bluuebunny/crossref_metadata_2025 huggingface dataset:
Uranium fusion implosion capsules see improved performance over gold
Authors: Liebendorfer Adam
Published: September 2018

Bare depleted uranium hohlraum capsules exhibit double the fusion neutron yield and considerably reduced X-ray flux in inertial confinement fusion experiments compared to commonly used gold.
Analysis of uncertainty in the surgical department: durations, requests and cancellations
Authors: Spratt Belinda , Kozan Erhan , Sinnott Michael
Published: September 2018

Objective
Analytical techniques are being implemented with increasing frequency to improve the management of surgical departments and to ensure that decisions are well informed. Often these analytical techniques rely on the validity of underlying statistical assumptions, including those around choice of distribution when modelling uncertainty. The aim of the present study was to determine a set of suitable statistical distributions and provide recommendations to assist hospital planning staff, based on three full years of historical data.

Methods
Statistical analysis was performed to determine the most appropriate distributions and models in a variety of surgical contexts. Data from 2013 to 2015 were collected from the surgical department at a large Australian public hospital.

Results
A log-normal distribution approximation of the total duration of surgeries in an operating room is appropriate when considering probability of overtime. Surgical requests can be modelled as a Poisson process with rate dependent on urgency and day of the week. Individual cancellations could be modelled as Bernoulli trials, with the probability of patient-, staff- and resource-based cancellations provided herein.

Conclusions
The analysis presented herein can be used to ensure that assumptions surrounding planning and scheduling in the surgical department are valid. Understanding the stochasticity in the surgical department may result in the implementation of more realistic decision models.

What is known about the topic?
Many surgical departments rely on crude estimates and general intuition to predict surgical duration, surgical requests (both elective and non-elective) and cancellations.

What does this paper add?
This paper describes how statistical analysis can be performed to validate common assumptions surrounding surgical uncertainty. The paper also provides a set of recommended distributions and associated parameters that can be used to model uncertainty in a large public hospital’s surgical department.

What are the implications for practitioners?
The insights on surgical uncertainty provided here will prove valuable for administrative staff who want to incorporate uncertainty in their surgical planning and scheduling decisions.
Toward the first quantum simulation with quantum speedup
Authors: Childs Andrew M. , Maslov Dmitri , Nam Yunseong , Ross Neil J. , Su Yuan
Published: September 2018

With quantum computers of significant size now on the horizon, we should understand how to best exploit their initially limited abilities. To this end, we aim to identify a practical problem that is beyond the reach of current classical computers, but that requires the fewest resources for a quantum computer. We consider quantum simulation of spin systems, which could be applied to understand condensed matter phenomena. We synthesize explicit circuits for three leading quantum simulation algorithms, using diverse techniques to tighten error bounds and optimize circuit implementations. Quantum signal processing appears to be preferred among algorithms with rigorous performance guarantees, whereas higher-order product formulas prevail if empirical error estimates suffice. Our circuits are orders of magnitude smaller than those for the simplest classically infeasible instances of factoring and quantum chemistry, bringing practical quantum computation closer to reality.
Photoaffinity-engineered protein scaffold for systematically exploring native phosphotyrosine signaling complexes in tumor samples
Authors: Chu Bizhu , He An , Tian Yeteng , He Wan , Chen Peizhong , Hu Jintao , Xu Ruilian , Zhou Wenbin , Zhang Mingjie , Yang Pengyuan , Li Shawn S. C. , Sun Ying , Li Pengfei , Hunter Tony , Tian Ruijun
Published: September 2018

Phosphotyrosine (pTyr)-regulated protein complexes play critical roles in cancer signaling. The systematic characterization of these protein complexes in tumor samples remains a challenge due to their limited access and the transient nature of pTyr-mediated interactions. We developed a hybrid chemical proteomics approach, termed Photo-pTyr-scaffold, by engineering Src homology 2 (SH2) domains, which specifically bind pTyr proteins, with both trifunctional chemical probes and genetic mutations to overcome these challenges. Dynamic SH2 domain-scaffolding protein complexes were efficiently cross-linked under mild UV light, captured by biotin tag, and identified by mass spectrometry. This approach was successfully used to profile native pTyr protein complexes from breast cancer tissue samples on a proteome scale with high selectivity, achieving about 100 times higher sensitivity for detecting pTyr signaling proteins than that afforded by traditional immunohistochemical methods. Among more than 1,000 identified pTyr proteins, receptor tyrosine kinase PDGFRB expressed on cancer-associated fibroblasts was validated as an important intercellular signaling regulator with poor expression correlation to ERBB2, and blockade of PDGFRB signaling could efficiently suppress tumor growth. The Photo-pTyr-scaffold approach may become a generic tool for readily profiling dynamic pTyr signaling complexes in clinically relevant samples.
Mechanics of diseased red blood cells in human spleen and consequences for hereditary blood disorders
Authors: Li He , Lu Lu , Li Xuejin , Buffet Pierre A. , Dao Ming , Karniadakis George E. , Suresh Subra
Published: September 2018

