bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary health care physicians’ prescribing patterns for children under five in Qassim, Saudi Arabia
Authors: Jahan Saulat , Al-Saigul Abdullah Mohammed , Hamdelsseed Salih Ahmed
Published: June 2019

Background:

Irrational prescription of drugs in children is reported to be widespread. There are scarce studies on the pediatric prescribing pattern especially at primary health care (PHC) level.

Aim:

To determine the physicians’ prescribing patterns for children under five years, to explore completeness of prescriptions’ recorded information, and to analyze the core indicators of drug prescribing at primary health care centers (PHCC) in Qassim.

Methods:

This cross-sectional study was conducted on 25 randomly selected PHCCs. All prescriptions, for the first week of first six months of the year 1437 Hijrah (October 2015 to April 2016), were reviewed. Among 25 012 prescriptions, 4125 (16.5%) were for children under five years. We randomly selected 1212 prescriptions for the study. World Health Organization (WHO) specified drug use indicators, and index of rational drug prescribing (IRDP) with a maximum value of 5, were calculated. The physicians and pharmacists of sampled PHCCs were also surveyed to explore prescribing issues.

Findings:

The completeness of recorded date, patient age, and gender was more than 90%. The diagnosis was legibly written in 842 (69.5%), while the patient weight was recorded in 307 (25.3%) prescriptions. The least commonly recorded instruction was the drug strength (26.8%), while the dose and frequency of use were stated for 91.3% and 90.8% of the drugs, respectively. The average number of drugs per prescription was 2.35 ± 0.89; 72.97% drugs were prescribed by generic name; in 65.98% patient encounters, antibiotics were prescribed. The overall IRDP was 3.56. Most of the physicians and pharmacists reported availability of the drug list and Saudi PHC formulary in their PHCCs.

Conclusion:

PHC physicians’ drug prescribing was not at the optimal level of rational use, especially regarding prescription of antibiotics. Creating awareness about rational drug use and hazards of overuse of antibiotics is needed.
Primary health care among rural pregnant women in China: achievements and challenges in maternal mortality ratio
Authors: Yang Le , Wang Hongman
Published: June 2019

Background:

The maternal mortality ratio (MMR) is not only an important indicator of maternal and infant safety, but also a sign of the development of economy, education, and medical care in a country. In the last 60 years, the Chinese government has implemented various strategies and policies to reduce the MMR, especially in the rural areas.

Aim:

This study aimed to discuss the strategies developed by the Chinese government, showing the successful experience of Chinese intervention programs and highlighting the challenges to the government in the context of current economic and social status.

Method:

This study probed into the Chinese government’s efforts and achievements in the MMR reducing by reviewing the relevant health policies, extracting the data from China Health Statistics Yearbook of 2015, analyzing the reduction of maternal death in rural areas and the major causes from 1991 to 2015, comparing the MMR trend in urban and rural areas, and discussing the changes of the situation in China.

Finding:

Although it seems that Chinese government’s efforts have brought evangel to the rural pregnant women and significantly reduced rural maternal mortality, the government still needs to develop more equitable and flexible primary health care policies to narrow the imbalance in health resource allocation and pay more attention to the health care for the rural-to-urban migration in China.
Electrocardiographic screening in primary care for cardiovascular disease risk and atrial fibrillation
Authors: Harskamp Ralf E.
Published: June 2019

Electrocardiograms (ECGs) are frequently recorded in primary care for screening purposes. An ECG is essential in diagnosing atrial fibrillation, and ECG abnormalities are associated with cardiovascular events. While recent studies show that ECGs adequately reclassify a proportion of patients based on the clinical risk score calculations, there are no data to support that this also results in improved health outcomes. When applied for screening for atrial fibrillation, more cases are found with routine care, but this would be undone when physicians would perform systematic pulse palpation. In most studies, the harms of routine ECG use (such as unnecessary diagnostic testing, emotional distress, increased health expenses) were poorly documented. As such, the routine performing of ECGs in asymptomatic primary care patients, whether it is for cardiovascular disease risk assessment or atrial fibrillation, cannot be recommended.
A Subannual Subsurface Pathway From the Gulf Stream to the Subpolar Gyre and Its Role in Warming and Salinification in the 1990s
Authors: Jacobs Zoe L. , Grist Jeremy P. , Marsh Robert , Josey Simon A.
Published: June 2019

The transport of warm, saline subtropical water to the subpolar gyre (SPG) in the North Atlantic has been the subject of a range of Lagrangian studies, establishing intergyre exchange on timescales of 2–7 years, with greater subsurface throughflow. Here calculating particle trajectories in a high‐resolution, global hindcast, we present new evidence for a direct, subsurface pathway to the SPG from the Gulf Stream (GS) on subannual timescales. The pathway is most evident for particles initially at 200‐m depth in the GS and is enhanced after a prolonged period of positive North Atlantic Oscillation. This occurred in the mid‐1990s and led to warming and salinification of the western SPG consistent with observations. The more realistic advective pathways and timescales in the high‐resolution model enable, for the first time, attribution of temperature and salinity changes in the SPG to a direct influx of GS water.
Evidence for Late Alluvial Activity in Gale Crater, Mars
Authors: Grant John A. , Wilson Sharon A.
Published: June 2019

