bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant expression of a stabilized β-catenin mutant in keratocytes inhibits mouse corneal epithelial stratification
Authors: Zhang Lingling , Wang Yen-Chiao , Okada Yuka , Zhang Suohui , Anderson Matthew , Liu Chia-Yang , Zhang Yujin
Published: February 2019

We previously reported that genetic deletion of β-catenin in mouse corneal keratocytes resulted in precocious corneal epithelial stratification. In this study, to strengthen the notion that corneal keratocyte-derived Wnt/β-catenin signaling regulates corneal epithelial stratification during mouse development, we examined the consequence of conditional overexpression of a stabilized β-catenin mutant (Ctnnb1ΔE3) in corneal keratocytes via a doxycycline (Dox)-inducible compound transgenic mouse strain. Histological analysis showed that conditional overexpression of Ctnnb1ΔE3 in keratocytes inhibited corneal epithelial stratification during postnatal development. Unlike the corneal epithelium of the littermate controls, which consisted of 5-6 cell layers at postnatal day 21 (P21), the mutant corneal epithelium contained 1-2 or 2-3 cell layers after Dox induction from embryonic day 0 (E0) to P21 and from E9 to P21, respectively. X-gal staining revealed that Wnt/β-catenin signaling activity was significantly elevated in the corneal keratocytes of the Dox-induced mutant mice, compared to the littermate controls. Furthermore, RT-qPCR and immunostaining data indicated that the expression of Bmp4 and ΔNp63 was downregulated in the mutant corneas, which was associated with reduced corneal epithelial proliferation in mutant epithelium, as revealed by immunofluorescent staining. However, the expression of Krt12, Krt14 and Pax6 in the mutant corneas was not altered after overexpression of Ctnnb1ΔE3 mutant protein in corneal keratocytes. Overall, mutant β-catenin accumulation in the corneal keratocytes inhibited corneal epithelial stratification probably through downregulation of Bmp4 and ΔNp63 in the corneal epithelium.
Ice recrystallization is strongly inhibited when antifreeze proteins bind to multiple ice planes
Authors: Rahman Anika T. , Arai Tatsuya , Yamauchi Akari , Miura Ai , Kondo Hidemasa , Ohyama Yasushi , Tsuda Sakae
Published: February 2019

Ice recrystallization is a phenomenon observed as the increase in ice crystal size within an already frozen material. Antifreeze proteins (AFPs), a class of proteins capable of arresting ice crystal growth, are known to inhibit this phenomenon even at sub milli-molar concentrations. A tremendous range in the possible applications of AFPs is hence expected in both medical and industrial fields, while a key determinant of the ice recrystallization inhibition (IRI) is hardly understood. Here, IRI efficiency and ice plane affinity were examined for the wild-type AFPI–III, a defective AFPIII isoform, and a fungal AFP isoform. To simplify the IRI analysis using the formal representation of Ostwald-ripening (r3 = r03 + kt), we monitored specific ice grains exhibiting only uniform growth, for which maximum Feret diameter was measured. The cube of an ice grain’s radius (r3) increased proportionately with time (t), and its slope gave the recrystallization rate (k). There was a significant difference in the IRI efficiency between the samples, and the fungal AFP possessing the activity with the smallest amount (0.27 μM) exhibited an affinity to multiple ice planes. These results suggest that the IRI efficiency is maximized when AFPs bind to a whole set of ice planes.
Highly Efficient Transgenesis in Ferrets Using CRISPR/Cas9-Mediated Homology-Independent Insertion at the ROSA26 Locus
Authors: Yu Miao , Sun Xingshen , Tyler Scott R. , Liang Bo , Swatek Anthony M. , Lynch Thomas J. , He Nan , Yuan Feng , Feng Zehua , Rotti Pavana G. , Choi Soon H. , Shahin Weam , Liu Xiaoming , Yan Ziying , Engelhardt John F.
Published: February 2019

The domestic ferret (Mustela putorius furo) has proven to be a useful species for modeling human genetic and infectious diseases of the lung and brain. However, biomedical research in ferrets has been hindered by the lack of rapid and cost-effective methods for genome engineering. Here, we utilized CRISPR/Cas9-mediated, homology-independent insertion at the ROSA26 “safe harbor” locus in ferret zygotes and created transgenic animals expressing a dual-fluorescent Cre-reporter system flanked by PhiC31 and Bxb1 integrase attP sites. Out of 151 zygotes injected with circular transgene-containing plasmid and Cas9 protein loaded with the ROSA26 intron-1 sgRNA, there were 23 births of which 5 had targeted integration events (22% efficiency). The encoded tdTomato transgene was highly expressed in all tissues evaluated. Targeted integration was verified by PCR analyses, Southern blot, and germ-line transmission. Function of the ROSA26-CAG-LoxPtdTomatoStopLoxPEGFP (ROSA-TG) Cre-reporter was confirmed in primary cells following Cre expression. The Phi31 and Bxb1 integrase attP sites flanking the transgene will also enable rapid directional insertion of any transgene without a size limitation at the ROSA26 locus. These methods and the model generated will greatly enhance biomedical research involving lineage tracing, the evaluation of stem cell therapy, and transgenesis in ferret models of human disease.
Reverse immunodynamics: a new method for identifying targets of protective immunity
Authors: Spensley Katrina J. , Wikramaratna Paul S. , Penman Bridget S. , Walker Andrew , Smith Adrian L. , Pybus Oliver G. , Jean Létitia , Gupta Sunetra , Lourenço José
Published: February 2019

Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. Epidemiological models predict that strong immune selection can cause antigenic variants to structure into genetically discordant sets of antigenic types (e.g. serotypes). A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations of amino acids among co-circulating antigenic variants. We propose a novel population genetics methodology that combines such predictions with phylogenetic analyses to identify genetic loci (epitopes) under strong immune selection. We apply this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and find evidence of epitopes among certain regions of low variability which could render them ideal vaccine candidates. The proposed method can be applied to a myriad of multi-strain pathogens for which vast amounts of genetic data has been collected in recent years.
A mechanical method of cerebral cortical folding development based on thermal expansion
Authors: Wang Linlin , Yao Jianyao , Hu Ning
Published: February 2019

Cortical folding malformations are associated with several severe neurological disorders, including epilepsy, schizophrenia and autism. However, the mechanism behind cerebral cortical folding development is not yet clear. In this paper, we propose a mechanical method based on thermal expansion to simulate the development of human cerebral cortical folding. The influences of stiffness ratio, growth rate ratio, and initial cortical plate thickness on cortical folding are discussed. The results of our thermal expansion model are consistent with previous studies, indicating that abnormal values of the aforementioned three factors could directly lead to cortical folding malformation in a generally fixed pattern.
Disappearance of white sharks leads to the novel emergence of an allopatric apex predator, the sevengill shark
Authors: Hammerschlag Neil , Williams Lacey , Fallows Monique , Fallows Chris
Published: February 2019

Despite global declines of apex predatory sharks, evidence for ecosystem consequences remains limited and debated. This is likely a result of both the logistical difficulties of measuring such processes in marine systems and also due to shifting baselines, whereby the ecosystem changes have occurred prior to monitoring. Between 2000–2018, we conducted standardized monitoring of white shark (Carcharodon carcharias) abundance patterns (N = 6,333 shark sightings) and predatory activity (N = 8,076 attacks on seals) at Seal Island, a Cape fur seal (Arctocephalus pusillus pusillus) colony in False Bay, South Africa. Over the 18-year study, declines in white shark abundance and attack rates were documented between 2015–2018, with anomalous lows occurring in 2017 and 2018. This included prolonged periods of complete white shark absence from Seal Island. The disappearance of white sharks from Seal Island coincided with the unprecedented appearance of sevengill sharks (Notorynchus cepedianus; N = 120 sightings), an otherwise allopatric kelp-associated apex predator in False Bay. We also recorded a sevengill shark attacking a live seal in the absence of white sharks. These data provide empirical evidence for behavioral shifts in an allopatric marine predator following the decline and disappearance of white sharks from a foraging site. This study demonstrates the importance of historical data and long-term monitoring for disentangling ecological consequences of apex predator declines.
Impact of diverse chemotherapeutic agents and external factors on activation of brown adipose tissue in a large patient collective
Authors: Brendle Cornelia , Stefan Norbert , Stef Irina , Ripkens Sabine , Soekler Martin , la Fougère Christian , Nikolaou Konstantin , Pfannenberg Christina
Published: February 2019

Increased activity of brown adipose tissue (BAT) activity in adults is thought to prevent obesity. Therefore, regulators of BAT activity might serve as anti-obesity therapy in future, but are not investigated thoroughly up to now. In our study, we assessed retrospectively the association of BAT activity with several external factors and diverse chemotherapeutic and immunosuppressive agents in a collective of 702 patients. The patients underwent at least two clinically indicated PET/CT examinations in the course of different oncological and inflammatory diseases. BAT activity was identified according to predefined PET/CT criteria in all examinations. In multivariate analysis, the type of disease, the disease activity and the therapeutic regimen did not influence BAT activity. In contrast, sex and age were confirmed as independent factors for BAT activity. For the association of therapeutic agents with BAT activity, we examined 53 different disease-related agents, which were applied to patients without initial BAT activity between their PET/CT examinations. Out of these, cytarabine therapy was significantly associated with increased new onset of BAT activity. Cytarabine is a therapeutic agent for lymphoma patients. Further targeted studies might investigate the usefulness of Cytarabine serving as possible therapeutic approach against obesity via BAT regulation.
Artificial neural networks for density-functional optimizations in fermionic systems
Authors: Custódio Caio A. , Filletti Érica R. , França Vivian V.
Published: February 2019

In this work we propose an artificial neural network functional to the ground-state energy of fermionic interacting particles in homogeneous chains described by the Hubbard model. Our neural network functional was proven to have an excellent performance: it deviates from numerically exact calculations by less than 0.15% for a vast regime of interactions and for all the regimes of filling factors and magnetizations. When compared to analytical functionals, the neural functional was found to be more precise for all the regimes of parameters, being particularly superior at the weakly interacting regime: where the analytical parametrization fails the most, ~7%, against only ~0.1% for the neural network. We have also applied our homogeneous functional to finite, localized impurities and harmonically confined systems within density-functional theory (DFT) methods. The results show that while our artificial neural network approach is substantially more accurate than other equivalently simple and fast DFT treatments, it has similar performance than more costly DFT calculations and other independent many-body calculations, at a fraction of the computational cost.
Global Disease Outbreaks Associated with the 2015–2016 El Niño Event
Authors: Anyamba Assaf , Chretien Jean-Paul , Britch Seth C. , Soebiyanto Radina P. , Small Jennifer L. , Jepsen Rikke , Forshey Brett M. , Sanchez Jose L. , Smith Ryan D. , Harris Ryan , Tucker Compton J. , Karesh William B. , Linthicum Kenneth J.
Published: February 2019

