bluuebunny/crossref_metadata_2025 huggingface dataset:
Pattern associated leukemia immunophenotypes and measurable disease detection in acute myeloid leukemia or myelodysplastic syndrome with mutated NPM1
Authors: Zhou Yi , Moon Andres , Hoyle Eric , Fromm Jonathan R. , Chen Xueyan , Soma Lori , Salipante Stephen J. , Wood Brent L. , Wu David
Published: November 2018

Background

The presence of measurable residual disease after therapy is a significant risk factor of relapse in patients with acute myeloid leukemia (AML). By detecting cells with leukemia‐associated immunophenotype (LAIP), multiparameter flow cytometry (MFC) can detect residual leukemia at a level significantly lower than that detected by morphology. However, changes in LAIPs during or after therapy may pose a challenge to MRD testing. AML with mutated NPM1 represents the largest subtype of AML sharing a common leukemogenic mechanism and similar LAIPs. Here, we identified a common pattern of LAIPs in myeloid blasts with mutated NPM1, and studied its stability and limit of detection after therapy.

Methods

We summarized aberrancies of leukemic blasts with mutated NPM1 at diagnosis in 61 patients and paired relapse in 25 patients. In addition, we examined the detection of leukemic blasts in 590 specimens collected from 152 patients in complete remission after induction for AML/MDS‐EB with mutated NPM1.

Results

Our findings demonstrate myeloid blasts with mutated NPM1 have a characteristic pattern of LAIPs that is present in nearly all cases of AML/MDS‐EB with mutated NPM1 at initial diagnosis and relapse, regardless of morphologic variations, FLT3 ITD status, or karyotype abnormality. The myeloid blasts with mutated NPM1 can be detected at an approximate level of 0.1% of total leukocytes in morphologic remission with high specificity validated by clinical outcome.

Conclusion

The characteristic pattern of LAIPs of myeloid blasts with mutated NPM1 is common and stable, and allows sensitive and specific detection of AML or MDS with mutated NPM1 after therapy. © 2018 International Clinical Cytometry Society
Muscle‐induced loading as an important source of variation in craniofacial skeletal shape
Authors: Conith Andrew J. , Lam Daniel T. , Albertson R. Craig
Published: November 2018

The shape of the craniofacial skeleton is constantly changing through ontogeny and reflects a balance between developmental patterning and mechanical‐load‐induced remodeling. Muscles are a major contributor to producing the mechanical environment that is crucial for “normal” skull development. Here, we use an F5hybrid population of Lake Malawi cichlids to characterize the strength and types of associations between craniofacial bones and muscles. We focus on four bones/bone complexes, with different developmental origins, alongside four muscles with distinct functions. We used micro‐computed tomography to extract 3D information on bones and muscles. 3D geometric morphometrics and volumetric measurements were used to characterize bone and muscle shape, respectively. Linear regressions were performed to test for associations between bone shape and muscle volume. We identified three types of associations between muscles and bones: weak, strong direct (i.e., muscles insert directly onto bone), and strong indirect (i.e., bone is influenced by muscles without a direct connection). In addition, we show that although the shape of some bones is relatively robust to muscle‐induced mechanical stimulus, others appear to be highly sensitive to muscular input. Our results imply that the roles for muscular input on skeletal shape extend beyond specific points of origin or insertion and hold significant potential to influence broader patterns of craniofacial geometry. Thus, changes in the loading environment, either as a normal course of ontogeny or if an organism is exposed to a novel environment, may have pronounced effects on skeletal shape via near and far‐ranging effects of muscular loading.
Genetic diversity in fishes is influenced by habitat type and life‐history variation
Authors: Martinez Alexander S. , Willoughby Janna R. , Christie Mark R.
Published: November 2018

Populations of fishes are increasingly threatened by over‐exploitation, pollution, habitat destruction, and climate change. In order to better understand the factors that can explain the amount of genetic diversity in wild populations of fishes, we collected estimates of genetic diversity (mean heterozygosity and mean rarefied number of alleles per locus) along with habitat associations, conservation status, and life‐history information for 463 fish species. We ran a series of phylogenetic generalized least squares models to determine which factors influence genetic diversity in fishes after accounting for shared evolutionary history among related taxa. We found that marine fishes had significantly higher genetic diversity than freshwater fishes with marine fishes averaging 11.3 more alleles per locus than their freshwater counterparts. However, contrary to our expectations, genetic diversity was not found to be lower in threatened versus not‐threatened fishes. Finally, we found that both age at maturity and fecundity were negatively related to genetic variation in both marine and freshwater fishes. Our results demonstrate that both life‐history characteristics and habitat play a role in shaping patterns of genetic diversity in fishes and should be considered when prioritizing species for conservation.
Population genetics and evolutionary history of the wild rice species Oryza rufipogon and O. nivara in Sri Lanka
Authors: Sandamal Salinda , Tennakoon Asanka , Meng Qing‐Lin , Marambe Buddhi , Ratnasekera Disna , Melo Arthur , Ge Song
Published: November 2018