The occurrence of past habitable conditions in Gale crater is generally associated with lacustrine and alluvial environments present >3 Ga ago, during the Hesperian Period on Mars. However, later‐occurring aqueous activity is consistent with superposition relations between some alluvial deposits and bounding materials on the crater walls, preservation of fine‐scale morphology on these alluvial deposits, and their superposing crater densities. The alluvial deposits include some not previously considered, and collectively lend confidence to the interpretation that local aqueous activity persisted in Gale crater into the Amazonian, or <2 Ga ago. Our conclusions are generally in accordance with late aqueous activity inferred from geochronology data (Martin et al., 2017, https://doi.org/10.1002/2017JE005445), in addition to late alluvial activity elsewhere. Interpreted late aqueous activity points to possible habitable settings in Gale later than previously recognized.
Geographical Distribution of Thermometers Gives the Appearance of Lower Historical Global Warming
Authors: Benestad R. E. , Erlandsen H.B. , Mezghani A. , Parding K. M.
Published: June 2019

Gaps with missing data in the observational temperature record are responsible for an underestimation of the global warming between 1881–1910 and 1986–2015 by 0.1 °C. We found that missing data in the historical observations introduce a warm bias in the early part of the record and a cold bias toward the end. The effect of the nonuniform sampling was explored by comparing the global mean temperature estimated from gridded observations, climate model simulations, and reanalysis. Output from global simulations was subsampled by masking the grid boxes corresponding to those with missing data in the observations to mimic the geographical availability of temperature measurements. A combination of variance depending on region and a varying geographical data sampling over time explains the bias in the global mean. We propose a methodology for estimating the global mean temperature that reduces the effect of the nonuniform variance.
Color Ratios of Subauroral (STEVE) Arcs
Authors: Mende S. B. , Turner C.
Published: June 2019

Photos of a spectacular optical phenomenon, nicknamed STEVE, show finely structured, purple‐colored, east‐west arcs spanning the sky. These purple Sub‐auroral Arc Emissions are associated with Sub‐Auroral Ion Drifts, often accompanied by separate green arcs frequently displaying magnetic field aligned rays suggesting charge particle excitation. Both types of these arcs and polar auroras appear in some photos. Splitting the images into red, green, and blue channels allowed comparison of color ratios of the three phenomena. Wavelength calibration of the camera verified that the dominant atmospheric auroral emissions, 630.0 nm O(1D), O(1S) 557.7 nm, and N2+1N bands, were cleanly separated in the red, green, and blue channels of the camera. In the absence of a spectrogram the ratios between the color channels were interpreted in terms of possible excitation mechanisms. The purple arcs contained an excess of blue, presumably N2+1N intensity. This excess production could be due to the excitation of N2+ ions that were ionized through charge exchange with O+. The green companion arcs appear to be purely green (557.7) with almost no blue and minimal red suggesting excitation by low‐energy electrons excitation at altitudes >100 and <150 km.
Constraints on Appalachian Orogenesis and Continental Rifting in the Southeastern United States From Wide‐Angle Seismic Data
Authors: Marzen Rachel E. , Shillington Donna J. , Lizarralde Daniel , Harder Steven H.
Published: June 2019

The Southeastern United States is an ideal location to understand the interactions between mountain building, rifting, and magmatism. Line 2 of the Suwannee suture and Georgia Rift basin refraction seismic experiment in eastern Georgia extends 420 km from the Inner Piedmont to the Georgia coast. We model crustal and upper mantle VP and upper crustal VS. The most dramatic model transition occurs at the Higgins‐Zietz magnetic boundary, north of which we observe higher upper crustal VP and VS and lower VP/VS. These observations support the interpretation of the Higgins‐Zietz boundary as the Alleghanian suture. North of this boundary, we observe a low‐velocity zone less than 2 km thick at ~5‐km depth, consistent with a layer of sheared metasedimentary rocks that forms the Appalachian detachment. To the southeast, we interpret synrift sediments and decreasing crustal thickness to represent crustal thinning associated with the South Georgia Rift Basin and subsequent continental breakup. The correspondence of the northern limit of thinning with the interpreted suture location suggests that the orogenic suture zone and/or the Gondwanan crust to the south of the suture helped localize subsequent extension. Lower crustal VP and VP/VS preclude volumetrically significant mafic magmatic addition during rifting or associated with the Central Atlantic Magmatic Province. Structures formed during orogenesis and/or extension appear to influence seismicity in Georgia today; earthquakes localize along a steeply dipping zone that coincides with the northern edge of the South Georgia Basin and the change in upper crustal velocities at the Higgins‐Zietz boundary.
A global multi-hazard risk analysis of road and railway infrastructure assets
Authors: Koks E. E. , Rozenberg J. , Zorn C. , Tariverdi M. , Vousdoukas M. , Fraser S. A. , Hall J. W. , Hallegatte S.
Published: June 2019

