bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Fatal Intoxications Due to Tramadol Alone
Authors: Gioia Sara , Lancia Massimo , Bacci Mauro , Suadoni Fabio
Published: August 2017

Since tramadol was marketed, it has been widely prescribed as a pain killer because of its relatively safe profile among opioids.

Nevertheless, intoxication can occur: overdose can lead to fatal outcomes mostly in association with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased central nervous system (CNS) depression.

Fatal outcomes only attributable to tramadol are a rare entity. In this case report, 2 fatal cases are described due to tramadol stand-alone intoxication with peculiar characteristics.

In case 1, gas chromatography - mass spectrometry analysis detected tramadol in all specimens (32 μg/mL in the heart blood, 23.9 μg/mL in the femoral blood, 3.3 μg/mL in the bile, and 1.4 μg/mL in the urine). No other CNS depressants were detected by toxicological analysis.

In case 2, gas chromatography - mass spectrometry analysis detected tramadol in all specimens (7.5 μg/mL in the heart blood, 5.8 μg/mL in the femoral blood, and 18 μg/mL in the urine). No other CNS depressants were detected by toxicological analysis.

Review of the literature was performed to clarify the actual knowledge on this topic.
Cardiac Arrest Secondary to Lightning Strike
Authors: Rotariu Elena L. , Manole Mioara D.
Published: August 2017

Lightning strike injuries, although less common than electrical injuries, have a higher morbidity rate because of critical alterations of the circulatory system, respiratory system, and central nervous system. Most lightning-related deaths occur immediately after injury because of arrhythmia or respiratory failure. We describe the case of a pediatric patient who experienced cardiorespiratory arrest secondary to a lightning strike, where the Advanced Cardiac Life Support and Basic Life Support chain of survival was well executed, leading to return of spontaneous circulation and intact neurological survival. We review the pathophysiology of lightning injuries, prognostic factors of favorable outcome after cardiac arrest, including bystander cardiopulmonary resuscitation, shockable rhythm, and automatic external defibrillator use, and the importance of temperature management after cardiac arrest.
A Spatial Analysis of Acute Myocardial Infarction Rates in New York State in Relation to Hospitals Along State Jurisdictional Borders
Authors: Stamm Abigail J. , Savadatti Sanghamitra S. , Kumar Sanjaya , Hwang Syni-An
Published: August 2017

Introduction:

Patients experiencing acute myocardial infarction (AMI) are likely to visit the nearest hospital providing appropriate services since timely care is a critical determinant in the treatment and progression of AMI. We comparatively examined AMI rates in border and nonborder census tracts. The New York State (NYS) Environmental Public Health Tracking (EPHT) program, in conjunction with the Statewide Planning and Research Cooperative System, will work on developing memoranda of understanding with neighboring states to be able to more comprehensively access NYS residents' out-of-state health records.

Objective:

To determine whether AMI rates in the NYS border census tracts differ from AMI rates in nonborder census tracts as a preliminary exploration of the utilization of out-of-state care for acute health conditions by NYS border residents.

Design:

We reviewed data on inpatient and emergency department visits in NYS with discharge dates from 2005 to 2014 retrospectively. We used the NYS EPHT tier 1 system database to locate hospitals. We geocoded all cases to NYS 2010 census tracts. We mapped differences between border and nonborder tracts and analyzed resulting spatial patterns. We computed tract-level AMI rates and differences between border and nonborder AMI rates.

Results:

The age-adjusted AMI rates differed by 8.2 cases per 10 000 people (95% confidence interval, 6.94-12.60). Maps showed patterns of differences in AMI rates, especially along the NYS border with New England and other geographically closer out-of-state hospitals.

Conclusions:

AMI rates that were geographically closer to out-of-state hospitals were lower, suggesting that people residing in border census tracts are utilizing out-of-state care. Our study adds to literature on the geographical component of health care accessibility and utilization in the context of acute conditions such as AMI and lends impetus to access out-of-state health records to better understand health care facility access and utilization for NYS residents.
Hand-assisted Approach as a Model to Teach Complex Laparoscopic Hepatectomies: Preliminary Results
Authors: Makdissi Fabio F. , Jeismann Vagner B. , Kruger Jaime A.P. , Coelho Fabricio F. , Ribeiro-Junior Ulysses , Cecconello Ivan , Herman Paulo
Published: August 2017

Background:

Currently, there are limited and scarce models to teach complex liver resections by laparoscopy. The aim of this study is to present a hand-assisted technique to teach complex laparoscopic hepatectomies for fellows in liver surgery.

Materials and Methods:

Laparoscopic hand-assisted approach for resections of liver lesions located in posterosuperior segments (7, 6/7, 7/8, 8) was performed by the trainees with guidance and intermittent intervention of a senior surgeon. Data as: (1) percentage of time that the senior surgeon takes the surgery as main surgeon, (2) need for the senior surgeon to finish the procedure, (3) necessity of conversion, (4) bleeding with hemodynamic instability, (5) need for transfusion, (6) oncological surgical margins, were evaluated.

