bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary fat-associated osteoarthritic chondrocytes gain resistance to lipotoxicity through PKCK2/STAMP2/FSP27
Authors: Lee Sung Won , Rho Jee Hyun , Lee Sang Yeob , Chung Won Tae , Oh Yoo Jin , Kim Jung Ha , Yoo Seung Hee , Kwon Woo Young , Bae Ju Yong , Seo Su Young , Sun Hokeun , Kim Hye Young , Yoo Young Hyun
Published: July 2018

Free fatty acids (FFAs), which are elevated with metabolic syndrome, are considered the principal offender exerting lipotoxicity. Few previous studies have reported a causal relationship between FFAs and osteoarthritis pathogenesis. However, the molecular mechanism by which FFAs exert lipotoxicity and induce osteoarthritis remains largely unknown. We here observed that oleate at the usual clinical range does not exert lipotoxicity while oleate at high pathological ranges exerted lipotoxicity through apoptosis in articular chondrocytes. By investigating the differential effect of oleate at toxic and nontoxic concentrations, we revealed that lipid droplet (LD) accumulation confers articular chondrocytes, the resistance to lipotoxicity. Using high fat diet-induced osteoarthritis models and articular chondrocytes treated with oleate alone or oleate plus palmitate, we demonstrated that articular chondrocytes gain resistance to lipotoxicity through protein kinase casein kinase 2 (PKCK2)—six-transmembrane protein of prostate 2 (STAMP2)—and fat-specific protein 27 (FSP27)-mediated LD accumulation. We further observed that the exertion of FFAs-induced lipotoxicity was correlated with the increased concentration of cellular FFAs freed from LDs, whether FFAs are saturated or not. In conclusion, PKCK2/STAMP2/FSP27-mediated sequestration of FFAs in LD rescues osteoarthritic chondrocytes. PKCK2/STAMP2/FSP27 should be considered for interventions against metabolic OA.
A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA
Authors: Bangaru Sandhya , Zhang Heng , Gilchuk Iuliia M. , Voss Thomas G. , Irving Ryan P. , Gilchuk Pavlo , Matta Pranathi , Zhu Xueyong , Lang Shanshan , Nieusma Travis , Richt Juergen A. , Albrecht Randy A. , Vanderven Hillary A. , Bombardi Robin , Kent Stephen J. , Ward Andrew B. , Wilson Ian A. , Crowe James E.
Published: July 2018

The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. Recent seasonal H3 vaccines do not protect against swine-origin H3N2 variant (H3N2v) strains that recently have caused severe human infections. Here, we report a human VH1-69 gene-encoded monoclonal antibody (mAb) designated H3v-47 that exhibits potent cross-reactive neutralization activity against human and swine H3N2 viruses that circulated since 1989. The crystal structure and electron microscopy reconstruction of H3v-47 Fab with the H3N2v hemagglutinin (HA) identify a unique epitope spanning the vestigial esterase and receptor-binding subdomains that is distinct from that of any known neutralizing antibody for influenza A H3 viruses. MAb H3v-47 functions largely by blocking viral egress from infected cells. Interestingly, H3v-47 also engages Fcγ receptor and mediates antibody dependent cellular cytotoxicity (ADCC). This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines.
Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes
Authors: Takahashi Koichi , Wang Feng , Morita Kiyomi , Yan Yuanqing , Hu Peter , Zhao Pei , Zhar Abdallah Abou , Wu Chang Jiun , Gumbs Curtis , Little Latasha , Tippen Samantha , Thornton Rebecca , Coyle Marcus , Mendoza Marisela , Thompson Erika , Zhang Jianhua , DiNardo Courtney D. , Jain Nitin , Ravandi Farhad , Cortes Jorge E. , Garcia-Manero Guillermo , Kornblau Steven , Andreeff Michael , Jabbour Elias , Bueso-Ramos Carlos , Takaori-Kondo Akifumi , Konopleva Marina , Patel Keyur , Kantarjian Hagop , Futreal P. Andrew
Published: July 2018

Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL.
Patterns of genomic evolution in advanced melanoma
Authors: Birkeland E. , Zhang S. , Poduval D. , Geisler J. , Nakken S. , Vodak D. , Meza-Zepeda L. A. , Hovig E. , Myklebost O. , Knappskog S. , Lønning P. E.
Published: July 2018

Genomic alterations occurring during melanoma progression and the resulting genomic heterogeneity between metastatic deposits remain incompletely understood. Analyzing 86 metastatic melanoma deposits from 53 patients with whole-exome sequencing (WES), we show a low branch to trunk mutation ratio and little intermetastatic heterogeneity, with driver mutations almost completely shared between lesions. Branch mutations consistent with UV damage indicate that metastases may arise from different subclones in the primary tumor. Selective gain of mutated BRAF alleles occurs as an early event, contrasting whole-genome duplication (WGD) occurring as a late truncal event in about 40% of cases. One patient revealed elevated mutational diversity, probably related to previous chemotherapy and DNA repair defects. In another patient having received radiotherapy toward a lymph node metastasis, we detected a radiotherapy-related mutational signature in two subsequent distant relapses, consistent with secondary metastatic seeding. Our findings add to the understanding of genomic evolution in metastatic melanomas.
Detection and removal of barcode swapping in single-cell RNA-seq data
Authors: Griffiths Jonathan A. , Richard Arianne C. , Bach Karsten , Lun Aaron T. L. , Marioni John C.
Published: July 2018