Transport infrastructure is exposed to natural hazards all around the world. Here we present the first global estimates of multi-hazard exposure and risk to road and rail infrastructure. Results reveal that ~27% of all global road and railway assets are exposed to at least one hazard and ~7.5% of all assets are exposed to a 1/100 year flood event. Global Expected Annual Damages (EAD) due to direct damage to road and railway assets range from 3.1 to 22 billion US dollars, of which ~73% is caused by surface and river flooding. Global EAD are small relative to global GDP (~0.02%). However, in some countries EAD reach 0.5 to 1% of GDP annually, which is the same order of magnitude as national transport infrastructure budgets. A cost-benefit analysis suggests that increasing flood protection would have positive returns on ~60% of roads exposed to a 1/100 year flood event.
Coordination mode engineering in stacked-nanosheet metal–organic frameworks to enhance catalytic reactivity and structural robustness
Authors: Huang Chuanhui , Dong Juncai , Sun Weiming , Xue Zhenjie , Ma Jun , Zheng Lirong , Liu Cong , Li Xiao , Zhou Kang , Qiao Xuezhi , Song Qian , Ma Wende , Zhang Lan , Lin Zhenyu , Wang Tie
Published: June 2019

Optimising the supported modes of atom or ion dispersal onto substrates, to synchronously integrate high reactivity and robust stability in catalytic conversion, is an important yet challenging area of research. Here, theoretical calculations first show that three-coordinated copper (Cu) sites have higher activity than four-, two- and one-coordinated sites. A site-selective etching method is then introduced to prepare a stacked-nanosheet metal–organic framework (MOF, CASFZU-1)-based catalyst with precisely controlled coordination number sites on its surface. The turnover frequency value of CASFZU-1 with three-coordinated Cu sites, for cycloaddition reaction of CO2 with epoxides, greatly exceed those of other catalysts reported to date. Five successive catalytic cycles reveal the superior stability of CASFZU-1 in the stacked-nanosheet structure. This study could form a basis for the rational design and construction of highly efficient and robust catalysts in the field of single-atom or ion catalysis.
m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade
Authors: Yang Seungwon , Wei Jiangbo , Cui Yan-Hong , Park Gayoung , Shah Palak , Deng Yu , Aplin Andrew E. , Lu Zhike , Hwang Seungmin , He Chuan , He Yu-Ying
Published: June 2019

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.
Mechanisms of Ca2+/calmodulin-dependent kinase II activation in single dendritic spines
Authors: Chang Jui-Yun , Nakahata Yoshihisa , Hayano Yuki , Yasuda Ryohei
Published: June 2019

CaMKIIα plays an essential role in decoding Ca2+ signaling in spines by acting as a leaky Ca2+ integrator with the time constant of several seconds. However, the mechanism by which CaMKIIα integrates Ca2+ signals remains elusive. Here, we imaged CaMKIIα-CaM association in single dendritic spines using a new FRET sensor and two-photon fluorescence lifetime imaging. In response to a glutamate uncaging pulse, CaMKIIα-CaM association increases in ~0.1 s and decays over ~3 s. During repetitive glutamate uncaging, which induces spine structural plasticity, CaMKIIα-CaM association did not show further increase but sustained at a constant level. Since CaMKIIα activity integrates Ca2+ signals over ~10 s under this condition, the integration of Ca2+ signal by CaMKIIα during spine structural plasticity is largely due to Ca2+/CaM-independent, autonomous activity. Based on these results, we propose a simple kinetic model of CaMKIIα activation in dendritic spines.
Mimicking immune signatures of flavivirus infection with targeted adjuvants improves dengue subunit vaccine immunogenicity
Authors: Bidet Katell , Ho Victor , Chu Collins Wenhan , Naim Ahmad Nazri Mohamed , Thazin Khaing , Chan Kuan Rong , Low Jenny G. H. , Choy Milly M. , Wong Lan Hiong , Florez de Sessions Paola , Lee Yie Hou , Hibberd Martin L. , Ooi Eng Eong , Fink Katja , Chen Jianzhu
Published: June 2019

Neutralizing antibodies (nAbs) are a critical component for protection against dengue virus (DENV) infection, but little is known about the immune mechanisms governing their induction and whether such mechanisms can be harnessed for vaccine development. In this study, we profiled the early immune responses to flaviviruses in human peripheral blood mononuclear cells and screened a panel of toll-like receptor (TLR) agonists that stimulate the same immune signatures. Monocyte/macrophage-driven inflammatory responses and interferon responses were characteristics of flavivirus infection and associated with induction of nAbs in humans immunized with the yellow fever vaccine YF-17D. The signatures were best reproduced by the combination of TLR agonists Pam3CSK4 and PolyI:C (PP). Immunization of both mice and macaques with a poorly immunogenic recombinant DENV-2 envelope domain III (EDIII) induced more consistent nAb and CD4+ T-cell responses with PP compared to alum plus monophosphoryl lipid A. Induction of nAbs by PP required interferon-mediated signals in macrophages in mice. However, EDIII + PP vaccination only provided partial protection against viral challenge. These results provide insights into mechanisms underlying nAb induction and a basis for further improving antigen/adjuvant combinations for dengue vaccine development.
Neural and behavioral signature of human social perception
Authors: Saitovitch Ana , Lemaitre Hervé , Rechtman Elza , Vinçon-Leite Alice , Calmon Raphael , Grévent David , Dangouloff-Ros Volodia , Brunelle Francis , Boddaert Nathalie , Zilbovicius Monica
Published: June 2019