Results:

In total, 12 cases of complex laparoscopic liver resections were performed by the trainee. All cases included deep lesions situated on liver segments 7 or 8. The senior surgeon intervention occurred in a mean of 20% of the total surgical time (range, 0% to 50%). A senior intervention >20% was necessary in 2 cases. There was no need for conversion or reoperation. Neither major bleeding nor complications resulted from the teaching program. All surgical margins were clear.

Conclusions:

This preliminary report shows that hand-assistance is a safe way to teach complex liver resections without compromising patient safety or oncological results. More cases are still necessary to draw definitive conclusions about this teaching method.
The Feasibility of Hand-assisted Laparoscopic and Laparoscopic Multivisceral Resection Compared With Open Surgery for Locally Advanced Colorectal Cancer
Authors: Zhang Guang-tan , Zhang Xue-dong
Published: August 2017

Background:

The role of hand-assisted laparoscopic and pure laparoscopic surgery for locally advanced colorectal cancer invading or adhering to neighboring organs is controversial. This study evaluated the safety and feasibility of laparoscopic multivisceral resection for colorectal cancer.

Patients and Methods:

This study included 201 patients who underwent multivisceral resection for locally advanced colorectal cancer from January 2007 to December 2013 in the Department of General Surgery, Henan Provincial Hospital. Perioperative outcomes and long-time outcomes were compared among hand-assisted laparoscopic, laparoscopic and open resections.

Results:

Estimated blood loss, wound length, time to the first flatus, and postoperative hospital stay were significantly less or shorter in the hand-assisted laparoscopic surgery (HALS) and laparoscopic surgery group than in open surgery (OS) group. There were no significant differences in tumor size, retrieved lymph nodes, and R0 resection rate of the primary tumor among the 3 groups. Surgeries started as laparoscopic surgery were completed in that manner 76.6% of the time with 10.6% being converted to OS and 12.8% converted to HALS and there were only 2 conversions (2.2%) to OS in the HALS group. No significant difference was noted for overall morbidity rate and reoperation rate among the 3 groups. The overall observed 5-year survival rate was 60.5% in the laparoscopic group, 55.4% in the HALS group, and 47.7% in the open group. There was no significant difference among the 3 groups in the 5-year survival rate.

Conclusions:

Hand-assisted laparoscopic and pure laparoscopic multivisceral resection for locally advanced colorectal cancer is safe and feasible in selected patients. HALS can be used judiciously to reduce the rate of conversion to an open procedure and may be a better alternative for laparoscopic approach.
Play as Regulation
Authors: Foley Gilbert M.
Published: August 2017

The nature of play and an overview of the stages of play in the first 5 years of childhood are discussed. The core features of sensorimotor, functional, and symbolic play are identified. Vignettes describing how play serves a regulatory function punctuate each section. A conceptual framework for the construct of regulation is presented and counterpointed against the primary sources of dysregulation in young children, including excessive psychosensory stimulation, states of intense emotional arousal, anxiety, and conditions of toxic stress. Factors are reviewed that contribute to the development of self-regulatory capacity, including temperament and constitutional factors, cognitive control in the form of executive function; positive parenting, attachment, and internal representation; and the capacity for symbolization, along with the expected progression of the acquisition of self-regulatory capacity. Specific regulatory functions of play are identified and explicated including play as regulatory practice, novelty and investigation, and roles and rules. The article concludes by summarizing the state of current empirical evidence with regard to play and self-regulation.
Adult sex ratios and partner scarcity among hunter–gatherers: implications for dispersal patterns and the evolution of human sociality
Authors: Kramer Karen L. , Schacht Ryan , Bell Adrian
Published: August 2017

Small populations are susceptible to high genetic loads and random fluctuations in birth and death rates. While these selective forces can adversely affect their viability, small populations persist across taxa. Here, we investigate the resilience of small groups to demographic uncertainty, and specifically to fluctuations in adult sex ratio (ASR), partner availability and dispersal patterns. Using 25 years of demographic data for two Savannah Pumé groups of South American hunter–gatherers, we show that in small human populations: (i) ASRs fluctuate substantially from year to year, but do not consistently trend in a sex-biased direction; (ii) the primary driver of local variation in partner availability is stochasticity in the sex ratio at maturity; and (iii) dispersal outside of the group is an important behavioural means to mediate locally constrained mating options. To then simulate conditions under which dispersal outside of the local group may have evolved, we develop two mathematical models. Model results predict that if the ASR is biased, the globally rarer sex should disperse. The model's utility is then evaluated by applying our empirical data to this central prediction. The results are consistent with the observed hunter–gatherer pattern of variation in the sex that disperses. Together, these findings offer an alternative explanation to resource provisioning for the evolution of traits central to human sociality (e.g. flexible dispersal, bilocal post-marital residence and cooperation across local groups). We argue that in small populations, looking outside of one's local group is necessary to find a mate and that, motivated by ASR imbalance, the alliances formed to facilitate the movement of partners are an important foundation for the human-typical pattern of network formation across local groups.