Barcode swapping results in the mislabelling of sequencing reads between multiplexed samples on patterned flow-cell Illumina sequencing machines. This may compromise the validity of numerous genomic assays; however, the severity and consequences of barcode swapping remain poorly understood. We have used two statistical approaches to robustly quantify the fraction of swapped reads in two plate-based single-cell RNA-sequencing datasets. We found that approximately 2.5% of reads were mislabelled between samples on the HiSeq 4000, which is lower than previous reports. We observed no correlation between the swapped fraction of reads and the concentration of free barcode across plates. Furthermore, we have demonstrated that barcode swapping may generate complex but artefactual cell libraries in droplet-based single-cell RNA-sequencing studies. To eliminate these artefacts, we have developed an algorithm to exclude individual molecules that have swapped between samples in 10x Genomics experiments, allowing the continued use of cutting-edge sequencing machines for these assays.
A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Authors: Tsuburaya Naomi , Homma Kengo , Higuchi Tsunehiko , Balia Andrii , Yamakoshi Hiroyuki , Shibata Norio , Nakamura Seiichi , Nakagawa Hidehiko , Ikeda Shin-ichi , Umezawa Naoki , Kato Nobuki , Yokoshima Satoshi , Shibuya Masatoshi , Shimonishi Manabu , Kojima Hirotatsu , Okabe Takayoshi , Nagano Tetsuo , Naguro Isao , Imamura Keiko , Inoue Haruhisa , Fujisawa Takao , Ichijo Hidenori
Published: July 2018

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1mut) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1mut from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment.
Non-Hermitian photonics promises exceptional topology of light
Authors: Midya Bikashkali , Zhao Han , Feng Liang
Published: July 2018

The band degeneracy, either the exceptional point of a non-Hermitian system or the Dirac point associated with a topological system, can feature distinct symmetry and topology. Their synergy will further produce more exotic topological effects in synthetic matter.
Positive and negative regulation of carbon nanotube catalysts through encapsulation within macrocycles
Authors: Blanco Matías , Nieto-Ortega Belén , de Juan Alberto , Vera-Hidalgo Mariano , López-Moreno Alejandro , Casado Santiago , González Luisa R. , Sawada Hidetaka , González-Calbet José M. , Pérez Emilio M.
Published: July 2018

One of the most attractive applications of carbon nanomaterials is as catalysts, due to their extreme surface-to-volume ratio. The substitution of C with heteroatoms (typically B and N as p- and n-dopants) has been explored to enhance their catalytic activity. Here we show that encapsulation within weakly doping macrocycles can be used to modify the catalytic properties of the nanotubes towards the reduction of nitroarenes, either enhancing it (n-doping) or slowing it down (p-doping). This artificial regulation strategy presents a unique combination of features found in the natural regulation of enzymes: binding of the effectors (the macrocycles) is noncovalent, yet stable thanks to the mechanical link, and their effect is remote, but not allosteric, since it does not affect the structure of the active site. By careful design of the macrocycles’ structure, we expect that this strategy will contribute to overcome the major hurdles in SWNT-based catalysts: activity, aggregation, and specificity.
The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial
Authors: Coler Rhea N. , Day Tracey A. , Ellis Ruth , Piazza Franco M. , Beckmann Anna Marie , Vergara Julie , Rolf Tom , Lu Lenette , Alter Galit , Hokey David , Jayashankar Lakshmi , Walker Robert , Snowden Margaret Ann , Evans Tom , Ginsberg Ann , Reed Steven G. ,   The TBVPX-113 Study Team, Ashman Jill , Sagawa Zachary K. , Tait D. , Ishmukhamedov Sadritdin , Blatner Gretta , Sutton Sharon , Shepherd Barbara , Johnson Casey
Published: July 2018

Tuberculosis (TB) is the leading cause of infectious death worldwide. Development of improved TB vaccines that boost or replace BCG is a major global health goal. ID93 + GLA-SE is a fusion protein TB vaccine candidate combined with the Toll-like Receptor 4 agonist adjuvant, GLA-SE. We conducted a phase 1, randomized, double-blind, dose-escalation clinical trial to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two dose levels of the GLA-SE adjuvant, in 60 BCG-naive, QuantiFERON-negative, healthy adults in the US (ClinicalTrials.gov identifier: NCT01599897). When administered as 3 injections, 28 days apart, all dose levels of ID93 alone and ID93 + GLA-SE demonstrated an acceptable safety profile. All regimens elicited vaccine-specific humoral and cellular responses. Compared with ID93 alone, vaccination with ID93 + GLA-SE elicited higher titers of ID93-specific antibodies, a preferential increase in IgG1 and IgG3 subclasses, and a multifaceted Fc-mediated effector function response. The addition of GLA-SE also enhanced the magnitude and polyfunctional cytokine profile of CD4+ T cells. The data demonstrate an acceptable safety profile and indicate that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response.
Tumor size classification of the 8th edition of TNM staging system is superior to that of the 7th edition in predicting the survival outcome of pancreatic cancer patients after radical resection and adjuvant chemotherapy
Authors: Cong Lin , Liu Qiaofei , Zhang Ronghua , Cui Ming , Zhang Xiang , Gao Xiang , Guo Junchao , Dai Menghua , Zhang Taiping , Liao Quan , Zhao Yupei
Published: July 2018