Genetic diversity and population genetic structure of the wild rice species Oryza rufipogon and O. nivara in Sri Lanka were studied using 33 microsatellite markers. A total of 315 individuals of 11 natural populations collected from the wet, intermediate, and dry zones of the country were used in the study. We found a moderate to high level of genetic diversity at the population level, with the polymorphic loci (P) ranging from 60.6% to 100% (average 81.8%) and the expected heterozygosity (HE) varying from 0.294 to 0.481 (average 0.369). A significant genetic differentiation between species and strong genetic structure within species were also observed. Based on species distribution modeling, we detected the dynamics of the preferred habitats for the two species in Sri Lanka and demonstrated that both O. rufipogon and O. nivara populations have expanded substantially since the last internal glacial. In addition, we showed that the geographical distribution of the two species corresponded to the climate zones and identified a few of key environmental variables that contribute to the distribution of the two species, implying the potential mechanism for ecological adaptation of these two species in Sri Lanka. These studies provided important insights into the population genetics and evolution of these wild species in Sri Lanka and are of great significance to the in situ conservation and utilization of these wild resources in genetic improvement of rice.
Indirect effects of a large mammalian herbivore on small mammal populations: Context‐dependent variation across habitat types, mammal species, and seasons
Authors: Ellis Taylor D. , Cushman J. Hall
Published: November 2018

Multiple consumer species frequently co‐occur in the same landscape and, through effects on surrounding environments, can interact in direct and indirect ways. These interactions can vary in occurrence and importance, and focusing on this variation is critical for understanding the dynamics of interactions among consumers. Large mammalian herbivores are important engineers of ecosystems worldwide, have substantial impacts on vegetation, and can indirectly affect small‐mammal populations. However, the degree to which such indirect effects vary within the same system has received minimal attention. We used a 16‐year‐old exclosure experiment, stratified across a heterogeneous landscape, to evaluate the importance of context‐dependent interactions between tule elk (Cervus canadensis nannodes) and small mammals (deer mice [Peromyscus maniculatus], meadow voles [Microtus californicus], and harvest mice [Reithrodontymys megalotis]) in a coastal grassland in California. Effects of elk on voles varied among habitats and seasons: In open grasslands, elk reduced vole numbers during fall 2013 but not summer 2014; in Lupinus‐dominated grasslands, elk reduced vole numbers during summer 2014 but not fall 2013; and in Baccharis‐dominated grasslands, elk had no effect on vole numbers in either season. Effects of elk on the two mice species also varied among habitats and seasons, but often in different ways from voles and each other. In fall 2013, elk decreased mice abundances in Lupinus‐dominated grasslands, but not in Baccharis‐dominated or open grasslands. In summer 2014, elk decreased the abundance of harvest mice consistently across habitat types. In contrast, elk increased deer‐mice numbers in open grasslands but not other habitats. Within the same heterogenous study system, the influence of elk on small mammals was strongly context‐dependent, varying among habitats, mammal species, and seasons. We hypothesize that such variability is common in nature and that failure to consider it may yield inaccurate findings and limit our understanding of interactions among co‐occurring consumers.
Interspecific transfer of parasites following a range‐shift in Ficedula flycatchers
Authors: Jones William , Kulma Katarzyna , Bensch Staffan , Cichoń Mariusz , Kerimov Anvar , Krist Miloš , Laaksonen Toni , Moreno Juan , Munclinger Pavel , Slater Fred M. , Szöllősi Eszter , Visser Marcel E. , Qvarnström Anna
Published: November 2018

Human‐induced climate change is expected to cause major biotic changes in species distributions and thereby including escalation of novel host‐parasite associations. Closely related host species that come into secondary contact are especially likely to exchange parasites and pathogens. Both the Enemy Release Hypothesis (where invading hosts escape their original parasites) and the Novel Weapon Hypothesis (where invading hosts bring new parasites that have detrimental effects on native hosts) predict that the local host will be most likely to experience a disadvantage. However, few studies evaluate the occurrence of interspecific parasite transfer by performing wide‐scale geographic sampling of pathogen lineages, both within and far from host contact zones. In this study, we investigate how haemosporidian (avian malaria) prevalence and lineage diversity vary in two, closely related species of passerine birds; the pied flycatcher Ficedula hypoleuca and the collared flycatcher F. albicollis in both allopatry and sympatry. We find that host species is generally a better predictor of parasite diversity than location, but both prevalence and diversity of parasites vary widely among populations of the same bird species. We also find a limited and unidirectional transfer of parasites from pied flycatchers to collared flycatchers in a recent contact zone. This study therefore rejects both the Enemy Release Hypothesis and the Novel Weapon Hypothesis and highlights the complexity and importance of studying host‐parasite relationships in an era of global climate change and species range shifts.
Time and ecological resilience: can diurnal animals compensate for climate change by shifting to nocturnal activity?
Authors: Levy Ofir , Dayan Tamar , Porter Warren P. , Kronfeld‐Schor Noga
Published: November 2018

