bluuebunny/crossref_metadata_2025 huggingface dataset:
Full annotation of serum virome in Chinese blood donors with elevated alanine aminotransferase levels
Authors: Li Gang , Zhou Zhihua , Yao Li , Xu Yanjuan , Wang Lan , Fan Xiaofeng
Published: August 2019

BACKGROUND

A serum alanine aminotransferase (ALT) test is currently demanded for blood donation in China. One of the major reasons to include such a test is possible etiology of known or unknown hepatotropic viruses. However, this hypothesis has never been examined convincingly.

STUDY DESIGN AND METHODS

The study recruited 90 Chinese blood donors that were divided into three groups based on their ALT values. Serum virome from these donors was explored using a metagenomics approach with enhanced sensitivity resolved at single sequencing reads.

RESULTS

Anellovirus and pegivirus C (GBV‐C) were detected among these donors. None of them were found solely in donors with abnormal liver enzyme. Anellovirus was highly prevalent (93.3%) and the co‐infection with multiple genera (alpha, beta, and gammatorquevirus) were more common in the donors with normal ALT values in comparison to those with elevated ALT (single/double/triple Anellovirus genera, 1/3/24 vs. 7/7/14 or 6/7/13, p = 0.009). For unmapped reads that accounted for 15 ± 14.9% of the data, similarity‐based (BLASTN, BLASTP, and HMMER3) and similarity‐independent (k‐mer frequency) analysis identified several circular rep encoding ssDNA (CRESS‐DNA) genomes. Direct PCR testing indicated these genomes were likely reagent contaminants.

CONCLUSION

Viral etiology is not responsible for elevated ALT levels in Chinese blood donors. The ALT test, if not abandoned, should be adjusted for its cutoff in response to donor shortage in China.
Middle Stone Age foragers resided in high elevations of the glaciated Bale Mountains, Ethiopia
Authors: Ossendorf Götz , Groos Alexander R. , Bromm Tobias , Tekelemariam Minassie Girma , Glaser Bruno , Lesur Joséphine , Schmidt Joachim , Akçar Naki , Bekele Tamrat , Beldados Alemseged , Demissew Sebsebe , Kahsay Trhas Hadush , Nash Barbara P. , Nauss Thomas , Negash Agazi , Nemomissa Sileshi , Veit Heinz , Vogelsang Ralf , Woldu Zerihun , Zech Wolfgang , Opgenoorth Lars , Miehe Georg
Published: August 2019

Middle Stone Age humans in high-altitude Africa

Recent archaeological research has produced evidence of the earliest human occupation of high-altitude habitats in the Andes and the Tibetan Plateau. Ossendorf
et al.
now present the oldest evidence of human settlement and adaptation to areas above 4000-meter elevation in Africa (see the Perspective by Aldenderfer). Their excavations at a rock shelter in the Bale Mountains of Ethiopia reveal obsidian artifacts and faunal remains, including abundant burnt bones, mostly of giant mole-rats. The findings reveal the environmental conditions and show how Late Pleistocene humans adapted to the harsh environments of these glaciated high-altitude African landscapes.

Science
, this issue p.
583
; see also p.
541
Black carbon lofts wildfire smoke high into the stratosphere to form a persistent plume
Authors: Yu Pengfei , Toon Owen B. , Bardeen Charles G. , Zhu Yunqian , Rosenlof Karen H. , Portmann Robert W. , Thornberry Troy D. , Gao Ru-Shan , Davis Sean M. , Wolf Eric T. , de Gouw Joost , Peterson David A. , Fromm Michael D. , Robock Alan
Published: August 2019

Up in smoke

Extensive and intense wildfires in the Pacific Northwest of the United States in 2017 injected large quantities of smoke into the stratosphere. Yu
et al.
used satellite observations and modeling to characterize the history and chemistry of that smoke. The smoke rose to altitudes between 12 and 23 kilometers within 2 months owing to solar heating of black carbon. The smoke then remained in the stratosphere for more than 8 months. Photochemical loss of organic carbon resulted in a smoke lifetime 40% shorter than expected.

Science
, this issue p.
587
A dominant-negative effect drives selection of
TP53
missense mutations in myeloid malignancies
Authors: Boettcher Steffen , Miller Peter G. , Sharma Rohan , McConkey Marie , Leventhal Matthew , Krivtsov Andrei V. , Giacomelli Andrew O. , Wong Waihay , Kim Jesi , Chao Sherry , Kurppa Kari J. , Yang Xiaoping , Milenkowic Kirsten , Piccioni Federica , Root David E. , Rücker Frank G. , Flamand Yael , Neuberg Donna , Lindsley R. Coleman , Jänne Pasi A. , Hahn William C. , Jacks Tyler , Döhner Hartmut , Armstrong Scott A. , Ebert Benjamin L.
Published: August 2019

p53—still hazy after all these years?

