bluuebunny/crossref_metadata_2025 huggingface dataset:
Auswirkungen des coronabedingten Lockdowns auf die stationäre Rehabilitation von Suchtkranken
Authors: Schöneck Robert
Published: October 2020

Zusammenfassung. Zielsetzung: Es gibt Hinweise, dass der coronabedingte Lockdown negative Folgen für Abhängige ohne Behandlungskontakte hatte. Die Arbeit befasst sich mit der Frage, ob bereits erste Folgen des Lockdowns für Patient_innen abzuleiten sind, welche sich während dieser Phase hoher coronabedingter Einschränkungen in einer stationären Rehabilitation für Suchtkranke befunden haben. Methodik: Es sollen erste Hypothesen in Bezug auf Erfolge der Behandlung während der ersten Welle der Pandemie abgeleitet und dies mit ersten Daten zu Rückfällen und Abbrüchen untermauert werden. Dabei sollen auch zwangsläufige Veränderungen in Folge der coronabedingten Einschränkungen auf die stationäre Rehabilitation von Suchtkranken und Erfahrungen im Umgang mit den Einschränkungen beschrieben werden. Ergebnisse: Während des Lockdowns hat die Anzahl der Rückfälle in unserer Klinik signifikant abgenommen. Anders als erwartet, ist die Rate an Behandlungsabbrüchen nicht signifikant angestiegen. Die Einschränkungen haben einen Beitrag geleistet, dass Betroffene aufgrund der coronabedingten Einschränkungen bereits während der stationären Rehabilitation grundlegende Verhaltensänderungen trainieren mussten und die Risikosituationen bereits während der stationären Rehabilitation deutlich reduziert bzw. besser vorbereitet wurden. Schlussfolgerungen: Es wird diskutiert, ob und wie die positiven Auswirkungen für die zukünftige Arbeit mit Suchtkranken genutzt werden können.
Effects of Fatigue on Cognitive Performance in Long-Duration Simulated Flight Missions
Authors: Rosa Eduardo , Eiken Ola , Grönkvist Mikael , Kölegård Roger , Dahlström Nicklas , Knez Igor , Ljung Robert , Jönsson Fredrik U. , Willander Johan
Published: October 2020

Abstract. Fighter pilots may be exposed to extended flight missions. Consequently, there is increasing concern about fatigue. We investigated the effects of fatigue and cognitive performance in a simulated 11-hr mission in the 39 Gripen fighter aircraft. Five cognitive tasks were used to assess cognitive performance. Fatigue was measured with the Samn–Perelli Fatigue Index. Results showed that performance in the non-executive task degraded after approximately 7 hr. Fatigue ratings showed a matching trend to the performance in this task. Performance in tasks taxing executive functions did not decline. We interpreted that fatigue can be overridden by increased attentional effort for executive tasks but not for non-executive components of cognition. Participants underestimated their performance and metacognitive accuracy was not influenced by fatigue.
Experimenting with Underwater Sediment Slides
Authors: Cook Terri
Published: October 2020

Sediment-laden currents caused by breaching flow slides are hazardous to flood defenses and seabed infrastructure. New research shows that these phenomena must be accounted for in erosion simulations.
Deposition History and Paleo‐Current Activity on the Southeastern Lomonosov Ridge and its Eurasian Flank Based on Seismic Data
Authors: Weigelt Estella , Jokat Wilfried , Eisermann Hannes
Published: October 2020

A regional seismic survey on the southeastern Lomonosov Ridge (LR) and adjacent basins provides constraints on the coupled evolution of ocean circulations, depositional regime, and tectonic processes. First, Mesozoic strata on the LR, its faulted flanks and the initial Amundsen Basin were covered with syn‐rift sediments of Paleocene to early Eocene age. Numerous vertical faults indicate differential compaction of possibly anoxic sediments deposited in the young, still isolated Eurasian Basin. The second stage, as indicated by a prominent high‐amplitude‐reflector sequence covering the ridge, was a time of widespread changes in deposition conditions, likely controlled by the ongoing subsidence of the LR and gradual opening of the Fram Strait. Episodic incursions of water masses from the North Atlantic probably were the consequences and led to the deposition of thin sedimentary layers of different lithology. The third stage is marked by continuous deposition since the early Miocene (20 Ma). At that time, the ridge no longer posed an obstacle between the Amerasia and Eurasia Basins and pelagic sedimentation was established. Drift bodies, sediment waves, and erosional structures indicate the onset of circulation. Faulting on the ridge slope has led to a series of terraces where sediment drifts have accumulated since the early Miocene. It is suggested that ongoing sagging of the ridge and currents may have shaped the steep sediment free flanks of the terraces. Lastly, a sequence of high‐amplitude reflectors marks the transition to the early Pliocene large‐scale Northern Hemisphere glaciations.
SPATS2, negatively regulated by miR-145-5p, promotes hepatocellular carcinoma progression through regulating cell cycle
Authors: Dong Gang , Zhang Shanshan , Shen Shen , Sun Lulu , Wang Xuemei , Wang Haiyu , Wu Jie , Liu Tingting , Wang Chaoyan , Wang Huanbin , Lu Taiying , Rao Benchen , Ren Zhigang
Published: October 2020