Considerable research is aimed at developing predictions of ecosystem responses to climate change, focusing on the spatial scale, such as range shifts and contractions, as well as activity restrictions to shaded microhabitats. On the other hand, the ability of species to shift their activity times during the diel cycle, and consequently to alter the environment in which activity occurs, has been largely neglected. Daily activity patterns are perceived as fairly fixed; however, natural changes in activity patterns have been reported in increasing numbers of species. Here, we present a framework that explores how shifts in activity patterns may buffer impacts of climate change. To demonstrate our framework, we simulated costs of activity of diurnal and nocturnal rodents and showed that future summers may decrease the energetic demands of nocturnal mammals while increasing water demands of diurnal mammals. Climate projections suggest that vegetation cover and water availability will decrease under future climate scenarios, especially in areas where water demands are expected to increase the most. These changes are expected to limit the ability of diurnal animals to restrict activity to shaded microhabitats and to keep a positive water balance. Our analysis shows that by shifting to nocturnality, diurnal mammals may mitigate the high water costs of future summers. We suggest that future research should explore the role of the diel time axis as an ecological resource when predicting the impacts of climate change.
Spatiotemporal variability of fire regimes in adjacent Native American and public forests, New Mexico, USA
Authors: Azpeleta Tarancón Alicia , Fulé Peter Z. , Sánchez Meador Andrew J. , Kim Yeon‐Su , Padilla Thora
Published: November 2018

Statistical descriptions of reconstructed fire regimes are often extrapolated from a composite of small forest stands to represent extensive geographical areas. However, statistical properties of fire regimes are scale‐dependent, thus causing some extrapolations from fine scale to coarse scale and comparisons between fire‐scar‐based reconstructions to be inappropriate. We assessed landscape fire regimes of the Sacramento Mountains, in southern New Mexico, using dendrochronological methods and a variety of fire statistics and analysis filters. We reconstructed historical and recent fire regimes for the Mescalero Apache Tribal Lands (MATL) at tree and site scale (25 ha). We then estimated the Sacramento Mountains historical and recent fire regimes by combining paleo fire data from this study with published data from the adjacent Lincoln National Forest (LNF). We applied filters to provide fire statistics that are relatively unbiased to the different spatial measurement extent of the studies. This is the first study to assess fire regime in the MATL over multiple spatial and temporal scales. The results show that frequent surface fires occurred at all scales in the Sacramento Mountains until fire was excluded from the landscape in the early 1900s. Historical fires were found to be synchronous with drought years, typically La Niña events, and often preceded by wet years. We did not find evidence supporting differences in fire regimes between the MATL and the LNF, suggesting that fire cessation following intensive Euro‐American settlement was widespread. The interruption of frequent surface fires, together with other changes in forest structure and climate, pose a significant threat to sustainability of forest ecosystems on Native American tribal lands.
Colloidal Energetic Systems
Authors: Chiolerio Alessandro , Quadrelli Marco B.
Published: November 2018

Colloidal devices—in the liquid state—possibly protected from harsh planetary environments by a soft protective deformable skin, represent a totally new paradigm in the field of robotics. They include the autonomy features of conventional robotics and the shape‐changing advantages of soft robotics and offer new opportunities to science and technology. For these systems, energy management is considered to be the most essential function to guarantee autonomy and operation. Herein, smart fluids as autonomous systems with energy‐harvesting/storage capabilities are described and an initial assessment of existing possibilities that can be leveraged to pursue the emerging topic of colloidal autonomous systems is provided.
Psychometric properties of the “Autonomous and Controlled Motivation for Treatment Questionnaire” in women with eating disorders
Authors: Sansfaçon Jeanne , Fletcher Émilie , Zuroff David C. , Schmitz Norbert , Miller Alexia , Israel Mimi , Steiger Howard
Published: November 2018

Objective

To validate the Autonomous and Controlled Motivation for Treatment Questionnaire (ACMTQ) for use in women with an eating disorder (ED).

Method

Data were available for 463 individuals. We assessed factor structure, internal reliability, test–retest reliability, convergent/divergent validity, and incremental predictive validity.

Results

Our data showed acceptable fit to our hypothesized model (comparative fit index = 0.92, root mean square error of approximation = 0.09, standardized root mean square residual = 0.09). We found test–retest reliability of 0.73 for both the autonomous (α = 0.85) and controlled (α = 0.80) subscales. Autonomous scores were more strongly associated with motivation measures (β = 0.37; 0.46) than with ED severity measures (β = −0.10; −0.18). Associations between autonomous motivation and symptom improvement over time supported predictive validity. Controlled motivation was associated with lower motivation (β = 0.02; −0.31) and with higher ED severity (β = 0.12; 0.47).

Conclusion

Our results suggest that the ACMTQ is valid for use in women with EDs and lend support to the validity of findings from previous ED studies that have used the ACMTQ.
Anchored Graphical Representations: A Graphical Alternative to Traditional Just Qualified Candidate Descriptors for Licensure Tests
Authors: Kannan Priya , Tannenbaum Richard J. , Hebert Delano
Published: November 2018