The gene encoding the p53 tumor suppressor protein is the most frequently mutated gene in human cancer. Yet decades after the gene's discovery, the biology of cancer-associated missense mutations in p53 is still being debated. Previous studies have suggested that missense mutations confer tumor-promoting functions to p53. Boettcher
et al.
conducted a detailed analysis of p53 missense mutations in human leukemia, drawing on methodologies including genome editing, a p53 saturation mutagenesis screen, mouse models, and clinical data (see the Perspective by Lane). They found no evidence that p53 missense mutations confer an oncogenic gain of function. Rather, the mutations exerted a dominant-negative effect that reduced the tumor suppressor activity of wild-type p53.

Science
, this issue p.
599
; see also p.
539
A vicious cycle of β amyloid–dependent neuronal hyperactivation
Authors: Zott Benedikt , Simon Manuel M. , Hong Wei , Unger Felix , Chen-Engerer Hsing-Jung , Frosch Matthew P. , Sakmann Bert , Walsh Dominic M. , Konnerth Arthur
Published: August 2019

Dissecting hyperactivation in AD

Progressive accumulation of amyloid β (Aβ) in the brain is a defining feature of Alzheimer's disease (AD). At late stages of AD, pathological Aβ accumulations cause neurodegeneration and cell death. However, neuronal dysfunction, consisting of an excessively increased activity in a fraction of brain neurons, already occurs in early stages of the disease. Zott
et al.
explored the cellular basis of this hyperactivity in mouse models of AD (see the Perspective by Selkoe). Aβ-mediated hyperactivation was linked to a defect in synaptic transmission exclusively in active neurons, with the most-active neurons having the highest risk of hyperactivation. Aβ-containing brain extracts from human AD patients sustained this vicious cycle, underscoring the potential relevance of this pathological mechanism in humans.

Science
, this issue p.
559
; see also p.
540
Response to Comment on “Observation of alkaline earth complexes M(CO)
8
(M = Ca, Sr, or Ba) that mimic transition metals”
Authors: Zhao Lili , Pan Sudip , Zhou Mingfei , Frenking Gernot
Published: August 2019

Landis
et al
. claim in their comment that Ca does not bind like a transition metal in Ca(CO)
8
. We reject their statement, which is based on a misconception of bonding models and misleading application and interpretation of quantum chemical methods for analyzing chemical bonds.
When science was groovy
Authors: McCray W. Patrick , Kaiser David
Published: August 2019

Counterculture-inspired research flourished in the Age of Aquarius
Population Pharmacokinetics of the Antituberculosis Agent Pretomanid
Authors: Salinger David H. , Subramoney Vishak , Everitt Daniel , Nedelman Jerry R.
Published: August 2019

A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months.
Instrumental rationality and suicide in schizophrenia: a case for rational suicide?
Authors: Grigoriou Markella , Upthegrove Rachel , Bortolotti Lisa
Published: August 2019

It is estimated that up to 7500 people develop schizophrenia each year in the UK. Schizophrenia has significant consequences, with 28% of the excess mortality in schizophrenia being attributed to suicide. Previous research suggests that suicide in schizophrenia may be more related to affective factors such as depression and hopelessness, rather than psychotic symptoms themselves. Considering suicide in schizophrenia within this framework enables us to develop a novel philosophical approach, in which suicide may not be related to loss of self-consciousness, thought processing dysfunctions or perception disturbances. The action of suicide may be due neither to persistent hallucinations nor other psychotic symptoms, such as delusional beliefs, but to other underexamined, perhaps rational reasons, such as extreme social isolation, severe depression or emotional withdrawal. This paper does not examine the moral character of suicide. Instead, it argues that we should conceive the action of suicide in schizophrenia as an act that is not necessarily irrational. People with schizophrenia might end their life based on reasons if suicide is the best means to achieve their ends. However, the paper does not support assisted suicide. It aims to provide a better understanding of the reasons why people take their own lives and suggests that understanding can inform effective interventions to reduce high rates of suicide.
Continuing the conversation about medical assistance in dying
Authors: DeMichelis Carey , Zlotnik Shaul Randi , Rapoport Adam
Published: August 2019

In their summary and critique, Gamble, Gamble, and Pruski mischaracterise both the central arguments and the primary objectives of our original paper. Our paper does not provide an ethical justification for paediatric Medical Assistance in Dying (MAID) by comparing it with other end of life care options. In fact, it does not offer arguments about the permissibility of MAID for capable young people at all. Instead, our paper focuses on the ethical questions that emerged as we worked to develop a policy for responding to MAID requests at our tertiary paediatric institution. Following the Supreme Court of Canada’s recent decriminalisation of MAID, our hospital needed to answer immediate on-the-ground questions such as: ‘What are we going to do if an 18-year-old patient in our care requested MAID today, as is now their legal right? How should we protect their privacy? What is the best way to ensure patients are informed when making these decisions?’ On these important questions, Gamble, Gamble, and Pruskiare silent.
Isolation and characterization ofBacillusspp. strains as potential probiotics for poultry
Authors: Penaloza-Vazquez Alejandro , Ma Li Maria , Rayas-Duarte Patricia
Published: August 2019