The 8th edition of TNM staging system has been released and it incorporates many changes to the T and N classifications for pancreatic cancer. Comparative study between the 7th and 8th edition of TNM staging system from Asian population has not been reported yet. This study aimed to compare the 7th and 8th edition of staging system for pancreatic cancer by using a cohort of pancreatic cancer patients from China after R0 pancreaticoduodenectomy and adjuvant chemotherapy. The results showed according to the pT classification of 7th edition, pT3 was predominant (87.25%), however, the new edition led to a more equal distribution of pT classification. pT1, pT2 and pT3 was 27.45%, 56.86% and 15.69%, respectively. According to the new pN classification, 18.63% of the patients were pN2. The pT classification in the 8th edition was significantly superior to that in the 7th edition at stratifying patients by overall survival. The pN classification in the 8th edition failed to show an advantage over the 7th edition in stratifying patients by overall survival. Therefore, the new pT classification, but not the new pN classification, showed a significant advantage over the previous edition at predicting the overall survival of pancreatic cancer patients.
Chimpanzees overcome the tragedy of the commons with dominance
Authors: Koomen Rebecca , Herrmann Esther
Published: July 2018

Competition over common-pool resources (CPR) is a ubiquitous challenge for social animals. Many species face similar dilemmas, yet our understanding of the evolutionary trajectory of CPR social strategies remains unexplored. Here, we provide a first look at the social strategies of our closest living relatives, chimpanzees (Pan troglodytes), in two novel resource dilemma experiments. Dyads of chimpanzees were presented with renewable resource systems, collapsible at a quantity-dependent threshold. Dyads had to continuously resist overconsumption to maximize collective gains. In study 1, dyads of chimpanzees sustained a renewing juice source. Inequality of juice acquisition between partners predicted sustaining success, indicating that one individual dominated the task while the partner inhibited. Dyads in study 2 fed together on accumulating carrot pieces but could end the accumulation any time by grabbing an immediate selfish source of carrots. Dyads with low tolerance were more successful at collectively sustaining the resource than highly tolerant dyads. Further, the dominant individual was more likely to cause collapse in dyads with low tolerance than dyads with high tolerance. These results indicate that chimpanzees use a dominance-based monopolisation strategy moderated by social tolerance to overcome the tragedy of the commons.
HIF-1α regulates COXIV subunits, a potential mechanism of self-protective response to microwave induced mitochondrial damages in neurons
Authors: Hao Yan-Hui , Zhang Jing , Wang Hui , Wang Hao-Yu , Dong Ji , Xu Xin-Ping , Yao Bin-Wei , Wang Li-Feng , Zhou Hong-Mei , Zhao Li , Peng Rui-Yun
Published: July 2018

Anxiety and speculation about potential health hazards of microwaves exposure are spreading in the past decades. Hypoxia-inducible factor-1α (HIF-1α), which can be activated by reactive oxygen species (ROS), played pivotal roles in protective responses against microwave in neuron-like cells. In this study, we established 30 mW/cm2 microwave exposed animal model, which could result in revisable injuries of neuronal mitochondria, including ultrastructure and functions, such as ROS generation and cytochrome c oxidase (COX) activity. We found that the ratio of COXIV-1/COXIV-2, two isoforms of COXIV, decreased at 1 d and increased from 3 d to 14 d. Similar expression changes of HIF-1α suggested that COXIV-1 and COXIV-2 might be regulated by HIF-1α. In neuron-like cells, 30 mW/cm2 microwave down-regulated COX activity from 30 min to 6 h, and then started to recover. And, both HIF-1α transcriptional activity and COXIV-1/COXIV-2 ratio were up-regulated at 6 h and 9 h after exposure. Moreover, HIF-1α inhibition down-regulated COXIV-1 expression, promoted ROS generation, impaired mitochondrial membrane potentials (MMP), as well as abolished microwave induced ATP production. In conclusion, microwave induced mitochondrial ROS production activated HIF-1α and regulated COXIV-1 expression to restore mitochondria functions. Therefore, HIF-1α might be a potential target to impair microwave induced injuries.
Efficient targeted integration into the bovine Rosa26 locus using TALENs
Authors: Wang Ming , Sun Zhaolin , Zou Zhiyuan , Ding Fangrong , Li Ling , Wang Haiping , Zhao Chunjiang , Li Ning , Dai Yunping
Published: July 2018