This article is part of the themed issue ‘Adult sex ratios and reproductive decisions: a critical re-examination of sex differences in human and animal societies’.
Change of physicochemical properties, phytochemical contents and biological activities during the vinegar fermentation of Elaeagnus multiflora fruit
Authors: Cho Kye Man , Hwang Chung Eun , Joo Ok Soo
Published: August 2017

This study evaluated the changes of physiochemical properties, phytochemical contents, and biological activities during the vinegar fermentation of Elaeagnus multiflora fruit. The contents of pH and reducing sugar decreased from 3.55 and 6.88 mg/mL 3.34 and 2.13 mg/mL, respectively. However the acidity increased from 0.48% to 5.48% during the vinegar fermentation. The alcohol contents increased up to a maximum value of 6.6% at 20 days, and it then decreased at the end fermentation days (2.0%). The viable numbers of acetic acid bacteria and yeasts increased from 4.32 log CFU/mL and 3.23 log CFU/mL at 10 days to 5.4 log CFU/mL and 5.5 log CFU/mL during the spontaneous fermentation, respectively. The major organic acids were acetic acid (38.84 mg/mL), lactic acid (4.92 mg/mL), and malic acid (1.51 mg/mL). The soluble phenolic and flavonoid contents increased from 0.79 mg/mL and 0.12 mg/mL of initial fermentation day to 1.22 mg/mL and 0.14 mg/mL during the spontaneous fermentation. Content of epicatechin gallate decreased from 168.1 μg/mL at 10 days to 115.97 μg/mL. However the content of gallic acid increased from 18.52 μg/mL to 95.07 μg/mL during fermentation. After 60 days of the fermentation, the antioxidant and digestive enzyme inhibitory activities were 71.35% (DPPH), 79.27% (ABTS), 68.72% (·OH), 85.42% (α-glucosidase), 52.12% (α-amylase), and 53.66% (pancreatic lipase), respectively.
Quality characteristics of Doenjang prepared with sweet potato
Authors: Cha Su-Jin , Park Sao-Ra , Kim Dong-Han
Published: August 2017

The effect of sweet potato on the quality of Doenjang was investigated during fermentation. Viable cells of yeast decreased gradually after 4 weeks of fermentation, but those of aerobic bacteria increased in the late stage. Amylase activity of Doenjang was higher in the late stage of fermentation, while neutral protease maintained high activity during fermentation. Hunter L and b values of Doenjang decreased gradually during fermentation, while a value was increased. The pH of Doenjang decreased gradually until 10 weeks of fermentation, and the titratable acidity was low in the sweet potato added groups. The acid value was low in the Shinyulmi sweet potato added Doenjang. Water activity and oxidation-reduction potential of Doenjang decreased during fermentation. Reducing sugar of Doenjang decreased in the middle stage of fermentation, and it was low in sweet potato added groups. The alcohol content of Doenjang decreased after 2 weeks of fermentation. Amino and ammonia-type nitrogen of Doenjang increased during fermentation and reached the maximum after 10 and 12 weeks of fermentation, respectively. After 12 weeks fermentation, 8% of Shinyulmi sweet potato added Doenjang was more favorable taste, flavor and overall acceptability (p<0.05) than the control or the Yeonwhangmi sweet potato added groups.
Anti-mutagenic and synergistic cytotoxic effect of cisplatin and Honey Bee venom on 4T1 invasive mammary carcinoma cell line
Authors: Arani Faranak Shiassi , Karimzadeh Latifeh , Ghafoori Seyed Mohammad , Nabiuni Mohammad
Published: August 2017

Honey Bee Venom has various biological activities such as inhibitory effect on several types of cancer. Cisplatin is an old and potent drug to treat the most of cancer. Our aims in this study were determination of the anti-mutagenic and cytotoxic effects of HBV on mammary carcinoma, lonely and in combination with cisplatin. In this study 4T1 cell line were cultured and incubated at 37 C in humidified CO2-incubator. The cell viabilities were examined by MTT assay. Also HBV was screened for its anti-mutagenic activity against sodium azide by Ames test. The result showed that 6μg/ml HBV, 20μg/ml cisplatin and 6μg/ml HBV with 10μg/ml cisplatin can induce an approximately 50% 4T1 cell death. 7mg/ml HBV with the inhibition of 62.76% sodium azide showed high potential in decreasing the mutagenic agents. MTT assay demonstrated that HBV and cisplatin can cause cell death in a dose-dependent manner. The cytotoxic effect of cisplatin is also promoted by HBV. Ames test results indicated that HBV can inhibit sodium azide as a mutagenic agent. Anti-mutagenic activity of HBV was increased significantly in presence of S9 mix. Hence, our findings reveal that HBV can enhance the cytotoxic effect of cisplatin drug and it has cancer preventing effects.
Social fluidity mobilizes contagion in human and animal populations
Authors: Colman Ewan , Colizza Vittoria , Hanks Ephraim M. , Hughes David P. , Bansal Shweta
Published: August 2017