Spermatogenesis associated serine rich 2 (SPATS2) has been reported to contribute to the tumorigenesis of multiple malignancies. The molecular function of SPATS2 in hepatocellular carcinoma (HCC) is still not fully understood. In this study, we aimed to investigate the expression pattern and function roles of SPATS2 in HCC. The regulation of SPATS2 expression was also explored. We found that SPATS2 was highly expressed in HCC tissues in comparison with that in adjacent normal tissues. High expression of SPATS2 was associated with vascular invasion, advanced TNM stages, tumor multiplicity, and poor survival. Functionally, SPATS2 was found to promote the proliferation and metastasis of HCC cells both in vitro and in vivo, while knockdown of SPATS2 enhanced apoptosis and G1 arrest of HCC cells in vitro. Mechanistically, bioinformatics analysis revealed that MiR-145-5p directly targeted SPATS2 and functional rescue experiments verified that MiR-145-5p overexpression could abolish the effect of SPATS2 on the regulation of HCC malignant phenotype. Taken together, our findings suggest that SPATS2 functions as an oncogene in HCC. The MiR-145-5p/SPATS2 axis provides a novel mechanism underlying HCC progression and may serve as a potential therapeutic target for HCC.
FATS regulates polyamine biosynthesis by promoting ODC degradation in an ERβ-dependent manner in non-small-cell lung cancer
Authors: Qiu Li , Hu Linfei , Wang Huijuan , Li Jinling , Ruan Xianhui , Sun Bingsheng , Zhi Jingtai , Zheng Xiangqian , Gu Lin , Gao Ming , Kong Pengzhou , Zhang Jun
Published: October 2020

Polyamine biosynthesis is an essential metabolic pathway for cell growth and differentiation in non-small-cell lung cancer (NSCLC). Fragile-site associated tumour suppressor (FATS) is a novel gene involved in cancer. The results of our previous study showed that FATS-mediated polyubiquitination of p53 promotes the activation of p53 in response to DNA damage; however, little is known about the role of FATS in metabolic reprogramming in NSCLC. In the present study, FATS was observed to be significantly downregulated in NSCLC tissues compared with paired adjacent normal tissues and was associated with the survival of NSCLC patients. We further showed that the presence of the tumour suppressor FATS in NSCLC cells led to apoptosis by inducing pro-death autophagy. In addition, FATS was shown to function as a suppressor of polyamine biosynthesis by inhibiting ornithine decarboxylase (ODC) at the protein and mRNA levels, which was partially dependent on oestrogen receptor (ER). Furthermore, FATS was observed to bind to ERβ and translocate to the cytosol, leading to ODC degradation. The findings of our study demonstrate that FATS plays important roles in polyamine metabolism in NSCLC and provides a new perspective for NSCLC progression.
Partners in crime: POPX2 phosphatase and its interacting proteins in cancer
Authors: Kim Pu Rum , Zhang Songjing , Rahmat Muhammad Bakhait , Koh Cheng-Gee
Published: October 2020

Protein phosphorylation and dephosphorylation govern intracellular signal transduction and cellular functions. Kinases and phosphatases are involved in the regulation and development of many diseases such as Alzheimer’s, diabetes, and cancer. While the functions and roles of many kinases, as well as their substrates, are well understood, phosphatases are comparatively less well studied. Recent studies have shown that rather than acting on fewer and more distinct substrates like the kinases, phosphatases can recognize specific phosphorylation sites on many different proteins, making the study of phosphatases and their substrates challenging. One approach to understand the biological functions of phosphatases is through understanding their protein–protein interaction network. POPX2 (Partner of PIX 2; also known as PPM1F or CaMKP) is a serine/threonine phosphatase that belongs to the PP2C family. It has been implicated in cancer cell motility and invasiveness. This review aims to summarize the different binding partners of POPX2 phosphatase and explore the various functions of POPX2 through its interactome in the cell. In particular, we focus on the impact of POPX2 on cancer progression. Acting via its different substrates and interacting proteins, POPX2’s involvement in metastasis is multifaceted and varied according to the stages of metastasis.
A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract
Authors: Hu Fengyu , Chen Fengjuan , Ou Zhihua , Fan Qinghong , Tan Xinghua , Wang Yaping , Pan Yuejun , Ke Bixia , Li Linghua , Guan Yujuan , Mo Xiaoneng , Wang Jian , Wang Jinlin , Luo Chun , Wen Xueliang , Li Min , Ren Peidi , Ke Changwen , Li Junhua , Lei Chunliang , Tang Xiaoping , Li Feng
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been redetected after discharge in some coronavirus disease 2019 (COVID-19) patients. The reason for the recurrent positivity of the test and the potential public health concern due to this occurrence are still unknown. Here, we analyzed the viral data and clinical manifestations of 289 domestic Chinese COVID-19 patients and found that 21 individuals (7.3%) were readmitted for hospitalization after detection of SARS-CoV-2 after discharge. First, we experimentally confirmed that the virus was involved in the initial infection and was not a secondary infection. In positive retests, the virus was usually found in anal samples (15 of 21, 71.4%). Through analysis of the intracellular viral subgenomic messenger RNA (sgmRNA), we verified that positive retest patients had active viral replication in their gastrointestinal tracts (3 of 16 patients, 18.7%) but not in their respiratory tracts. Then, we found that viral persistence was not associated with high viral titers, delayed viral clearance, old age, or more severe clinical symptoms during the first hospitalization. In contrast, viral rebound was associated with significantly lower levels of and slower generation of viral receptor-binding domain (RBD)-specific IgA and IgG antibodies. Our study demonstrated that the positive retest patients failed to create a robust protective humoral immune response, which might result in SARS-CoV-2 persistence in the gastrointestinal tract and possibly in active viral shedding. Further exploration of the mechanism underlying the rebound in SARS-CoV-2 in this population will be crucial for preventing virus spread and developing effective vaccines.
Development and evaluation of an artificial intelligence system for COVID-19 diagnosis
Authors: Jin Cheng , Chen Weixiang , Cao Yukun , Xu Zhanwei , Tan Zimeng , Zhang Xin , Deng Lei , Zheng Chuansheng , Zhou Jie , Shi Heshui , Feng Jianjiang
Published: October 2020