The genetic modification of cattle has many agricultural and biomedical applications. However, random integration often results in the unstable expression of transgenes and unpredictable phenotypes. Targeting genes to the “safe locus” and stably expressing foreign genes at a high level are desirable methods for overcoming these hurdles. The Rosa26 locus has been widely used to produce genetically modified animals in some species expressing transgenes at high and consistent levels. For the first time, we identified a bovine orthologue of the mouse Rosa26 locus through a genomic sequence homology analysis. According to 5′ rapid-amplification of cDNA ends (5′RACE), 3′ rapid-amplification of cDNA ends (3′RACE), reverse transcription PCR (RT-PCR) and quantitative PCR (Q-PCR) experiments, this locus encodes a long noncoding RNA (lncRNA) comprising two exons that is expressed ubiquitously and stably in different tissues. The bovine Rosa26 (bRosa26) locus appears to be highly amenable to transcription activator-like effector nucleases (TALENs)-mediated knock-in, and ubiquitous expression of enhanced green fluorescent protein (EGFP) inserted in the bRosa26 locus was observed in various stages, including cells, embryos, fetus and cattle. Finally, we created a valuable master bRosa26-EGFP fetal fibroblast cell line in which any gene of interest can be efficiently introduced and stably expressed using recombinase-mediated cassette exchange (RMCE). The new tools described here will be useful for a variety of studies using cattle.
Competing contagion processes: Complex contagion triggered by simple contagion
Authors: Min Byungjoon , San Miguel Maxi
Published: July 2018

Empirical evidence reveals that contagion processes often occur with competition of simple and complex contagion, meaning that while some agents follow simple contagion, others follow complex contagion. Simple contagion refers to spreading processes induced by a single exposure to a contagious entity while complex contagion demands multiple exposures for transmission. Inspired by this observation, we propose a model of contagion dynamics with a transmission probability that initiates a process of complex contagion. With this probability nodes subject to simple contagion get adopted and trigger a process of complex contagion. We obtain a phase diagram in the parameter space of the transmission probability and the fraction of nodes subject to complex contagion. Our contagion model exhibits a rich variety of phase transitions such as continuous, discontinuous, and hybrid phase transitions, criticality, tricriticality, and double transitions. In particular, we find a double phase transition showing a continuous transition and a following discontinuous transition in the density of adopted nodes with respect to the transmission probability. We show that the double transition occurs with an intermediate phase in which nodes following simple contagion become adopted but nodes with complex contagion remain susceptible.
Femtosecond-laser-written Microstructured Waveguides in BK7 Glass
Authors: Chen George Y. , Piantedosi Fiorina , Otten Dale , Kang Yvonne Qiongyue , Zhang Wen Qi , Zhou Xiaohong , Monro Tanya M. , Lancaster David G.
Published: July 2018

There is a deficiency of low-loss microstructured waveguides that can be fabricated with a single laser-pass to minimize stress build-up, which can enable enhanced functionality and higher compactness for integrated optical devices. We demonstrate, for the first time, a series of multi-ring claddings each with a pair of cores in BK7 glass. Each waveguide was fabricated using only a single laser-pass at 1 MHz pulse repetition rate, 5 mm/s translation speed, 250 fs pulse width, over a set of pulse energies. We obtained the lowest-reported propagation loss of 0.062 dB/cm, measured at 1155 nm wavelength from the waveguide written with 340 nJ pulse energy. The maximum observed numerical aperture is 0.020, measured at 1155 nm wavelength from the waveguide written with 620 nJ pulse energy. Such waveguides could be incorporated in integrated Raman laser platforms for biomedical applications.
Non-dissociative structural transitions of the Watson-Crick and reverse Watson-Crick А·Т DNA base pairs into the Hoogsteen and reverse Hoogsteen forms
Authors: Brovarets’ Ol’ha O. , Tsiupa Kostiantyn S. , Hovorun Dmytro M.
Published: July 2018

In this study it was theoretically shown that discovered by us recently (Brovarets’et al.,Frontiers in Chemistry, 2018, 6:8; doi: 10.3389/fchem.2018.00008) high-energetical, significantly non-planar (symmetry C1), short-lived wobbled conformers of the classical Watson-Crick А·Т(WC), reverse Watson-Crick А·Т(rWC), Hoogsteen А·Т(Н) and reverse Hoogsteen А·Т(rН) DNA base pairs are the intermediates of their pairwise А∙Т(WC)/А∙Т(rWC) ↔ А∙Т(H)/А∙Т(rH) conformational transformations. These transitions do not require for their realization the energy-consumable anisotropic rotation of the amino group of A around the exocyclic C6-N6 bond. They are controlled by the non-planar transition states with quasi-orthogonal geometry (symmetry C1) joined by the single intermolecular (Т)N3H···N6(А) H-bond (~4 kcal∙mol−1). The Gibbs free energies of activation for these non-dissociative, dipole-active conformational transitions consist 7.33 and 7.81 kcal∙mol−1, accordingly. Quantum-mechanical (QM) calculations in combination with Bader’s quantum theory of “Atoms in Molecules” (QTAIM) have been performed at the MP2/aug-cc-pVDZ//B3LYP/6-311++G(d,p) level of QM theory in the continuum with ε = 4 under normal conditions.
Stochastic sequestration dynamics: a minimal model with extrinsic noise for bimodal distributions and competitors correlation
Authors: Del Giudice Marco , Bosia Carla , Grigolon Silvia , Bo Stefano
Published: July 2018