Social behavior is extremely variable among individuals, and the neural basis of this variability is still poorly understood. In this study, we aimed to investigate the neural basis of interindividual variability in the first step of social behavior, that is, social perception. For that purpose, we first used eye-tracking to measure social perception during the passive visualization of socially relevant movie clips. Second, we correlated eye-tracking data with measures of rest cerebral blood flow (CBF) obtained using arterial spin-labeling (ASL) MRI, an index of local rest brain function. The results showed a large interindividual variability in the number of fixations to the eyes of characters during passive visualization of movie clips displaying social interactions. Moreover, individual patterns remained stable across time, suggesting an individual signature of social behavior. Whole-brain analyses showed significant positive correlation between the number of fixations to the eyes and rest CBF: individuals who looked more to the eyes were those with higher rest CBF levels within the right superior temporal regions. Our results indicate the existence of a neural and behavioral signature associated with the interindividual variability in social perception.
Publisher Correction: Transcriptomic and neurochemical analysis of the stellate ganglia in mice highlights sex differences
Authors: Bayles R. G. , Olivas A. , Denfeld Q. , Woodward W. R. , Fei S. S. , Gao L. , Habecker B. A.
Published: June 2019

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Publisher Correction: Randomized controlled trial on the influence of dietary intervention on epigenetic mechanisms in children with cow’s milk allergy: the EPICMA study
Authors: Paparo Lorella , Nocerino Rita , Bruno Cristina , Di Scala Carmen , Cosenza Linda , Bedogni Giorgio , Di Costanzo Margherita , Mennini Maurizio , D’Argenio Valeria , Salvatore Francesco , Berni Canani Roberto
Published: June 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Author Correction: Lifeact-TagGFP2 alters F-actin organization, cellular morphology and biophysical behaviour
Authors: Flores Luis R. , Keeling Michael C. , Zhang Xiaoli , Sliogeryte Kristina , Gavara Núria
Published: June 2019

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Auditory metabolomics, an approach to identify acute molecular effects of noise trauma
Authors: Ji Lingchao , Lee Ho-Joon , Wan Guoqiang , Wang Guo-Peng , Zhang Li , Sajjakulnukit Peter , Schacht Jochen , Lyssiotis Costas A. , Corfas Gabriel
Published: June 2019

Animal-based studies have provided important insights into the structural and functional consequences of noise exposure on the cochlea. Yet, less is known about the molecular mechanisms by which noise induces cochlear damage, particularly at relatively low exposure levels. While there is ample evidence that noise exposure leads to changes in inner ear metabolism, the specific effects of noise exposure on the cochlear metabolome are poorly understood. In this study we applied liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS)-based metabolomics to analyze the effects of noise on the mouse inner ear. Mice were exposed to noise that induces temporary threshold shifts, synaptopathy and permanent hidden hearing loss. Inner ears were harvested immediately after exposure and analyzed by targeted metabolomics for the relative abundance of 220 metabolites across the major metabolic pathways in central carbon metabolism. We identified 40 metabolites differentially affected by noise. Our approach detected novel noise-modulated metabolites and pathways, as well as some already linked to noise exposure or cochlear function such as neurotransmission and oxidative stress. Furthermore, it showed that metabolic effects of noise on the inner ear depend on the intensity and duration of exposure. Collectively, our results illustrate that metabolomics provides a powerful approach for the characterization of inner ear metabolites affected by auditory trauma. This type of information could lead to the identification of drug targets and novel therapies for noise-induced hearing loss.
Genome-wide analysis of genetic variations between dominant and recessive NILs of glanded and glandless cottons
Authors: Zhao Tianlun , Li Cheng , Li Cong , Zhang Fan , Mei Lei , Chindudzi Elmon , Chen Jinhong , Zhu Shuijin
Published: June 2019

Cotton is an important economic crop in worldwide. It produces fiber for the textile industry and provides cottonseeds with high-quality protein and oil. However, the presence of gossypol limits the utilization of cottonseed. Two pairs of cotton near isogenic lines (NILs) with different pigment glands, i.e., Coker 312 vs Coker 312 W and CCRI12 vs CCRI12W, exhibit different gossypol contents. The glandless traits of Coker 312 W and CCRI12W are controlled by recessive and dominant genes, respectively. However, knowledge regarding the genomic variations in the NILs is limited. Therefore, the NILs genomes were resequenced and the sequencing depths were greater than 34×. Compared with the TM-1 genome, numerous SNPs, Indels, SVs, and CNVs were discovered. KEGG pathway analysis revealed that genes with SNPs and Indels from the recessive NILs and genes with Indels from the dominant NILs shared only one enriched pathway, i.e., the sesquiterpenoid and triterpenoid biosynthesis pathway, which is relevant to gossypol biosynthesis. Expression analysis revealed that key genes with variations that participate in the gossypol biosynthesis and pigment gland formation pathways had different expression patterns among the dominant, recessive glandless and glanded plants. The expression levels in the glanded organs were higher than those in their NILs. Altogether, our results provide deeper insight into cotton NILs with different pigment glands.
Counterconditioning following memory retrieval diminishes the reinstatement of appetitive memories in humans
Authors: Gera Rani , Barak Segev , Schonberg Tom
Published: June 2019