Humans and other group-living animals tend to distribute their social effort disproportionately. Individuals predominantly interact with a small number of close companions while maintaining weaker social bonds with less familiar group members. By incorporating this behaviour into a mathematical model we find that a single parameter, which we refer to as social fluidity, controls the rate of social mixing within the group. We compare the social fluidity of 13 species by applying the model to empirical human and animal social interaction data. To investigate how social behavior influences the likelihood of an epidemic outbreak we derive an analytical expression of the relationship between social fluidity and the basic reproductive number of an infectious disease. For highly fluid social behaviour disease transmission is revealed to be density-dependent. For species that form more stable social bonds, the model describes frequency-dependent transmission that is sensitive to changes in social fluidity.
Linear Assembly of a Human Y Centromere
Authors: Jain Miten , Olsen Hugh E. , Turner Daniel J. , Stoddart David , Bulazel Kira V. , Paten Benedict , Haussler David , Willard Huntington F. , Akeson Mark , Miga Karen H.
Published: August 2017

The human genome reference sequence remains incomplete due to the challenge of assembling long tracts of near-identical tandem repeats-in centromeric regions. To address this, we have implemented a nanopore sequencing strategy to generate high quality reads that span hundreds of kilobases of highly repetitive DNAs. Here, we use this advance to produce a sequence assembly and characterization of the centromeric region of a human Y chromosome.
Does size matter? The relationship between predictive power of single-subject morphometric networks to spatial scale and edge weight
Authors: Raamana Pradeep Reddy , Strother Stephen C. ,   for the Australian Imaging Biomarkers and Lifestyle flagship study of ageing,   for The Alzheimer’s Disease Neuroimaging Initiative
Published: August 2017

Network-level analysis based on anatomical, pairwise similarities (e.g., cortical thickness) has been gaining increasing attention recently. However, there has not been a systematic study of the impact of spatial scale and edge definitions on predictive performance. In order to obtain a clear understanding of relative performance, there is a need for systematic comparison. In this study, we present a histogram-based approach to construct subject-wise weighted networks that enable a principled comparison across different methods of network analysis. We design several weighted networks based on three large publicly available datasets and perform a robust evaluation of their predictive power under four levels of separability. An interesting insight generated is that changes in nodal size (spatial scale) have no significant impact on predictive power among the three classification experiments and two disease cohorts studied, i.e., mild cognitive impairment and Alzheimer’s disease from ADNI, and Autism from the ABIDE dataset. We also release an open source python package calledgraynetto enable others to implement the novel network feature extraction algorithm, which is applicable to other modalities as well (due to its domain- and feature-agnostic nature) in diverse applications of connectivity research. In addition, the findings from the ADNI dataset are replicated in the AIBL dataset using an open source machine learning tool calledneuropredict.
Opposing effects of floral visitors and soil conditions on the determinants of competitive outcomes maintain species diversity in heterogeneous landscapes
Authors: Lanuza Jose B. , Bartomeus Ignasi , Godoy Oscar
Published: August 2017

Theory argues that both soil conditions and aboveground trophic interactions are equally important for determining plant species diversity. However, it remains unexplored how they modify the niche differences that stabilise species coexistence and the average fitness differences driving competitive dominance. We conducted a field study in Mediterranean annual grasslands to parameterise population models of six competing plant species. Spatially explicit floral visitor assemblages and soil salinity variation were characterized for each species. Both floral visitors and soil salinity modified species population dynamics via direct changes in seed production and indirect changes in competitive responses. Although the magnitude and sign of these changes were species specific, floral visitors promoted coexistence at neighbourhood scales while soil salinity did so over larger scales by changing the superior competitor's identity. Our results show how below and aboveground interactions maintain diversity in heterogeneous landscapes through their opposing effects on the determinants of competitive outcomes.
Species composition and environmental adaptation of indigenous Chinese cattle
Authors: Gao Yahui , Gautier Mathieu , Ding Xiangdong , Zhang Hao , Wang Yachun , Wang Xi , Faruque MD Omar , Li Junya , Ye Shaohui , Gou Xiao , Han Jianlin , Lenstra Johannes A. , Zhang Yi
Published: August 2017

Indigenous Chinese cattle combine taurine and indicine origins and occupy a broad range of different environments. By 50K SNP genotyping we found a discontinuous distribution of taurine and indicine cattle ancestries with extremes of less than 10% indicine cattle in the north and more than 90% in the far south and southwest China. Model-based clustering andf4-statistics indicate introgression of both banteng and gayal into southern Chinese cattle while the sporadic yak influence in cattle in or near Tibetan area validate earlier findings of mitochondrial DNA analysis. Geographic patterns of taurine and indicine mitochondrial and Y-chromosomal DNA diversity largely agree with the autosomal cline. The geographic distribution of the genomic admixture of different bovine species is proposed to be the combined effect of prehistoric immigrations, gene flow, major rivers acting as genetic barriers, local breeding objectives and environmental adaptation. Whole-genome scan for genetic differentiation and association analyses with both environmental and morphological covariables are remarkably consistent with previous studies and identify a number of genes implicated in adaptation, which includeTNFRSF19,RFX4,SP4and several coat color genes. We propose indigenous Chinese cattle as a unique and informative resource for gene-level studies of climate adaptation in mammals.
Targetable genetic alterations ofTCF4(E2-2) drive immunoglobulin expression in the activated B-cell subtype of diffuse large B-cell lymphoma
Authors: Jain Neeraj , Hartert Keenan , Tadros Saber , Fiskus Warren , Havranek Ondrej , John Ma Man-Chun , Bouska Alyssa , Heavican Tayla , Kumar Dhiraj , Deng Qing , Moore Dalia , Pak Christine , Liu Chih Long , Gentles Andrew , Hartmann Elena , Kridel Robert , Smedby Karin Ekstrom , Juliusson Gunnar , Rosenquist Richard , Gascoyne Randy D. , Rosenwald Andreas , Giancotti Filippo , Neelapu Sattva S. , Westin Jason , Vose Julie , Lunning Matthew , Greiner Timothy , Rodig Scott , Iqbal Javeed , Alizadeh Ash , Davis R. Eric , Bhalla Kapil , Green Michael R.
Published: August 2017