Many biological processes are known to be based on molecular sequestration. This kind of dynamics involves two types of molecular species, namely targets and sequestrants, that bind to form a complex. In the simple framework of mass-action law, key features of these systems appear to be threshold-like profiles of the amounts of free molecules as a function of the parameters determining their possible maximum abundance. However, biochemical processes are probabilistic and take place in stochastically fluctuating environments. How these different sources of noise affect the final outcome of the network is not completely characterised yet. In this paper we specifically investigate the effects induced by a source of extrinsic noise onto a minimal stochastic model of molecular sequestration. We analytically show how bimodal distributions of the targets can appear and characterise them as a result of noise filtering mediated by the threshold response. We then address the correlations between target species induced by the sequestrant and discuss how extrinsic noise can turn the negative correlation caused by competition into a positive one. Finally, we consider the more complex scenario of competitive inhibition for enzymatic kinetics and discuss the relevance of our findings with respect to applications.
Structural insights into ubiquitin phosphorylation by PINK1
Authors: Okatsu Kei , Sato Yusuke , Yamano Koji , Matsuda Noriyuki , Negishi Lumi , Takahashi Akiko , Yamagata Atsushi , Goto-Ito Sakurako , Mishima Masaki , Ito Yutaka , Oka Toshihiko , Tanaka Keiji , Fukai Shuya
Published: July 2018

Mutations of PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin (Ub) ligase parkin can cause familial parkinsonism. These two proteins are essential for ubiquitylation of damaged mitochondria and subsequent degradation. PINK1 phosphorylates Ser65 of Ub and the Ub-like (UBL) domain of parkin to allosterically relieve the autoinhibition of parkin. To understand the structural mechanism of the Ub/UBL-specific phosphorylation by PINK1, we determined the crystal structure of Tribolium castaneum PINK1 kinase domain (TcPINK1) in complex with a nonhydrolyzable ATP analogue at 2.5 Å resolution. TcPINK1 consists of the N- and C-terminal lobes with the PINK1-specific extension. The ATP analogue is bound in the cleft between the N- and C-terminal lobes. The adenine ring of the ATP analogue is bound to a hydrophobic pocket, whereas the triphosphate group of the ATP analogue and two coordinated Mg ions interact with the catalytic hydrophilic residues. Comparison with protein kinases A and C (PKA and PKC, respectively) unveils a putative Ub/UBL-binding groove, which is wider than the peptide-binding groove of PKA or PKC to accommodate the globular head of Ub or UBL. Further crosslinking analyses suggested a PINK1-interacting surface of Ub. Structure-guided mutational analyses support the findings from the present structural analysis of PINK1.
Enhanced physicochemical stability and efficacy of angiotensin I-converting enzyme (ACE) - inhibitory biopeptides by chitosan nanoparticles optimized using Box-Behnken design
Authors: Auwal Shehu Muhammad , Zarei Mohammad , Tan Chin Ping , Basri Mahiran , Saari Nazamid
Published: July 2018

Bromelain-generated biopeptides from stone fish protein exhibit strong inhibitory effect against ACE and can potentially serve as designer food (DF) with blood pressure lowering effect. Contextually, the DF refer to the biopeptides specifically produced to act as ACE-inhibitors other than their primary role in nutrition and can be used in the management of hypertension. However, the biopeptides are unstable under gastrointestinal tract (GIT) digestion and need to be stabilized for effective oral administration. In the present study, the stone fish biopeptides (SBs) were stabilized by their encapsulation in sodium tripolyphosphate (TPP) cross-linked chitosan nanoparticles produced by ionotropic gelation method. The nanoparticles formulation was then optimized via Box-Behnken experimental design to achieve smaller particle size (162.70 nm) and high encapsulation efficiency (75.36%) under the optimum condition of SBs:Chitosan mass ratio (0.35), homogenization speed (8000 rpm) and homogenization time (30 min). The SBs-loaded nanoparticles were characterized for morphology by transmission electron microscopy (TEM), physicochemical stability and efficacy. The nanoparticles were then lyophilized and analyzed using Fourier transform infra-red spectroscopy (FTIR) and X-ray diffraction (XRD). The results obtained indicated a sustained in vitro release and enhanced physicochemical stability of the SBs-loaded nanoparticles with smaller particle size and high encapsulation efficiency following long period of storage. Moreover, the efficacy study revealed improved inhibitory effect of the encapsulated SBs against ACE following simulated GIT digestion.
AU040320 deficiency leads to disruption of acrosome biogenesis and infertility in homozygous mutant mice
Authors: Guidi Luiz G. , Holloway Zoe G. , Arnoult Christophe , Ray Pierre F. , Monaco Anthony P. , Molnár Zoltán , Velayos-Baeza Antonio
Published: July 2018