Probiotics have become one of the potential solutions to global restriction on antibiotic use in food animal production. Bacillus species have been attractive probiotics partially due to their long-term stability during storage. In this study, 200 endospore-forming bacteria isolates were recovered from sourdough and the gastrointestinal tract (GIT) of young broiler chicks. Based on the production of a series of exoenzymes and survivability under stress conditions similar to those in the poultry GIT, 42 isolates were selected and identified by 16S rRNA gene sequencing. Seven strains with a profile of high enzymatic activities were further evaluated for sporulation efficiency, biofilm formation, compatibility among themselves (Bacillus spp.), and antagonistic effects against three bacteria pathogenic to poultry and humans: Enterococcus cecorum, Salmonella enterica, and Shiga-toxin-producing Escherichia coli. The strains from sourdough were identified as Bacillus amyloliquefaciens whereas the ones from the chicks’ GIT were Bacillus subtilis. These strains demonstrated remarkable potential as probiotics for poultry.
Hybridization between resistant and susceptible fenugreek accessions and evaluation of Cercospora leaf spot resistance in segregating generations
Authors: Subedi U. , Acharya S. , Chatterton S. , Thomas J. , Friebel D.
Published: August 2019

Cercospora leaf spot (CLS), caused by Cercospora traversoana, is an important phyto-pathological problem of self-pollinated fenugreek (Trigonella-foenum graecum). Developing resistant genotypes in crop plants has been considered the best option to control diseases for economic, environmental, and social reasons. However, before this can be accomplished, knowledge about the inheritance of disease-resistant genes is necessary for creating high-yielding resistant genotypes. One susceptible fenugreek cultivar, Tristar, and two resistant accessions L3717 and PI138687 were used in two-way crosses using hand emasculation and pollination technique in a greenhouse. F1 plants were grown in a greenhouse and allowed to grow till maturity to produce F2 seeds. Some flowers from F1 plants were crossed back to both resistant and susceptible parents separately to generate backcross (BC1) seeds. Parents, F1, F2, and BC1 populations were grown in the greenhouse using a RCBD with four replications. Plants were inoculated 30 d after sowing with a suspension of C. traversoana at 2 × 105 conidia mL−1. Symptoms were observed and rated on individual plants 25 d after inoculation, and plants were categorized according to susceptible or resistant reactions based on rating scores. Mean disease score was significantly different (p < 0.0001) among generations. In both the cross combinations, results showed CLS resistance in fenugreek (from L3717 and PI138687) was governed by a single dominant gene which is moderately heritable (46% narrow sense heritability). This indicates a relatively simple pathway for transfer of genes to adapted fenugreek cultivars.
Trace element and stable isotope analysis elucidate stock structure in a narwhal (Monodon monoceros) population with no genetic substructure
Authors: Watt Cortney A. , Hornby Claire , Ferguson Steven H.
Published: August 2019

Chemical composition of tissues can act as a biological tag to discriminate among groups of animals that inhabit different areas. In Canada, subsistence hunting of the Baffin Bay narwhal (Monodon monoceros Linnaeus, 1758) population is managed as stocks represented by summer aggregations. However, narwhals are highly mobile and are hunted during the migration while stocks mix. Thus, information that can help managers decipher the stock origin of hunted individuals to prevent overexploitation of animals adapted to particular summering grounds is needed. Stable isotope and trace element analyses were conducted on narwhal skin tissues from five stocks in the eastern Canadian Arctic from 1990 to 2015. Discriminant analysis showed a significant difference between Admiralty Inlet and Eclipse Sound stocks in the summer residency period and both differed from Jones Sound and Somerset Island. During the migration season, there was more overlap and less distinction among stocks, but 75% of animals were classified correctly to their defined stocks in both periods. Together stable isotope and trace element analyses are useful for delineating stocks and could be used to complement other stock discrimination approaches.
Trans-Planckian quantum corrections and inflationary vacuum fluctuations of non-minimally coupled scalar fields
Authors: Matsui Hiroki
Published: August 2019

In this paper, we discuss how trans-Planckian physics affects inflationary vacuum fluctuations and primordial density perturbations. The trans-Planckian problem during inflation has been widely discussed in the literature, but it is still under debate. We reconsider this problem by using the two-point correlation function of the non-minimally coupled scalar fields and constructing the effective potential with the adiabatic (WKB) regularization or approximation. First, we clearly show that the cut-off divergence of the quantum fluctuations does not drastically change during inflation under reasonable assumptions and the corrections can be embedded in standard effective potential. Thus, the UV effects on the primordial density perturbation are well translated into the effective potential. Then, we find out the modified effective potential from the inflationary fluctuations and show how the trans-Planckian or UV corrections change the potential during inflation. We clearly show that the new physics strongly affects the inflation potential during inflation and we obtain an inflationary constraint [Formula: see text], where [Formula: see text] is the interaction coupling at the UV scale [Formula: see text].
Anisotropic quantum cosmology with minimally coupled scalar field
Authors: Ghosh Saumya , Gangopadhyay Sunandan , Panigrahi Prasanta K.
Published: August 2019

