bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesopredators change temporal activity in response to a recolonizing apex predator
Authors: Shores Carolyn R , Dellinger Justin A , Newkirk Eric S , Kachel Shannon M , Wirsing Aaron J
Published: May 2019

Apex predators can influence ecosystems through density and behaviorally mediated effects on herbivores and mesopredators. In many parts of the world, apex predators live in, or are returning to, landscapes that have been modified by people; so, it is important to understand their ecological role in anthropogenic landscapes. We used motion-activated game cameras to compare the activity patterns of humans and 2 mesopredators, coyotes (Canis latrans) and bobcats (Lynx rufus), in areas with and without an apex predator, the gray wolf (Canis lupus), in a multiuse landscape of the northwestern United States. In areas with wolves, there was a significant increase in temporal niche overlap between the mesopredators owing to higher levels of coyote activity at all time periods of the day. Temporal overlap between mesopredators and humans also increased significantly in the presence of wolves. Coyotes exposed to wolves increased their activity during dawn, day, and dusk hours. The increase in coyote activity was greatest during the day, when wolves were least active. The direction of change in bobcat activity in areas with wolves was opposite to coyotes, suggesting a behaviorally mediated cascade between wolves, coyotes, and bobcats, although these findings would need to be confirmed with further research. Our findings suggest that mesopredators in human-dominated systems may perceive humans as less dangerous than apex predators, that humans may be more likely to encounter mesopredators in areas occupied by top predators, and that behaviorally mediated effects of apex predators on mesopredators persist in human-dominated landscapes.
Sperm-borne glutathione-S-transferase omega 2 accelerates the nuclear decondensation of spermatozoa during fertilization in mice†
Authors: Hamilton Lauren E , Suzuki Joao , Aguila Luis , Meinsohn Marie-Charlotte , Smith Olivia E , Protopapas Nicole , Xu Wei , Sutovsky Peter , Oko Richard
Published: May 2019

The postacrosomal sheath (PAS) of the perinuclear theca (PT) is the first compartment of the sperm head to solubilize into the ooplasm upon sperm-oocyte fusion, implicating its constituents in zygotic development. This study investigates the role of one such constituent, glutathione-S-transferase omega 2 (GSTO2), an oxidative-reductive enzyme found in the PAS and perforatorial regions of the PT. GSTO2 uses the conjugation of reduced glutathione, an electron donor shown to be compulsory in sperm disassembly within the ooplasm. The proximity of GSTO2 to the condensed sperm nucleus led us to hypothesize that this enzyme may facilitate nuclear decondensation by reducing disulfide bonds before the recruitment of GSTO enzymes from within the ooplasm. To test this hypothesis, we utilized a cell permeable isozyme-specific inhibitor, which fluoresces when bound to the active site of GSTO2, to functionally inhibit spermatozoa before performing intracytoplasmic sperm injections (ICSI) in mice. The technique allowed for targeted inhibition of solely PT-residing GSTO2, as all that is required for complete zygotic development is the injection of the mouse spermatozoon head. ICSI showed that inhibition of PT-anchored GSTO2 caused a delay in sperm nuclear decondensation, and further resulted in untimely embryo cleavage, and an increase in fragmentation beginning at the morula stage. The confounding effects of these developmental delays ultimately resulted in decreased blastocyst formation. This study implicates PT-anchored GSTO2 as an important facilitator of nuclear decondensation and reinforces the notion that the PAS-PT is a critical sperm compartment harboring molecules that facilitate zygotic development.
Drowning In Neoliberal Lies: State Responses Towards People Seeking Asylum
Authors: Green Belinda A
Published: May 2019

This article argues that further enhancement of critical social work education and practice is needed to counter politicised and restrictive policies towards people seeking asylum in advanced globalised market economies. This means social workers giving more emphasis and prominence to the role of neoliberalism rather than solely focusing on the adverse moral and mental health impacts of state responses. Drawing on current debates and practices within critical social work and seven years’ experience in the Australian refugee sector, this article will demonstrate the punitive and deterrent configurations adopted by states like Australia to respond to people seeking asylum. The article then highlights the importance of social workers critically analysing historicised discourses which normalise such people as ‘dangerous’, ‘illegitimate’, ‘othered’ and a ‘burden’. Further interrogation of the social and cultural logic(s) of neoliberalism which serve to justify the former discourses will also be included. Finally, reflections on a range of strategies and solutions will be presented for critical social work educators and practitioners to resist and subvert neoliberalism and to secure better outcomes for people seeking asylum in Australia and elsewhere.
On Equivalence of Cascade Connections of Two Nonlinear Feedback Shift Registers
Authors: Zhong Jianghua , Lin Dongdai
Published: May 2019