A well‐constructed just qualified candidate (JQC) description is needed to arrive at a reasonable passing score for licensure tests. Traditionally, such descriptions consist of a list of knowledge and skill statements without sufficient context to internalize its intended meaning, allowing the standard‐setting panelists to make idiosyncratic interpretations. In a series of studies, we evaluated an alternative JQC description called anchored graphical representation (AGR). AGRs are intended to provide both text and visual organizers by each tested domain to contextualize the meaning of the JQC. In Study 1, 22 mathematics educators participated in a mock standard‐setting study and were randomly assigned to conditions in which they used either the AGR‐based or the text‐based definitions in making standard‐setting judgments. In Study 2, 17 social studies educators were randomly assigned to either the AGR‐based or text‐based condition. While the overall passing score did not noticeably vary between the conditions, consistent with our expectations, results from both studies showed that the domain passing scores for the AGR groups reflected the relative importance of each test domain for the JQC and that the inter‐panelist variability was smaller for the AGR groups. Collectively, our results indicate that use of the AGR resulted in standard‐setting ratings that were more aligned with the panelists' differential expectations of JQCs' performance for each domain, and the results add to the procedural validity evidence supporting the reasonableness of standard‐setting recommendations.
Association of whole grain, refined grain, and cereal consumption with gastric cancer risk: A meta‐analysis of observational studies
Authors: Xu Yujie , Yang Jie , Du Liang , Li Ka , Zhou Yong
Published: November 2018

Many studies have analyzed the relationship between cereal, whole, or refined grain and the risk of gastric cancer (GC) and have yielded mixed results. Therefore, we performed a meta‐analysis of observational studies to summarize the available evidence on this topic. Databases such as PubMed, EMBASE, Web of Science, MEDLINE, and the Cochrane Library were searched for studies focusing on these associations from inception to October 2017. Summary odd ratios (OR) and 95% confidence intervals (CI) were calculated by using either a random‐ or fixed‐effect model according to the between‐studies heterogeneity. Subgroup analysis was also performed. In total, eleven studies that included 530,176 participants were identified. In a pooled analysis of all studies, cereal exposure was not associated with GC risk (OR, 1.11, 95%CI, 0.85–1.36). Specific analyses indicated that whole grain consumption was associated with decreased GC risk (OR, 0.61, 95%CI, 0.40–0.83) and that refined grain consumption was associated with increased GC risk (OR, 1.65, 95%CI, 1.36–1.94). Higher whole grain and lower refined grain intake but not cereal consumption reduces GC risk. This study has been registered at ClinicalTrials.gov (ID: NCT03419663).
Microglia shape presynaptic properties at developing glutamatergic synapses
Authors: Basilico Bernadette , Pagani Francesca , Grimaldi Alfonso , Cortese Barbara , Di Angelantonio Silvia , Weinhard Laetitia , Gross Cornelius , Limatola Cristina , Maggi Laura , Ragozzino Davide
Published: November 2018

Deficient neuron–microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron‐to‐microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3–CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+/Mg2+ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron–microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.
Microglial activation occurs late during preclinical Alzheimer's disease
Authors: Streit Wolfgang J. , Braak Heiko , Del Tredici Kelly , Leyh Judith , Lier Julia , Khoshbouei Habibeh , Eisenlöffel Christian , Müller Wolf , Bechmann Ingo
Published: November 2018

Sporadic Alzheimer's disease (AD) is marked by a lengthy preclinical phase during which patients are nonsymptomatic but show pathology in variable manifestations. Whether or not neuroinflammation occurs in such nondemented individuals is unknown. We evaluated the medial temporal lobe of 66 nondemented subjects, aged 42–93, in terms of tau pathology, Aβ deposition, and microglial activation. We show that 100% of subjects had neurofibrillary degeneration (NFD), 35% had Aβ deposits, and 8% revealed microglial activation in individuals where early amyloid formation was apparent by Congo Red staining. Amyloid‐induced neuroinflammatory clusters of Iba1, CD68, and ferritin‐positive microglia were evident in the immediate vicinity of aggregated Aβ. Microglia in the adjacent neuropil were nonactivated. Thus, neuroinflammation in AD represents a highly localized phagocyte reaction, essentially a foreign body response, geared toward removal of insoluble Aβ. Because clustered microglia in some amyloid plaques were dystrophic and ferritin‐positive, we hypothesize that these cells were exhausted by their attempts to remove the aggregated, insoluble Aβ. Our findings show that the sequence of pathologic events in AD begins with tau pathology, followed by Aβ deposition, and then by microglial activation. Because only 8% of our subjects revealed all three hallmark pathologic features, we propose that these nondemented individuals were near the threshold of transitioning from nonsymptomatic to symptomatic disease. The onset of neuroinflammation in AD may thus represent a tipping point in AD pathogenesis. Our study suggests that the role of microglia in AD pathogenesis entails primarily the attempted removal of potentially toxic, extracellular material.
Group 13 metal carbochalcogenoato complexes: Synthesis, X‐ray structure analysis, and reactions
Authors: Nakata Norio , Kato Shinzi , Niyomura Osamu , Ebihara Masahiro
Published: November 2018