In this paper, we perform the Wheeler–DeWitt quantization for Bianchi type I anisotropic cosmological model in the presence of a scalar field minimally coupled to the Einstein–Hilbert gravity theory. We also consider the cosmological (perfect) fluid to construct the matter sector of the model whose dynamics plays the role of time. After obtaining the Wheeler–DeWitt equation from the Hamiltonian formalism, we then define the self-adjointness relations properly. Doing that, we proceed to get a solution for the Wheeler–DeWitt equation and construct a well-behaved wave function for the universe. The wave packet is next constructed from a superposition of the wave functions with different energy eigenvalues together with a suitable weight factor which renders the norm of the wave packet finite. It is then concluded that the Big-Bang singularity can be removed in the context of quantum cosmology.
Mutual semi-quantum key agreement protocol using Bell states
Authors: Yan Li Li , Zhang Shi Bin , Chang Yan , Sheng Zhi Wei , Yang Fan
Published: August 2019

Quantum key agreement (QKA) can generate a shared secret key which is equally negotiated by all the participants in the protocol. In most of the QKA protocols, all the participants require quantum capabilities. But the quantum devices are too expensive for participants. This paper proposes a mutual semi-quantum key agreement protocol which allows two parties (Alice and Bob) to negotiate a shared secret key equally. In the protocol, Alice can perform any quantum operation, but Bob is a classical participant which can only perform reflection, measurement and reorder operation. Even though Bob has fewer quantum resources, Alice and Bob have an equal contribution to the shared final key, no one can determine the shared key alone. In addition, we demonstrate the security of the proposed protocol. The analysis results show that the proposed protocol not only resists against some common attacks but also assures the fairness property. It is significant for communication participant without enough quantum devices to achieve quantum communication. The proposed protocol can be implemented with present quantum technologies.
A note on Alexander polynomials of 2-bridge links
Authors: Hoste Jim
Published: August 2019

A formula for the Alexander polynomial of a 2-bridge knot or link given by Hartley and also by Minkus has a beautiful interpretation as a walk on the integers. We extend this to the 2-variable Alexander polynomial of a 2-component, 2-bridge link, obtaining a formula that corresponds to a walk on the 2-dimensional integer lattice.
Fast Matrix-Free Evaluation of Discontinuous Galerkin Finite Element Operators
Authors: Kronbichler Martin , Kormann Katharina
Published: August 2019

We present an algorithmic framework for matrix-free evaluation of discontinuous Galerkin finite element operators. It relies on fast quadrature with sum factorization on quadrilateral and hexahedral meshes, targeting general weak forms of linear and nonlinear partial differential equations. Different algorithms and data structures are compared in an in-depth performance analysis. The implementations of the local integrals are optimized by vectorization over several cells and faces and an even-odd decomposition of the one-dimensional interpolations. Up to 60% of the arithmetic peak on Intel Haswell, Broadwell, and Knights Landing processors is reached when running from caches and up to 40% of peak when also considering the access to vectors from main memory. On 2×14 Broadwell cores, the throughput is up to 2.2 billion unknowns per second for the 3D Laplacian and up to 4 billion unknowns per second for the 3D advection on affine geometries, close to a simple copy operation at 4.7 billion unknowns per second. Our experiments show that MPI ghost exchange has a considerable impact on performance and we present strategies to mitigate this effect. Finally, various options for evaluating geometry terms and their performance are discussed. Our implementations are publicly available through the deal.II finite element library.
Computing Hypergeometric Functions Rigorously
Authors: Johansson Fredrik
Published: August 2019

We present an efficient implementation of hypergeometric functions in arbitrary-precision interval arithmetic. The functions
0
F
1
,
1
F
1
,
2
F
1
, and
2
F
0
(or the Kummer
U
-function) are supported for unrestricted complex parameters and argument, and, by extension, we cover exponential and trigonometric integrals, error functions, Fresnel integrals, incomplete gamma and beta functions, Bessel functions, Airy functions, Legendre functions, Jacobi polynomials, complete elliptic integrals, and other special functions. The output can be used directly for interval computations or to generate provably correct floating-point approximations in any format. Performance is competitive with earlier arbitrary-precision software and sometimes orders of magnitude faster. We also partially cover the generalized hypergeometric function 

p

F

q

and computation of high-order parameter derivatives.
Pseudo-3D Attention Transfer Network with Content-aware Strategy for Image Captioning
Authors: Wu Jie , Hu Haifeng , Yang Liang
Published: August 2019

In this article, we propose a novel Pseudo-3D Attention Transfer network with Content-aware Strategy (P3DAT-CAS) for the image captioning task. Our model is composed of three parts: the Pseudo-3D Attention (P3DA) network, the P3DA-based Transfer (P3DAT) network, and the Content-aware Strategy (CAS). First, we propose P3DA to take full advantage of three-dimensional (3D) information in convolutional feature maps and capture more details. Most existing attention-based models only extract the 2D spatial representation from convolutional feature maps to decide which area should be paid more attention to. However, convolutional feature maps are 3D and different channel features can detect diverse semantic attributes associated with images. P3DA is proposed to combine 2D spatial maps with 1D semantic-channel attributes and generate more informative captions. Second, we design the transfer network to maintain and transfer the key previous attention information. The traditional attention-based approaches only utilize the current attention information to predict words directly, whereas transfer network is able to learn long-term attention dependencies and explore global modeling pattern. Finally, we present CAS to provide a more relevant and distinct caption for each image. The captioning model trained by maximum likelihood estimation may generate the captions that have a weak correlation with image contents, resulting in the cross-modal gap between vision and linguistics. However, CAS is helpful to convey the meaningful visual contents accurately. P3DAT-CAS is evaluated on Flickr30k and MSCOCO, and it achieves very competitive performance among the state-of-the-art models.
Cell Motility and Cytokinesis: From Mysteries to Molecular Mechanisms in Five Decades
Authors: Pollard Thomas D.
Published: August 2019