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin-μ (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target theTCF4(E2-2) transcription factor, and that over-expression ofTCF4leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. TheTCF4gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killedin vitroandin vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.
The global biogeography of amino acid variants within a single SAR11 population is governed by natural selection
Authors: Delmont Tom O. , Kiefl Evan , Kilinc Ozsel , Esen Özcan C. , Uysal Ismail , Rappé Michael S. , Giovannoni Stephen , Eren A. Murat
Published: August 2017

The diversity and geographical distribution of populations within major marine microbial lineages are largely governed by temperature and its co-variables. However, neither the mechanisms by which genomic heterogeneity emerges within a single population nor how it drives the partitioning of ecological niches are well understood. Here we took advantage of billions of metagenomic reads to study one of the most abundant and widespread microbial populations in the surface ocean. We characterized its substantial amount of genomic heterogeneity using single-amino acid variants (SAAVs), and identified systematic purifying selection and adaptive mechanisms governing non-synonymous variation within this population. Our Deep Learning analysis of SAAVs across metagenomes revealed two main ecological niches that reflect large-scale oceanic current temperatures, as well as six proteotypes demarcating finer-resolved niches. We identified significantly more protein variants in cold currents and an increased number of protein sweeps in warm currents, exposing a global pattern of alternating genomic diversity for this SAR11 population as it drifts along with surface ocean currents. Overall, the geographic partitioning of SAAVs suggests natural selection, rather than neutral evolution, is the main driver of the evolution of SAR11 in surface oceans.
The Epstein-Barr Virus miR-BHRF1 microRNAs Regulate Viral Gene Expression incis
Authors: Poling Brigid Chiyoko , Price Alexander M. , Luftig Micah A. , Cullen Bryan R.
Published: August 2017

The Epstein-Barr virus (EBV) miR-BHRF1 microRNA (miRNA) cluster has been shown to facilitate B-cell transformation and promote the rapid growth of the resultant lymphoblastoid cell lines (LCLs). However, we find that expression of physiological levels of the miR-BHRF1 miRNAs in LCLs transformed with a miR-BHRF1 null mutant (∆123) fails to increase their growth rate. We demonstrate that the pri-miR-BHRF1-2 and 1–3 stem-loops are present in the 3’UTR of transcripts encoding EBNA-LP and that excision of pre-miR-BHRF1-2 and 1–3 by Drosha destabilizes these mRNAs and reduces expression of the encoded protein. Therefore, mutational inactivation of primiR-BHRF1-2 and 1–3 in the ∆123 mutant upregulates the expression of not only EBNA-LP but also EBNA-LP-regulated mRNAs and proteins, including LMP1. We hypothesize that this overexpression causes the reduced transformation capacity of the ∆123 EBV mutant. Thus, in addition to regulating cellular mRNAs intrans, miR-BHRF1-2 and 1–3 also regulate EBNA-LP mRNA expression incis.

Highlights

The EBV miR-BHRF1 microRNAs do not up upregulate B cell growth intrans.

EBNA-LP expression is downregulated by pri-miR-BHRF1-2 and 1–3 acting incis.

Loss of miR-BHRF1-2 and 1–3 causes EBNA-LP overexpression and inhibits B cell growth.

Novel alternative splicing of EBV Cp/Wp transcripts was identified.
Polymodal Allosteric Regulation of Type 1 Serine/Threonine Kinase Receptors via a Conserved Electrostatic Lock
Authors: Botello-Smith Wesley M. , Alsamarah Abdelaziz , Chatterjee Payal , Xie Chen , Lacroix Jerome J. , Hao Jijun , Luo Yun
Published: August 2017