Grain is a hardware-oriented finalist in the eSTREAM Stream Cipher Project. As a particular Galois nonlinear feedback shift register (NFSR), cascade connection of two NFSRs has been used as the main building block in the Grain family of stream ciphers. Two NFSRs are said to be equivalent if their sets of output sequences are equal. Finding properties of equivalent cascade connections of two NFSRs is useful to the design of the Grain family of stream ciphers. This paper first gives some properties of feedback functions between equivalent cascade connections of two NFSRs. It then shows that a cascade connection of two NFSRs and its equivalent Galois NFSR have isomorphic state diagrams if they have the same stage number. Finally, the paper reveals that for any given cascade connection of an $m$-stage NFSR1 into an $n$-stage NFSR2, there is only another one equivalent cascade connection of an $m$-stage NFSR3 into an $n$-stage NFSR4; moreover, the feedback functions of NFSR1 and NFSR3 are dual complementary, and the feedback functions of NFSR2 and NFSR4 are complementary. As an application of this property, the paper shows that the existing Grain family of stream ciphers have used the ones with lower cost of hardware implementations between their own two equivalent cascade connections, confirming their good design criteria.
On Computing Component (Edge) Connectivities of Balanced Hypercubes
Authors: Gu Mei-Mei , Chang Jou-Ming , Hao Rong-Xia
Published: May 2019

For an integer $\ell \geqslant 2$, the $\ell $-component connectivity (resp. $\ell $-component edge connectivity) of a graph $G$, denoted by $\kappa _{\ell }(G)$ (resp. $\lambda _{\ell }(G)$), is the minimum number of vertices (resp. edges) whose removal from $G$ results in a disconnected graph with at least $\ell $ components. The two parameters naturally generalize the classical connectivity and edge connectivity of graphs defined in term of the minimum vertex-cut and the minimum edge-cut, respectively. The two kinds of connectivities can help us to measure the robustness of the graph corresponding to a network. In this paper, by exploring algebraic and combinatorial properties of $n$-dimensional balanced hypercubes $BH_n$, we obtain the $\ell $-component (edge) connectivity $\kappa _{\ell }(BH_n)$ ($\lambda _{\ell }(BH_n)$). For $\ell $-component connectivity, we prove that $\kappa _2(BH_n)=\kappa _3(BH_n)=2n$ for $n\geq 2$, $\kappa _4(BH_n)=\kappa _5(BH_n)=4n-2$ for $n\geq 4$, $\kappa _6(BH_n)=\kappa _7(BH_n)=6n-6$ for $n\geq 5$. For $\ell $-component edge connectivity, we prove that $\lambda _3(BH_n)=4n-1$, $\lambda _4(BH_n)=6n-2$ for $n\geq 2$ and $\lambda _5(BH_n)=8n-4$ for $n\geq 3$. Moreover, we also prove $\lambda _\ell (BH_n)\leq 2n(\ell -1)-2\ell +6$ for $4\leq \ell \leq 2n+3$ and the upper bound of $\lambda _\ell (BH_n)$ we obtained is tight for $\ell =4,5$.
Drones over Pompeii: cinematic perspectives on antiquity in the digital era
Authors: Paul Joanna
Published: May 2019

Cityscapes have always been an important part of films set in antiquity, but little attention has yet been paid to the way in which digital cinema uses the ancient city to offer different kinds of access to the past. This article explores how twenty-first century cinema sees the city and apprehends history in new ways in films including Pompeii (2014), Agora (2009), and Gladiator (2000). It focuses on how digital cinema affords the opportunity to ‘see’ the past from above, a quintessentially modern perspective which prompts a range of important questions about the viewer’s relationship to history. The aerial view of the cinematic city encourages reflection on our familiarity with an ancient city, by utilizing the imagery and techniques of digital mapping and virtual reality reconstructions; and it explores our ability to gain mastery over the past, privileging godlike omniscience over the immersiveness that usually characterizes contemporary film. Finally, adopting the perspective of the drone, it suggests a more disturbing, dehumanized version of the past – and future. The discourse around these cinematic cities prompts important and timely consideration of whether digital technology necessarily improves our access to the past, or rather compromises it.
Thromboembolism after electrical isolation of the left atrial appendage: a new indication for interventional closure?
Authors: Zender Niklas , Weise Felix K , Bordignon Stefano , Herrmann Eva , Konstantinou Athanasios , Bologna Fabrizio , Nagase Takahiko , Chen Shaojie , Chun Kyoung Ryul Julian , Schmidt Boris
Published: May 2019

Aims

Left atrial appendage electrical isolation (LAAI) may improve the rhythm outcome in selected patients with atrial fibrillation (AF). Controversy exists if LAAI is associated with an increased rate of thromboembolic complications. We sought to assess the feasibility, efficacy, and safety of interventional left atrial appendage closure (LAAC) in comparison to oral anticoagulation (OAC) after electrical LAAI.