This is the story of someone who has been fortunate to work in a field of research where essentially nothing was known at the outset but that blossomed with the discovery of profound insights about two basic biological processes: cell motility and cytokinesis. The field started with no molecules, just a few people, and primitive methods. Over time, technological advances in biophysics, biochemistry, and microscopy allowed the combined efforts of scientists in hundreds of laboratories to explain mysterious processes with molecular mechanisms that can be embodied in mathematical equations and simulated by computers. The success of this field is a tribute to the power of the reductionist strategy for understanding biology.
Deep Learning: The Good, the Bad, and the Ugly
Authors: Serre Thomas
Published: August 2019

Artificial vision has often been described as one of the key remaining challenges to be solved before machines can act intelligently. Recent developments in a branch of machine learning known as deep learning have catalyzed impressive gains in machine vision—giving a sense that the problem of vision is getting closer to being solved. The goal of this review is to provide a comprehensive overview of recent deep learning developments and to critically assess actual progress toward achieving human-level visual intelligence. I discuss the implications of the successes and limitations of modern machine vision algorithms for biological vision and the prospect for neuroscience to inform the design of future artificial vision systems.
Sex differences in GABAergic neurotransmission to rat DMV neurons
Authors: Jiang Yanyan , Babic Tanja , Travagli R. Alberto
Published: August 2019

Functional gastrointestinal disorders, including delayed gastric emptying and decreased gastric motility, are more prevalent in women, suggesting a potential role for circulating gonadal hormones, including estrogen. Gastric motility is tuned by the vagal inputs arising from the dorsal motor nucleus of the vagus (DMV), which is itself controlled by tonic GABAergic inputs. Estrogen increases GABA functions in various central nervous system areas; however, the effect of the estrus cycle in modulating GABAergic inputs onto DMV neurons, hence vagal control of gastric motility, has not been investigated. The aim of the present study was to test the hypothesis that GABAergic tone to DMV neurons, hence the vagal output to the stomach, varies according to sex and the estrus cycle. Experiments were performed on age-matched Sprague-Dawley male and virgin female rats; females were subdivided according to the high-estrogen (HE) or low-estrogen (LE) period of their cycle. Whole-cell patch-clamp recordings were made from gastric-projecting DMV neurons, and the response to perfusion with the GABAA receptor antagonist bicuculline was examined. The response of corpus and antrum tone and motility to bicuculline microinjected in the dorsal vagal complex, recorded via strain gauges sewn to the anterior gastric surface, was also assessed. Bicuculline increased the firing rate of DMV neurons, as well as gastric tone and motility, to a larger extent in HE compared with LE or male rats, suggesting a higher GABAergic tone in HE female rats. Taken together, the data support the hypothesis that GABAergic tone to DMV neurons varies according to sex and estrus cycle.

NEW & NOTEWORTHY GABAergic neurotransmission to the dorsal motor nucleus of the vagus (DMV) plays a pivotal role in the modulation of gastric tone and motility. Gastric motility is reduced in women and may contribute to the higher incidence of functional gastrointestinal disorders. In the present study, we report that GABAergic tone to rat DMV neurons, hence vagal output to the stomach, varies according to sex and estrus cycle, and the GABAergic tone is increased during the high-estrogen period of the estrus cycle.
Left Ventricular Noncompaction: A Rare Case of Nonischemic Cardiomyopathy
Authors: Tian Julia , Uddin Asif , Akhrass Philippe
Published: August 2019

Isolated left ventricular noncompaction (LVNC) is a rare form of cardiomyopathy that is characterized by deep intertrabecular recesses and abnormal trabeculations that can be observed on transthoracic echocardiogram (TTE) or cardiac MRI (CMR) studies. Our case describes a 41-year-old male who presented with exertional chest pain and was discovered to have significantly reduced left ventricular ejection fraction (LVEF) which was nonischemic in etiology as confirmed by cardiac catheterization. Subsequent evaluation with CMR imaging revealed noncompaction of the left ventricle. The patient received defibrillation and lifelong anticoagulation given his elevated risk of sudden cardiac death (SCD). This case highlights the importance of considering unconventional etiologies of cardiomyopathy when investigating new-onset heart failure as well as the necessity of life-saving measures such as anticoagulation and defibrillator implantation in view of arrhythmogenic structural heart diseases.
Mofette Vegetation as an Indicator for Geogenic CO2 Emission: A Case Study on the Banks of the Laacher See Volcano, Vulkaneifel, Germany
Authors: Pfanz Hardy , Saßmannshausen Frank , Wittmann Christiane , Pfanz Benny , Thomalla Annika
Published: August 2019