Type 1 Serine/Threonine Kinase Receptors (STKR1) transduce a wide spectrum of biological signals mediated by TGF-β superfamily members. The STKR1 activity is tightly controlled by their regulatory glycine-serine rich (GS) domain adjacent to the kinase domain. Despite decades of studies, it remains unknown how physiological or pathological GS domain modifications are coupled to STKR1 kinase activity. Here, by performing molecular dynamics simulations and free energy calculation of Activin-Like Kinase 2 (ALK2), we found that GS domain phosphorylation, FKBP12 dissociation, and disease mutations all destabilize a D354-R375 salt-bridge, which normally acts as an electrostatic lock to prevent coordination of adenosine triphosphate (ATP) to the catalytic site. We developed a WAFEX-guided principal analysis and unraveled how phosphorylation destabilizes this highly conserved salt-bridge in temporal and physical space. Using current-flow betweenness scores, we identified an allosteric network of residue-residue contacts between the GS domain and the catalytic site that controls the formation and disruption of this salt bridge. Importantly, our novel network analysis approach revealed how certain disease-causing mutations bypass FKBP12-mediated kinase inhibition to produce leaky signaling in the absence of ligand. We further provide experimental evidence that this salt-bridge lock exists in other STKR1s, and acts as a general safety mechanism in STKR1 to prevent pathological leaky signaling. In summary, our study provides a compelling and unifying allosteric activation mechanism in STKR1 kinases that reconciles a large number of experimental studies and sheds light on a novel therapeutic avenue to target disease-related STKR1 mutants.

AUTHOR SUMMARY

Kinases play central role in essential physiological process and are attractive therapeutic drug targets. One of the important kinase families is Type 1 Serine/Threonine Kinase Receptors (STKR1), which control gene expression in response to extracellular growth factors. The activities of STKR1 are tightly controlled by their regulatory domain, which is distant from the kinase catalytic site. The underlying molecular mechanism is elucidated here. We identified that formation or disruption of a highly conserved charge-charge interaction located near the ATP binding site, mediates the physiological inhibition or activation of STKR1. We find that the stability of this charge-charge interaction is remotely controlled by interactions propagated from the distant regulatory domain. Several disease-causing mutations are located at the regulatory domain. We demonstrate how those mutations bypass these endogenous STKR1 inhibition mechanisms to produce pathological phenotypes. This study provides a general activation mechanism in STKR1 kinases, thus may benefit understanding the molecular mechanism of diseases and drug development.
Identification of TMEM230 mutations in familial Parkinson’s disease (response to comments)
Authors: Deng Han-Xiang , Siddique Teepu
Published: August 2017

We recently reported mutations in TMEM230 in familial Parkinson’s disease (PD). Farrer et al raised the concern that mutations in TMEM230 may not be pathogenic to PD. We seriously evaluated Dr. Farrer’s assertions. We obtained updated clinical information and performed several new experiments, including MegaEx chip screening of the family DNA samples with ∼2 million SNPs for whole-genome linkage study and re-analysis of whole-exome sequencing data. We did not find any other locus more robust than the chromosome 20p (TMEM230), nor any other variants with better segregation than TMEM230-R141L to explain the inheritance of PD in the large Mennonite family. Based on the new genetic data from the Mennonite PD family, and the robust genetic data showing additional TMEM230 mutations in multiple PD families, we are confident to conclude thatTMEM230is a new PD-causing gene. Further studies ofTMEM230should provide important mechanistic insights into understanding the vesicle/endosome trafficking/recycling defects in the pathogenesis of PD.
Kinetic Machine Learning Unravels Ligand-Directed Conformational Change of μ Opioid Receptor
Authors: Feinberg Evan N. , Farimani Amir B. , Hernandez Carlos X. , Pande Vijay S.
Published: August 2017

The μ Opioid Receptor (μOR) is a G-Protein Coupled Receptor (GPCR) that mediates pain and is a key target for clinically administered analgesics. The current generation of prescribed opiates – drugs that bind to μOR – engender dangerous side effects such as respiratory depression and addiction in part by stabilizing off-target conformations of the receptor. To determine both the key conformations of μOR to atomic resolution as well as the transitions between them, long timescale molecular dynamics (MD) simulations were conducted and analyzed. These simulations predict new and potentially druggable metastable states that have not been observed by crystallography. We applied cutting edge algorithms (e.g., tICA and Transfer Entropy) to guide our analysis and distill the key events and conformations from simulation, presenting a transferrable and systematic analysis scheme. Our approach provides a complete, predictive model of the dynamics, structure of states, and structure–ligand relationships of μOR with broad applicability to GPCR biophysics and medicinal chemistry.
Ethyl Methanesulfonate Mutagenesis in Schizosaccharomyces pombe
Authors: Ekwall Karl , Thon Geneviève
Published: August 2017

Here we provide an ethyl methanesulfonate (EMS) mutagenesis protocol for Schizosaccharomyces pombe cells.
Pronuclear Transplantation in the Mouse Embryo
Authors: McGrath James , Solter Davor , Mann Jeff
Published: August 2017

This protocol describes an example of complete zygote enucleation and transplantation of male and female pronuclei; however, single pronuclei can also be removed and transplanted. In this method, pronuclei are removed without penetrating the plasma membrane of the zygote. Instead, they are withdrawn individually or together into a membrane-bound karyoplast that can then be fused with a recipient enucleated zygote using inactivated Sendai virus or electrofusion. Preincubation of the embryos in the presence of the cytoskeletal inhibitors cytochalasin B and colcemid is critical for the survival of the embryos during this microsurgical procedure. The protocol is divided into five parts: (1) isolating embryos, (2) making an enucleation/injection pipette, (3) enucleating a zygote, (4) preparing inactivated Sendai virus, and (5) introducing pronuclei into enucleated zygotes.
Agarose Gel Size Selection for DNA Sequencing Libraries
Authors: Mardis Elaine , McCombie W. Richard
Published: August 2017