Methods and results

Weeks after index LAAI using the cryoballoon or a linear maze like ablation strategy patients’ left atrial appendage was invasively remapped. In case of persistent LAAI, LAAC was performed. Patients who refused invasive remapping continued OAC. The primary endpoint was composed of any stroke or systemic embolism (SE) and the occurrence of intracardiac thrombus. Secondary endpoints included stroke/SE, major bleeding, and all-cause death. Of 166 patients (51% female; mean age 70 ± 8 years; mean CHAD2S2VASc score 3.4 ± 1.8) after LAAI, 94 patients received LAAC (LAAC group) and 72 continued OAC (no LAAC). After LAAC, 83% of patients received dual antiplatelet therapy for 6 weeks and aspirin thereafter. During a mean follow-up of 778 ± 630 days, 5 and 11 primary endpoint events were observed in the LAAC and no LAAC group, respectively [hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.10–0.75; P = 0.010]. The calculated annual thromboembolic event rates were 6.9% (no LAAC) and 2.3% (LAAC), respectively. Left atrial appendage closure significantly reduced the incidence of stroke and SE (HR 0.31, CI 0.1–0.98; P = 0.04).

Conclusion

After electrical LAAI for rhythm control in AF patients, interventional LAAC was associated with fewer thromboembolic complications when compared with OAC.
Avoidance Behavior Is an Independent Indicator of Poorer On-road Driving Skills in Older Adults
Authors: Schulz Philipp , Beblo Thomas , Spannhorst Stefan , Labudda Kirsten , Wagner Thomas , Bertke Volkmar , Boedeker Sebastian , Driessen Martin , Kreisel Stefan H , Toepper Max
Published: May 2019

Objectives

The aim of the current work was to investigate the relationship between avoidance of specific driving situations and on-road driving skills in older drivers considering factors found to be related to both avoidance behavior and driving skills.

Method

Seventy-two older drivers (M = 76 years) from the general population were included in this study. Self-reported avoidance behavior, driving practice, perceived driving difficulties, driving-related cognitive functions, as well as medical conditions were assessed within two sessions. Standardized on-road assessments served for assessing on-road driving skills in a third session.

Results

Self-reported avoidance behavior was associated with reduced driving skills (r = −.41), and this relationship remained significant beyond the influence of cognitive skills, self-reported health, driving practice, and perceived driving difficulties. Specifically, avoidance of driving in bad weather, poor visibility and complicated parking was found to be associated with reduced driving skills.

Discussion

This study suggest that avoidance behavior is an independent indicator of impaired driving skills in older drivers. Our results argue against the assumption that avoidance behavior may be a reasonable strategy for safe traffic participation. Longitudinal studies are urgently needed to get more evidence on safety aspects of avoidance behavior.
Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation
Authors: Rhodes Steven D , He Yongzheng , Smith Abbi , Jiang Li , Lu Qingbo , Mund Julie , Li Xiaohong , Bessler Waylan , Qian Shaomin , Dyer William , Sandusky George E , Horvai Andrew E , Armstrong Amy E , Clapp D Wade
Published: May 2019

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1−/− SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
Mouse model of severe recessive RYR1-related myopathy
Authors: Brennan Stephanie , Garcia-Castañeda Maricela , Michelucci Antonio , Sabha Nesrin , Malik Sundeep , Groom Linda , Wei LaPierre Lan , Dowling James J , Dirksen Robert T
Published: May 2019

Ryanodine receptor type I (RYR1)-related myopathies (RYR1 RM) are a clinically and histopathologically heterogeneous group of conditions that represent the most common subtype of childhood onset non-dystrophic muscle disorders. There are no treatments for this severe group of diseases. A major barrier to therapy development is the lack of an animal model that mirrors the clinical severity of pediatric cases of the disease. To address this, we used CRISPR/Cas9 gene editing to generate a novel recessive mouse model of RYR1 RM. This mouse (Ryr1TM/Indel) possesses a patient-relevant point mutation (T4706M) engineered into 1 allele and a 16 base pair frameshift deletion engineered into the second allele. Ryr1TM/Indel mice exhibit an overt phenotype beginning at 14 days of age that consists of reduced body/muscle mass and myofibre hypotrophy. Ryr1TM/Indel mice become progressively inactive from that point onward and die at a median age of 42 days. Histopathological assessment shows myofibre hypotrophy, increased central nuclei and decreased triad number but no clear evidence of metabolic cores. Biochemical analysis reveals a marked decrease in RYR1 protein levels (20% of normal) as compared to only a 50% decrease in transcript. Functional studies at end stage show significantly reduced electrically evoked Ca2+ release and force production. In summary, Ryr1TM/Indel mice exhibit a post-natal lethal recessive form of RYR1 RM that pheno-copies the severe congenital clinical presentation seen in a subgroup of RYR1 RM children. Thus, Ryr1TM/Indel mice represent a powerful model for both establishing the pathomechanisms of recessive RYR1 RM and pre-clinical testing of therapies for efficacy.
Health Care Indicators of Moderate to Severe IBD and Subsequent IBD-Related Disability: A Longitudinal Study
Authors: Shafer Leigh Anne , Walker John R , Chhibba Tarun , Targownik Laura E , Singh Harminder , Ivekovic Melony , Bernstein Charles N
Published: May 2019

Using administrative health data of a population based sample of persons with IBD we found that milestones of health care utilization suggesting moderate to severe disease (higher number of IBD-related hospitalizations, IBD-related surgeries, and corticosteroid or anti-TNF usage) predicted later development of IBD-related disability.
The Tilting–Cotilting Correspondence
Authors: Positselski Leonid , Šťovíček Jan
Published: May 2019