Interannual climate variability patterns associated with the El Niño-Southern Oscillation phenomenon result in climate and environmental anomaly conditions in specific regions worldwide that directly favor outbreaks and/or amplification of variety of diseases of public health concern including chikungunya, hantavirus, Rift Valley fever, cholera, plague, and Zika. We analyzed patterns of some disease outbreaks during the strong 2015–2016 El Niño event in relation to climate anomalies derived from satellite measurements. Disease outbreaks in multiple El Niño-connected regions worldwide (including Southeast Asia, Tanzania, western US, and Brazil) followed shifts in rainfall, temperature, and vegetation in which both drought and flooding occurred in excess (14–81% precipitation departures from normal). These shifts favored ecological conditions appropriate for pathogens and their vectors to emerge and propagate clusters of diseases activity in these regions. Our analysis indicates that intensity of disease activity in some ENSO-teleconnected regions were approximately 2.5–28% higher during years with El Niño events than those without. Plague in Colorado and New Mexico as well as cholera in Tanzania were significantly associated with above normal rainfall (p < 0.05); while dengue in Brazil and southeast Asia were significantly associated with above normal land surface temperature (p < 0.05). Routine and ongoing global satellite monitoring of key climate variable anomalies calibrated to specific regions could identify regions at risk for emergence and propagation of disease vectors. Such information can provide sufficient lead-time for outbreak prevention and potentially reduce the burden and spread of ecologically coupled diseases.
Solitonic State in Microscopic Dynamic Failures
Authors: Ghaffari H. O. , Griffith W. A. , Pec M.
Published: February 2019

Onset of permanent deformation in crystalline materials under a sharp indenter tip is accompanied by nucleation and propagation of defects. By measuring the spatio-temporal strain field near the indenter tip during indentation tests, we demonstrate that the dynamic strain history at the moment of a displacement burst carries characteristics of the formation and interaction of local excitations, or solitons. We show that dynamic propagation of multiple solitons is followed by a short time interval where the propagating fronts can accelerate suddenly. As a result of such abrupt local accelerations, duration of the fast-slip phase of a failure event is shortened. Our results show that formation and annihilation of solitons mediate the microscopic fast weakening phase, during which extreme acceleration and collision of solitons lead to non-Newtonian behavior and Lorentz contraction, i.e., shortening of solitons’ characteristic length. The results open new horizons for understanding dynamic material response during failure and, more generally, complexity of earthquake sources.
Towards functional restoration for persons with limb amputation: A dual-stage implementation of regenerative agonist-antagonist myoneural interfaces
Authors: Srinivasan Shriya S. , Diaz Maurizio , Carty Matthew , Herr Hugh M.
Published: February 2019

While amputation has traditionally been viewed as a failure of therapy, recent developments in amputation surgery and neural interfacing demonstrate improved functionality and bidirectional communication with prosthetic devices. The agonist antagonist myoneural interface (AMI) is one such bi-directional neural communication model comprised of two muscles, an agonist and an antagonist, surgically connected in series within the amputated residuum such that contraction of one muscle stretches the other. By preserving agonist-antagonist muscle dynamics, the AMI allows proprioceptive signals from mechanoreceptors within both muscles to be communicated to the central nervous system. Preliminary human evidence suggests that AMIs have the capacity to provide high fidelity control of a prosthetic device, force feedback, and natural proprioception. However, AMIs have been implemented only in planned amputations and require healthy distal tissues, whereas the majority of amputations occur in patients who do not have healthy distal tissues. Through the use of a dual-stage surgical procedure which leverages existent tissues, this study proposes a revision model for implementation of the AMI in patients who are undergoing traumatic amputation or have already undergone a standard amputation. This paper validates the resulting AMI’s physiology, revealing robust viability and mechanical and electrophysiological function. We demonstrate the presence of H-waves in regenerative grafts, indicating the incorporation of the AMI into physiological reflexive loops.
Comparative studies of catalytic pathways for Streptococcus pneumoniae sialidases NanA, NanB and NanC
Authors: Xiao Kela , Wang Xingyong , Yu Haibo
Published: February 2019

Streptococcus pneumoniae (S. pneumoniae) is a leading human pathogen, which takes large responsibility for severe otitis media, acute meningitis and septicaemia. It encodes up to three distinct sialidases: NanA, NanB and NanC, which are promising drug targets. Recent experimental studies have shown that these three sialidases might work together up to the ultimate step, where NanA and NanB produce N-acetylneuraminic acid (Neu5Ac) and 2,7-anhydro-Neu5Ac following the functions of sialidase and intramolecular trans-sialidase, whilst NanC carries on a ping-pong mechanism that produces or removes 2-deoxy-2,3-didehydro-Neu5AC. It is intriguing that these sialidases have similar active sites but operate via three distinct reaction pathways. To clarify this issue, herein we present the first systematic computational investigation on the catalytic pathways for S. pneumoniae NanA, NanB and NanC based on combined quantum mechanics/molecular mechanics simulations, and propose the most preferred routes for the three S. pneumoniae sialidases. Our findings support the mechanisms of NanA and NanC that were proposed by previous experimental studies, whereas the role of water in NanB was found to differ slightly from our current understandings. The mechanistic insights obtained from this work are expected to assist in the design of potent inhibitors targeting these key enzymes for therapeutic applications.
Structural analysis of a calix[4]arene-based Platonic Micelle
Authors: Mylonas Efstratios , Yagi Naoto , Fujii Shota , Ikesue Kodai , Ueda Tomoya , Moriyama Hideaki , Sanada Yusuke , Uezu Kazuya , Sakurai Kazuo , Okobira Tadashi
Published: February 2019