Significance

The interendothelial slit (IES) is the narrowest circulatory pathway in the human spleen where aged and diseased red blood cells (RBCs) are filtered. We use a two-component RBC model to probe the dynamics of healthy and diseased RBCs traversing IES. Our simulations reveal that the spleen not only senses and clears RBCs with abnormal shapes and deformability but also alters the geometries of RBCs that contain protein defects arising from hereditary blood disorders. The framework presented here is sufficiently general to be extended to elucidate the pathophysiological roles of the spleen in other blood diseases.
A plant-responsive bacterial-signaling system senses an ethanolamine derivative
Authors: Coutinho Bruna G. , Mevers Emily , Schaefer Amy L. , Pelletier Dale A. , Harwood Caroline S. , Clardy Jon , Greenberg E. Peter
Published: September 2018

Significance

A number of plant-associated bacteria possess transcription factors homologous to LuxR that respond to compounds found in plant tissue. These LuxR homologs are known to regulate virulence or symbiosis. Although the first of these proteins were described more than a decade ago, the factors they respond to remain unknown. Here we identify a compound that functions with PipR, a plant-responsive LuxR homolog from a tree root endopytic
Pseudomonas
isolate. The inducer is an ethanolamine derivative. Ethanolamine is a building block for plant membrane phospholipids and signaling molecules. This discovery connects at least one of the plant-responsive LuxR homolog systems to a growing understanding of ethanolamine chemistry and responses of bacterial cells to ethanolamine and ethanolamine derivatives.
Deep learning to represent subgrid processes in climate models
Authors: Rasp Stephan , Pritchard Michael S. , Gentine Pierre
Published: September 2018

The representation of nonlinear subgrid processes, especially clouds, has been a major source of uncertainty in climate models for decades. Cloud-resolving models better represent many of these processes and can now be run globally but only for short-term simulations of at most a few years because of computational limitations. Here we demonstrate that deep learning can be used to capture many advantages of cloud-resolving modeling at a fraction of the computational cost. We train a deep neural network to represent all atmospheric subgrid processes in a climate model by learning from a multiscale model in which convection is treated explicitly. The trained neural network then replaces the traditional subgrid parameterizations in a global general circulation model in which it freely interacts with the resolved dynamics and the surface-flux scheme. The prognostic multiyear simulations are stable and closely reproduce not only the mean climate of the cloud-resolving simulation but also key aspects of variability, including precipitation extremes and the equatorial wave spectrum. Furthermore, the neural network approximately conserves energy despite not being explicitly instructed to. Finally, we show that the neural network parameterization generalizes to new surface forcing patterns but struggles to cope with temperatures far outside its training manifold. Our results show the feasibility of using deep learning for climate model parameterization. In a broader context, we anticipate that data-driven Earth system model development could play a key role in reducing climate prediction uncertainty in the coming decade.
Citrus peel polymethoxyflavones, sudachitin and nobiletin, induce distinct cellular responses in human keratinocyte HaCaT cells
Authors: Abe Shogo , Hirose Saki , Nishitani Mami , Yoshida Ichiro , Tsukayama Masao , Tsuji Akihiko , Yuasa Keizo
Published: September 2018

A variety of polyphenols have been isolated from plants, and their biological activities have been examined. Sudachitin (5,7,4′-trihydroxy-6,8,3′-trimethoxyflavone) is a polymethoxyflavone that is isolated from the peel of Citrus sudachi. Although we previously reported that sudachitin possesses an anti-inflammatory activity, its other biological activities are not yet understood. In this study, we report a novel biological activity of sudachitin, which selectively induced apoptosis in human keratinocyte HaCaT cells. Another polymethoxyflavone, nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone), promoted autophagy but not apoptosis in HaCaT cells. On the other hand, 3′-demethoxysudachitin (5,7,4′-trihydroxy-6,8-dimethoxyflavone) failed to induce apoptosis and autophagy. These results show that three polymethoxyflavones have different effects on apoptosis and autophagy in HaCaT cells. Understanding the structure and biological activity of polymethoxyflavones may lead to the discovery of potential candidates for cancer drug development without significant toxic side effects.

Abbreviations: ROS: reactive oxygen species; DMSO: dimethyl sulfoxide; MTT: 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; PARP: poly(ADP-ribose) polymerase; PI: propidium iodide; MAPK: mitogen-activated protein kinase.
Benzyl isothiocyanate ameliorates lipid accumulation in 3T3-L1 preadipocytes during adipocyte differentiation
Authors: Liang Ying , Sasaki Ikumi , Takeda Yuki , Zhu Beiwei , Munemasa Shintaro , Nakamura Toshiyuki , Murata Yoshiyuki , Nakamura Yoshimasa
Published: September 2018

Benzyl isothiocyanate (BITC) is an organosulfur compound derived from cruciferous vegetables and papaya seeds. In this study, we investigated the effect of BITC on the lipid accumulation in 3T3-L1 preadipocytes during adipocyte differentiation. The treatment of BITC during the differentiation-inducing stage significantly ameliorated the lipid accumulation, whereas it had no inhibitory effect during the differentiation-maintaining stage. BITC also significantly suppressed the mRNA expression of the adipocyte-specific markers, such as CCAAT/enhancer-binding protein α (C/EBPα), C/EBPβ, C/EBPδ and peroxisome proliferator-activated receptor γ. BITC significantly inhibited the phosphorylation of extracellular signal-regulated kinase phosphorylation, whereas it enhanced that of AMP-activated protein kinase. Furthermore, BITC significantly suppressed the intracellular 2-deoxyglucose uptake as well as glucose transporter 4 expression. These results suggest that inhibition of the adipocyte differentiation and glucose uptake may mainly contribute to the inhibitory effect of BITC on the lipid accumulation in 3T3-L1 preadipocytes.