To a big $n$-tilting object in a complete, cocomplete abelian category ${\textsf{A}}$ with an injective cogenerator we assign a big $n$-cotilting object in a complete, cocomplete abelian category ${\textsf{B}}$ with a projective generator and vice versa. Then we construct an equivalence between the (conventional or absolute) derived categories of ${\textsf{A}}$ and ${\textsf{B}}$. Under various assumptions on ${\textsf{A}}$, which cover a wide range of examples (for instance, if ${\textsf{A}}$ is a module category or, more generally, a locally finitely presentable Grothendieck abelian category), we show that ${\textsf{B}}$ is the abelian category of contramodules over a topological ring and that the derived equivalences are realized by a contramodule-valued variant of the usual derived Hom functor.
Impact of window views on recovery—an example of post-cesarean section women
Authors: Wang Chia-Hui , Kuo Nai-Wen , Anthony Kathryn
Published: May 2019

Objective

The objective of this study was to examine the impact of urban landscape from window views on quality of care for women who underwent Cesarean Section (C-section) in Taiwan.

Design

The participants were randomly assigned into 46 different hospital rooms to see the effects of various window views and daylight exposure on women’s recovery from post C-section care.

Setting

We carried out this study in the obstetrics departments of three tertiary hospitals located in two major cities of Taiwan: Taipei City and New Taipei City.

Participants

A total of 296 women who underwent C-sections and used patient-controlled analgesic (PCA) for pain control after their surgery during the 10-month data collection period were recruited for this study.

Intervention

The 46 different patient rooms provided diverse window views and different daylight exposure for the participants.

Main Outcome Measures

Recovery for the women who underwent C-sections in this study was defined as PCA usage and perceived pain measured by Brief Pain Inventory (BFI).

Results

Higher satisfaction of window view significantly decreased analgesic usage (P = 0.057), reduced the scores of overall perceived pain (P = 0.046), pain severity (P = 0.004), and ‘pain’s interference with relations with others, enjoyment of life, and mood (REM).’ (P = 0.095).

Conclusions

To maximize benefit and well-being of patients recovering from surgery, health care architects should design patient rooms to create maximum satisfaction with visual impacts and optimize window views. By doing so, it may decrease the use of pain medication and substantially reduce healthcare costs.
Fatwa, Discursivity, and the Art of Ethical Embedding
Authors: Awass Omer
Published: May 2019

This paper theorizes the role of iftāʾ, the process of producing fatwas (Islamic legal opinions), on the formation of Muslim societies. I argue in this paper that iftāʾ is an ethical embedding mechanism that historically carried out this function through a set of discursive and nondiscursive relations. “Ethical embedding” signifies the situating of the various spheres of the social world into an ethical domain. As for iftāʾs discursive relations, the historical manifestations of its procedures and the production of fatwas represented a discursive formation because they manifested a particular regularity in their discursive operations. As for their nondiscursive relations, fatwas position actions and practices within the Islamic moral field through a definite social process. Finally, these operations generate a social field of power that structures the relations between the individuals and institutions of iftāʾ and induces personal dispositions that facilitate the practice of the norms embedded in the fatwa.
Genome-wide association study and genomic predictions for exterior traits in Yorkshire pigs1
Authors: Lee Jungjae , Lee SeokHyun , Park Jong-Eun , Moon Sung-Ho , Choi Sung-Woon , Go Gwang-Woong , Lim Dajeong , Kim Jun-Mo
Published: May 2019

The objectives of this study were to identify informative genomic regions that affect the exterior traits of purebred Korean Yorkshire pigs and to investigate and compare the accuracy of genomic prediction for response variables. Phenotypic data on body height (BH), body length (BL), and total teat number (TTN) from 2,432 Yorkshire pigs were used to obtain breeding values including as response variable the estimated breeding value (EBV) and 2 types of deregressed EBVs—one including the parent average (DEBVincPA) and the other excluding it (DEBVexcPA). A final genotype panel comprising 46,199 SNP markers was retained for analysis after quality control for common SNPs. The BayesB and BayesC methods—with various π and weighted response variables (EBV, DEBVincPA, or DEBVexcPA)—were used to estimate SNP effects, through the genome-wide association study. The significance of genomic windows (1 Mb) was obtained at 1.0% additive genetic variance and was subsequently used to identify informative genomic regions. Furthermore, SNPs with a high model frequency (≥0.90) were considered informative. The accuracy of genomic prediction was estimated using a 5-fold cross-validation with the K-means clustering method. Genomic accuracy was measured as the genomic correlation between the molecular breeding value and the individual weighted response variables (EBV, DEBVincPA, or DEBVexcPA). The number of identified informative windows (1 Mb) for BH, BL, and TTN was 4, 3, and 4, respectively. The number of significant SNPs for BH, BL, and TTN was 6, 4, and 5, respectively. Diversity π did not influence the accuracy of genomic prediction. The BayesB method showed slightly higher genomic accuracy for exterior traits than BayesC method in this study. In addition, the genomic accuracy using DEBVincPA as response variable was higher than that using other response variables. Therefore, the genomic accuracy using BayesB (π = 0.90) with DEBVinPA as a response variable was the most effective in this study. The genomic accuracy values for BH, BL, and TTN were calculated to be 0.52, 0.60, and 0.51, respectively.
Slovak Telekom/Deutsche Telekom AG: The Interplay Between EU Competition Law and Sector Specific Rules in the Electronic Communications Sector
Authors: Liberatore Francesco , Tsochas Kety , Buckwell Matthew
Published: May 2019

Case T-827/14, Deutsche Telekom AG v Commission, and Case T-851/14 Slovak Telekom a.s. v Commission, Judgments of 13 December 2018.