Appetitive memories play a crucial role in learning and behavior, but under certain circumstances, such memories become maladaptive and play a vital role in addiction and other psychopathologies. Recent scientific research has demonstrated that memories can be modified following their reactivation through memory retrieval in a process termed memory reconsolidation. Several nonpharmacological behavioral manipulations yielded mixed results in their capacity to alter maladaptive memories in humans. Here, we aimed to translate the promising findings observed in rodents to humans. We constructed a novel three-day procedure using aversive counterconditioning to alter appetitive memories after short memory retrieval. On the first day, we used appetitive conditioning to form appetitive memories. On the second day, we retrieved these appetitive memories in one group (Retrieval group) but not in a second group. Subsequently, all participants underwent counterconditioning. On the third day, we attempted to reinstate the appetitive memories from day one. We observed a significant reduction in the reinstatement of the original appetitive memory when counterconditioning was induced following memory retrieval. Here, we provide a novel human paradigm that models several memory processes and demonstrate memory attenuation when counterconditioned after its retrieval. This paradigm can be used to study complex appetitive memory dynamics, e.g., memory reconsolidation and its underlying brain mechanisms.
miR-20a suppresses chondrogenic differentiation of ATDC5 cells by regulating Atg7
Authors: Xu Rui , Wei Yuhao , Yin Xing , Shi Bing , Li Jingtao
Published: June 2019

Both the miR-17-92 cluster and autophagy have been suggested as critical regulators of bone development, but the potential correlation between the two factors is largely unknown. Hence, we investigated whether members of this cluster can regulate chondrogenesis through an autophagy-related signalling pathway. In this study, the expression of miR-17-92 cluster members and the level of autophagic activity were investigated during chondrogenic induction in ATDC5 cells. miR-17, miR-18a, miR-20a, and miR-92-1 showed significant changes, and the level of autophagic activity was enhanced. Among the miR-17-92 cluster members, miR-20a showed the most significant change. Histological, cellular and molecular analyses were performed after the regulation of miR-20a and autophagy. miR-20a and autophagy had the opposite effect on chondrogenic differentiation, and there was a negative correlation between them. Moreover, the expression of the autophagy regulatory gene Atg7 was inhibited by miR-20a. siRNA was then used to knock down Atg7, and the results further indicated that Atg7 might be a potential target of miR-20a in chondrogenic differentiation. In conclusion, miR-20a is a critical negative regulator of chondrogenic differentiation because it inhibits autophagy via Atg7. Other members of the miR-17-92 cluster may have a similar effect, but this hypothesis requires further investigation.
Reprogramming Escherichia coli for the production of prenylated indole diketopiperazine alkaloids
Authors: Dubois Pavlina , Correia Isabelle , Le Chevalier Fabien , Dubois Steven , Jacques Isabelle , Canu Nicolas , Moutiez Mireille , Thai Robert , Gondry Muriel , Lequin Olivier , Belin Pascal
Published: June 2019

Prenylated indole diketopiperazine (DKP) alkaloids are important bioactive molecules or their precursors. In the context of synthetic biology, efficient means for their biological production would increase their chemical diversification and the discovery of novel bioactive compounds. Here, we prove the suitability of the Escherichia coli chassis for the production of prenylated indole DKP alkaloids. We used enzyme combinations not found in nature by co-expressing bacterial cyclodipeptide synthases (CDPSs) that assemble the DKP ring and fungal prenyltransferases (PTs) that transfer the allylic moiety from the dimethylallyl diphosphate (DMAPP) to the indole ring of tryptophanyl-containing cyclodipeptides. Of the 11 tested combinations, seven resulted in the production of eight different prenylated indole DKP alkaloids as determined by LC-MS/MS and NMR characterization. Two were previously undescribed. Engineering E. coli by introducing a hybrid mevalonate pathway for increasing intracellular DMAPP levels improved prenylated indole DKP alkaloid production. Purified product yields of 2–26 mg/L per culture were obtained from culture supernatants. Our study paves the way for the bioproduction of novel prenylated indole DKP alkaloids in a tractable chassis that can exploit the cyclodipeptide diversity achievable with CDPSs and the numerous described PT activities.
Terpene Synthase Genes Originated from Bacteria through Horizontal Gene Transfer Contribute to Terpenoid Diversity in Fungi
Authors: Jia Qidong , Chen Xinlu , Köllner Tobias G. , Rinkel Jan , Fu Jianyu , Labbé Jessy , Xiong Wangdan , Dickschat Jeroen S. , Gershenzon Jonathan , Chen Feng
Published: June 2019