Early detection of COVID-19 based on chest CT enables timely treatment of patients and helps control the spread of the disease. We proposed an artificial intelligence (AI) system for rapid COVID-19 detection and performed extensive statistical analysis of CTs of COVID-19 based on the AI system. We developed and evaluated our system on a large dataset with more than 10 thousand CT volumes from COVID-19, influenza-A/B, non-viral community acquired pneumonia (CAP) and non-pneumonia subjects. In such a difficult multi-class diagnosis task, our deep convolutional neural network-based system is able to achieve an area under the receiver operating characteristic curve (AUC) of 97.81% for multi-way classification on test cohort of 3,199 scans, AUC of 92.99% and 93.25% on two publicly available datasets, CC-CCII and MosMedData respectively. In a reader study involving five radiologists, the AI system outperforms all of radiologists in more challenging tasks at a speed of two orders of magnitude above them. Diagnosis performance of chest x-ray (CXR) is compared to that of CT. Detailed interpretation of deep network is also performed to relate system outputs with CT presentations. The code is available at https://github.com/ChenWWWeixiang/diagnosis_covid19.
Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers
Authors: Dos Santos Matthieu , Backer Stéphanie , Saintpierre Benjamin , Izac Brigitte , Andrieu Muriel , Letourneur Franck , Relaix Frederic , Sotiropoulos Athanassia , Maire Pascal
Published: October 2020

Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.
The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress
Authors: Bauer Michael , Nascakova Zuzana , Mihai Anca-Irina , Cheng Phil F. , Levesque Mitchell P. , Lampart Simon , Hurwitz Robert , Pfannkuch Lennart , Dobrovolna Jana , Jacobs Melanie , Bartfeld Sina , Dohlman Anders , Shen Xiling , Gall Alevtina A. , Salama Nina R. , Töpfer Antonia , Weber Achim , Meyer Thomas F. , Janscak Pavel , Müller Anne
Published: October 2020

Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.
High-resolution cryo-EM structure of urease from the pathogen Yersinia enterocolitica
Authors: Righetto Ricardo D. , Anton Leonie , Adaixo Ricardo , Jakob Roman P. , Zivanov Jasenko , Mahi Mohamed-Ali , Ringler Philippe , Schwede Torsten , Maier Timm , Stahlberg Henning
Published: October 2020

Urease converts urea into ammonia and carbon dioxide and makes urea available as a nitrogen source for all forms of life except animals. In human bacterial pathogens, ureases also aid in the invasion of acidic environments such as the stomach by raising the surrounding pH. Here, we report the structure of urease from the pathogen Yersinia enterocolitica at 2 Å resolution from cryo-electron microscopy. Y. enterocolitica urease is a dodecameric assembly of a trimer of three protein chains, ureA, ureB and ureC. The high data quality enables detailed visualization of the urease bimetal active site and of the impact of radiation damage. The obtained structure is of sufficient quality to support drug development efforts.
Structural insights into assembly of the ribosomal nascent polypeptide exit tunnel
Authors: Wilson Daniel M. , Li Yu , LaPeruta Amber , Gamalinda Michael , Gao Ning , Woolford John L.
Published: October 2020

