antigens, to erythrocytes, and to various human cell lines than their unselected counterparts. However, selection did not result in marked qualitative changes in transcript levels of the genes encoding the best-described VSA families, PfEMP1 and RIFIN. Rather, overall transcription of both gene families tended to decline following selection. Furthermore, selection-induced increases in the adhesion to ABO occurred in the absence of marked changes in immune IgG recognition of IE surface antigens, generally assumed to target mainly VSAs. Our study sheds new light on our understanding of the processes and molecules involved in IE sequestration and rosetting.
System wide channel network analysis reveals hotspots of morphological change in anthropogenically modified regions of the Ganges Delta
Authors: Jarriel Teresa , Isikdogan Leo F. , Bovik Alan , Passalacqua Paola
Published: July 2020

The Ganges Brahmaputra Meghna Delta (GBMD) is a large and complex coastal system whose channel network is vulnerable to morphological changes caused by sea level rise, subsidence, anthropogenic modifications, and changes to water and sediment loads. Locating and characterizing change is particularly challenging because of the wide range of forcings acting on the GBMD and because of the large range of scales over which these forcings act. In this study, we examine the spatial variability of change in the GBMD channel network. We quantify the relative magnitudes and directions of change across multiple scales and relate the spatial distribution of change to the spatial distribution of a variety of known system forcings. We quantify how the channelization varies by computing the Channelized Response Variance (CRV) on 30 years of remotely sensed imagery of the entire delta extent. The CRV analysis reveals hotspots of morphological change across the delta. We find that the magnitude of these hotspots are related to the spatial distribution of the dominant physiographic forcings in the system (tidal and fluvial influence levels, channel connectivity, and anthropogenic interference levels). We find that the anthropogenically modified embanked regions have much higher levels of geomorphic change than the adjacent natural Sundarban forest and that this change is primarily due to channel infilling and increased rates of channel migration. Having a better understanding of how anthropogenic changes affect delta channel networks over human timescales will help to inform policy decisions affecting the human and ecological presences on deltas around the world.
Congruent geographic variation in saccular otolith shape across multiple species of African cichlids
Authors: Bose Aneesh P. H. , Zimmermann Holger , Winkler Georg , Kaufmann Alexandra , Strohmeier Thomas , Koblmüller Stephan , Sefc Kristina M.
Published: July 2020

The otoliths of teleost fishes exhibit a great deal of inter- and intra-species shape variation. The ecomorphology of the saccular otolith is often studied by comparing its shape across species and populations inhabiting a range of environments. However, formal tests are often lacking to examine how closely variation in otolith shape follows the genetic drift of a neutral trait. Here, we examine patterns of saccular otolith shape variation in four species of African cichlid fishes, each sampled from three field sites. All four species showed the greatest level of otolith shape variation along two principal component axes, one pertaining to otolith height and another to the prominence of an anterior notch. Fish collected from the same site possessed similarities in saccular otolith shape relative to fish from other sites, and these ‘site-difference’ signatures were consistent across species and observable in both sexes. Sex-differences in saccular otolith shape differed in magnitude from site to site. Population differences in saccular otolith shape did not covary with neutral genetic differentiation between those populations. Otolith height, in particular, displayed large site similarities across species, weak correlation with neutral genetic variation, and strong sex differences, collectively suggesting that otolith shape represents a selectively non-neutral trait.
Fluorescence-assisted sequential insertion of transgenes (FASIT): an approach for increasing specific productivity in mammalian cells
Authors: Bravo Felipe E. , Parra Natalie C. , Camacho Frank , Acosta Jannel , González Alaín , Toledo Jorge R. , Sanchez Oliberto
Published: July 2020

Currently, the generation of cell lines for the production of recombinant proteins has the limitation of unstable gene expression due to the repeat-induced gene silencing or the loss of transgene copies resulting from recombination events. In this work, we developed a new strategy based on the sequential insertion of transgenes for generating stable clones producing high levels of a chimeric human follicle-stimulating hormone (hscFSH). Gene insertion was done by transducing HEK-293 cells with a lentiviral vector containing a bicistronic transcriptional unit for expressing hscFSH and GFP genes. Clone selection was performed by flow cytometry coupled to cell sorting, and the GFP gene was further removed by CRE-mediated site-specific recombination. High-producing clones of hscFSH were obtained after three rounds of lentiviral transduction. Expression levels increased in a step-wise manner from 7 to 23 pg/cell/day, with a relatively constant rate of 7 pg/cell/day in each round of transduction. The GFP gene was successfully removed from the cell genome without disturbing the hscFSH gene expression. Clones generated using this approach showed stable expression levels for more than two years. This is the first report describing the sequential insertion of transgenes as an alternative for increasing the expression levels of transformed cell lines. The methodology described here could notably impact on biotechnological industry by improving the capacity of mammalian cells to produce biopharmaceuticals.