We have recently introduced the concept of “Platonic micelles”, the preference of spherical micelles to specific aggregation numbers mostly coinciding with the number of faces of platonic solids. This effect was observed on bulky, mostly calix[4]arene-based surfactant systems with small aggregation numbers. The preferred aggregation numbers result in better sphere coverage, highliting the packing and the “protection” of hydrophobic cores from the aqueous solvent as the most important factor for this preference. In the present study we further explore the interactions that drive the packing of the highly charged PACaL3 surfactant into highly symmetrical hexameric micelles. We performed a series of molecular dynamics simulations that yielded a large set of structures and an ensemble in good agreement with the experimental Small Angle X-ray Scattering data was selected. The geometry and the rigidity of the calix[4]arene group with proper tail length and headgroup volume are the driving forces for the high symmetry and monodispersity of the micelle. The charge of the headgroups is mainly responsible for inhibiting the formation of higher order structures. Sodium, shown to be important for the stability of the micelle, is not directly interacting with the micelle implying that the calix[4]arene ring is a C2ν symmetry conformation.
Single molecule tracking reveals functions for RarA at replication forks but also independently from replication during DNA repair in Bacillus subtilis
Authors: Romero Hector , Rösch Thomas C. , Hernández-Tamayo Rogelio , Lucena Daniella , Ayora Silvia , Alonso Juan C. , Graumann Peter L.
Published: February 2019

RarA is a widely conserved protein proposed to be involved in recombination-dependent replication. We present a cell biological approach to identify functional connections between RarA and other proteins using single molecule tracking. We found that 50% of RarA molecules were static, mostly close to replication forks and likely DNA-bound, while the remaining fraction was highly dynamic throughout the cells. RarA alternated between static and dynamic states. Exposure to H2O2 increased the fraction of dynamic molecules, but not treatment with mitomycin C or with methyl methanesulfonate, which was exacerbated by the absence of RecJ, RecD2, RecS and RecU proteins. The ratio between static and dynamic RarA also changed in replication temperature-sensitive mutants, but in opposite manners, dependent upon inhibition of DnaB or of DnaC (pre)primosomal proteins, revealing an intricate function related to DNA replication restart. RarA likely acts in the context of collapsed replication forks, as well as in conjunction with a network of proteins that affect the activity of the RecA recombinase. Our novel approach reveals intricate interactions of RarA, and is widely applicable for in vivo protein studies, to underpin genetic or biochemical connections, and is especially helpful for investigating proteins whose absence does not lead to any detectable phenotype.
Tumorigenicity assay essential for facilitating safety studies of hiPSC-derived cardiomyocytes for clinical application
Authors: Ito Emiko , Miyagawa Shigeru , Takeda Maki , Kawamura Ai , Harada Akima , Iseoka Hiroko , Yajima Shin , Sougawa Nagako , Mochizuki-Oda Noriko , Yasuda Satoshi , Sato Yoji , Sawa Yoshiki
Published: February 2019

Transplantation of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC-CMs) is a promising treatment for heart failure, but residual undifferentiated hiPSCs and malignant transformed cells may lead to tumor formation. Here we describe a highly sensitive tumorigenicity assay for the detection of these cells in hiPSC-CMs. The soft agar colony formation assay and cell growth analysis were unable to detect malignantly transformed cells in hiPSC-CMs. There were no karyotypic abnormalities during hiPSCs subculture and differentiation. The hiPSC markers TRA1-60 and LIN28 showed the highest sensitivity for detecting undifferentiated hiPSCs among primary cardiomyocytes. Transplantation of hiPSC-CMs with a LIN28-positive fraction > 0.33% resulted in tumor formation in nude rats, whereas no tumors were formed when the fraction was < 0.1%. These findings suggested that combination of these in vitro and in vivo tumorigenecity assays can verify the safety of hiPSC-CMs for cell transplantation therapy.
Basic Units of Inter-Individual Variation in Resting State Connectomes
Authors: Sripada Chandra , Angstadt Mike , Rutherford Saige , Kessler Daniel , Kim Yura , Yee Mike , Levina Elizaveta
Published: February 2019

Resting state functional connectomes are massive and complex. It is an open question, however, whether connectomes differ across individuals in a correspondingly massive number of ways, or whether most differences take a small number of characteristic forms. We systematically investigated this question and found clear evidence of low-rank structure in which a modest number of connectomic components, around 50–150, account for a sizable portion of inter-individual connectomic variation. This number was convergently arrived at with multiple methods including estimation of intrinsic dimensionality and assessment of reconstruction of out-of-sample data. In addition, we show that these connectomic components enable prediction of a broad array of neurocognitive and clinical symptom variables at levels comparable to a leading method that is trained on the whole connectome. Qualitative observation reveals that these connectomic components exhibit extensive community structure reflecting interrelationships between intrinsic connectivity networks. We provide quantitative validation of this observation using novel stochastic block model-based methods. We propose that these connectivity components form an effective basis set for quantifying and interpreting inter-individual connectomic differences, and for predicting behavioral/clinical phenotypes.
L-PGDS-produced PGD2 in premature, but not in mature, adipocytes increases obesity and insulin resistance
Authors: Fujimori Ko , Aritake Kosuke , Oishi Yo , Nagata Nanae , Maehara Toko , Lazarus Michael , Urade Yoshihiro
Published: February 2019