A geogenic CO2 emitting site (mofette U1) at the banks of the Laacher See, Eifel Mountains, was chosen to study the relationship between heavy postvolcanic soil degassing and vegetation during spring season. To test any interrelation between soil CO2 degassing and vegetation, soil chemism (pH, water content, conductivity, and humus content) and vegetation studies (number of species, plant-soil coverage) were performed. Geogenic soil degassing patterns of carbon dioxide and oxygen were clearly inhomogeneous, resembling soil porosity and distinct permeation channels within the soil. CO2 concentrations ranged from zero to 100%. Soil CO2 increased, while soil oxygen decreased with increasing soil depth. There was a reasonable correlation between CO2 degassing and soil pH as well as soil conductivity. Soil organic matter (SOM) resembled soil water distribution. The number of plant species (from a total of 69 species) as well as plant coverage strongly followed geogenic CO2 degassing. The total number of growing species was highest in low CO2 soils (max. 17 species per m2) and lowest at high CO2-emitting sites (one species per m2). Plant coverage followed the same pattern. Total plant coverage reached values of up to 84% in slightly degassing soils and only 5-6% on heavy CO2-venting sites. One plant species proved to be highly mofettophilic (marsh sedge, Carex acutiformis) and strictly grew on CO2 degassing sites. Most other species like grove windflower, spring fumewort, fig buttercup, wood bluegrass, addersmeat, and common snowberry showed a mofettophobic behavior and strictly avoided degassing areas. Specific plant species can thus be used to detect and monitor pre- or postvolcanic CO2 degassing.
Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation
Authors: Singh Pankaj K. , Deorukhkar Amit A. , Venkatesulu Bhanu P. , Li Xiaolin , Tailor Ramesh , Bomalaski John S. , Krishnan Sunil
Published: August 2019

Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosensitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent in vivo studies in two xenograft models confirmed significant tumor growth delays, which were associated with enhanced expression of ER stress proteins and apoptosis markers and reduced expression of proliferation and angiogenesis markers. ADI-PEG20 augmented the effects of radiation by triggering the ER stress pathway, leading to apoptosis in pancreatic tumor cells.
Development of Therapeutic Anti-JAGGED1 Antibodies for Cancer Therapy
Authors: Masiero Massimo , Li Demin , Whiteman Pat , Bentley Carol , Greig Jenny , Hassanali Tasneem , Watts Sarah , Stribbling Stephen , Yates Jenna , Bealing Ellen , Li Ji-Liang , Chillakuri Chandramouli , Sheppard Devon , Serres Sébastien , Sarmiento-Soto Manuel , Larkin James , Sibson Nicola R. , Handford Penny A. , Harris Adrian L. , Banham Alison H.
Published: August 2019

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology has been firmly established, making them appealing therapeutic targets for cancer treatment. Here, we report the development and characterization of human/rat-specific JAG1-neutralizing mAbs. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 ortholog. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells, and block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired three-dimensional growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal-expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor-negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic growth. MRI imaging demonstrated that this was associated with a substantial improvement in blood–brain barrier function and tumor perfusion. Lastly, JAG1-targeting antibody treatment did not cause any detectable toxicity, further supporting its clinical potential for cancer therapy.
Preclinical Development of the Anti-LAG-3 Antibody REGN3767: Characterization and Activity in Combination with the Anti-PD-1 Antibody Cemiplimab in Human PD-1xLAG-3–Knockin Mice
Authors: Burova Elena , Hermann Aynur , Dai Jie , Ullman Erica , Halasz Gabor , Potocky Terra , Hong Seongwon , Liu Matt , Allbritton Omaira , Woodruff Amy , Pei Jerry , Rafique Ashique , Poueymirou William , Martin Joel , MacDonald Douglas , Olson William C. , Murphy Andrew , Ioffe Ella , Thurston Gavin , Mohrs Markus
Published: August 2019

In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigen-presenting cell bioassay, REGN3767 alone, or in combination with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.
A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity
Authors: Vega Mario I. , Shi Yijiang , Frost Patrick , Huerta-Yepez Sara , Antonio-Andres Gabriela , Hernandez-Pando Rogelio , Lee Jihye , Jung Michael E. , Gera Joseph F. , Lichtenstein Alan
Published: August 2019