Granting access to a product or service, which is required under sector specific regulation, on unfair, unreasonably complicated or delayed terms amounts to constructive refusal to supply, without the need to demonstrate that the regulated access product or service is an indispensable input. In addition, a margin squeeze test, to assess whether the difference between wholesale and retail prices is negative, should be carried out on a year-by-year basis, and not on a multi-period basis. Finally, when a parent is jointly and severally liable for anti-competitive conduct of its subsidiary, the liability of the parent can exceed that of the subsidiary only if it reflects the parent’s individual conduct in the infringement at issue.
The Governance of Global Banking in the Face of Complexity
Authors: Ortino Matteo
Published: May 2019

The Basel Committee on Banking Supervision and the composite wider legal and institutional environment to which it is part provide a useful case study to illustrate how complexity is addressed in the public policy realm. As its central proposition, this article argues that it is possible to identify a specific pattern and logic underlying the governance of global banking today. The pattern concerns the institutional dimension of global banking regulation, particularly with respect to the distribution of regulatory powers among the various actors involved, and the legal relationships between these actors. The overall pattern seems to follow a certain logic, which will be explored and explained borrowing the military distinction between strategy, operations, and tactics.
Public Administrative Law in a Globalized Concept: Legal Nature of the Collaboration of the EU and the Basel Committee
Authors: Csatlós Erzsébet
Published: May 2019

Multilevel governance describes a global system that enrolls some State functions to perform global solutions for global problems. Multilevel-governance and multilevel administration has legality and accountability concerns on their own, although, there are multilevel structures with non-State playground of trans-regulatory nature at the supranational level of cooperation which means additional shades to the colourful palette. The procedure and the structure concerning the creation and the evaluation of effective banking supervision standards in Europe is unique. Given the fact that the European administrative system is also unique, and as Basel rules are produced in a trans-regulatory network, the collaboration of the two sui generis systems requires the rethinking of the classical legal order features. Rule of law which is the basis of classical international relations in the view of public administration of States is challenged by the newly emerged solutions. Necessity and proportionality are put on a scale with classical values and requirements of public administration and efficiency and effectiveness seem to put it on the side of the new type of collaboration. The normative background of such structure is still immature. The multilevel administrative system of financial supervision including the European Union and the Basel Committee for Banking Supervision at supranational level or speaking in a wider context: the framework for multilevel governance with non-state actors at supranational level, is therefore an example for global administrative law of infant status.
Casein kinase 2 regulates telomere protein complex formation through Rap1 phosphorylation
Authors: Inoue Haruna , Horiguchi Mayuri , Ono Kota , Kanoh Junko
Published: May 2019

Telomeres located at the ends of linear chromosomes play important roles in the maintenance of life. Rap1, a component of the shelterin telomere protein complex, interacts with multiple proteins to perform various functions; further, formation of shelterin requires Rap1 binding to other components such as Taz1 and Poz1, and telomere tethering to the nuclear envelope (NE) involves interactions between Rap1 and Bqt4, a nuclear membrane protein. Although Rap1 is a hub for telomere protein complexes, the regulatory mechanisms of its interactions with partner proteins are not fully understood. Here, we show that Rap1 is phosphorylated by casein kinase 2 (CK2) at multiple sites, which promotes interactions with Bqt4 and Poz1. Among the multiple CK2-mediated phosphorylation sites of Rap1, phosphorylation at Ser496 was found to be crucial for both Rap1–Bqt4 and Rap1–Poz1 interactions. These mechanisms mediate proper telomere tethering to the NE and the formation of the silenced chromatin structure at chromosome ends.
Acute depletion of CTCF directly affects MYC regulation through loss of enhancer–promoter looping
Authors: Hyle Judith , Zhang Yang , Wright Shaela , Xu Beisi , Shao Ying , Easton John , Tian Liqing , Feng Ruopeng , Xu Peng , Li Chunliang
Published: May 2019