Abbreviations: PPARγ: peroxisome proliferator-activated receptor γ; CEBP: CCAAT/enhancer-binding protein; GLUT4: glucose transporter 4; AMPK: AMP-activated protein kinase; ERK1/2: extracellular signal-regulated kinase 1/2; MAPK: a mitogen-activated protein kinase; ITCs: isothiocyanates; BITC: benzyl isothiocyanate; FBS: fetal bovine serum; CS: calf serum; AITC: allyl ITC; IBMX: 3-isobutyl-1-methylxanthine; LDH: lactate dehydrogenase; KRH: Krebs-Ringer-Hepes-bicarbonate; 2-DG: 2-deoxy-d-glucose
Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation
Authors: Vaibhav Kumar , Braun Molly , Khan Mohammad Badruzzaman , Fatima Sumbul , Saad Nancy , Shankar Adarsh , Khan Zenab T. , Harris Ruth B.S. , Yang Qiuhua , Huo Yuqing , Arbab Ali S. , Giri Shailendra , Alleyne Cargill H. , Vender John R. , Hess David C. , Baban Babak , Hoda Md Nasrul , Dhandapani Krishnan M.
Published: September 2018

Spontaneous intracerebral hemorrhage (ICH) produces the highest acute mortality and worst outcomes of all stroke subtypes. Hematoma volume is an independent determinant of ICH patient outcomes, making clot resolution a primary goal of clinical management. Herein, remote-limb ischemic post-conditioning (RIC), the repetitive inflation–deflation of a blood pressure cuff on a limb, accelerated hematoma resolution and improved neurological outcomes after ICH in mice. Parabiosis studies revealed RIC accelerated clot resolution via a humoral-mediated mechanism. Whereas RIC increased anti-inflammatory macrophage activation, myeloid cell depletion eliminated the beneficial effects of RIC after ICH. Myeloid-specific inactivation of the metabolic regulator, AMPKα1, attenuated RIC-induced anti-inflammatory macrophage polarization and delayed hematoma resolution, providing a molecular link between RIC and immune activation. Finally, chimera studies implicated myeloid CD36 expression in RIC-mediated neurological recovery after ICH. Thus, RIC, a clinically well-tolerated therapy, noninvasively modulates innate immune responses to improve ICH outcomes. Moreover, immunometabolic changes may provide pharmacodynamic blood biomarkers to clinically monitor the therapeutic efficacy of RIC.
Vesicular trafficking plays a role in centriole disengagement and duplication
Authors: Xie Shuwei , Reinecke James B. , Farmer Trey , Bahl Kriti , Yeow Ivana , Nichols Benjamin J. , McLamarrah Tiffany A. , Naslavsky Naava , Rogers Gregory C. , Caplan Steve
Published: September 2018

Centrosomes are the major microtubule-nucleating and microtubule-organizing centers of cells and play crucial roles in microtubule anchoring, organelle positioning, and ciliogenesis. At the centrosome core lies a tightly associated or “engaged” mother–daughter centriole pair.  During mitotic exit, removal of centrosomal proteins pericentrin and Cep215 promotes “disengagement” by the dissolution of intercentriolar linkers, ensuring a single centriole duplication event per cell cycle.  Herein, we explore a new mechanism involving vesicular trafficking for the removal of centrosomal Cep215. Using small interfering RNA and CRISPR/Cas9 gene-edited cells, we show that the endocytic protein EHD1 regulates Cep215 transport from centrosomes to the spindle midbody, thus facilitating disengagement and duplication. We demonstrate that EHD1 and Cep215 interact and show that Cep215 displays increased localization to vesicles containing EHD1 during mitosis. Moreover, Cep215-containing vesicles are positive for internalized transferrin, demonstrating their endocytic origin. Thus, we describe a novel relationship between endocytic trafficking and the centrosome cycle, whereby vesicles of endocytic origin are used to remove key regulatory proteins from centrosomes to control centriole duplication.
Inhibition of TrkB- and TrkC-Signaling Pathways Affects Neurogenesis in the Opossum Developing Neocortex
Authors: Bartkowska K , Tepper B , Gawda A , Jarosik M , Sobolewska P , Turlejski K , Djavadian R L
Published: September 2018

We have previously reported that the blockage of TrkB and TrkC signaling in primary culture of opossum neocortical cells affects neurogenesis that involves a range of processes including cell proliferation, differentiation, and survival. Here, we studied whether TrkB and TrkC activity specifically affects various types of progenitor cell populations during neocortex formation in the Monodelphis opossum in vivo. We found that the inhibition of TrkB and TrkC activities affects the same proliferative cellular phenotype, but TrkC causes more pronounced changes in the rate of cell divisions. Additionally, inhibition of TrkB and TrkC does not affect apoptosis in vivo, which was found in cell culture experiments. The lack of TrkB and TrkC receptor activity caused the arrest of newly generated neurons; therefore, they could not penetrate the subplate zone. We suggest that at this time point in development, migration consists of 2 steps. During the initial step, neurons migrate and reach the base of the subplate, whereas during the next step the migration of neurons to their final position is regulated by TrkB or TrkC signaling.
Prey and predators perceive orb-web spider conspicuousness differently: evaluating alternative hypotheses for color polymorphism evolution
Authors: Ximenes Nathalia G , Gawryszewski Felipe M
Published: September 2018