Prior work indicates DEPTOR expression in multiple myeloma cells could be a therapeutic target. DEPTOR binds to mTOR via its PDZ domain and inhibits mTOR kinase activity. We previously identified a drug, which prevented mTOR–DEPTOR binding (NSC126405) and induced multiple myeloma cytotoxicity. We now report on a related therapeutic, drug 3g, which induces proteasomal degradation of DEPTOR. DEPTOR degradation followed drug 3g binding to its PDZ domain and was not due to caspase activation or enhanced mTOR phosphorylation of DEPTOR. Drug 3g enhanced mTOR activity, and engaged the IRS-1/PI3K/AKT feedback loop with reduced phosphorylation of AKT on T308. Activation of TORC1, in part, mediated multiple myeloma cytotoxicity. Drug 3g was more effective than NSC126405 in preventing binding of recombinant DEPTOR to mTOR, preventing binding of DEPTOR to mTOR inside multiple myeloma cells, in activating mTOR and inducing apoptosis in multiple myeloma cells. In vivo, drug 3g injected daily abrogated DEPTOR expression in xenograft tumors and induced an antitumor effect although modest weight loss was seen. Every-other-day treatment, however, was equally effective without weight loss. Drug 3g also reduced DEPTOR expression in normal tissues. Although no potential toxicity was identified in hematopoietic or hepatic function, moderate cardiac enlargement and glomerular mesangial hypertrophy was seen. DEPTOR protected multiple myeloma cells against bortezomib suggesting anti-DEPTOR drugs could synergize with proteasome inhibitors (PI). Indeed, combinations of drug NSC126405 + bortezomib were synergistic. In contrast, drug 3g was not and was even antagonistic. This antagonism was probably due to prevention of proteasomal DEPTOR degradation.
U3-1402, a Novel HER3-Targeting Antibody–Drug Conjugate, for the Treatment of Colorectal Cancer
Authors: Koganemaru Shigehiro , Kuboki Yasutoshi , Koga Yoshikatsu , Kojima Takashi , Yamauchi Mayumi , Maeda Naoyuki , Kagari Takashi , Hirotani Kenji , Yasunaga Masahiro , Matsumura Yasuhiro , Doi Toshihiko
Published: August 2019

HER3 is overexpressed in several cancers, including colorectal cancer. Although therapies with anti-HER3 antibodies have been investigated, significant clinical benefits have not been reported. U3-1402 is a novel HER3-antibody–drug conjugate (ADC) composed of the HER3 antibody patritumab and a novel topoisomerase I inhibitor, DX-8951 derivative (DXd). The sensitivity of DXd was evaluated by a growth inhibition assay. The antitumor activity of U3-1402 was evaluated in a murine xenograft model in which its effects on cells, with a range of HER3 expression levels, were compared with those of patritumab alone, irinotecan, control-ADC, and saline. In the growth inhibition assay, all colorectal cancer cell lines were sensitive to DXd. In the tumor xenograft model, significant tumor regression with U3-1402 was observed both in the DiFi cell line (high HER3 expression; KRAS wild type) and in SW620 (high HER3 expression; KRAS mutation), but no treatment effect was observed in Colo320DM (low HER3 expression). Notably, SW620 tumor growth was significantly suppressed with U3-1402 compared with the saline-treated group (P < 0.001) and showed greater activity compared with the irinotecan group. By contrast, patritumab alone, control-ADC, and saline did not significantly differ in tumor growth inhibition. The antitumor activity of U3-1402 was dependent on HER3 expression level, but not on KRAS mutation status. These results support further investigation of development strategies for U3-1402 in patients with HER3-expressing colorectal cancer.
ОСОБЛИВОСТІ УЛЬТРАСТРУКТУРНОЇ РЕОРГАНІЗАЦІЇ ПЕРЕДСЕРДНИХ КАРДІОМІОЦИТІВ ПРИ ЕКСПЕРИМЕНТАЛЬНІЙ ТЕРМІЧНІЙ ТРАВМІ ТА ЗА УМОВ ЗАСТОСУВАННЯ ЛІОФІЛІЗОВАНИХ КСЕНОДЕРМОТРАНСПЛАНТАТІВ
Authors: Hetmaniuk I. B. , Nebesna Z. M. , Lykhatskyi P. H. , Shuturma O. Ya.
Published: August 2019

Опікова травма у розвинених країнах є одним із найпоширеніших видів ушкоджень мирного часу. Лікування опіків визначається складністю та багатоплановістю, термічні ушкодження – одні з найнебезпечніших, вони призводять до руйнування складних білків – основи клітин і тканин органів. Ключову роль при розвитку та патогенезі опікової хвороби, що розвивається після термічної травми ІІІ ступеня, відіграє серцево-судинна система.

Мета дослідження – встановити закономірності ультраструктурних змін у передсердних кардіоміоцитах після тяжкої термічної травми за умов застосування ліофілізованих ксенодермотрансплантатів.

Матеріали і методи. Опік ІІІ ступеня наносили під кетаміновим наркозом мідними пластинами, нагрітими у кип’яченій воді до температури 97–100 оС. Евтаназію тварин проводили після кетамінового наркозу шляхом декапітації. Розміри ділянки ураження склали 18–20 % епільованої поверхні тіла морських свинок. Для електронно-мікроскопічного дослідження брали шматочки передсердь, фіксували у 2,5 % розчині глютаральдегіду, постфіксували 1 % розчином тетраокису осмію на фосфатному буфері. Подальшу обробку проводили згідно з загальноприйнятою методикою [3]. Ультратонкі зрізи, виготовлені на ультрамікротомі LKB-3, контрастували уранілацетатом, цитратом свинцю відповідно до методу Рейнольдса та вивчали в електронному мікроскопі ПЕМ-125 К.