Numerous pieces of evidence support the complex, 3D spatial organization of the genome dictates gene expression. CTCF is essential to define topologically associated domain boundaries and to facilitate the formation of insulated chromatin loop structures. To understand CTCF’s direct role in global transcriptional regulation, we integrated the miniAID-mClover3 cassette to the endogenous CTCF locus in a human pediatric B-ALL cell line, SEM, and an immortal erythroid precursor cell line, HUDEP-2, to allow for acute depletion of CTCF protein by the auxin-inducible degron system. In SEM cells, CTCF loss notably disrupted intra-TAD loops and TAD integrity in concurrence with a reduction in CTCF-binding affinity, while showing no perturbation to nuclear compartment integrity. Strikingly, the overall effect of CTCF’s loss on transcription was minimal. Whole transcriptome analysis showed hundreds of genes differentially expressed in CTCF-depleted cells, among which MYC and a number of MYC target genes were specifically downregulated. Mechanically, acute depletion of CTCF disrupted the direct interaction between the MYC promoter and its distal enhancer cluster residing ∼1.8 Mb downstream. Notably, MYC expression was not profoundly affected upon CTCF loss in HUDEP-2 cells suggesting that CTCF could play a B-ALL cell line specific role in maintaining MYC expression.
Modulation of endothelial cell responses and vascular function by dietary fatty acids
Authors: Du Youjia , Taylor Carla G , Zahradka Peter
Published: May 2019

Healthy and functional endothelial cells play important roles in maintaining vascular homeostasis, whereas endothelial dysfunction initiates and exacerbates vascular disease progression. Interventional studies with dietary fatty acids have shown that these molecules have varying effects on vascular function. It is hypothesized that the actions of dietary fatty acids on vascular function may be mediated in part through endothelial cells. This review summarizes the results of studies that have examined the acute and chronic effects of dietary fatty acids on endothelial function and vascular properties in humans, as well as the potential mechanisms by which n-3 polyunsaturated fatty acids regulate endothelial function. Altogether, this article provides an extensive review of how fatty acids contribute to vascular function through their ability to modulate endothelial cells and discusses relationships between dietary fatty acids and endothelial cells in the context of vascular dysfunction.
Potential health benefits of (poly)phenols derived from fruit and 100% fruit juice
Authors: Ho Kacie K H Y , Ferruzzi Mario G , Wightman JoLynne D
Published: May 2019

(Poly)phenol-rich diets have been associated with reduced risk of various diseases. Coffee and tea are typically identified as dietary sources of chlorogenic acid and flavan-3-ols; however, 100% fruit juice greatly contributes to anthocyanin, flavonol, flavan-3-ols, and flavanone intake, making them complementary sources of dietary (poly)phenols. Thus, the aim of this narrative review was to provide an overview of fruit (poly)phenols and their potential health benefits. Fruit (poly)phenols have been associated with several health benefits (eg, reduced risk of cardiovascular disease and neurocognitive benefits). Although perspectives on 100% fruit juice consumption are controversial due to the perception of sugar content, growing evidence supports the role of fruit in whole and 100% juice forms to provide consumer benefits in alignment with dietary guidance. However, differences in (poly)phenol profiles and bioavailability likely exist between whole fruit and 100% fruit juice due to processing and the presence/absence of fiber. Ongoing studies are better defining similarities and differences between whole fruit and 100% fruit juice to elucidate protective mechanisms and align with processing and consumer products.
Diagnostic Delays and Treatment Implications for Patients with Isoniazid-Resistant Tuberculosis: A Case Report and Review of the Literature
Authors: Olson Gregory , Nathavitharana Ruvandhi R , Lederer Philip A
Published: May 2019

Drug-resistant tuberculosis (DR-TB) remains a major public health threat. A 23-year-old man presented with fever, dyspnea, and a pleural effusion. After a delay, he was diagnosed with isoniazid (INH)-resistant TB. We review the literature describing the epidemiological and clinical significance of INH-resistant TB and its relevance for low-incidence countries, such as the United States.
Mechanisms of Action by Which Local Anesthetics Reduce Cancer Recurrence: A Systematic Review
Authors: Grandhi Ravi K , Perona Barbara
Published: May 2019

Background

Surgery in concert with anesthesia is a key part of the management of advanced-stage cancers. Anesthetic agents such as opioids and volatile anesthetics have been shown to promote recurrence in preclinical models, whereas some animal models have shown that the use of lidocaine may be beneficial in reducing cancer recurrence. The purpose of this article is to review the current literature to highlight the mechanisms of action by which local anesthetics are thought to reduce cancer recurrence.

Methods

A systematic review was conducted using the PubMed (1966 to 2018) electronic database. Search terms included “lidocaine,” “ropivicaine,” “procaine,” “bupivicaine,” “mepivicaine,” “metastasis,” “cancer recurrence,” “angiogenesis,” and “local anesthetics” in various combinations. The search yielded 146 total abstracts for initial review, 20 of which met criteria for inclusion. Theories for lidocaine’s effect on cancer recurrence were recorded. All studies were reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.

Results

Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms include those that are centered on endothelial growth factor receptor, voltage-gated sodium and calcium channels, transient receptor melanoplastin 7, hyperthermia, cell cycle, and demyelination.