The nascent polypeptide exit tunnel (NPET) is a major functional center of 60S ribosomal subunits. However, little is known about how the NPET is constructed during ribosome assembly. We utilized molecular genetics, biochemistry, and cryo-electron microscopy (cryo-EM) to investigate the functions of two NPET-associated proteins, ribosomal protein uL4 and assembly factor Nog1, in NPET assembly. Structures of mutant pre-ribosomes lacking the tunnel domain of uL4 reveal a misassembled NPET, including an aberrantly flexible ribosomal RNA helix 74, resulting in at least three different blocks in 60S assembly. Structures of pre-ribosomes lacking the C-terminal extension of Nog1 demonstrate that this extension scaffolds the tunnel domain of uL4 in the NPET to help maintain stability in the core of pre-60S subunits. Our data reveal that uL4 and Nog1 work together in the maturation of ribosomal RNA helix 74, which is required to ensure proper construction of the NPET and 60S ribosomal subunits.
Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner
Authors: Dorst Matthijs C. , Tokarska Anna , Zhou Ming , Lee Kwang , Stagkourakis Stefanos , Broberger Christian , Masmanidis Sotiris , Silberberg Gilad
Published: October 2020

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.
Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk
Authors: Sieh Weiva , Rothstein Joseph H. , Klein Robert J. , Alexeeff Stacey E. , Sakoda Lori C. , Jorgenson Eric , McBride Russell B. , Graff Rebecca E. , McGuire Valerie , Achacoso Ninah , Acton Luana , Liang Rhea Y. , Lipson Jafi A. , Rubin Daniel L. , Yaffe Martin J. , Easton Douglas F. , Schaefer Catherine , Risch Neil , Whittemore Alice S. , Habel Laurel A.
Published: October 2020

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10−8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.
A versatile soluble siglec scaffold for sensitive and quantitative detection of glycan ligands
Authors: Rodrigues Emily , Jung Jaesoo , Park Heajin , Loo Caleb , Soukhtehzari Sepideh , Kitova Elena N. , Mozaneh Fahima , Daskhan Gour , Schmidt Edward N. , Aghanya Vivian , Sarkar Susmita , Streith Laura , St. Laurent Chris D. , Nguyen Linh , Julien Jean-Philippe , West Lori J. , Williams Karla C. , Klassen John S. , Macauley Matthew S.
Published: October 2020

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. The connections between Siglecs and human disease motivate improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands are systematically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs are clarified. For CD33 (Siglec-3), we demonstrate that it recognizes both α2-3 and α2-6 sialosides in solution and on cells, which has implications for its link to Alzheimer’s disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.
Synthesis runs counter to directional folding of a nascent protein domain
Authors: Chen Xiuqi , Rajasekaran Nandakumar , Liu Kaixian , Kaiser Christian M.
Published: October 2020

Folding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.
Suppression of phase transitions and glass phase signatures in mixed cation halide perovskites
Authors: Simenas Mantas , Balciunas Sergejus , Wilson Jacob N. , Svirskas Sarunas , Kinka Martynas , Garbaras Andrius , Kalendra Vidmantas , Gagor Anna , Szewczyk Daria , Sieradzki Adam , Maczka Miroslaw , Samulionis Vytautas , Walsh Aron , Grigalaitis Robertas , Banys Juras
Published: October 2020

Cation engineering provides a route to control the structure and properties of hybrid halide perovskites, which has resulted in the highest performance solar cells based on mixtures of Cs, methylammonium, and formamidinium. Here, we present a multi-technique experimental and theoretical study of structural phase transitions, structural phases and dipolar dynamics in the mixed methylammonium/dimethylammonium MA1-xDMAxPbBr3 hybrid perovskites (0 ≤ x ≤ 1). Our results demonstrate a significant suppression of the structural phase transitions, enhanced disorder and stabilization of the cubic phase even for a small amount of dimethylammonium cations. As the dimethylammonium concentration approaches the solubility limit in MAPbBr3, we observe the disappearance of the structural phase transitions and indications of a glassy dipolar phase. We also reveal a significant tunability of the dielectric permittivity upon mixing of the molecular cations that arises from frustrated electric dipoles.
Rational design of a robust aluminum metal-organic framework for multi-purpose water-sorption-driven heat allocations
Authors: Cho Kyung Ho , Borges D. Damasceno , Lee U-Hwang , Lee Ji Sun , Yoon Ji Woong , Cho Sung June , Park Jaedeuk , Lombardo Walter , Moon Dohyun , Sapienza Alessio , Maurin Guillaume , Chang Jong-San
Published: October 2020