Agarose gel electrophoresis may be used to purify fragmented genomic DNA after ligation of adaptors. After electrophoresis, the region of the gel containing the desired size range of DNA is excised, and the DNA is subsequently extracted from the gel and purified by passage through a spin column.
Al Qatef Holding: a case of a rough landing in the Gulf-based real estate industry
Authors: Abou Soueid Mona , Spraggon Martin , Bodolica Virginia
Published: August 2017

Subject area

Organizational behavior.

Study level/applicability

Upper-level undergraduate courses, introductory MBA courses.

Case overview

This case study unveils the story of Al Qatef Holding, a Gulf-based real estate company that was created on the vision of one ambitious businessman. The case begins in 1999 when Faisal Al Qatef decided to pursue his dream of establishing a full-fledged corporation to serve the mounting real estate needs in the Gulf region. Faisal started his company by launching a number of residential and commercial property developments in his home country, Kuwait. During its early years of operation, Al Qatef Holding witnessed an impressive success and an increasing appetite for growth. A couple of years down the road, the founder made the strategic decision to open a new branch in Doha to seize the opportunity that the Qatari real estate market presented at that time. Yet, along with the rapid expansion came the company’s incapacity to deliver on its promises, generating many customer complaints and a damaged reputation owing to poor construction quality and significant delays in project delivery. The case describes the multiple challenges experienced by Al Qatef Holding throughout its evolution and portrays the external and internal dynamics that led to its initial success and subsequent decline.

Expected learning outcomes

Assess the internal dynamics and challenges that are associated with the management of small firms; discuss how leadership styles and characteristics affect the organizational climate and employee performance; demonstrate understanding of how corporate culture drives human behavior in the workplace; perform an analysis of firm structure to estimate its impact on individual and organizational outcomes; apply different techniques for enhancing employee motivation in organizations; and evaluate the effectiveness of managerial decisions and provide recommendations for securing corporate survival.

Supplementary Materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS 6: Human Resource Management.
NCR hospital: turnaround dilemmas of a leader
Authors: Awasthy Richa , Gupta Rajen K.
Published: August 2017

Subject area

Organizational diagnosis. The case addresses the issue of an outsider at a senior position in a family-run business.

Study level/applicability

MBA.

Case overview

NCR-Delhi is a multi-specialty hospital in Delhi and is essentially a family-run business. Though it had done well in the early years since its inception, it had been plagued by many problems and had undergone many changes in management and processes. An outsider joined it as the Facility Director (FD) two years ago. In these two years, he introduced multi-directional changes. However, he has not been able to achieve a complete turnaround of the hospital. The major issues facing him are financial, operational and personnel-related issues. The hospital is currently in a major financial crisis, which has been causing delays in disbursement of salaries and creating resource crunches in daily operations. Most of the patients are government empanelled patients, and collection of payments from such patients usually takes at least three months. Employee attrition and customer satisfaction are also continuing challenges. Other issues include lack of proper support and interference from top management. The FD has been showing considerable prowess and capability in leading the organization, but has not been able to achieve the desired results owing to the above factors.

Expected learning outcomes

To understand the frameworks and process of organizational diagnosis; to understand the influence of change initiatives on organizational culture; and to understand the complexity of family business and what happens when an outsider leader joins family business.

Supplementary materials

Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code

CSS 6: Human Resource Management.
Redesigning tourism in CEE countries: the main areas of change and the communist past
Authors: Mihalic Tanja
Published: August 2017

Purpose

The purpose of this paper is to provide details of the communist and socialist past to inform the debate on redesigning tourism in Central and Eastern European (CEE) countries as impacted by the transition and accelerated by European Union (EU) membership.

Design/methodology/approach

The issues from two sides are addressed: academic and practical. Based on a literature review, the authors propose a model of five main research topics that represent the main areas of change and conceptualise the general EU accession research debate on tourism. Content analysis is conducted on each of the revealed main research topics that are presented and discussed from the standpoint of tourism-relevant socialist and communist stature and image. On the other hand, this paper engages with reality as it surveys real-life practices in tourism development and business operation based on the personal experience of the researcher regarding the social situation under consideration.

Findings

The findings concerning the revealed main areas of tourism change in CEE countries following EU accession refer to the: change from communism towards a new image (Europeanisation and re-imaging), change from communism to capitalism (transformation and marketisation), change from old communist tourism products to new products (rejuvenation, diversification), change from communist towards sustainability values (sustainability) and change from tourism inside the communist block to international tourism (re-internationalisation) The discussion indicates how each area of change relates to socialist and communist content and its tourism relevance and the potential for tourism development, policy and business.

Research limitations/implications

The list of relevant works is not exhaustive as only tourism-focussed quality journals are surveyed in order to define the main areas of change.