Color polymorphisms have been traditionally attributed to apostatic selection. The perception of color depends on the visual system of the observer. Theoretical models predict that differently perceived degrees of conspicuousness by two predator and prey species may cause the evolution of polymorphisms in the presence of anti-apostatic and apostatic selection. The spider Gasteracantha cancriformis (Araneidae) possesses several conspicuous color morphs. In orb-web spiders, the prey attraction hypothesis states that conspicuous colors are prey lures that increase spider foraging success via flower mimicry. Therefore, polymorphism could be maintained if each morph attracted a different prey species (multiple prey hypothesis) and each spider mimicked a different flower color (flower mimicry hypothesis). Conspicuous colors could be a warning signal to predators because of the spider’s hard abdomen and spines. Multiple predators could perceive morphs differently and exert different degrees of selective pressures (multiple predator hypothesis). We explored these 3 hypotheses using reflectance data and color vision modeling to estimate the chromatic and achromatic contrast of G. cancriformis morphs as perceived by several potential prey and predator taxa. Our results revealed that individual taxa perceive the conspicuousness of morphs differently. Therefore, the multiple prey hypothesis and, in part, the multiple predator hypothesis may explain the evolution of color polymorphism in G. cancriformis, even in the presence of anti-apostatic selection. The flower mimicry hypothesis received support by color metrics, but not by color vision models. Other parameters not evaluated by color vision models could also affect the perception of morphs and influence morph survival and polymorphism stability.
Metagenomic sequencing provides insights into microbial detoxification in the guts of small mammalian herbivores (Neotoma spp.)
Authors: Kohl Kevin D , Oakeson Kelly F , Orr Teri J , Miller Aaron W , Forbey Jennifer Sorensen , Phillips Caleb D , Dale Colin , Weiss Robert B , Dearing M Denise
Published: September 2018

Microbial detoxification of plant toxins influences the use of plants as food sources by herbivores. Stephen's woodrats (Neotoma stephensi) specialize on juniper, which is defended by oxalate, phenolics and monoterpenes, while closely related N. albigula specialize on cactus, which only contains oxalate. Woodrats maintain two gut chambers harboring dense microbial communities: a foregut chamber proximal to the major site of toxin absorption, and a cecal chamber in their hindgut. We performed several experiments to investigate the location and nature of microbial detoxification in the woodrat gut. First, we measured toxin concentrations across gut chambers of N. stephensi. Compared to food material, oxalate concentrations were immediately lower in the foregut, while concentrations of terpenes remained high in the foregut, and were lowest in the cecal chamber. We conducted metagenomic sequencing of the foregut chambers of both woodrat species and cecal chambers of N. stephensi to compare microbial functions. We found that most genes associated with detoxification were more abundant in the cecal chambers of N. stephensi. However, some genes associated with degradation of oxalate and phenolic compounds were more abundant in the foregut chambers. Thus, microbial detoxification may take place in various chambers depending on the class of chemical compound.
Translating an Evidence-based Multicomponent Intervention for Older Adults With Dementia and Caregivers
Authors: Teri Linda , Logsdon Rebecca G , McCurry Susan M , Pike Kenneth C , McGough Ellen L
Published: September 2018

Background and Objectives

Effective community-based programs to maintain health and well-being of adults with dementia are needed. This article describes the translation, implementation, and effectiveness of a multicomponent exercise plus behavioral/psychosocial intervention (Reducing Disability in Alzheimer’s Disease-NorthWest [RDAD-NW]) conducted by staff in regional Area Agencies on Aging (AAAs).

Research Design and Methods

Staggered multiple baseline design was used; 10 AAAs, 20 case managers, and 255 community-residing persons with dementia (PWDs), and family caregivers were enrolled. RDAD-NW was conducted in-home over 6 weeks with aerobic/endurance, strength, and balance/flexibility exercises, dementia education, training to increase pleasant events, and activator-behavior-consequence problem-solving approach. Outcomes included case manager treatment fidelity, and caregiver/PWD physical activity, restricted activity days, physical functioning, quality of life, and affect.

Results

RDAD-NW was successfully translated and implemented by AAA agency staff through their usual service provision mechanisms. Staff responded positively and delivered the program with a high degree of fidelity. Caregiver/PWD dyads also responded favorably engaging in both exercise and behavioral/psychosocial portions of the program. A total of 207 dyads (81%) completed the intervention and 140 (55%) completed the 13-month follow-up. PWD physical activity increased significantly pre- to posttreatment (p < .001, ES = .54), and 13 months (p < .01, ES = .21). Quality of life of PWD increased significantly pre- to posttreatment (p < .001, ES = .29); caregiver depression improved pre- to posttreatment (p = .01, ES = −.18).

Discussion and Implications

RDAD-NW was successfully translated and implemented by AAA case managers and resulted in increased physical activity and improved behavioral and emotional outcomes of caregiver/PWDs. Results support continued dissemination and implementation of RDAD-NW.