Adsorption-driven heat transfer technology using water as working fluid is a promising eco-friendly strategy to address the exponential increase of global energy demands for cooling and heating purposes. Here we present the water sorption properties of a porous aluminum carboxylate metal-organic framework, [Al(OH)(C6H3NO4)]·nH2O, KMF-1, discovered by a joint computational predictive and experimental approaches, which exhibits step-like sorption isotherms, record volumetric working capacity (0.36 mL mL−1) and specific energy capacity (263 kWh m−3) under cooling working conditions, very high coefficient of performances of 0.75 (cooling) and 1.74 (heating) together with low driving temperature below 70 °C which allows the exploitation of solar heat, high cycling stability and remarkable heat storage capacity (348 kWh m−3). This level of performances makes this porous material as a unique and ideal multi-purpose water adsorbent to tackle the challenges of thermal energy storage and its further efficient exploitation for both cooling and heating applications.
Author Correction: Bayesian reassessment of the epigenetic architecture of complex traits
Authors: Banos Daniel Trejo , McCartney Daniel L. , Patxot Marion , Anchieri Lucas , Battram Thomas , Christiansen Colette , Costeira Ricardo , Walker Rosie M. , Morris Stewart W. , Campbell Archie , Zhang Qian , Porteous David J. , McRae Allan F. , Wray Naomi R. , Visscher Peter M. , Haley Chris S. , Evans Kathryn L. , Deary Ian J. , McIntosh Andrew M. , Hemani Gibran , Bell Jordana T. , Marioni Riccardo E. , Robinson Matthew R.
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Insulin-producing organoids engineered from islet and amniotic epithelial cells to treat diabetes
Authors: Lebreton Fanny , Lavallard Vanessa , Bellofatto Kevin , Bonnet Romain , Wassmer Charles H. , Perez Lisa , Kalandadze Vakhtang , Follenzi Antonia , Boulvain Michel , Kerr-Conte Julie , Goodman David J. , Bosco Domenico , Berney Thierry , Berishvili Ekaterine
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Pre-existing Helicobacter pylori serum IgG enhances the vibriocidal antibody response to CVD 103-HgR live oral cholera vaccine in Malian adults
Authors: Muhsen Khitam , Sow Samba O. , Tapia Milagritos D. , Haidara Fadima C. , Reymann Mardi , Asato Valeria , Chen Wilbur H. , Pasetti Marcela F. , Levine Myron M.
Published: October 2020

Accumulating evidence indicates that persistent Helicobacter pylori gastric infection influences immune responses to oral enteric vaccines. We studied the association between pre-existing H. pylori serum IgG and serum pepsinogens levels (PGs) as markers of gastric inflammation and the immune response to single-dose live oral cholera vaccine CVD 103-HgR in Malian adults. Baseline sera obtained during a phase 2 safety/immunogenicity clinical trial of cholera vaccine CVD 103-HgR among 93 healthy Malian adults were tested for H. pylori IgG antibodies and PGI and PGII levels using enzyme linked immunosorbent assays. Overall 74/93 (80%) vaccine recipients were H. pylori IgG seropositive at baseline. Vibriocidal antibody seroconversion (≥ fourfold increase 14 days following administration of CVD 103-HgR compared to baseline) among vaccine recipients was 56%. However, vibriocidal antibody seroconversion was markedly higher among H. pylori seropositives than seronegatives 64% vs. 26% (p = 0.004); adjusted relative risk: 2.20 (95% confidence intervals 1.00–4.80; p = 0.049). Among H. pylori seropositive vaccine recipients, there were no significant associations between PGI, PGII and PGI:PGII levels and vibriocidal seroconversion. The enhanced seroconversion to oral cholera vaccine CVD 103-HgR among H. pylori seropositive African adults provides further evidence of the immunomodulating impact of H. pylori on oral vaccine immunogenicity.
TrkA inhibitor promotes motor functional regeneration of recurrent laryngeal nerve by suppression of sensory nerve regeneration
Authors: Suzuki Hiroshi , Araki Koji , Matsui Toshiyasu , Tanaka Yuya , Uno Kosuke , Tomifuji Masayuki , Yamashita Taku , Satoh Yasushi , Kobayashi Yasushi , Shiotani Akihiro
Published: October 2020

Recurrent laryngeal nerve (RLN) injury, in which hoarseness and dysphagia arise as a result of impaired vocal fold movement, is a serious complication. Misdirected regeneration is an issue for functional regeneration. In this study, we demonstrated the effect of TrkA inhibitors, which blocks the NGF-TrkA pathway that acts on the sensory/automatic nerves thus preventing misdirected regeneration among motor and sensory nerves, and thereby promoting the regeneration of motor neurons to achieve functional recovery. RLN axotomy rat models were used in this study, in which cut ends of the nerve were bridged with polyglycolic acid-collagen tube with and without TrkA inhibitor (TrkAi) infiltration. Our study revealed significant improvement in motor nerve fiber regeneration and function, in assessment of vocal fold movement, myelinated nerve regeneration, compound muscle action potential, and prevention of laryngeal muscle atrophy. Retrograde labeling demonstrated fewer labeled neurons in the vagus ganglion, which confirmed reduced misdirected regeneration among motor and sensory fibers, and a change in distribution of the labeled neurons in the nucleus ambiguus. Our study demonstrated that TrkAi have a strong potential for clinical application in the treatment of RLN injury.
Prediction of creep failure time using machine learning
Authors: Biswas Soumyajyoti , Fernandez Castellanos David , Zaiser Michael
Published: October 2020