A series of alkali metal tetrakis(carbochalcogenoato)‐gallates and ‐indates M[M′(EOCR)4](solv.) (M = alkali metal; M′ = Ga, In; E = S, Se) and tris(carbodithioato)aluminum, ‐gallates and ‐indates M′ (SSCR)3(M′ = Al, Ga, In) were prepared by the reactions of alkali metal carbochalcogenate with metal trihalogenides (M′X3; M′ = Al, Ga, In; X = Cl, Br) and by those of piperidinium carbodithioates or carbodithioic and carboselenoic acids with M′X3, respectively. An X‐ray molecular structure analysis revealed that they have an acetone molecule as a crystal solvent. The reactions of the potassium complexes K[M′ (EOCR)4](H2O) (E = S, Se) with methanol and primary and secondary amines gave the corresponding methyl ester and amides in good yields, while the reactions with iodomethane and iodine gaveS‐ andSe‐methyl chalcogenoestersRCOEMe (E = S, Se) in good yields. Similar reactions of the tris(carbodithioato)gallates and ‐indates led to the correspondingO‐methyl thioesters, thioamides, andS‐methyl dithioesters in moderate to good yields. Oxidation of the tetrakis‐ and tris‐derivatives with iodine afforded the corresponding diacyl dichalcogenides (RCOE)2(E = S, Se) and di(carbothioyl) disulfides in quantitative yields. These reactions appeared to occur on the carbonyl or selenium atom of the tetrakis compounds and on the sulfide sulfur or thiocarbonyl carbon atom of the tris‐compounds, respectively. A possible mechanism for these I2‐oxidation reactions is discussed.
The arginine detection and cytotoxicity of fluorescent probes based on naphthalene derivatives
Authors: Shang Xuefang , Li Congshu , Li Jie , Chen Yanmei , Chen Hongli , Wang Tianyun
Published: November 2018

From a biological point of view, Schiff base probes containing fluorescent groups are chemically modified to provide an effective method for the detection of amino acids. According to this method, three molecular probes containing Schiff base and hydroxyl group have been designed and synthesized. UV‐Vis and fluorescent data indicated that compound 2 showed strong sensitivity and high selectivity for arginine (Arg) among normal twenty kinds of amino acids. In addition, compound 2 displayed high combining ability with Arg and low cytotoxicity in MCF‐7 cell from 0 to 150 μg/mL. The above results showed the synthesized probes also can be used a biosensor for the Arg detection in vivo.
A model of cholinergic suppression of hippocampal ripples through disruption of balanced excitation/inhibition
Authors: Melonakos Eric D. , White John A. , Fernandez Fernando R.
Published: November 2018

Sharp wave‐ripples (140–220 Hz) are patterns of brain activity observed in the local field potential of the hippocampus which are present during memory consolidation. As rodents switch from memory consolidation to memory encoding behaviors, cholinergic inputs to the hippocampus from neurons in the medial septum‐diagonal band of Broca cause a marked reduction in ripple incidence. The mechanism for this disruption in ripple power is not fully understood. In isolated neurons, the major effect of cholinergic input on hippocampal neurons is depolarization of the membrane potential, which affects both hippocampal pyramidal neurons and inhibitory interneurons. Using an existing model of ripple‐frequency oscillations that includes both pyramidal neurons and interneurons, we investigated the mechanism whereby depolarizing inputs to these neurons can affect ripple power and frequency. We observed that ripple power and frequency are maintained, as long as inputs to pyramidal neurons and interneurons are balanced. Preferential drive to pyramidal neurons or interneurons, however, affects ripple power and can disrupt ripple oscillations by pushing ripple frequency higher or lower. Thus, an imbalance in drive to pyramidal neurons and interneurons provides a means whereby cholinergic input can suppress hippocampal ripples.
Two‐step technique of early adrenal artery ligation in open adrenalectomy of giant right adrenal pheochromocytomas: Three case reports
Authors: Ochi Atsuhiko , Fan Bo , Kimura Natsuo , Watanabe Hisaki , Toki Sari , Fukuokaya Wataru , Okada Daigo , Aikawa Koichi , Huang Tingwen , Suzuki Koichiro , Shiga Naoki , Kitagawa Yasuhide , Abe Hirokazu
Published: November 2018

Introduction

Surgical manipulation of a pheochromocytoma carries the risk of releasing catecholamines into bloodstream leading to severe intraoperative hypertension.

Case presentation

We present three patients with right adrenal pheochromocytoma over 10 cm diameter: a 40‐year‐old woman, 63‐year‐old man, and 66‐year‐old woman. They were diagnosed by 123I‐MIBG scintigraphy and received preoperative antihypertensive treatment with 16 mg/day of doxazosin. Open adrenalectomy was performed with early right adrenal artery ligation between the inferior vena cava and ventral aorta (Step 1) as well as between the tumor and upper pole of the right kidney (Step 2). There was no severe intraoperative hypertension, and no recurrence was observed over 33 months, postoperatively.