Study of knockout (KO) mice has helped understand the link between many genes/proteins and human diseases. Identification of infertile KO mice provides valuable tools to characterize the molecular mechanisms underlying gamete formation. The KIAA0319L gene has been described to have a putative association with dyslexia; surprisingly, we observed that homozygous KO males for AU040320, KIAA0319L ortholog, are infertile and present a globozoospermia-like phenotype. Mutant spermatozoa are mostly immotile and display a malformed roundish head with no acrosome. In round spermatids, proacrosomal vesicles accumulate close to the acroplaxome but fail to coalesce into a single acrosomal vesicle. In wild-type mice AU040320 localises to the trans-Golgi-Network of germ cells but cannot be detected in mature acrosomes. Our results suggest AU040320 may be necessary for the normal formation of proacrosomal vesicles or the recruitment of cargo proteins required for downstream events leading to acrosomal fusion. Mutations in KIAA0319L could lead to human infertility; we screened for KIAA0319L mutations in a selected cohort of globozoospermia patients in which no genetic abnormalities have been previously identified, but detected no pathogenic changes in this particular cohort.
Prognostic role of c-Met in head and neck squamous cell cancer tissues: a meta-analysis
Authors: Vsiansky Vit , Gumulec Jaromir , Raudenska Martina , Masarik Michal
Published: July 2018

This meta-analysis aims to evaluate the effects of high c-Met levels in head and neck squamous cell carcinomas (HNSCC) on survival and clinicopathological features. Publications concerned with the clinical significance of c-Met protein expression in HNSCC were identified from the Scopus and Web of Science database searches. To elucidate the relationship between c-Met expression and clinical outcomes, a meta-analysis of the selected articles was conducted. Seventeen publications involving a total of 1724 patients met the inclusion criteria. c-Met overexpression was significantly correlated with poor overall survival (hazard ratio (HR) = 2.19, 95% confidence interval (CI) = 1.55–3.10). c-Met immunohistochemical staining positivity was also associated with worse relapse-free survival (HR = 1.64, 95% CI = 1.24–2.17) and presence of regional lymph node metastases (odds ratio (OR) = 1.76, 95% CI = 1.26–2.45). High levels of c-Met expression in HNSCC predict unfavorable prognosis associated with common clinicopathological features.
Oligomerization of a G protein-coupled receptor in neurons controlled by its structural dynamics
Authors: Møller Thor C. , Hottin Jerome , Clerté Caroline , Zwier Jurriaan M. , Durroux Thierry , Rondard Philippe , Prézeau Laurent , Royer Catherine A. , Pin Jean-Philippe , Margeat Emmanuel , Kniazeff Julie
Published: July 2018

G protein coupled receptors (GPCRs) play essential roles in intercellular communication. Although reported two decades ago, the assembly of GPCRs into dimer and larger oligomers in their native environment is still a matter of intense debate. Here, using number and brightness analysis of fluorescently labeled receptors in cultured hippocampal neurons, we confirm that the metabotropic glutamate receptor type 2 (mGlu2) is a homodimer at expression levels in the physiological range, while heterodimeric GABAB receptors form larger complexes. Surprisingly, we observed the formation of larger mGlu2 oligomers upon both activation and inhibition of the receptor. Stabilizing the receptor in its inactive conformation using biochemical constraints also led to the observation of oligomers. Following our recent observation that mGlu receptors are in constant and rapid equilibrium between several states under basal conditions, we propose that this structural heterogeneity limits receptor oligomerization. Such assemblies are expected to stabilize either the active or the inactive state of the receptor.
Selective laser sintering of inkjet-printed silver nanoparticle inks on paper substrates to achieve highly conductive patterns
Authors: Balliu Enkeleda , Andersson Henrik , Engholm Magnus , Öhlund Thomas , Nilsson Hans-Erik , Olin Håkan
Published: July 2018

Development of cost-effective and environmentally friendly manufacturing methods will enable important advances for the production of large-scale flexible electronics. Laser processing has shown to be a promising candidate that offers a fast and non-destructive way to produce highly conductive patterns on flexible substrates such as plastics. However, an emerging option with a lower environmental impact is instead the use of cellulose-based flexible substrates, such as paper. In this work we investigate the use of laser sintering of silver nanoparticle inks, which were inkjet-printed on three different types of paper. Patterns with a high conductivity could be manufactured where a special care was taken to prevent the substrates from damage by the intense laser light. We found that the best results was obtained for a photopaper, with a conductivity of 1.63 ∗ 107 S/m corresponding to nearly 26% of the bulk silver conductivity. In addition, we demonstrate laser sintering to fabricate a fully functional near field communication tag printed on a photopaper. Our results can have an important bearing for the development of cost-effective and environmentally friendly production methods for flexible electronics on a large scale.
Author Correction: Strong constraint on modelled global carbon uptake using solar-induced chlorophyll fluorescence data
Authors: MacBean Natasha , Maignan Fabienne , Bacour Cédric , Lewis Philip , Peylin Philippe , Guanter Luis , Köhler Philipp , Gómez-Dans Jose , Disney Mathias
Published: July 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Differential Effects of E-Cigarette on Microvascular Endothelial Function, Arterial Stiffness and Oxidative Stress: A Randomized Crossover Trial
Authors: Chaumont Martin , de Becker Benjamin , Zaher Wael , Culié Antoine , Deprez Guillaume , Mélot Christian , Reyé Florence , Van Antwerpen Pierre , Delporte Cédric , Debbas Nadia , Boudjeltia Karim Zouaoui , van de Borne Philippe
Published: July 2018