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD2 in adipocytes and is selectively induced by a high-fat diet (HFD) in adipose tissue. In this study, we investigated the effects of HFD on obesity and insulin resistance in two distinct types of adipose-specific L-PGDS gene knockout (KO) mice: fatty acid binding protein 4 (fabp4, aP2)-Cre/L-PGDSflox/flox and adiponectin (AdipoQ)-Cre/L-PGDSflox/flox mice. The L-PGDS gene was deleted in adipocytes in the premature stage of the former strain and after maturation of the latter strain. The L-PGDS expression and PGD2 production levels decreased in white adipose tissue (WAT) under HFD conditions only in the aP2-Cre/L-PGDSflox/flox mice, but were unchanged in the AdipoQ-Cre/L-PGDSflox/flox mice. When fed an HFD, aP2-Cre/L-PGDSflox/flox mice significantly reduced body weight gain, adipocyte size, and serum cholesterol and triglyceride levels. In WAT of the HFD-fed aP2-Cre/L-PGDSflox/flox mice, the expression levels of the adipogenic, lipogenic, and M1 macrophage marker genes were decreased, whereas those of the lipolytic and M2 macrophage marker genes were enhanced or unchanged. Insulin sensitivity was improved in the HFD-fed aP2-Cre/L-PGDSflox/flox mice. These results indicate that PGD2 produced by L-PGDS in premature adipocytes is involved in the regulation of body weight gain and insulin resistance under nutrient-dense conditions.
Trans-pairing between osteoclasts and osteoblasts shapes the cranial base during development
Authors: Edamoto Mio , Kuroda Yukiko , Yoda Masaki , Kawaai Katsuhiro , Matsuo Koichi
Published: February 2019

Bone growth is linked to expansion of nearby organs, as is the case for the cranial base and the brain. Here, we focused on development of the mouse clivus, a sloping surface of the basioccipital bone, to define mechanisms underlying morphological changes in bone in response to brain enlargement. Histological analysis indicated that both endocranial and ectocranial cortical bone layers in the basioccipital carry the osteoclast surface dorsally and the osteoblast surface ventrally. Finite element analysis of mechanical stress on the clivus revealed that compressive and tensile stresses appeared mainly on respective dorsal and ventral surfaces of the basioccipital bone. Osteoclastic bone resorption occurred primarily in the compression area, whereas areas of bone formation largely coincided with the tension area. These data collectively suggest that compressive and tensile stresses govern respective localization of osteoclasts and osteoblasts. Developmental analysis of the basioccipital bone revealed the clivus to be angled in early postnatal wild-type mice, whereas its slope was less prominent in Tnfsf11−/− mice, which lack osteoclasts. We propose that osteoclast-osteoblast “trans-pairing” across cortical bone is primarily induced by mechanical stress from growing organs and regulates shape and size of bones that encase the brain.
Changes in overall and regional body fatness from childhood to early adolescence
Authors: Santos Leonardo Pozza , Santos Ina S. , Matijasevich Alicia , Barros Aluísio J. D.
Published: February 2019

Children weight gain is mostly due to fat-free mass than fat mass, but the changes in body composition dynamics related to child growth can be attributed to the obesity epidemic. We aimed to assess changes in measures of body composition from 6 to 11 years of age according to sex, and to examine whether changes in these measures are associated with sociodemographic characteristics. A longitudinal study using data from the 2004 Pelotas Birth Cohort was conducted, and assessed body composition and fat distribution through measures of BMI, fat mass index, fat-free mass index, and android and gynoid fat mass percentages from DXA. Changes in body fatness were calculated as the difference between measures collected at 6 and 11 years of age, and linear regression models were used to assess changes in body composition according to sociodemographic characteristics. An increase in mean BMI z-score from 6 to 11 years was observed only in boys and obesity prevalence reached one out of four boys and one out of five girls. There was an increase in fat mass percentage, fat mass index and android fat mass, with this effect more accentuated in boys when compared to girls. Maternal BMI was the most consistent factor associated with change in body fatness. Children from mothers with obesity showed larger increases in fat mass percentage, fat mass index and android fat mass. There was an increase in body fatness and a centralisation of body shape, mostly associated with male sex and maternal obesity. These results may indicate an early risk of non-communicable diseases in children from the Pelotas 2004 Birth Cohort.
Exploring cold quarantine to mango fruit against fruit fly using artificial ripening
Authors: Patil Abhinandan S. , Maurer Dalia , Feygenberg Oleg , Alkan Noam
Published: February 2019