Clinical Trials Registration

NCT01708304
Sequana coverage: detection and characterization of genomic variations using running median and mixture models
Authors: Desvillechabrol Dimitri , Bouchier Christiane , Kennedy Sean , Cokelaer Thomas
Published: September 2018

Background

In addition to mapping quality information, the Genome coverage contains valuable biological information such as the presence of repetitive regions, deleted genes, or copy number variations (CNVs). It is essential to take into consideration atypical regions, trends (e.g., origin of replication), or known and unknown biases that influence coverage. It is also important that reported events have robust statistics (e.g. z-score) associated with their detections as well as precise location.

Results

We provide a stand-alone application, sequana_coverage, that reports genomic regions of interest (ROIs) that are significantly over- or underrepresented in high-throughput sequencing data. Significance is associated with the events as well as characteristics such as length of the regions. The algorithm first detrends the data using an efficient running median algorithm. It then estimates the distribution of the normalized genome coverage with a Gaussian mixture model. Finally, a z-score statistic is assigned to each base position and used to separate the central distribution from the ROIs (i.e., under- and overcovered regions). A double thresholds mechanism is used to cluster the genomic ROIs. HTML reports provide a summary with interactive visual representations of the genomic ROIs with standard plots and metrics. Genomic variations such as single-nucleotide variants or CNVs can be effectively identified at the same time.
CO observations toward the isolated mid-infrared bubble S44: External triggering of O-star formation by a cloud–cloud collision
Authors: Kohno Mikito , Tachihara Kengo , Fujita Shinji , Hattori Yusuke , Torii Kazufumi , Nishimura Atsushi , Hanaoka Misaki , Yoshiike Satoshi , Enokiya Rei , Hasegawa Keisuke , Ohama Akio , Sano Hidetoshi , Yamamoto Hiroaki , Fukui Yasuo
Published: September 2018

We have performed a multi-wavelength study of the mid-infrared bubble S44 to investigate the origin of isolated high-mass star(s) and the star-formation process around the bubble formed by the H ii region. We report on the results of new CO observations (12CO, 13CO J = 1–0, and 12CO J = 3–2) toward the isolated bubble S44 using the NANTEN2, Mopra, and ASTE radio telescopes. We found two velocity components at −84 km s−1 and −79 km s−1 in the direction of the bubble. These two clouds are likely to be physically associated with the bubble, because of the enhanced 12CO J = 3–2/1–0 intensity ratio from a ring-like structure affected by ultraviolet radiation from embedded high-mass star(s) and of the morphological correspondence between the 8 μm emission and the CO distribution. Assuming a single object, we estimate a spectral type of the embedded star inside the bubble to be O8.5–9 $({\sim}20\,M_{\odot})$ from the radio-continuum free–free emission. We hypothesize that the two clouds collided with each other 3 Myr ago, triggering the formation of the isolated high-mass star in S44, as also occurred in RCW 120 and RCW 79. We argue that this scenario can explain the origin of the isolated O-star inside the bubble.
Cultural Processes of Ethnoracial Disadvantage among Native American College Students
Authors: Cech Erin A , Smith Jessi L , Metz Anneke
Published: September 2018

Although indigenous populations have been subjected to some of the worst forms of institutionalized oppression in the United States, little social science research has sought to understand the day-to-day ethnoracial biases that contemporary Native American populations face. Seeking to expand this knowledge, we present a theoretical framework of the cultural processes of ethnoracial disadvantage experienced by Native American students in predominantly white colleges. Drawing on 65 in-depth interviews with 50 Native students, we identify four cultural processes of disadvantage: derogatory stereotyping, exoticized othering, delegitimation, and assimilation pressures related to cultural hegemony. Intertwined with these processes is the cultural permissibility of ignorance, a willful dearth of knowledge—and lack of accountability for knowledge—about indigenous peoples, traditions, and histories of oppression which enable these biases and exclusions. Students tend to respond to these cultural processes of disadvantage in three ways: educating others, working to disprove stereotypes, and spanning two worlds. We end by discussing how these results help advance theoretical understanding of ethnoracial bias toward indigenous populations and cultural processes of ethnoracial inequality in the United States more broadly.
Evolutionary potential varies across populations and traits in the neotropical oak Quercus oleoides
Authors: Ramírez-Valiente José A , Etterson Julie R , Deacon Nicholas J , Cavender-Bares Jeannine
Published: September 2018