Propylene glycol and glycerol are electronic cigarettes vehicles allowing liquid vaporization and nicotine transport. The respective effects of these different constituents on the cardiovascular system are unknown. We assessed the differential effects of vehicles (propylene glycol and glycerol) and nicotine on microcirculatory function, arterial stiffness, hemodynamic parameters and oxidative stress. Twenty-five tobacco smokers were exposed to vaping with and without nicotine, and sham vaping, in a randomized, single blind, 3-period crossover design study. Neither sham-vaping nor vaping in the absence of nicotine resulted in modifications of cardiovascular parameters or oxidative stress. In contrast, vaping with nicotine: 1) impaired acetylcholine mediated vasodilation (mean ± standard error mean) (area under curve, perfusion unit (PU), 3385 ± 27PU to 2271 ± 27PU, p < 0.0001); 2) increased indices of arterial stiffness, namely augmentation index corrected for heart rhythm (−3.5 ± 1.5% to 1.9 ± 2.3%; p = 0.013) and pulse wave velocity (4.9 ± 0.1 m.s−1 to 5.3 ± 0.1 m.s−1; p < 0.0001); 3) increased systolic and diastolic blood pressures as well as heart rate (all p < 0.0001) and finally; 4) raised plasma myeloperoxidase (median [interquartile range]) (13.6 ng.ml−1 [10–17.7] to 18.9 ng.ml−1 [12.2–54.4], p = 0.005). Our findings demonstrated that high temperature e-cigarette vehicle vaporization does not alter micro- and macro-vascular function, and oxidative stress, and that these effects are solely attributable to nicotine.
Intrinsic and synaptic properties of hippocampal CA1 pyramidal neurons of the Wistar Audiogenic Rat (WAR) strain, a genetic model of epilepsy
Authors: Cunha Alexandra Olimpio Siqueira , Ceballos Cesar Celis , de Deus Júnia Lara , Pena Rodrigo Felipe de Oliveira , de Oliveira José Antonio Cortes , Roque Antonio Carlos , Garcia-Cairasco Norberto , Leão Ricardo Maurício
Published: July 2018

Despite the many studies focusing on epilepsy, a lot of the basic mechanisms underlying seizure susceptibility are mainly unclear. Here, we studied cellular electrical excitability, as well as excitatory and inhibitory synaptic neurotransmission of CA1 pyramidal neurons from the dorsal hippocampus of a genetic model of epilepsy, the Wistar Audiogenic Rat (WARs) in which limbic seizures appear after repeated audiogenic stimulation. We examined intrinsic properties of neurons, as well as EPSCs evoked by Schaffer-collateral stimulation in slices from WARs and Wistar parental strain. We also analyzed spontaneous IPSCs and quantal miniature inhibitory events. Our data show that even in the absence of previous seizures, GABAergic neurotransmission is reduced in the dorsal hippocampus of WARs. We observed a decrease in the frequency of IPSCs and mIPSCs. Moreover, mIPSCs of WARs had faster rise times, indicating that they probably arise from more proximal synapses. Finally, intrinsic membrane properties, firing and excitatory neurotransmission mediated by both NMDA and non-NMDA receptors are similar to the parental strain. Since GABAergic inhibition towards CA1 pyramidal neurons is reduced in WARs, the inhibitory network could be ineffective to prevent the seizure-dependent spread of hyperexcitation. These functional changes could make these animals more susceptible to the limbic seizures observed during the audiogenic kindling.
Surface analysis and depth profiling using time-of-flight elastic recoil detection analysis with argon sputtering
Authors: Siketić Zdravko , Bogdanović Radović Iva , Sudić Ivan , Jakšić Milko
Published: July 2018

The recent development of new advanced materials demands extensive effort in developing new analytical techniques that can provide insight into material composition at the nanoscale, particularly at surfaces and interfaces, which is important for both fabrication and material performance. Here, we present a proof of principle for a new setup used for thin-film characterisation and depth profiling based on a combination of time-of-flight elastic recoil detection analysis (TOF-ERDA) and Ar sputtering. A quantitative depth profiling with a best achievable surface depth resolution of ~2 nm can be realised for the entire layer, which is important for the precise determination of thickness and composition of samples that are several tenths of a nanometre thick. The performance of TOF-ERDA with Ar sputtering was demonstrated using 15 nm Cu evaporated onto a Si substrate. The advantages and limits of the method are discussed in detail.
Identifying a panel of genes/proteins/miRNAs modulated by arsenicals in bladder, prostate, kidney cancers
Authors: Polo Andrea , Marchese Silvia , De Petro Giuseppina , Montella Maurizio , Ciliberto Gennaro , Budillon Alfredo , Costantini Susan
Published: July 2018