Conclusion

Early adrenal artery ligation may stop tumor blood supply and significantly reduce the catecholamine release. Our technique was thought to be safe and useful for preventing severe intraoperative hypertension in giant right adrenal pheochromocytoma.
Hacking in the cloud
Authors: Gregorio Nick , Mathanamohan Janahan , Mahmoud Qusay H. , AlTaei May
Published: November 2018

Cloud computing is a widely expanding and rapidly adopted field of technology. The ability to grant significantly more computational resources than a single machine allows, through use of virtual machines, is incredibly helpful to enterprises that need to meet the demands of hundreds of thousands of concurrent users. However, just as these resources can be used for meaningful purposes, they can also be used for malicious attacks. In this paper, we present the legal and ethical challenges of hacking in the cloud citing specific cyber laws from Canada and the United Arab Emirates, along with the terms of use of cloud service providers. We also present the results of a legal SYN (synchronization) flood attack experiment, utilizing packets with spoofed source internet protocol addresses to determine if this attack works on a cloud service provider. We offer recommendations based on whether or not the cloud platform provides sufficient utility to be used in aiding hackers with their tasks, or if the legal and ethical issues surrounding the implementations ruin any opportunities before development even begins.
Heart valve tissue‐derived hydrogels: Preparation and characterization of mitral valve chordae, aortic valve, and mitral valve gels
Authors: Wu Jinglei , Brazile Bryn , McMahan Sara R. , Liao Jun , Hong Yi
Published: November 2018

Heart valve (HV) diseases are among the leading causes of death and continue to threaten public health worldwide. The current clinical options for HV replacement include mechanical and biological prostheses. However, an ongoing problem with current HV prostheses is their failure to integrate with the host tissue and their inability grow and remodel within the body. Tissue engineered heart valves (TEHVs) are a promising solution to these problems, as they are able to grow and remodel somatically with the rest of the body. Recently, decellularized HVs have demonstrated great potential as valve replacements because they are tissue specific, but recellularization is still a challenge due to the dense HV extracellular matrix (ECM) network. In this proof‐of‐concept work, we decellularized porcine mitral valve chordae, aortic valve leaflets, and mitral valve leaflets and processed them into injectable hydrogels that could accommodate any geometry. While the three valvular ECMs contained various amounts of collagen, they displayed similar glycosaminoglycan contents. The hydrogels had similar nanofibrous structures and gelation kinetics with various compressive strengths. When encapsulated with NIH 3 T3 fibroblasts, all the hydrogels supported cell survivals up to 7 days. Decellularized HV ECM hydrogels may show promising potential HV tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1732–1740, 2019.
Leucine aminopeptidase 3 promotes migration and invasion of breast cancer cells through upregulation of fascin and matrix metalloproteinases‐2/9 expression
Authors: Fang Chunyan , Zhang Jian , Yang Hanlin , Peng Lili , Wang Kun , Wang Yanjie , Zhao Xin , Liu Huijie , Dou Chunhui , Shi Lihong , Zhao Chunling , Liang Shujuan , Li Daqi , Wang Xuejian
Published: November 2018

Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA‐MB‐231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose‐dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase‐2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target.
Lycium barbarum polysaccharides promoted proliferation and differentiation in osteoblasts
Authors: Zhang Huiying , Zheng Lei , Yuan Zhanpeng
Published: November 2018

Osteoblasts have the capacity to differentiate into several different cell types, including adipocyte, chondrocyte, and muscle lineages. Therefore, osteoblast can be potentially applied in the treatment of bone diseases. The factors controlling osteoblast differentiation is complex. Recently, it has been reported that some natural products regulate the differentiation in osteoblasts and promote bone formation. Based on these findings, this study demonstrated that Lycium barbarum polysaccharides (LBP) could promote proliferation of osteoblast MC3T3‐E1 cells through 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Besides, expression of key proteins correlated with cellular proliferation such as proliferating cell nuclear antigen (PCNA) and Ki67 was enhanced in the presence of LBP. We also detected the increased expression of bone‐specific matrix proteins such as morphogenetic protein 2 (BMP2), bone Gla protein (BGP), osteopontin (OPN), and α‐1 type‐I collagen (COL1A1) when treated with LBP. This process was mediated by some signals, such as smad1, smad8, Runt‐related transcription factor 2 (RUNX2), and Osterix. Furthermore, RUNX2 silencing inhibited osteoblast differentiation by decreasing expression of bone‐specific matrix proteins. Collectively, we proposed a previously unidentified function of LBP in osteoblast differentiation, suggesting its potential clinical role in bone disease treatment.
BET inhibitors reduce cell size and induce reversible cell cycle arrest in AML
Authors: Zhang Susu , Zhao Yue , Heaster Tiffany M. , Fischer Melissa A. , Stengel Kristy R. , Zhou Xiaofan , Ramsey Haley , Zhou Ming‐Ming , Savona Michael R. , Skala Melissa C. , Hiebert Scott W.
Published: November 2018

Inhibitors of the bromodomain and extraterminal domain family (BETi) offer a new approach to treat hematological malignancies, with leukemias containing mixed lineage leukemia rearrangements being especially sensitive due to a reliance on the regulation of transcription elongation. We explored the mechanism of action of BETi in cells expressing the t(8;21), and show that these compounds reduced the size of acute myeloid leukemia cells, triggered a rapid but reversible G0/G1 arrest, and with time, cause cell death. Meta‐analysis of PRO‐seq data identified ribosomal genes, which are regulated by MYC, were downregulated within 3 hours of addition of the BETi. This reduction of MYC regulated metabolic genes coincided with the loss of mitochondrial respiration and large reductions in the glycolytic rate. In addition, gene expression analysis showed that transcription of BCL2 was rapidly affected by BETi but this did not cause dramatic increases in cell death. Cell cycle arrest, lowered metabolic activity, and reduced BCL2 levels suggested that a second compound was needed to push these cells over the apoptotic threshold. Indeed, low doses of the BCL2 inhibitor, venetoclax, in combination with the BETi was a potent combination in t(8;21) containing cells. Thus, BET inhibitors that affect MYC and BCL2 expression should be considered for combination therapy with venetoclax.
MicroRNA‐382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells
Authors: Dahlmans Dennis , Houzelle Alexandre , Andreux Pénélope , Wang Xu , Jörgensen Johanna A. , Moullan Norman , Daemen Sabine , Kersten Sander , Auwerx Johan , Hoeks Joris
Published: November 2018