Mango quarantine is based mainly on heat treatment, with a possible deterioration of fruit quality. We studied the effects of cold quarantine (19 days storage at 2 °C) on fruit quality of commercial mango cvs. Keitt and Shelly for three consecutive years. Chilling injury (CI) occurs in mango fruit stored at temperatures lower than 12 °C. By reanalysing our previous transcriptome, we found that under sub-optimal temperature storage (5 °C), the fruit increases its ethylene biosynthesis and osmolarity by activating sugar metabolism, thereby probably reducing its freezing point. Similarly, ripe fruit with higher sugar concentration should be more resistant to cold-storage stress. Here, mango fruit was artificially ripened with 150 ppm ethylene. The control group, stored at 2 °C, suffered from severe CI, whereas the combined treatment of artificial ripening, modified atmosphere (fruit were enclosed in perforated bags) and subsequent low-temperature conditioning resulted in a significant reduction in CI to satisfactory levels for consumer acceptance (taste, aroma and texture). The combined treatment reduced lipid peroxidation and maintained flavour, leading to a novel cold-quarantine treatment for mango fruit. Thus, by reversing the supply chain and storing ripe and ready-to-eat fruit, cold quarantine was enabled for mango, and possibly other chilling-susceptible fruits.
Ambient and controlled exposures to particulate air pollution and acute changes in heart rate variability and repolarization
Authors: Breitner Susanne , Peters Annette , Zareba Wojciech , Hampel Regina , Oakes David , Wiltshire Jelani , Frampton Mark W. , Hopke Philip K. , Cyrys Josef , Utell Mark J. , Kane Cathleen , Schneider Alexandra , Rich David Q.
Published: February 2019

Previous studies have reported increased risks of myocardial infarction in association with elevated ambient particulate matter (PM) in the previous hour(s). However, whether PM can trigger mechanisms that act on this time scale is still unclear. We hypothesized that increases in PM are associated with rapid changes in measures of heart rate variability and repolarization. We used data from panel studies in Augsburg, Germany, and Rochester, New York, USA, and two controlled human exposure studies in Rochester. Data included ECG recordings from all four studies, controlled exposures to (concentrated) ultrafine particles (UFP; particles with an aerodynamic diameter <100 nm) and ambient concentrations of UFP and fine PM (PM2.5, aerodynamic diameter <2.5 μm). Factor analysis identified three representative ECG parameters: standard deviation of NN-intervals (SDNN), root mean square of successive differences (RMSSD), and T-wave complexity. Associations between air pollutants and ECG parameters in the concurrent and previous six hours were estimated using additive mixed models adjusting for long- and short-term time trends, meteorology, and study visit number. We found decreases in SDNN in relation to increased exposures to UFP in the previous five hours in both of the panel studies (e.g. Augsburg study, lag 3 hours: −2.26%, 95% confidence interval [CI]: −3.98% to −0.53%; Rochester panel study, lag 1 hour: −2.69%; 95% CI: −5.13% to −0.26%) and one of the two controlled human exposure studies (1-hour lag: −13.22%; 95% CI: −24.11% to −2.33%). Similarly, we observed consistent decreases in SDNN and RMSSD in association with elevated PM2.5 concentrations in the preceding six hours in both panel studies. We did not find consistent associations between particle metrics and T-wave complexity. This study provided consistent evidence that recent exposures to UFP and PM2.5 can induce acute pathophysiological responses.
The cyclic peptide labaditin does not alter the outer membrane integrity of Salmonella enterica serovar Typhimurium
Authors: Barbosa Simone C. , Nobre Thatyane M. , Volpati Diogo , Cilli Eduardo M. , Correa Daniel S. , Oliveira Osvaldo N.
Published: February 2019

Antimicrobial peptides are a promising class of new antibiotics with the ability to kill bacteria by disrupting their cell membrane, which is especially difficult for Gram-negative bacteria whose cell wall contains an outer layer of lipopolysaccharides (LPS). Here we show that the cyclic decapeptide Labaditin (Lo), with proven activity against the Gram-positive Staphylococcus aureus and Streptococcus mutans, is not able to kill the Gram-negative Salmonella enterica serovar Typhimurium (S.e.s. Typhimurium). We found that Lo induced significant changes in the surface pressure isotherms of Langmuir monolayers representing the Salmonella enterica serovar Typhimurium inner membrane (S.e.s. Typhimurium IM), and caused leakage in large unilamellar vesicles made with this IM lipid composition. On the basis of these results one should expect bactericidal activity against S.e.s. Typhimurium. However, Lo could not interact with a monolayer of LPS, causing no significant changes in either the surface pressure isotherms or in the polarization-modulated infrared reflection absorption spectra (PM-IRRAS). Therefore, the failure of Lo to kill S.e.s. Typhimurium is associated with the lack of interaction with LPS from the outer bacteria membrane. Our approach with distinct monolayer compositions and combined techniques to investigate molecular-level interactions is useful for drug design to fight antibiotic-resistant bacteria.
The Th17/Treg Cytokine Imbalance in Chronic Obstructive Pulmonary Disease Exacerbation in an Animal Model of Cigarette Smoke Exposure and Lipopolysaccharide Challenge Association
Authors: Cervilha Daniela A. B. , Ito Juliana T. , Lourenço Juliana D. , Olivo Clarice R. , Saraiva-Romanholo Beatriz M. , Volpini Rildo A. , Oliveira-Junior Manoel C. , Mauad Thais , Martins Milton A. , Tibério Iolanda F. L. C. , Vieira Rodolfo P. , Lopes Fernanda D. T. Q. S.
Published: February 2019