A subcritical load on a disordered material can induce creep damage. The creep rate in this case exhibits three temporal regimes viz. an initial decelerating regime followed by a steady-state regime and a stage of accelerating creep that ultimately leads to catastrophic breakdown. Due to the statistical regularities in the creep rate, the time evolution of creep rate has often been used to predict residual lifetime until catastrophic breakdown. However, in disordered samples, these efforts met with limited success. Nevertheless, it is clear that as the failure is approached, the damage become increasingly spatially correlated, and the spatio-temporal patterns of acoustic emission, which serve as a proxy for damage accumulation activity, are likely to mirror such correlations. However, due to the high dimensionality of the data and the complex nature of the correlations it is not straightforward to identify the said correlations and thereby the precursory signals of failure. Here we use supervised machine learning to estimate the remaining time to failure of samples of disordered materials. The machine learning algorithm uses as input the temporal signal provided by a mesoscale elastoplastic model for the evolution of creep damage in disordered solids. Machine learning algorithms are well-suited for assessing the proximity to failure from the time series of the acoustic emissions of sheared samples. We show that materials are relatively more predictable for higher disorder while are relatively less predictable for larger system sizes. We find that machine learning predictions, in the vast majority of cases, perform substantially better than other prediction approaches proposed in the literature.
Five-year trajectories of multimorbidity patterns in an elderly Mediterranean population using Hidden Markov Models
Authors: Violán Concepción , Fernández-Bertolín Sergio , Guisado-Clavero Marina , Foguet-Boreu Quintí , Valderas Jose M. , Vidal Manzano Josep , Roso-Llorach Albert , Cabrera-Bean Margarita
Published: October 2020

This study aimed to analyse the trajectories and mortality of multimorbidity patterns in patients aged 65 to 99 years in Catalonia (Spain). Five year (2012–2016) data of 916,619 participants from a primary care, population-based electronic health record database (Information System for Research in Primary Care, SIDIAP) were included in this retrospective cohort study. Individual longitudinal trajectories were modelled with a Hidden Markov Model across multimorbidity patterns. We computed the mortality hazard using Cox regression models to estimate survival in multimorbidity patterns. Ten multimorbidity patterns were originally identified and two more states (death and drop-outs) were subsequently added. At baseline, the most frequent cluster was theNon-Specific Pattern(42%), and the least frequent theMultisystem Pattern(1.6%).Most participants stayed in the same cluster over the 5 year follow-up period, from 92.1% in theNervous, Musculoskeletalpattern to 59.2% in theCardio-Circulatory and Renalpattern. The highest mortality rates were observed for patterns that included cardio-circulatory diseases:Cardio-Circulatory and Renal(37.1%);Nervous, Digestive and Circulatory(31.8%); andCardio-Circulatory, Mental, Respiratory and Genitourinary(28.8%). This study demonstrates the feasibility of characterizing multimorbidity patterns along time. Multimorbidity trajectories were generally stable, although changes in specific multimorbidity patterns were observed. The Hidden Markov Model is useful for modelling transitions across multimorbidity patterns and mortality risk. Our findings suggest that health interventions targeting specific multimorbidity patterns may reduce mortality in patients with multimorbidity.
Identifying the sources of structural sensitivity in partially specified biological models
Authors: Adamson Matthew W. , Morozov Andrew Yu.
Published: October 2020

Biological systems are characterised by a high degree of uncertainty and complexity, which implies that exact mathematical equations to describe biological processes cannot generally be justified. Moreover, models can exhibit sensitivity to the precise formulations of their component functions—a property known as structural sensitivity. Structural sensitivity can be revealed and quantified by considering partially specified models with uncertain functions, but this goes beyond well-established, parameter-based sensitivity analysis, and currently presents a mathematical challenge. Here we build upon previous work in this direction by addressing the crucial question of identifying the processes which act as the major sources of model uncertainty and those which are less influential. To achieve this goal, we introduce two related concepts: (1) the gradient of structural sensitivity, accounting for errors made in specifying unknown functions, and (2) the partial degree of sensitivity with respect to each function, a global measure of the uncertainty due to possible variation of the given function while the others are kept fixed. We propose an iterative framework of experiments and analysis to inform a heuristic reduction of structural sensitivity in a model. To demonstrate the framework introduced, we investigate the sources of structural sensitivity in a tritrophic food chain model.
How attitudes generated by humanoid robots shape human brain activity
Authors: Di Cesare G. , Vannucci F. , Rea F. , Sciutti A. , Sandini G.
Published: October 2020

During interpersonal interactions, people perform actions with different forms of vitality, communicating their positive or negative attitude toward others. For example, a handshake can be “soft” or “vigorous”, a caress can be ‘kind’ or ‘rushed’. While previous studies have shown that the dorso-central insula is a key area for the processing of human vitality forms, there is no information on the perception of vitality forms generated by a humanoid robot. In this study, two fMRI experiments were conducted in order to investigate whether and how the observation of actions generated by a humanoid robot (iCub) with low and fast velocities (Study 1) or replicating gentle and rude human forms (Study 2) may convey vitality forms eliciting the activation of the dorso-central insula. These studies showed that the observation of robotic actions, generated with low and high velocities, resulted in activation of the parieto-frontal circuit typically involved in the recognition and the execution of human actions but not of the insula (Study 1). Most interestingly, the observation of robotic actions, generated by replicating gentle and rude human vitality forms, produced a BOLD signal increase in the dorso-central insula (Study 2). In conclusion, these data highlight the selective role of dorso-central insula in the processing of vitality forms opening future perspectives on the perception and understanding of actions performed by humanoid robots.
Investigation of a new graphene strain sensor based on surface plasmon resonance
Authors: Ma Zenghong , Chen Zijian , Xu Jian , Li Weiping , Zhang Lian , Wang Lei
Published: October 2020