Conclusions

In vivo models suggest that local anesthetic administration leads to reduced cancer recurrence. The etiology of this effect is likely multifactorial through both inhibition of certain pathways and direct induction of apoptosis, a decrease in tumor migration, and an association with cell cycle–mediated and DNA-mediated effects. Additional research is required to further define the clinical implications.
Indwelling pleural catheters: an overview and real-life experience
Authors: Messeder S J , Thomson M C , Hu M K , Chetty M , Currie G P
Published: May 2019

Background

Indwelling pleural catheters (IPCs) are most frequently used in those with malignant pleural effusions, although their use is expanding to patients with non-malignant diseases.

Aim

To provide an overview of IPCs and highlight how, when and why they can be used including our own real-life experience.

Design

Data were collected retrospectively from a large tertiary centre for all individuals who received an IPC between June 2010 and February 2018 inclusive. The data collected included gender, age, origin of malignancy, number of drains prior to IPC, whether they had received pleurodesis prior to IPC, presence of a trapped lung, date of insertion, documented complications, overall outcome and date of death.

Results

A total of 68 patients received an IPC, the majority were female (n = 38, 57%) with an overall median age of 68 years (range 40–90 years). The most common site of cancer origin was lung (n = 33, 49%) followed by pleura (n = 10, 15%) and breast (n = 9, 13%). The median survival of all patients was 141 days (IQR 26–181). Sixteen percent (n = 11) of patients underwent a spontaneous pleurodesis resulting in their IPC being removed. Only three individuals had a complication (4.4%).

Conclusions

IPC insertion is a safe procedure and represents an exciting and expanding field in the management of pleural disease. Further longitudinal studies are required to fully delineate their place in the management of both malignant and benign effusions.
The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia
Authors: Richards Alexander L , Pardiñas Antonio F , Frizzati Aura , Tansey Katherine E , Lynham Amy J , Holmans Peter , Legge Sophie E , Savage Jeanne E , Agartz Ingrid , Andreassen Ole A , Blokland Gabriella A M , Corvin Aiden , Cosgrove Donna , Degenhardt Franziska , Djurovic Srdjan , Espeseth Thomas , Ferraro Laura , Gayer-Anderson Charlotte , Giegling Ina , van Haren Neeltje E , Hartmann Annette M , Hubert John J , Jönsson Erik G , Konte Bettina , Lennertz Leonhard , Olde Loohuis Loes M , Melle Ingrid , Morgan Craig , Morris Derek W , Murray Robin M , Nyman Håkan , Ophoff Roel A ,   GROUP Investigators, van Os Jim ,   EUGEI WP2 Group,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, Petryshen Tracey L , Quattrone Diego , Rietschel Marcella , Rujescu Dan , Rutten Bart P F , Streit Fabian , Strohmaier Jana , Sullivan Patrick F , Sundet Kjetil , Wagner Michael , Escott-Price Valentina , Owen Michael J , Donohoe Gary , O’Donovan Michael C , Walters James T R
Published: May 2019

Background

Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.

Methods

We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.

Results

PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.

Conclusions

Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.
Population Pharmacokinetic Analysis of Phenytoin After Intravenous Administration of Fosphenytoin in Adult and Elderly Epileptic Patients
Authors: Higuchi Kanae , Yamashita Daiki , Kashihara Yushi , Kakara Makoto , Hirota Takeshi , Hirakawa Masaaki , Ieiri Ichiro
Published: May 2019

Background:

Fosphenytoin, the diphosphate ester salt of phenytoin, is widely used to treat status epilepticus. The aim of this study was to develop a population pharmacokinetic (PPK) model to describe serum phenytoin concentrations after the intravenous administration of fosphenytoin in adult and elderly epileptic patients.

Methods:

Patient backgrounds, laboratory tests, and prescribed drugs were retrospectively collected from electronic medical records. Patients who received fosphenytoin were enrolled. The PPK analysis was performed using NONMEM 7.3.0 with the first-order conditional estimation method with interaction. Age, sex, laboratory tests, and coadministered drugs were selected as candidates for covariates. Significance levels for forward inclusion and backward elimination were set at 0.05 and 0.01, respectively. The study protocol was approved by the Fukuoka Tokushukai Ethics Committee.

Results:

A total of 340 serum phenytoin concentrations from 200 patients treated with fosphenytoin were available. The median age and body weight of the population were 71 years and 53.4 kg, respectively. A linear 1-compartment model with the conversion rate of fosphenytoin to phenytoin clearly described the pharmacokinetics of phenytoin after the intravenous administration of fosphenytoin. Age was detected as a covariate of clearance (CL): CL (L/h) = 1.99 × (body weight/53.4)0.75 × (age/71)−0.308. Goodness-of-fit plots revealed the high-predictive performance of the final PPK model, and systematic deviations were not observed. The final model was validated by a prediction-corrected visual predictive check and bootstrap analysis.

Conclusions:

We herein developed a PPK model to describe phenytoin concentrations after the intravenous administration of fosphenytoin. Age was identified as a significant covariate for CL.
CHANGES IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AND DISEASE ACTIVITY IN TYPE 3 NEOVASCULARIZATION AFTER ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT
Authors: Han Jae Wook , Cho Han Joo , Kang Dong Hyun , Jung Seoung Heon , Park Saemi , Kim Jong Woo
Published: May 2019

Purpose:

To investigate disease activity in patients with Type 3 neovascularization undergoing anti–vascular endothelial growth factor treatment through image analysis using optical coherence tomography angiography (OCTA).