Proper mitochondrial function plays a central role in cellular metabolism. Various diseases as well as aging are associated with diminished mitochondrial function. Previously, we identified 19 miRNAs putatively involved in the regulation of mitochondrial metabolism in skeletal muscle, a highly metabolically active tissue. In the current study, these 19 miRNAs were individually silenced in C2C12 myotubes using antisense oligonucleotides, followed by measurement of the expression of 27 genes known to play a major role in regulating mitochondrial metabolism. Based on the outcomes, we then focused on miR‐382‐5p and identified pathways affected by its silencing using microarrays, investigated protein expression, and studied cellular respiration. Silencing of miRNA‐382‐5p significantly increased the expression of several genes involved in mitochondrial dynamics and biogenesis. Conventional microarray analysis in C2C12 myotubes silenced for miRNA‐382‐5p revealed a collective downregulation of mitochondrial ribosomal proteins and respiratory chain proteins. This effect was accompanied by an imbalance between mitochondrial proteins encoded by the nuclear and mitochondrial DNA (1.35‐fold, p < 0.01) and an induction of HSP60 protein (1.31‐fold,
p < 0.05), indicating activation of the mitochondrial unfolded protein response (mtUPR). Furthermore, silencing of miR‐382‐5p reduced basal oxygen consumption rate by 14% (
p < 0.05) without affecting mitochondrial content, pointing towards a more efficient mitochondrial function as a result of improved mitochondrial quality control. Taken together, silencing of miR‐382‐5p induces a mitonuclear protein imbalance and activates the mtUPR in skeletal muscle, a phenomenon that was previously associated with improved longevity.
Inflammation and pericarditis: Are neutrophils actors behind the scenes?
Authors: Bonaventura Aldo , Montecucco Fabrizio
Published: November 2018

The morbidity of acute pericarditis is increasing over time impacting on patient quality of life. Recent clinical trials focused especially on clinical aspects, with a modest interest in pathophysiological mechanisms. This narrative review, based on papers in English language obtained via PubMed up to April 2018, aims at focusing on the role of the innate immunity in pericarditis and discussing future potential therapeutic strategies impacting on disease pathophysiology.

In developed countries, most cases of pericarditis are referred to as idiopathic, although etiological causes have been described, with autoreactive/lymphocytic, malignant, and infectious ones as the most frequent causes. Apart the known impairment of the adaptive immunity, recently a large body evidence indicated the central role of the innate immune system in the pathogenesis of recurrent pericarditis, starting from similarities with autoinflammatory diseases. Accordingly, the “inflammasome” has been shown to behave as an important player in pericarditis development. Similarly, the beneficial effect of colchicine in recurrent pericarditis confirms that neutrophils are important effectors as colchicine, which can block neutrophil chemotaxis, interferes with neutrophil adhesion and recruitment to injured tissues and abrogate superoxide production. Anyway, the role of the adaptive immune system in pericarditis cannot be reduced to a black or white issue as mechanisms often overlap. Therefore, we believe that more efficient therapeutic strategies have to be investigated by targeting neutrophil‐derived mediators (such as metalloproteinases) and disentangling the strict interplay between neutrophils and platelets. In this view, some progress has been done by using the recombinant human interleukin‐1 receptor antagonist anakinra.
Inhibition of PI3K/Akt/NF‐κB signaling with leonurine for ameliorating the progression of osteoarthritis: In vitro and in vivo studies
Authors: Hu Zhi‐Chao , Gong Lan‐Fang , Li Xiao‐Bin , Fu Xin , Xuan Jiang‐Wei , Feng Zhen‐Hua , Ni Wen‐Fei
Published: November 2018

Osteoarthritis (OA) is characterized as the degeneration and destruction of articular cartilage. In recent decades, leonurine (LN), the main active component in medical and edible dual purpose plant Herba Leonuri, has been shown associated with potent anti‐inflammatory effects in several diseases. In the current study, we examined the protective effects of LN in the inhibition of OA development as well as its underlying mechanism both in vitro and in vivo experiments. In vitro, interleukin‐1 beta (IL‐1β) induced over‐production of prostaglandin E2, nitric oxide, inducible nitric oxide synthase, cyclooxygenase‐2, interleukin‐6 and tumor necrosis factor alpha were all inhibited significantly by the pretreatment of LN at a dose‐dependent manner (5, 10, and 20 µM). Moreover, the expression of thrombospondin motifs 5 (ADAMTS5) and metalloproteinase 13 (MMP13) was downregulated by LN. All these changes led to the IL‐1β induced degradation of extracellular matrix. Mechanistically, the LN suppressed IL‐1β induced activation of the PI3K/Akt/NF‐κB signaling pathway cascades. Meanwhile, it was also demonstrated in our molecular docking studies that LN had strong binding abilities to PI3K. In addition, LN was observed exerting protective effects in a surgical induced model of OA. To sum up, this study indicated LN could be applied as a promising therapeutic agent in the treatment of OA.
Between an ugly truth and a perfect lie: Wiping off fearful memories using beta‐adrenergic receptors antagonists
Authors: AlOkda Abdelrahman M. , Nasr Mostafa M. , Amin Shaimaa N.
Published: November 2018