Fungi are successful eukaryotes of wide distribution. They are known as rich producers of secondary metabolites, especially terpenoids, which are important for fungi-environment interactions. Horizontal gene transfer (HGT) is an important mechanism contributing to genetic innovation of fungi. However, it remains unclear whether HGT has played a role in creating the enormous chemical diversity of fungal terpenoids. Here we report that fungi have acquired terpene synthase genes (TPSs), which encode pivotal enzymes for terpenoid biosynthesis, from bacteria through HGT. Phylogenetic analysis placed the majority of fungal and bacterial TPS genes from diverse taxa into two clades, indicating ancient divergence. Nested in the bacterial TPS clade is a number of fungal TPS genes that are inferred as the outcome of HGT. These include a monophyletic clade of nine fungal TPS genes, designated as BTPSL for bacterial TPS-like genes, from eight species of related entomopathogenic fungi, including seven TPSs from six species in the genus Metarhizium. In vitro enzyme assays demonstrate that all seven BTPSL genes from the genus Metarhizium encode active enzymes with sesquiterpene synthase activities of two general product profiles. By analyzing the catalytic activity of two resurrected ancestral BTPSLs and one closely related bacterial TPS, the trajectory of functional evolution of BTPSLs after HGT from bacteria to fungi and functional divergence within Metarhizium could be traced. Using M. brunneum as a model species, both BTPSLs and typical fungal TPSs were demonstrated to be involved in the in vivo production of terpenoids, illustrating the general importance of HGT of TPS genes from bacteria as a mechanism contributing to terpenoid diversity in fungi.
CD163+ immune cell infiltrates and presence of CD54+ microvessels are prognostic markers for patients with embryonal rhabdomyosarcoma
Authors: Kather Jakob Nikolas , Hörner Christian , Weis Cleo-Aron , Aung Thiha , Vokuhl Christian , Weiss Christel , Scheer Monika , Marx Alexander , Simon-Keller Katja
Published: June 2019

Rhabdomyosarcomas (RMS) are rare and often lethal diseases. It is assumed that the tumor microenvironment (TME) of RMS exerts an immunosuppressive function, but there is currently no systematic analysis of the immune cells infiltrating sarcoma tissue. Focusing on two common types of RMS (alveolar [RMA] and embryonal [RME]), we performed a comprehensive immunohistochemical analysis of tumor-infiltrating immune cells in the TME. We performed a qualitative estimation of infiltrating immune cells in the tumor microenvironment by an experienced pathologist as well as a quantitative digital pathology analysis. We found that (1) manual and automatic quantification of tumor-infiltrating immune cells were consistent; (2) RME tumors showed a higher degree of immune cell infiltration than RMA tumors but (3) the number of tumor infiltrating lymphocytes was low compared to other solid tumor types; (4) microvascular density correlated with immune cell infiltration and (5) CD163 positive macrophages as well as CD54 positive microvessels were more often detected in RME than in RMA and correlated with patient overall and event free survival. Our systematic analysis provides a comprehensive view of the immune landscape of RMS which needs to be taken into account for developing immunotherapies for this rare type of cancer.
Detection of circulating tumor cells in blood by shell-isolated nanoparticle – enhanced Raman spectroscopy (SHINERS) in microfluidic device
Authors: Niciński K. , Krajczewski J. , Kudelski A. , Witkowska E. , Trzcińska-Danielewicz J. , Girstun A. , Kamińska A.
Published: June 2019

Isolation and detection of circulating tumor cells (CTCs) from human blood plays an important role in non- invasive screening of cancer evolution and in predictive therapeutic treatment. Here, we present the novel tool utilizing: (i) the microfluidic device with (ii) incorporated photovoltaic (PV) based SERS-active platform, and (iii) shell-isolated nanoparticles (SHINs) for simultaneous separation and label-free analysis of circulating tumour cells CTCs in the blood specimens with high specificity and sensitivity. The proposed microfluidic chip enables the efficient size – based inertial separation of circulating cancer cells from the whole blood samples. The SERS-active platform incorporated into the microfluidic device permits the label-free detection and identification of isolated cells through the insight into their molecular and biochemical structure. Additionally, the silver nanoparticles coated with an ultrathin shell of silica (Ag@SiO2) was used to improve the detection accuracy and sensitivity of analysed tumor cells via taking advantages of shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS). The empirical analysis of SHINERS spectra revealed that there are some differences among studied (HeLa), renal cell carcinoma (Caki-1), and blood cells. Unique SHINERS features and differences in bands intensities between healthy and cancer cells might be associated with the variations in the quantity and quality of molecules such as lipid, protein, and DNA or their structure during the metastasis cancer formation. To demonstrate the statistical efficiency of the developed method and improve the differentiation for circulating tumors cells detection the principal component analysis (PCA) has been performed for all SHINERS data. PCA method has been applied to recognize the most significant differences in SHINERS data among the three analyzed cells: Caki-1, HeLa, and blood cells. The proposed approach challenges the current multi-steps CTCs detection methods in the terms of simplicity, sensitivity, invasiveness, destructivity, time and cost of analysis, and also prevents the defragmentation/damage of tumor cells and thus leads to improving the accuracy of analysis. The results of this research work show the potential of developed SERS based tool for the separation of tumor cells from whole blood samples in a simple and minimally invasive manner, their detection and molecular characterization using one single technology.
Power Doppler ultrasound and contrast-enhanced ultrasound demonstrate non-invasive tumour vascular response to anti-vascular therapy in canine cancer patients
Authors: Abma Eline , Stock Emmelie , De Spiegelaere Ward , Van Brantegem Leen , Vanderperren Katrien , Ni Yicheng , Vynck Matthijs , Daminet Sylvie , De Clercq Kaat , de Rooster Hilde
Published: June 2019