Heritable variation in polygenic (quantitative) traits is critical for adaptive evolution and is especially important in this era of rapid climate change. In this study, we examined the levels of quantitative genetic variation of populations of the tropical tree Quercus oleoides Cham. and Schlect. for a suite of traits related to resource use and drought resistance. We tested whether quantitative genetic variation differed across traits, populations and watering treatments. We also tested potential evolutionary factors that might have shaped such a pattern: selection by climate and genetic drift. We measured 15 functional traits on 1322 1-year-old seedlings of 84 maternal half-sib families originating from five populations growing under two watering treatments in a greenhouse. We estimated the additive genetic variance, coefficient of additive genetic variation and narrow-sense heritability for each combination of traits, populations and treatments. In addition, we genotyped a total of 119 individuals (with at least 20 individuals per population) using nuclear microsatellites to estimate genetic diversity and population genetic structure. Our results showed that gas exchange traits and growth exhibited strikingly high quantitative genetic variation compared with traits related to leaf morphology, anatomy and photochemistry. Quantitative genetic variation differed between populations even at geographical scales as small as a few kilometers. Climate was associated with quantitative genetic variation, but only weakly. Genetic structure and diversity in neutral markers did not relate to coefficient of additive genetic variation. Our study demonstrates that quantitative genetic variation is not homogeneous across traits and populations of Q. oleoides. More importantly, our findings suggest that predictions about potential responses of species to climate change need to consider population-specific evolutionary characteristics.
The BET-bromodomain inhibitor JQ1 mitigates vemurafenib drug resistance in melanoma
Authors: Zhao Bei , Cheng Xiankui , Zhou Xiyuan
Published: September 2018

Inhibition of BRAF improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to BRAF inhibitor is inevitable, and the drug resistance mechanisms still remain to be elucidated. Here, BRAFV600E mutant cells A375 and SK-MEL-28 were chosen and treated with BRAF inhibitor vemurafenib, and the results showed that the ERK signaling pathway was blocked in these cells. Then, vemurafenib-resistant cells were constructed, and we found that drug resistance-related gene P-gp was overexpressed in the two cell lines. In addition, the histone acetylation was significantly increased on the P-gp promoter region, which suggested that the epigenetic modification participated in the P-gp overexpression. Furthermore, JQ1, a bromodomain inhibitor, was added to the vemurafenib-resistant cells and sensitizes the vemurafenib-induced melanoma cell apoptosis. In C57BL/6 mice intravenously injected with vemurafenib-resistant melanoma cells, cotreatment of vemurafenib and JQ1 also severely suppressed melanoma lung metastasis. Taken together, our findings may have important implications for the combined use of vemurafenib and JQ1 in the therapy for melanoma treatment.
Pretibial Lymphoplasmacytic Plaque in Children: Case Report and Review of the Literature
Authors: Bierbrier Rachel M. , Amdemichael Esiahas , Adam David N.
Published: September 2018

An 8-year-old girl presented with a persistent 5 × 2-cm violaceous doughy plaque on the left lower leg. Histologic examination revealed hyperkeratosis, variable but mild epidermal hyperplasia, and vacuolar interface changes with melanin pigment incontinence confined to the papillary dermis. A diagnosis of pretibial lymphoplasmacytic plaque in children was made. This report outlines the clinical characteristics of this entity and a review of other cases reported in the literature.
The ALCCaS Trial: A Randomized Controlled Trial Comparing Quality of Life Following Laparoscopic Versus Open Colectomy for Colon Cancer
Authors: McCombie Andrew M. , Frizelle Frank , Bagshaw Philip Frederick , Frampton Chris M. , Hewett Peter J. , McMurrick Paul John , Rieger Nicholas , Solomon Michael J. , Stevenson Andrew R.
Published: September 2018

BACKGROUND:

This study reports the quality-of-life assessment of the ALCCaS trial. The ALCCaS trial compared laparoscopic and open resection for colon cancer. It reported equivalence of survival at 5 years. Quality of life was measured as a secondary outcome.

OBJECTIVE:

This study aimed to report on the quality of life data of the ALCCaS Trial.

DESIGN:

This study reports a randomized controlled trial comparing laparoscopic with open colonic resection.

SETTINGS:

The study was conducted in Australasia.

PATIENTS:

Patients with a single adenocarcinoma of the right, left, or sigmoid colon, presenting for elective treatment, were eligible for randomization.

INTERVENTIONS:

Open and laparoscopic colonic resections were performed.

MAIN OUTCOME MEASURES:

Patient symptoms and quality of life were measured using the Symptoms Distress Scale, the Quality of Life Index, and the Global Quality of Life Score preoperatively, and at 2 days, 2 weeks, and 2 months postoperatively.

RESULTS:

Of the 592 patients enrolled in ALCCaS, 425 completed at least 1 quality-of-life measure at 4 time points (71.8% of cohort). Those who received the laparoscopic intervention had better quality of life postoperatively in terms of the Symptoms Distress Scale (p < 0.01), Quality of Life Index (p < 0.01), and Global Quality of Life (p < 0.01). In intention-to-treat analyses, those assigned to laparoscopic surgery had a better quality of life postoperatively in terms of the Symptoms Distress Scale (p < 0.01) and Quality of Life Index (p < 0.01), whereas Global Quality of Life was not significant (p = 0.056). The subscales better for laparoscopic resection at all 3 postoperative time points were appetite, insomnia, pain, fatigue, bowel, daily living, and health (p < 0.05).

LIMITATIONS:

The primary limitation was the different response rates for the 3 quality-of-life measures.

CONCLUSIONS:

There was a short-term gain in quality of life maintained at 2 months postsurgery for those who received laparoscopic relative to open colonic resection. See Video Abstract at http://links.lww.com/DCR/A691.
Extended Venous Thromboembolism Prophylaxis After Elective Surgery for IBD Patients: Nomogram-Based Risk Assessment and Prediction from Nationwide Cohort
Authors: Benlice Cigdem , Holubar Stefan D. , Gorgun Emre , Stocchi Luca , Lipman Jeremy M. , Kalady Matthew F. , Champagne Bradley J. , Steele Scott R.
Published: September 2018

BACKGROUND:

Identification of risk factors for postoperative venous thromboembolism is an important step to reduce the morbidity associated with this potentially preventable complication after elective surgery for patients with IBD.