Psychiatric disorders such as anxiety, phobias, and post‐traumatic stress disorder are considered of high global prevalence. Currently, a therapeutic approach to treat these disorders using beta‐blockers, which antagonize the beta‐adrenergic receptors (B1, B2, and B3) is being studied. This approach claims that beta‐blockers, such as propranolol, inhibit fear memory reconsolidation. However, there are several studies refuting such claims by discrediting their experimental design and pointing out both the drugs pharmacokinetic properties and confounding factors. In this review, we explore the different effects of central beta‐adrenergic agonists and antagonists on the fear memory consolidation providing mixed‐evidence, limitations, and future directions.
Activation of Pyk2 by CaM kinase II in cultured hypothalamic neurons and gonadotroph cells
Authors: Okitsu‐Sakurayama Shiho , Higa‐Nakamine Sayomi , Torihara Hidetsugu , Takahashi Hana , Higashiyama Shigeki , Yamamoto Hideyuki
Published: November 2018

Gonadotropin‐releasing hormone (GnRH) is secreted from hypothalamic GnRH neurons and stimulates a GnRH receptor in gonadotroph cells and GnRH neurons. The GnRH receptor belongs to the G‐protein‐coupled receptors, and stimulation of the GnRH receptor activates extracellular signal‐regulated protein kinase (ERK). We reported previously that the δ2 isoform of Ca2+/calmodulin‐dependent protein kinase II (CaM kinase IIδ2) was involved in GnRH‐induced ERK activation in cultured GnRH neurons (GT1–7 cells). Recently, we found that GnRH treatment of GT1–7 cells activated proline‐rich tyrosine kinase 2 (Pyk2), and Pyk2 was involved in ERK activation. In the current study, we examined the possibility that CaM kinase IIδ2 might activate Pyk2. Knockdown of CaM kinase IIδ2 and KN93, an inhibitor of CaM kinases, inhibited the GnRH‐induced activation of Pyk2. In the case of cultured gonadotroph cells (αT3‐1 cells), knockdown of CaM kinase IIβ’e inhibited GnRH‐induced Pyk2 activation. In addition, our inhibitor studies indicated that Pyk2 and CaM kinase II were involved in the GnRH‐induced shedding of proHB‐EGF in GT1–7 cells. These results suggested that CaM kinase II activated the ERK pathway through Pyk2 activation and HB‐EGF production in response to GnRH.
Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR‐181b/SIRT1/HO‐1 signaling
Authors: Hou Xuhui , Yang Songbai , Zheng Yan
Published: November 2018

Licochalcone A (LA), a chalcone derived from liquorice, exhibits multiple biological activities, including anti‐oxidation and anti‐inflammation. This study aimed to investigate the role and underlying mechanism of LA in the abdominal aortic aneurysm (AAA). AAA model was established by continuous infusion of 1000 ng/kg/min of angiotensin II (AngII) in ApoE
‐/‐ mice for 4 weeks. At 7 days before AngII administration, 5 mg/kg/day or 10 mg/kg/day of LA was intraperitoneally administered to mice and continued for 4 weeks. The characteristics and quantification of AAAs were determined in situ. Real‐time PCR or western blot was used to measure mRNA or protein levels of matrix metalloproteinase 2 and matrix metalloproteinase 9; pro‐inflammatory cytokines tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6; apoptosis‐related proteins Bax, Bcl‐2, and active caspase‐3; miR‐181b; Sirtuin 1 (SIRT1); and heme oxygenase‐1 (HO‐1). Mouse‐aorta‐origin vascular smooth muscle (MOVAS) cells were used to confirm the involved pathways in vitro. We found LA administration dose‐dependently reduced the incidence of AngII‐induced AAA, aneurysm diameter enlargement, elastin degradation, matrix metalloproteinase production, pro‐inflammatory cytokines and miR‐181b expression, and vascular smooth muscle cell apoptosis. It elevated SIRT1 and HO‐1 expression that was suppressed by AngII. AngII enhanced miR‐181b but reduced SIRT1 and HO‐1 expression in MOVAS cells. In AngII‐stimulated MOVAS cells, downregulation of miR‐181b significantly upregulated the expression of SIRT1 and HO‐1, the effect of which was abrogated by SIRT1 siRNA. Collectively, LA could attenuate AngII‐induced AAA by modulating the miR‐181b/SIRT1/HO‐1 signaling. LA might be a potential medical therapy for small AAA.