The high confinement of surface plasmon polaritons in graphene nanostructures at infrared frequencies can enhance the light-matter interactions, which open up intriguing possibilities for the sensing. Strain sensors have attracted much attention due to their unique electromechanical properties. In this paper, a surface plasmon resonance based graphene strain sensor is presented. The considered sensing platform consists of arrays of graphene ribbons placed on a flexible substrate which enables efficient coupling of an electromagnetic field into localized surface plasmons. When the strain stretching is applied to the configuration, the localized surface plasmon resonance frequency sensitively shift. The strain is then detected by measuring the frequency shifts of the localized plasmon resonances. This provides a new optical method for graphene strain sensing. Our results show that the tensile direction is the key parameter for strain sensing. Besides, the sensitivity and the figure of merit were calculated to evaluate the performance of the proposed sensor. The calculated figure of merit can be up to two orders of magnitude, which could be potentially useful from a practical point of view.
Direct stimulation of ERBB2 highlights a novel cytostatic signaling pathway driven by the receptor Thr701 phosphorylation
Authors: Gaviraghi Marco , Rabellino Andrea , Andolfo Annapaola , Brand Matthias , Brombin Chiara , Bagnato Paola , De Feudis Giuseppina , Raimondi Andrea , Locatelli Alberta , Tosoni Daniela , Mazza Davide , Gianni Luca , Tonon Giovanni , Yarden Yosef , Tacchetti Carlo , Daniele Tiziana
Published: October 2020

ERBB2 is a ligand-less tyrosine kinase receptor expressed at very low levels in normal tissues; when overexpressed, it is involved in malignant transformation and tumorigenesis in several carcinomas. In cancer cells, ERBB2 represents the preferred partner of other members of the ERBB receptor family, leading to stronger oncogenic signals, by promoting both ERK and AKT activation. The identification of the specific signaling downstream of ERBB2 has been impaired by the lack of a ligand and of an efficient way to selectively activate the receptor. In this paper, we found that antibodies (Abs) targeting different epitopes on the ERBB2 extracellular domain foster the activation of ERBB2 homodimers, and surprisingly induce a unique cytostatic signaling cascade promoting an ERK-dependent ERBB2 Thr701 phosphorylation, leading to AKT de-phosphorylation, via PP2A Ser/Thr phosphatases. Furthermore, the immunophilin Cyclophilin A plays a crucial role in this pathway, acting as a negative modulator of AKT de-phosphorylation, possibly by competing with Ser/Thr phosphatases for binding to AKT. Altogether, our data show that Ab recognizing ERBB2 extracellular domain function as receptor agonists, promoting ERBB2 homodimer activation, leading to an anti-proliferative signaling. Thus, the ultimate outcome of ERBB2 activity might depend on the dimerization status: pro-oncogenic in the hetero-, and anti-oncogenic in the homo-dimeric form.
Describing fluctuating indoor aerosol dust measurements with application to house dust mite allergens
Authors: van Boven F. E. , de Jong N. W. , Loomans M. G. L. C. , Braunstahl G. J. , Gerth van Wijk R. , Arends L. R.
Published: October 2020

Measuring house dust mite aeroallergen concentrations is essential in understanding mite allergen exposure. Physically, the aerolized house dust mite faeces are part of indoor particulate matter. We studied the statistical ways of summarizing measurements of fluctuating mite aeroallergen exposure inside homes through indoor particulate matter. To study emissions from beddings, we measured the time-related airborne dust concentration after shaking a duvet. Analysis was performed both by a method based on the estimated mean and by a non-linear model. Twenty-eight studies reported a sum of concentrations; only one also reported the peak. In our four experiments on shaking a duvet (245 to 275 measurements each), the peak value was two to four times higher than the mean. The mean-based and non-linear models both predicted the sum of concentrations exactly. A 1% upper prediction bound and the non-linear model predicted the peak emission rate moderately well (64 to 92%, and 63 to 93%, respectively). Mean levels of indoor particulate matter measurements differ substantially from peak concentrations. The use of the mean is only sufficient to predict the sum of concentrations. We suggest that, mite aeroallergen measurements should include information on the peak as well as the mean.
Predicting toxins found in toxin–antitoxin systems with a role in host-induced Burkholderia pseudomallei persistence
Authors: Ross Brittany N. , Thiriot Joseph D. , Wilson Shane M. , Torres Alfredo G.
Published: October 2020