OBJECTIVE:

This study aimed to determine the risk factors for 30-day venous thromboembolism after abdominal surgery for patients with venous thromboembolism, identify potential indications for extended thromboprophylaxis, and develop a nomogram for prediction of risk.

DESIGN:

This is a retrospective cohort study from a prospectively collected database.

SETTING:

The American College of Surgeons National Surgical Quality Improvement Program Participant User File from 2005 to 2016 was used for data analysis.

PATIENTS:

All patients with IBD undergoing elective abdominopelvic bowel surgery were included.

MAIN OUTCOME MEASURES:

The primary outcomes were the incidence of in-hospital and postdischarge venous thromboembolism within 30 days of the index abdominopelvic surgery.

RESULTS:

A total of 24,182 patients met the inclusion criteria. Thirty-day total and postdischarge rates of venous thromboembolism were 2.5% (n = 614) and 1% (n =252). Forty-one percent (252/614) of venous thromboembolism events occurred after hospital discharge. Univariate analysis assessed 37 variables for association with study outcomes. On multivariate logistic regression analysis, older age, steroid use, bleeding disorders, open surgery, hypertension, longer operative time, and preoperative hospitalization were associated with venous thromboembolism before discharge and also postoperative transfusion, steroid use, pelvic and enterocutaneous fistula surgery, and longer operative time were associated with venous thromboembolism after discharge. A nomogram was constructed for each outcome, translating multivariate model parameter estimates into a visual scoring system where the estimated probability of venous thromboembolism can be calculated.

LIMITATIONS:

This study was limited by its retrospective nature and the limitations inherent to a database.

CONCLUSION:

Given the higher risk of venous thromboembolism in patients with IBD after elective abdominopelvic surgery compared with other indications, an accurate prediction of venous thromboembolism before and after discharge using the proposed nomogram can facilitate decision making for individualized extended thromboprophylaxis in the preoperative setting as a screening tool. See Video Abstract at http://links.lww.com/DCR/A711.
Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial
Authors: Marco Michael R. , Zhou Lihong , Patil Sujata , Marcet Jorge E. , Varma Madhulika G. , Oommen Samuel , Cataldo Peter A. , Hunt Steven R. , Kumar Anjali , Herzig Daniel O. , Fichera Alessandro , Polite Blase N. , Hyman Neil H. , Ternent Charles A. , Stamos Michael J. , Pigazzi Alessio , Dietz David , Yakunina Yuliya , Pelossof Raphael , Garcia-Aguilar Julio
Published: September 2018

BACKGROUND:

Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response.

OBJECTIVE:

The purpose of this study was to analyze disease-free and overall survival.

DESIGN:

This was a nonrandomized phase II trial.

SETTINGS:

The study was conducted at multiple institutions.

PATIENTS:

Four sequential study groups with stage II or III rectal cancer were included.

INTERVENTION:

All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6.

MAIN OUTCOME MEASURES:

The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study.

RESULTS:

Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9–125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03).

LIMITATIONS:

The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients.

CONCLUSIONS:

Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.
Repair of Apical Triangle Defects Using Melolabial Rotation Flaps
Authors: Orangi Maideh , Dyson Mary E. , Goldberg Leonard H. , Kimyai-Asadi Arash
Published: September 2018

BACKGROUND

The apical triangle of the upper cutaneous lip, also known as the alar-facial sulcus, is an anatomical structure bound medially by the nasal ala, laterally by the medial cheek, and inferiorly by the remainder of the upper cutaneous lip. During reconstruction, retaining the central concavity and the convex lateral and medial outlines of this location is required to maintain midfacial symmetry.

OBJECTIVE

This is a retrospective study of our use of the melolabial rotation flap for reconstruction of surgical defects of the apical triangle.

METHODS AND MATERIALS

Eighty-six surgical defects involving the apical triangle that were repaired with melolabial rotation flaps were included. All tumors were treated with Mohs micrographic surgery before reconstruction. Preoperative, intraoperative, and postoperative details of each case were analyzed.

RESULTS

Of the 86 defects included in the study, 68 (79%) were evaluated postoperatively. The apical triangle was preserved in all cases. Clinical asymmetry was noted in 3 patients (3.4%). No major complications were noted, and no patient required surgical revision.

CONCLUSION

Melolabial rotation flaps may be considered for single-stage reconstruction of surgical defects involving the apical triangle.
Oral Hedgehog Pathway Inhibition as a Means for Ocular Salvage in Locally Advanced Intraorbital Basal Cell Carcinoma
Authors: Mathis Jason , Doerr Timothy , Lin Edward , Ibrahim Sherrif F.
Published: September 2018

BACKGROUND

Basal cell cancer is the most common cutaneous malignancy. It rarely presents with locally advanced or metastatic disease. Rare presentations such as intraorbital invasion remain a difficult clinical problem with significant potential morbidity. There is no review of sonic hedgehog pathway inhibitors (HPIs) for intraorbital basal cell cancer, and evidence regarding optimal management is limited.