Practical implications

A very relevant source of information and impartial advice for tourism developers and policymakers in ex-socialist and communist countries is provided regarding tourism development at the strategic and managerial levels.

Originality/value

This paper fills an identified information/resource gap concerning the potential and contribution of communist and socialist heritage to tourism development and business, and places this in the context of the changes CEE countries have made in order to stay and/or become tourism destinations. It introduces a new term “tourism redesign” which explains the transition in tourism development, policy and management through different areas of change.
A novel continuous berth scheduling model at multiple marine container terminals with tidal considerations
Authors: Dadashi Ali , Dulebenets Maxim A. , Golias Mihalis M. , Sheikholeslami Abdolreza
Published: August 2017

Purpose

The paper aims to propose a new mathematical model for allocation and scheduling of vessels at multiple marine container terminals of the same port, considering the access channel depth variations by time of day.

Design/methodology/approach

This paper proposes a new mathematical model for allocation and scheduling of vessels at multiple marine container terminals of the same port, considering the access channel depth variations by time of day. The access channel serves as a gate for vessels entering or leaving the port. During low-depth tidal periods the vessels with deep drafts have to wait until the depth of the access channel reaches the required depth.

Findings

A number of numerical experiments are performed using the operational data collected from Port of Bandar Abbas (Iran). Results demonstrate that the suggested methodology is able to improve the existing port operations and significantly decrease delayed vessel departures.

Originality/value

The contribution of this study to the state of the art is a novel mathematical model for allocation and scheduling of vessels at multiple terminals of the same port, taking into consideration channel depth variations by time of day. To the best of the authors’ knowledge, this is the first continuous berth scheduling linear model that addresses the tidal effects on berth scheduling (both in terms of vessel arrival and departure at/from the berth) at multiple marine container terminals.
Fuel exports, aid and terrorism
Authors: Asongu Simplice , Nwachukwu Jacinta
Published: August 2017

Purpose

This study aims to use interactive quantile regressions to assess the conditional role of foreign aid in reducing the potentially negative effect of terrorism on fuel exports in 78 developing countries for the period of 1984-2008.

Design/methodology/approach

Bilateral and multilateral aid indicators have been used, whereas terrorism includes domestic, transnational, unclear and total terrorism dynamics. Interactive quantile regressions have been used.

Findings

First, with the exception of unclear terrorism, bilateral aid can be used to mitigate the potentially negative effects of terrorism on fuel exports in bottom quantiles of the fuel export distribution. Second, multilateral aid can be used to reduce the negative effect of transnational terrorism on fuel exports exclusively in the highest (90th) quantile of fuel exports. The corresponding modifying thresholds are within policy ranges disclosed in the summary statistics.

Practical implications

While the policy instrument of bilateral aid is most relevant in countries with below-median fuel exports, the policy instrument of multilateral aid is effective with respect to transnational terrorism in countries with the highest levels of fuel exports.

Originality/value

This study contributes to the literature on the role of external flows in reducing the negative externalities of terrorism on development outcomes.
Soil‐mediated filtering organizes tree assemblages in regenerating tropical forests
Authors: Pinho Bruno Ximenes , de Melo Felipe Pimentel Lopes , Arroyo‐Rodríguez Víctor , Pierce Simon , Lohbeck Madelon , Tabarelli Marcelo
Published: August 2017

Secondary forests are increasingly dominant in human‐modified tropical landscapes, but the drivers of forest recovery remain poorly understood. Soil conditions influence plant community composition, and are expected to change over a gradient of succession. However, the role of soil conditions as an environmental filter driving community assembly during forest succession has rarely been explicitly assessed.

We evaluated the role of stand basal area and soil conditions on community assembly and its consequences for community functional properties along a chronosequence of Atlantic forest regeneration following sugar cane cultivation. Specifically, we tested whether community functional properties are related to stand basal area, soil fertility and soil moisture. Our expectations were that edaphic environmental filters play an increasingly important role along secondary succession by increasing functional trait convergence towards more conservative attributes.

We sampled soil and woody vegetation features across 15 second‐growth (3–30 years) and 11 old‐growth forest plots (300 m2 each). We recorded tree functional traits related to resource‐use strategies (specific leaf area, SLA; leaf dry matter content, LDMC; leaf area, LA; leaf thickness, LT; and leaf succulence, LS) and calculated community functional properties using the community‐weighted mean (CWM) of each trait and the functional dispersion (FDis) of each trait separately and all traits together.

With exception of LA, all leaf traits were strongly associated with stand basal area; LDMC and SLA increased, while LT and LS decreased with forest development. Such changes in LDMC, LT and LS were also related to the decrease in soil nutrient availability and pH along succession, while soil moisture was weakly related to community functional properties. Considering all traits, as well as leaf thickness and succulence separately, FDis strongly decreased with increasing basal area and decreasing soil fertility along forest succession, presenting the lowest values in old‐growth forests.

Synthesis. Our findings suggest that tropical forest regeneration may be a deterministic process shaped by soil conditions. Soil fertility operates as a key filter causing functional convergence towards more conservative resource‐use strategies, such as leaves with higher leaf dry matter content.