Methods:

Thirty-nine treatment-naive eyes with Type 3 neovascularization were included in the retrospective analysis. All patients were treated with three loading injections of an anti–vascular endothelial growth factor agent, followed by further injections as needed. Changes in the Type 3 lesion were analyzed through OCTA imaging during the 12 months of follow-up.

Results:

The high-flow signal of Type 3 neovascularization on OCTA images disappeared in 46.2% eyes (19 of 39) and was persistent in 53.8% eyes (20 of 39) after loading injections. A persistent high-flow signal on OCTA after treatment was found at the sub–retinal pigment epithelium in 65.0% eyes (13 of 20), deep vascular plexus in 30.0% eyes (6 of 20), and outer neurosensory retina in 15.0% eyes (3 of 20). Eyes without lesions on OCTA images received significantly fewer injections (3.7 vs. 5.5; P = 0.016) and showed a longer retreatment-free period (mean 7.57 vs. 4.07 months; P = 0.002) during the 12-month follow-up than eyes with a persistent high-flow signal on OCTA. However, no significant between-group difference was observed in terms of improved visual acuity.

Conclusion:

Patients with Type 3 neovascularization who had no lesion on an OCTA scan after anti–vascular endothelial growth factor treatment showed a lower recurrence rate and maintained visual acuity with fewer injections than those with persistent high-flow lesions on an OCTA scan. Optical coherence tomography angiography may provide an additional biomarker for clinical guidance in the treatment and monitoring of disease activity in Type 3 neovascularization.
In Vivo Confocal Microscopy Automated Morphometric Analysis of Corneal Subbasal Nerve Plexus in Patients With Dry Eye Treated With Different Sources of Homologous Serum Eye Drops
Authors: Giannaccare Giuseppe , Pellegrini Marco , Bernabei Federico , Moscardelli Fabiana , Buzzi Marina , Versura Piera , Campos Emilio C
Published: May 2019

Purpose:

To investigate the comparative effect of allogeneic peripheral blood serum (allo-PBS) and cord blood serum (CBS) eye drops on the status of the corneal subbasal nerve plexus in patients with dry eye disease by using an automated analysis system of in vivo confocal microscopy images.

Methods:

This prospective, randomized, double-blind study included 30 patients with severe dry eye disease assigned to receive allo-PBS (group 1) or CBS (group 2) eye drops 8 times a day for 30 days. The following in vivo confocal microscopy parameters were calculated with ACCMetrics before (visit 1 [V1]) and after treatment (visit 2 [V2]): corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve total branch density, corneal nerve fiber area, corneal nerve fiber width, and corneal nerve fractal dimension (CNFrD).

Results:

In overall patients, the values of corneal nerve fiber density, corneal nerve fiber length, and CNFrD significantly increased, whereas the value of corneal nerve fiber width significantly decreased at V2 compared with V1 (respectively, 20.4 ± 7.9 vs. 17.4 ± 10.1 n/mm2; 13.5 ± 4.0 vs. 12.0 ± 5.1 mm/mm2; 1.466 ± 0.046 vs. 1.475 ± 0.033; and 0.022 ± 0.002 vs. 0.023 ± 0.002; all P < 0.05). In the subanalysis according to the treatment type, the increase of CNFrD value from V1 to V2 was higher in group 2 compared with group 1 (respectively, from 1.455 ± 0.041 to 1.471 ± 0.030 and from 1.479 ± 0.050 to 1.481 ± 0.035; P = 0.030).

Conclusions:

Overall, both treatments significantly improved corneal subbasal nerve plexus parameters, and in particular, nerve density, length, width, and fractal dimension. Treatment with CBS eye drops was associated with a higher increase of CNFrD compared with allo-PBS.
Personalized Pancreatic Cancer Management
Authors: Bradley Alison , van der Meer Robert , McKay Colin
Published: May 2019

This review critically analyzes how machine learning is being used to support clinical decision-making in the management of potentially resectable pancreatic cancer. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, electronic searches of MEDLINE, Embase, PubMed, and Cochrane Database were undertaken. Studies were assessed using the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies (CHARMS) checklist. In total 89,959 citations were retrieved. Six studies met the inclusion criteria. Three studies were Markov decision-analysis models comparing neoadjuvant therapy versus upfront surgery. Three studies predicted survival time using Bayesian modeling (n = 1) and artificial neural network (n = 1), and one study explored machine learning algorithms including Bayesian network, decision trees, k-nearest neighbor, and artificial neural networks. The main methodological issues identified were limited data sources, which limits generalizability and potentiates bias; lack of external validation; and the need for transparency in methods of internal validation, consecutive sampling, and selection of candidate predictors. The future direction of research relies on expanding our view of the multidisciplinary team to include professionals from computing and data science with algorithms developed in conjunction with clinicians and viewed as aids, not replacement, to traditional clinical decision-making.