Combretastatin A4-phosphate (CA4P) is an anti-vascular agent which selectively shuts down blood supply in tumours, resulting in extensive tumour necrosis. The aim of this study was to assess in vivo, non-invasive ultrasound techniques for the early evaluation of tumour perfusion following CA4P treatment of spontaneous tumours. Eight dogs that bore spontaneous tumours were enrolled and were subsequently treated with a single dose of intravenous CA4P. Perfusion of tumours was evaluated by power Doppler ultrasound (PDUS) pre-treatment (0 h), during the injection (10 min, 20 min, 30 min) and after CA4P infusion (24 and 72 h). Vascularity index (VI) of the tumour tissue was quantitatively analysed and accuracy was verified by correlation analysis with the results of immunohistochemical evaluation of microvessel density (MVD). Central and peripheral perfusion was evaluated by contrast-enhanced ultrasound (CEUS) pre-treatment and at 72 h post-treatment. Post-treatment, PDUS demonstrated a significant decrease in VI within 10 min of CA4P infusion. CEUS parameters demonstrated a significant decrease in blood velocity and volume in the central aspect of the tumour. Histology revealed a 4.4-fold reduction (p < 0.001, 95% CI [2.2,9.4]) in MVD and a 4.1-fold increase (p = 0.003, 95% CI [1.4,11.8]) in necrotic tumour tissue. A strong correlation between PDUS results and immunohistochemical results was found (Pearson R2 = 0.957, p < 0.001). Furthermore, the findings of PDUS were supported by the objective results of the CEUS analyses. These data suggest a role for ultrasound in real-time, non-invasive monitoring of tumour vascular response as an early indicator of CA4P treatment efficacy.
Relevant Word Order Vectorization for Improved Natural Language Processing in Electronic Health Records
Authors: Thompson Jeffrey , Hu Jinxiang , Mudaranthakam Dinesh Pal , Streeter David , Neums Lisa , Park Michele , Koestler Devin C. , Gajewski Byron , Jensen Roy , Mayo Matthew S.
Published: June 2019

Electronic health records (EHR) represent a rich resource for conducting observational studies, supporting clinical trials, and more. However, much of the data contains unstructured text, presenting an obstacle to automated extraction. Natural language processing (NLP) can structure and learn from text, but NLP algorithms were not designed for the unique characteristics of EHR. Here, we propose Relevant Word Order Vectorization (RWOV) to aid with structuring. RWOV is based on finding the positional relationship between the most relevant words to predicting the class of a text. This facilitates machine learning algorithms to use the interaction of not just keywords but positional dependencies (e.g. a relevant word occurs 5 relevant words before some term of interest). As a proof-of-concept, we attempted to classify the hormone receptor status of breast cancer patients treated at the University of Kansas Medical Center, comparing RWOV to other methods using the F1 score and AUC. RWOV performed as well as, or better than other methods in all but one case. For F1 score, RWOV had a clear edge on most tasks. AUC tended to be closer, but for HER2, RWOV was significantly better for most comparisons. These results suggest RWOV should be further developed for EHR-related NLP.
Elasmobranch bycatch in the demersal prawn trawl fishery in the Gulf of Papua, Papua New Guinea
Authors: White W. T. , Baje L. , Simpfendorfer C. A. , Appleyard S. A. , Chin A. , Sabub B. , Rochel E. , Naylor G. J. P.
Published: June 2019

The elasmobranch bycatch of the Gulf of Papua Prawn Fishery is investigated in detail for the first time. Fisheries observers collected data on the elasmobranch bycatch from a total of 403 trawl sets (1,273 hrs) in the Gulf of Papua. A total of 40 species of elasmobranchs were recorded ranging in size from a 12 cm disc width stingray to a 350 cm total length sawfish. High mortality rates were recorded (>80%), attributed to the long trawl durations (up to 4 hours). The future inclusion of bycatch reduction devices would likely reduce the number of larger elasmobranchs being caught, based on evidence from the prawn trawl fisheries of northern Australia, and is being investigated by the PNG National Fisheries Authority. Differences in catch compositions were detected across the management zones as well as between the two monsoonal seasons (SE Monsoon and NW Monsoon). Increased monitoring and additional research is required and management plans should address the elasmobranch bycatch and in particular their high mortality rate.
Neurocognitive mechanisms of reactions to second- and third-party justice violations
Authors: Civai Claudia , Huijsmans Inge , Sanfey Alan G.
Published: June 2019

The aim of the current study was threefold: (i) understand people’s willingness to engage in either punishment of the perpetrator or compensation of the victim in order to counteract injustice; (ii) look into the differences between victims of and witnesses to injustice; (iii) investigate the different role played by social preference and affective experience in determining these choices. The sample tested here showed an equal preference for punishment and compensation; neuroimaging findings suggested that compensation, as opposed to punishment, was related to Theory of Mind. Partially supporting previous literature, choosing how to react to an injustice as victims, rather than witnesses, triggered a stronger affective response (striatal and prefrontal activation). Moreover, results supported the idea that deciding whether or not to react to an injustice and then how severely to react are two distinct decisional stages underpinned by different neurocognitive mechanisms, i.e., sensitivity to unfairness (anterior insula) and negative affectivity (amygdala). These findings provide a fine-grained description of the psychological mechanisms underlying important aspects of social norm compliance.
Episodic tremor and slip silently invades strongly locked megathrust in the Nankai Trough
Authors: Kano Masayuki , Kato Aitaro , Obara Kazushige
Published: June 2019