We proposed an experimental model to verify the Th17/Treg cytokine imbalance in COPD exacerbation. Forty C57BL/6 mice were exposed to room air or cigarette smoke (CS) (12 ± 1 cigarettes, twice a day, 30 min/exposure and 5 days/week) and received saline (50 µl) or lipopolysaccharide (LPS) (1 mg/kg in 50 µl of saline) intratracheal instillations. We analyzed the mean linear intercept, epithelial thickness and inflammatory profiles of the bronchoalveolar lavage fluid and lungs. We evaluated macrophages, neutrophils, CD4+ and CD8+ T cells, Treg cells, and IL-10+ and IL-17+ cells, as well as STAT-3, STAT-5, phospho-STAT3 and phospho-STAT5 levels using immunohistochemistry and IL-17, IL-6, IL-10, INF-γ, CXCL1 and CXCL2 levels using ELISA. The study showed that CS exposure and LPS challenge increased the numbers of neutrophils, macrophages, and CD4+ and CD8+ T cells. Simultaneous exposure to CS/LPS intensified this response and lung parenchymal damage. The densities of Tregs and IL-17+ cells and levels of IL-17 and IL-6 were increased in both LPS groups, while IL-10 level was only increased in the Control/LPS group. The increased numbers of STAT-3, phospho-STAT3, STAT-5 and phospho-STAT5+ cells corroborated the increased numbers of IL-17+ and Treg cells. These findings point to simultaneous challenge with CS and LPS exacerbated the inflammatory response and induced diffuse structural changes in the alveolar parenchyma characterized by an increase in Th17 cytokine release. Although the Treg cell differentiation was observed, the lack of IL-10 expression and the decrease in the density of IL-10+ cells observed in the CS/LPS group suggest that a failure to release this cytokine plays a pivotal role in the exacerbated inflammatory response in this proposed model.
High Tensile Ductility and Strength in Dual-phase Bimodal Steel through Stationary Friction Stir Processing
Authors: Arora H. S. , Ayyagari A. , Saini J. , Selvam K. , Riyadh S. , Pole M. , Grewal H. S. , Mukherjee S.
Published: February 2019

The combination of high strength and good ductility are very desirable for advanced structural and functional applications. However, measures to enhance strength typically lead to ductility reduction due to their inverse correlation, nano-grained structures for an instance. Bi-modal grain structure is promising in this regard, but its realization is limited by multiple complex processing steps. Here, we demonstrate a facile single-step processing route for the development of bimodal grain structure in austenitic stainless steel, SS316L. The bimodal structure comprised of fine martensite grains (<500 nm) sandwiched between coarse austenite grains (~10 µm). The dual-phase bimodal structure demonstrated higher yield strength (~620 MPa) compared to ultra-fine grain structure (~450 MPa) concurrent with high uniform tensile ductility (~35%). These exceptional properties are attributed to unique dual-phase, bimodal grain structure which delayed the onset of plastic instability resulting in higher strength as well as larger uniform elongation and work-hardening rate. Our approach may be easily extended to a wide range of material systems to engineer superior performance.
Genomic blueprints of sponge-prokaryote symbiosis are shared by low abundant and cultivatable Alphaproteobacteria
Authors: Karimi Elham , Keller-Costa Tina , Slaby Beate M. , Cox Cymon J. , da Rocha Ulisses N. , Hentschel Ute , Costa Rodrigo
Published: February 2019

Marine sponges are early-branching, filter-feeding metazoans that usually host complex microbiomes comprised of several, currently uncultivatable symbiotic lineages. Here, we use a low-carbon based strategy to cultivate low-abundance bacteria from Spongia officinalis. This approach favoured the growth of Alphaproteobacteria strains in the genera Anderseniella, Erythrobacter, Labrenzia, Loktanella, Ruegeria, Sphingorhabdus, Tateyamaria and Pseudovibrio, besides two likely new genera in the Rhodobacteraceae family. Mapping of complete genomes against the metagenomes of S. officinalis, seawater, and sediments confirmed the rare status of all the above-mentioned lineages in the marine realm. Remarkably, this community of low-abundance Alphaproteobacteria possesses several genomic attributes common to dominant, presently uncultivatable sponge symbionts, potentially contributing to host fitness through detoxification mechanisms (e.g. heavy metal and metabolic waste removal, degradation of aromatic compounds), provision of essential vitamins (e.g. B6 and B12 biosynthesis), nutritional exchange (especially regarding the processing of organic sulphur and nitrogen) and chemical defence (e.g. polyketide and terpenoid biosynthesis). None of the studied taxa displayed signs of genome reduction, indicative of obligate mutualism. Instead, versatile nutrient metabolisms along with motility, chemotaxis, and tight-adherence capacities - also known to confer environmental hardiness – were inferred, underlying dual host-associated and free-living life strategies adopted by these diverse sponge-associated Alphaproteobacteria.
Dissociable components of the reward circuit are involved in appraisal versus choice
Authors: Shenhav Amitai , Karmarkar Uma R.
Published: February 2019

People can evaluate a set of options as a whole, or they can approach those same options with the purpose of making a choice between them. A common network has been implicated across these two types of evaluations, including regions of ventromedial prefrontal cortex and the posterior midline. We test the hypothesis that sub-components of this reward circuit are differentially involved in triggering more automatic appraisal of one’s options (Dorsal Value Network) versus explicitly comparing between those options (Ventral Value Network). Participants undergoing fMRI were instructed to appraise how much they liked a set of products (Like) or to choose the product they most preferred (Choose). Activity in the Dorsal Value Network consistently tracked set liking, across both task-relevant (Like) and task-irrelevant (Choose) trials. In contrast, the Ventral Value Network was particularly sensitive to evaluation condition (more active during Choose than Like trials). Within vmPFC, anatomically distinct regions were dissociated in their sensitivity to choice (ventrally, in medial OFC) versus appraisal (dorsally, in pregenual ACC). Dorsal regions additionally tracked decision certainty across both types of evaluation. These findings suggest that separable mechanisms drive decisions about how good one’s options are versus decisions about which option is best.
Genome-wide expression analysis reveals six contravened targets of EZH2 associated with breast cancer patient survival
Authors: Kumari Kanchan , Das Biswajit , Adhya Amit K. , Rath Arabinda K. , Mishra Sandip K.
Published: February 2019