Burkholderia pseudomallei (Bpm) is a bacterial pathogen that causes Melioidosis, a disease with up to 40% mortality and an infection relapse of 15–23% despite antibiotic treatment. Ineffective clearance of Bpm by antibiotics is believed to be due to persistence, a hibernation-like survival mechanism modulated, in part, by toxin–antitoxin systems (TAS). Several organisms possess a repertoire of TASs but defining environmental cues eliciting their activity is hindered by laborious in vitro experiments, especially when there are many toxins with redundant function. Here, we identified which of 103 proteins in Bpm that share features found in toxins of the TAS and repurposed transcriptional data to identify which ones play a role in surviving intracellular host defenses. Putative toxins with the strongest transcriptional response were found to have low conservation between Bpm strains, while toxins that were constitutively expressed were highly conserved. Further examination of highly conserved toxins BPSS0899, BPSS1321, and BPSL1494 showed that they were functional, and their mutation led to reduce survival within macrophages and reduced in vivo persistence-associated pathology (abscesses) during treatment, but did not affect macrophages persistence. These findings highlight the utility of a data-driven approach to select putative toxins and suggests a selective role for some TAS in host survival.
Altered metabolomic profiling of overweight and obese adolescents after combined training is associated with reduced insulin resistance
Authors: Duft Renata G. , Castro Alex , Bonfante Ivan L. P. , Lopes Wendell A. , da Silva Larissa R. , Chacon-Mikahil Mara P. T. , Leite Neiva , Cavaglieri Cláudia R.
Published: October 2020

Exercise training and a healthy diet are the main non-pharmacological strategies for treating chronic conditions, such as obesity and insulin resistance (IR), in adolescents. However, the isolated metabolic changes caused by exercise training without dietary intervention have not yet been established. We investigated how combined training (CT) without dietary intervention altered the concentrations of serum metabolites, biochemical, anthropometric and functional parameters in overweight and obese adolescents. Thirty-seven adolescents (14.6 ± 1.05 years), of both sexes, were randomly assigned to the control group (CG, n = 19) or the training group (TG, n = 18). The CT was composed by resistance training and aerobic training performed in the same session (~ 60 min), three times a week, for 12 weeks. All assessments were performed pre and post-intervention. Metabolomics analyses were conducted using nuclear magnetic resonance spectroscopy (1H NMR) in a 600 MHz spectrometer. There was a decrease in body weight (BW), body mass index (BMI), waist circumference (WC), % body fat (%BF), fasting glucose, insulin levels, and insulin resistance (IR), by HOMA-IR, in the TG. An increase in fat-free mass (FFM) was also observed in the CG. The metabolic changes were given mainly by changes in the levels of metabolites 2-oxoisocaproate (↓TG), 3-hydroxyisobutyrate (↑CG and ↓TG), glucose (↓TG), glutamine (↓CG and ↑TG) and pyruvate (↓TG). These findings demonstrate the positive effects of CT program without dietary intervention on metabolomic profile, body composition, biochemical markers, and glucose metabolism in overweight and obese adolescents.
Analysis of microRNA-34a expression profile and rs2666433 variant in colorectal cancer: a pilot study
Authors: Fawzy Manal S. , Ibrahiem Afaf T. , AlSel Baraah T. Abu , Alghamdi Saleh A. , Toraih Eman A.
Published: October 2020

MicroRNAs (miRNAs) are implicated in every stage of carcinogenesis and play an essential role as genetic biomarkers of cancer. We aimed to evaluate microRNA-34a gene (MIR34A) expression in colorectal cancer (CRC) tissues compared with non-cancer one and to preliminarily explore the association of one related variant to CRC risk. A total of 116 paraffin-embedded colon specimens were enrolled. MiR-34a was quantified by qPCR, and rs2666433 (A/G) genotyping was performed by TaqMan Real-Time PCR. Also, the somatic mutation burden was assessed. MIR34A expression in the CRC specimens was significantly upregulated (median = 21.50, IQR: 7.0–209.2; P = 0.001) relative to the non-cancer tissues. Allele (A) was highly prevalent in CRC tissues represented 0.56 (P < 0.001). AA/AG genotype carriers were 5.7 and 2.8 more likely to develop cancer than GG carriers. Tumor-normal tissue paired analysis revealed genotype concordance in 33 out of 58 tissue samples. Approximately 43% of the specimens showed a tendency for G to A shift. Additionally, a higher frequency of somatic mutation (92%) was observed in adenocarcinoma (P = 0.006). MIR34A expression and gene variant did not show associations with the clinicopathological data. However, G > A somatic mutation carriers had more prolonged DFS and OS. Bioinformatics analysis revealed miR-34a could target 30 genes that are implied in all steps of CRC tumorigenesis. In conclusion, this study confirms MIR34A upregulation in CRC tissues, and its rs2666433 (A/G) variant showed association with CRC and a high somatic mutation rate in cancer tissues. MiR-34a could provide a novel targeted therapy after validation in large-scale studies.