Recent seismic and geodetic observations in subduction zones have revealed that slow earthquakes have preceded some large earthquakes. Characterization of slow earthquakes and their relation to large earthquakes provides important clues to constrain a wide spectrum of slip rates on tectonic faults. Here, we report new evidence of a slow slip transient at the downdip edge of the strongly locked seismogenic zone in the western Nankai Trough in southwest Japan. This slow slip transient was excited during an episodic tremor and slip at the downdip extension of the locked zone. Through this triggering, the frequent occurrence of the deep episodic tremor and slip invades the strongly locked megathrust zone and may intermittently increase the probability of large earthquakes in the Nankai Trough.
Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets
Authors: Audard Jules , Godet Thomas , Blondonnet Raiko , Joffredo Jean-Baptiste , Paquette Bertille , Belville Corinne , Lavergne Marilyne , Gross Christelle , Pasteur Justine , Bouvier Damien , Blanchon Loic , Sapin Vincent , Pereira Bruno , Constantin Jean-Michel , Jabaudon Matthieu
Published: June 2019

The receptor for advanced glycation end-products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will require assessment of this strategy in larger animals. Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid (i) alone; (ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), or (iii) recombinant soluble (s)RAGE. The primary outcome was net AFC at 4 h. Arterial oxygenation was assessed hourly and alveolar-capillary permeability, alveolar inflammation and lung histology were assessed at 4 h. Treatment with either RAP or sRAGE improved net AFC (median [interquartile range], 21.2 [18.8–21.7] and 19.5 [17.1–21.5] %/h, respectively, versus 12.6 [3.2–18.8] %/h in injured, untreated controls), oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after ARDS. These findings suggest that RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.
Diversity and distribution of Laonice species (Annelida: Spionidae) in the tropical North Atlantic and Puerto Rico Trench
Authors: Guggolz Theresa , Meißner Karin , Schwentner Martin , Brandt Angelika
Published: June 2019

LaoniceMalmgren, 1867 (Annelida: Spionidae) is a common polychaete genus in the deep-sea. Although most species are quite well studied morphologically, fragmentation and other damage that occurs during sampling often hampers morphological species identification of deep-sea specimens. In this study, we employ three molecular markers (16S, COI and 18S) to study the biodiversity and the distribution patterns ofLaonicefrom the tropical North Atlantic and the Puerto Rico Trench. Based upon different molecular analyses (Automated Barcode Gap Discovery, pairwise genetic distances, phylogenetics, haplotype networks) we were able to identify and differentiate eightLaonicespecies. Up to four of these species co-occurred sympatrically at the same station. The majority of species were found at multiple stations and two species in the eastern as well as western Atlantic had ranges of up to 4,000 km. Genetic differentiation across these extensive geographic distances was very low. Surprisingly, one 16S haplotype was shared between individuals 2,776 km apart and individuals from the Caribbean and the abyssal plain in the eastern Atlantic (>3,389 km) differed in only a single mutation in 16S. Our results suggest that members of this genus successfully disperse across large geographic distances and are largely unaffected by topographic barriers.
Real-world heart rate norms in the Health eHeart study
Authors: Avram Robert , Tison Geoffrey H. , Aschbacher Kirstin , Kuhar Peter , Vittinghoff Eric , Butzner Michael , Runge Ryan , Wu Nancy , Pletcher Mark J. , Marcus Gregory M. , Olgin Jeffrey
Published: June 2019

Emerging technology allows patients to measure and record their heart rate (HR) remotely by photoplethysmography (PPG) using smart devices like smartphones. However, the validity and expected distribution of such measurements are unclear, making it difficult for physicians to help patients interpret real-world, remote and on-demand HR measurements. Our goal was to validate HR-PPG, measured using a smartphone app, against HR-electrocardiogram (ECG) measurements and describe out-of-clinic, real-world, HR-PPG values according to age, demographics, body mass index, physical activity level, and disease. To validate the measurements, we obtained simultaneous HR-PPG and HR-ECG in 50 consecutive patients at our cardiology clinic. We then used data from participants enrolled in the Health eHeart cohort between 1 April 2014 and 30 April 2018 to derive real-world norms of HR-PPG according to demographics and medical conditions. HR-PPG and HR-ECG were highly correlated (Intraclass correlation = 0.90). A total of 66,788 Health eHeart Study participants contributed 3,144,332 HR-PPG measurements. The mean real-world HR was 79.1 bpm ± 14.5. The 95th percentile of real-world HR was ≤110 in individuals aged 18–45, ≤100 in those aged 45–60 and ≤95 bpm in individuals older than 60 years old. In multivariable linear regression, the number of medical conditions, female gender, increasing body mass index, and being Hispanic was associated with an increased HR, whereas increasing age was associated with a reduced HR. Our study provides the largest real-world norms for remotely obtained, real-world HR according to various strata and they may help physicians interpret and engage with patients presenting such data.