Several pioneering work have established that apart from genetic alterations, epigenetic modifications contribute significantly in tumor progression. Remarkable role of EZH2 in cancer highlights the importance of identifying its targets. Although much emphasis has been placed in recent years in designing drugs and inhibitors targeting EZH2, less effort has been given in exploring its existing targets that will help in understanding the oncogenic role of EZH2 in turn which may provide a more stringent method of targeting EZH2. In the present study, we validated six direct targets of EZH2 that are GPNMB, PMEPA1, CoL5A1, VGLL4, POMT2 and SUMF1 associated with cancer related pathways. Upon EZH2 knockdown, more than two fold increase in the target gene expression was evident. CHIP-qPCR performed in both MCF-7 and MDA-MDA-231 confirmed the in-vivo binding of EZH2 on its identified target. Thirty invasive breast carcinoma cases with their adjacent normal tissues were included in the study. Immunohistochemistry in primary breast tumor tissue array showed tumor dependent expression of EZH2. Array of MERAV expression database revealed the strength of association of EZH2 with its target genes. Real time PCR performed with RNA extracted from breast tumor tissues further authenticated the existing negative correlation between EZH2 and its target genes. Pearson correlation coefficient & statistical significance computed using the matrix provided in the database strengthened the negative correlation between identified target genes and EZH2. KM plotter analysis showed improved relapse-free survival with increased expression of PMEPA1, POMT2, VGLL4 and SUMF1 in breast cancer patients indicating their therapeutic potential. While investigating the relevance of these target genes, different mutations of them were found in breast cancer patients. Seeking the clinical relevance of our study, following our recent publication that reports the role of EZH2 in nicotine-mediated breast cancer development and progression, we observed significant reduced expression of SUMF1 in breast cancer patient samples with smoking history in comparison to never-smoked patient samples.
Plastic-scale-model assembly of ultrathin film MEMS piezoresistive strain sensor with conventional vacuum-suction chip mounter
Authors: Takamatsu Seiichi , Goto Shintaro , Yamamoto Michitaka , Yamashita Takahiro , Kobayashi Takeshi , Itoh Toshihiro
Published: February 2019

We developed a plastic-scale-model assembly of an ultrathin film piezoresistive microelectromechanical systems (MEMS) strain sensor with a conventional vacuum-suction chip mounter for the application to flexible and wearable strain sensors. A plastic-scale-model MEMS chip consists of 5-μm ultrathin piezoresistive strain sensor film, ultrathin disconnection parts, and a thick outer frame. The chip mounter applies pressure to the ultrathin piezoresistive strain sensor film and cuts the disconnection parts to separate the sensor film from the outer frame. The sensor film is then picked up and placed on the desired area of a flexible substrate. To cut off and pick up the sensor film in the same manner as with a plastic scale model, the design of the sensor film and disconnection parts of MEMS chips were optimized through numerical simulation and chip-mounting experiments. The success rate of the 5-μm ultrathin sensor film mounting increased by decreasing the number and width of the disconnection parts. For a 5-μm-thick 1 × 5 mm2 sensor film, 4 disconnection parts of 20 μm in width achieved 100% success rate. The fabricated ultrathin MEMS piezoresistive strain sensor exhibited a gauge factor of 100 and high flexibility to withstand 0.37 [1/mm] bending curvature. Our plastic-scale-model assembly with a conventional vacuum-suction chip mounter will contribute to more practical manufacturing of ultrathin MEMS sensors.
The antibacterial effect of non-thermal atmospheric pressure plasma treatment of titanium surfaces according to the bacterial wall structure
Authors: Lee Myung-Jin , Kwon Jae-Sung , Jiang Heng Bo , Choi Eun Ha , Park Gyungsoon , Kim Kwang-Mahn
Published: February 2019

Titanium is commonly used as a biomaterial for dental implants. In this study, we investigated the antibacterial properties of titanium samples following treatment with a non-thermal atmospheric pressure plasma jet (NTAPPJ) on bacteria with two different cell wall structures, including gram-positive and gram-negative bacteria. The hydrophilicity and surface energy of titanium surfaces were significantly increased after NTAPPJ treatment without altering topographical features. Changes in the chemical composition and reductive potential were observed on the NTAPPJ-treated titanium surfaces. The adhesion and biofilm formation rate of bacteria were significantly reduced on the NTAPPJ-treated titanium surfaces compared with the untreated samples, which was confirmed by fluorescent imaging. Regarding the comparison between gram-positive and gram-negative bacteria, both adhesion and the biofilm formation rate were significantly lower for gram-negative bacteria than gram-positive bacteria on samples treated for longer durations with the NTAPPJ. Transmission electron microscopy imaging showed a comparably more disruptive membrane structure of gram-negative bacteria than gram-positive bacteria on the NTAPPJ-treated surfaces. Our results indicated that the NTAPPJ treatment could be useful for preventing bacterial adhesion and biofilm formation on titanium dental implant surfaces, while the reductive potential on surfaces treated by the NTAPPJ could cause oxidation of bacteria, which could be more sensitive to gram-negative bacteria due to differences in the cell wall structure.