OBJECTIVE

To evaluate the evidence for the management of intraorbital basal cell cancer with HPIs.

METHODS

A search to identify evidence for treatment intraorbital basal cell cancers with HPIs to date was performed in PubMed database and OVID using the phrases “basal cell cancer/carcinoma/BCC,” “intraorbital,” “orbital,” “ocular,” “periocular,” “vismodegib,” “GDC-0449,” “sonidegib,” and “LDE224,” in various combinations with Boolean operators “AND” and “OR.”

RESULTS

Rigorous clinical trials have previously reported the use of vismodegib and sonidegib in locally advanced and metastatic basal cell carcinoma (BCC). However, specific descriptions of treatment of intraorbital tumors are rarely presented in detail adequate for analysis. Twenty-two cases of intraorbital BCC treated with vismodegib have been described in the literature, and no cases using sonidegib were identified. These vary in quality, but highlight important questions regarding optimal treatment duration, follow-up, and adjunctive therapies. Reports describing locally advanced BCC in various facial and periocular locations, but without specific mention of intraorbital invasion, were excluded.

CONCLUSION

Vismodegib is an attractive eye and vision-sparing option in patients with locally advanced intraorbital basal cell cancer whose other options often include exenteration, radiation, or other radical surgery.
Dopamine effects on stress-induced working memory deficits
Authors: Bahari Zahra , Meftahi Gholam H. , Meftahi Mohammad A.
Published: September 2018

The prefrontal cortex (PFC) plays a critical role in mediating executive functions and orchestrating the way in which we think, decide, and behave. Many studies have shown that PFC neurons not only play a major role in mediating behavioral responses to stress but are also sensitive to stress and undergo remodeling following stress exposure. Activation of the hypothalamic–pituitary–adrenal axis as a result of stress initiates a flood of alterations in prefrontal neurotransmitter release. Dopamine (DA) neurotransmission in the PFC is involved in the modulation of stress responsiveness. Compelling results show that stressful events are associated with increased DA concentrations in the medial PFC. Excessive DA-ergic activity in the medial prefrontal cortex following stress has a negative impact on working memory and executive functions in rodents, monkeys, and humans, making them unable to processing information selectively and impairing cognitive function. Therefore, an exact understanding of these mechanisms may provide important insights into the pathophysiology of executive dysfunction and novel treatment avenues. The present review provides a summary of the neuronal circuitry involved in alterations of PFC dopaminergic neurons under conditions of stress, and then addresses the interaction of PFC DA with glucocorticoids leading to impairment of working memory under conditions of stress.
Distinct Inflammatory Changes of the Pancreas of Slowly Progressive Insulin-dependent (Type 1) Diabetes
Authors: Aida Kaoru , Fukui Tomoyasu , Jimbo Erika , Yagihashi Soroku , Shimada Akira , Oikawa Yoichi , Mori Yasumichi , Fujii Takeshi , Nishida Yoriko , Koyama Rikako , Kobayashi Tetsuro
Published: September 2018

Objective

The aim of this study was to identify the distinct pathological changes on the endocrine and exocrine pancreas of slowly progressive insulin-dependent diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults.

Methods

The pancreases from 12 islet autoantibody–positive SPIDDM patients and 19 age-matched subjects with no diabetes were examined histologically for islet inflammation/insulitis, expressions of cytokines, and enterovirus VP1 protein, exocrine pancreatic inflammation, pancreatic ductal changes, major histocompatibility complex class I hyperexpression, and amylin-positive amyloid in the islets.

Results

Insulitis dominant for CD8+ T-cells and CD68+ macrophages was observed in all SPIDDM cases irrespective of duration of diabetes and weight of residual beta cells. Major histocompatibility complex class I hyperexpression on residual beta cells was observed in SPIDDM. All SPIDDM exocrine pancreases showed extensive inflammation, dilated pancreatic ducts, and periductal fibrosis. As many as 75% (9/12) of pancreases had pancreatic intraepithelial neoplasia, which is assumed to be associated with ductal obstruction/narrowing and exocrine pancreatic inflammation, in SPIDDM. Amylin-positive amyloid deposition was not detected in SPIDDM.

Conclusions

Persistent insulitis with preserved beta cells and major histocompatibility complex class I hyperexpression and exocrine pancreatic inflammation with pancreatic intraepithelial neoplasia are distinct histological features of SPIDDM pancreas.
Red Flags and Off Ramps
Authors: Pastor Diane K. , Arms Tamatha , Jones Andrea L.
Published: September 2018

Driving safety for older adults with dementia presents a continuing complex challenge in the community. More than 5 million people in the United States suffer from dementia, and their numbers are expected to grow. Evidence-based resources to identify and manage driving risks in older adults with dementia do exist, but the challenges of limited time in primary care and outpatient settings can make application difficult. This innovative project, funded by a Hartford Foundation Change Agents Action grant award, focused on interprofessional work to address the educational need for primary care professionals and family caregivers to manage driving safety for their loved ones with dementia. An interactive theater performance with development of an educational DVD was tested in a sample of professional and family caregivers. This project also forged new sustainable interprofessional community partnerships among educators/researchers and healthcare providers caring for this vulnerable community population.