Arsenic and arsenic-derivative compounds, named as arsenicals, represent a worldwide problem for their effect on the human health and, in particular, for their capability to increase the risk of developing cancer such as kidney, bladder and prostate cancer. The main source of arsenical exposure is drinking water. Nowadays, it is well known that the chronic exposure to arsenicals leads to a series of epigenetic alterations that have a role in arsenic-induced effects on human health including cancer. Based on these observations, the aim of our study was to select by network analysis the genes/proteins/miRNAs implicated in kidney, bladder and prostate cancer development upon arsenical exposure. From this analysis we identified: (i) the nodes linking the three molecular networks specific for kidney, bladder and prostate cancer; (ii) the relative HUB nodes (RXRA, MAP3K7, NR3C1, PABPC1, NDRG1, RELA and CTNNB1) that link the three cancer networks; (iii) the miRNAs able to target these HUB nodes. In conclusion, we highlighted a panel of potential molecules related to the molecular mechanisms of arsenical-induced cancerogenesis and suggest their utility as biomarkers or therapeutic targets.
Site-specific ion occupation in the selectivity filter causes voltage-dependent gating in a viral K+ channel
Authors: Rauh O. , Hansen U. P. , Scheub D. D. , Thiel G. , Schroeder I.
Published: July 2018

Many potassium channels show voltage-dependent gating without a dedicated voltage sensor domain. This is not fully understood yet, but often explained by voltage-induced changes of ion occupation in the five distinct K+ binding sites in the selectivity filter. To better understand this mechanism of filter gating we measured the single-channel current and the rate constant of sub-millisecond channel closure of the viral K+ channel KcvNTS for a wide range of voltages and symmetric and asymmetric K+ concentrations in planar lipid membranes. A model-based analysis employed a global fit of all experimental data, i.e., using a common set of parameters for current and channel closure under all conditions. Three different established models of ion permeation and various relationships between ion occupation and gating were tested. Only one of the models described the data adequately. It revealed that the most extracellular binding site (S0) in the selectivity filter functions as the voltage sensor for the rate constant of channel closure. The ion occupation outside of S0 modulates its dependence on K+ concentration. The analysis uncovers an important role of changes in protein flexibility in mediating the effect from the sensor to the gate.
Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
Authors: Moore Bryn S. , Mirshahi Tooraj
Published: July 2018

Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity.
Social Event Memory Test (SEMT): A Video-based Memory Test for Predicting Amyloid Positivity for Alzheimer’s Disease
Authors: Kim Ko Woon , Choi Jong Doo , Lee Hyejoo , Lee Na Kyung , Park Seongbeom , Chin Juhee , Lee Byung Hwa , Shin Jiwon , Kim Yeshin , Jang Hyemin , Choi Jee Hyun , Na Duk L.
Published: July 2018

Recent improvements in neuroimaging and molecular markers of Alzheimer’s disease (AD) have aided diagnosis in the early stage of the disease, which greatly increases the chance for successful prevention and treatment. However, the expanding resources for AD diagnosis are unlikely to benefit all elderly due to economic burden. Here, we aimed to develop an inexpensive and sensitive method to detect early-stage AD. A scenario for real-world social event memory test (SEMT) was created and filmed in 360° video. Participants watched the 7-min video through head-mounted display (HMD) and then answered questionnaire about the video. We categorized the SEMT score into recall, recognition, and place-matching scores and compared them to scores on the Mini-Mental State Examination and Seoul Verbal Learning Test. Using the SEMT scores, we built a logistic regression model that discriminated between amyloid positivity and negativity of the participants, with a cross-validation AUC. Furthermore, a classifier was created using support vector machine, which produced 93.8–95.1% sensitivity in classifying individuals into four groups of normal, mild cognitive impairment with or without amyloid, and AD elderly. The high correlation between the SEMT score and amyloid positivity in individuals who experienced virtual social gathering through an HMD opens a new possibility for early diagnosis of AD.
Time-related association between fluid balance and mortality in sepsis patients: interaction between fluid balance and haemodynamics
Authors: Shen Yanfei , Ru Weizhe , Huang Xinmei , Zhang Weimin
Published: July 2018

This study aimed to investigate the time-related association between cumulative fluid balance (FB) and mortality. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC) III. FB data on 8584 patients at the first (FB-fir24hr) and second (FB-sec24hr) 24 hours after intensive care unit admission were analysed. Compared to the combination of FB-fir24hr ≤ 0 and FB-sec24 hr ≤ 0, the combination of FB-fir24hr > 0 and FB-sec24hr ≤ 0 had significantly higher FB, with an insignificant odds ratio (OR) for mortality. However, the mortality ORs of two other combinations (FB-fir24hr ≤ 0 and FB-sec24hr > 0; FB-fir24hr > 0 and FB-sec24hr > 0) were significantly high. Furthermore, multivariable logistic analysis showed a significant stepwise increase ORs for mortality with increasing FB-sec24hr quartiles, with no significant increase in FB-fir24hr quartiles aside from quartile 4. In patients with negative FB, a stepwise decrease in mortality ORs with increasing FB-sec24hr quartiles was found with no significant difference in FB-fir24hr quartiles. In conclusion, the positive FB during the second but not the first 24 hours was associated with increased mortality in sepsis. Achieving more negative FB was associated with decreased mortality only in the second 24 hours.