Результати досліджень та їх обговорення. В експерименті вивчено субмікроскопічні зміни передсердних кардіоміоцитів після тяжкої термічної травми в умовах проведення ранньої некректомії та застосуванні ліофілізованих ксенодермотрансплантів для закриття опікової рани. Встановлено, що після опіку III ступеня відбуваються значні ультраструктурні зміни в передсердних кардіоміоцитах, ступінь ураження яких збільшувався в динаміці експерименту. При стадіях опікового шоку та ранньої токсемії у структурах серця розвиваються пристосувально-компенсаторні процеси, а при стадіях пізньої токсемії та септикотоксемії – наявні глибокі незворотні деструктивні зміни. Доведено, що використання ліофілізованих ксенодермотрансплантатів після ранньої некректомії уражених тканин запобігає розвитку деструктивних змін у компонентах серця на ранніх термінах досліду, активізує регенераторні процеси скоротливих та ендокринних міоцитів передсердь на пізніх термінах експерименту.

Висновки. Застосування ліофілізованих ксенодермотрансплантатів позитивно впливає на перебіг регенераторних процесів та покращує стан ультраструктури передсердя в динаміці експерименту. На ранніх термінах досліду застосування ліофілізованої ксеношкіри зменшує ступінь ушкодження цитоплазматичних мембран кардіоміоцитів передсердь, активізуються регенераторні процеси в клітинах.
Polyunsaturated Fatty Acid Impact on Clinical Outcomes in Acute Coronary Syndrome Patients With Dyslipidemia: Subanalysis of HIJ‐PROPER
Authors: Arashi Hiroyuki , Yamaguchi Junichi , Kawada‐Watanabe Erisa , Koyanagi Ryo , Sekiguchi Haruki , Mori Fumiaki , Haruta Shoji , Ishii Yasuhiro , Murasaki Satoshi , Suzuki Kazuhito , Yamauchi Takao , Ogawa Hiroshi , Hagiwara Nobuhisa
Published: August 2019

Background

This study aimed to examine the impact of baseline eicosapentaenoic acid (
EPA
) to arachidonic acid (
AA
) ratio on clinical outcomes of patients with acute coronary syndrome.

Methods and Results

In the HIJ‐PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1734 patients with acute coronary syndrome and dyslipidemia were randomly assigned to pitavastatin+ezetimibe therapy or pitavastatin monotherapy. We divided the patients into 2 groups based on
EPA
/
AA
ratio on admission (cutoff 0.34 μg/mL as median of baseline
EPA
/
AA
ratio) and examined their clinical outcomes. The primary end point comprised all‐cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris, or ischemia‐driven revascularization. Percentage reduction of low‐density lipoprotein cholesterol and triglyceride from baseline to follow‐up was similar regardless of baseline
EPA
/
AA
ratio. Despite the mean low‐density lipoprotein cholesterol level during follow‐up being similar between the low‐ and high‐
EPA
/
AA
groups, the mean triglyceride levels during follow‐up were significantly higher in the low‐ than in the high‐
EPA
/
AA
group. After 3 years of follow‐up, the cumulative incidence of the primary end point in patients with low
EPA
/
AA
was 27.2% in the pitavastatin+ezetimibe group compared with 36.6% in the pitavastatin‐monotherapy group (hazard ratio 0.69; 95%
CI
, 0.52‐0.93;
P
=0.015). However, there was no effect of pitavastatin+ezetimibe therapy on the primary end point in patients with high
EPA
/
AA
(hazard ratio 0.92; 95%
CI
, 0.70‐1.20;
P
=0.52).

Conclusions

Among acute coronary syndrome patients who have dyslipidemia and low
EPA
/
AA
ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy.

Clinical Trial Registration

URL
:
http://www.umin.ac.jp/ctr
. Unique identifier:
UMIN
000002742
Targeted Infarction of the Internal Capsule in the Rat Using Microstimulation Guidance
Authors: Wen Tong-Chun , Sindhurakar Anil , Ramirez Violeta Contreras , Park HongGeun , Gupta Disha , Carmel Jason B.
Published: August 2019

Background and Purpose—

Lacunar strokes are subcortical infarcts with small size and high disability rates, largely due to injury of the corticospinal tract in the internal capsule (IC). Current rodent models of lacunar infarcts are created based on stereotactic coordinates. We tested the hypothesis that better understanding of the somatotopy of the IC and guiding the lesion with electrical stimulation would allow a more accurate lesion to the forelimb axons of the IC.

Methods—

We performed electrophysiological motor mapping and viral tracing to define the somatotopy of the IC of Sprague Dawley rats. For the lesion, we used an optrode, which contains an electrode to localize forelimb responses and an optical fiber to deliver light. The infarct was induced when light activated the photothrombotic agent Rose Bengal, which was administered systemically.

Results—

We found largely a separate distribution of the forelimb and hindlimb axons in the IC, both by microstimulation mapping and tract tracing. Microstimulation-guided IC lesions ablated the forelimb axons of the IC in rats and caused lasting forelimb impairments while largely preserving the hindlimb axons of the IC and surrounding gray matter.

Conclusions—

Stimulation guidance enabled selective and reproducible infarcts of the forelimb axons of the IC in rats.

Visual Overview—

An online
visual overview
is available for this article.