bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTType 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 SUMMARYKinases 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.
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

ABSTRACTThe 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.
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

Abstract

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.
Differential expression of two genes Oct‐4 and MUC5AC associates with poor outcome in patients with gastric cancer
Authors: Javanbakht Milad , Akhavanmoghadam Jamal , Talaei Amir Jouya , Aghyani Maryam , Mozafari Mohamad , Khedmat Leila , Mohebbi Mahdi 
Published: August 2017

SummaryGastric cancer (GC) is the most frequent leading cause of cancer‐associated mortality worldwide that is linked to poor prognosis due to the lack of appropriate biomarkers. Our aim was to evaluate the MUC5AC and Oct‐4 expression levels in GC and to assess their association with clinical factors. Immunohistochemical analysis (IHC) and qRT‐PCR were performed in GC patients to examine the MUC5AC and Oct‐4 expression levels. The mRNA level of MUC5AC was significantly decreased in tumour tissues compared with non‐cancerous tissues (1.11 ± 0.69 vs 3.7 ± 0.71; P = .024). On the other hand, Oct‐4 mRNA level was upregulated in tumour tissues as compared to normal tissues (2. 86 ± 0.78 vs 0.87 ± 0.54; P = .0015). Decreased expression of MUC5AC was detected in 27 patients (67.5%), while high to moderate expression levels were observed in 13 cases (32.5%), but in normal tissues the expression levels of MUC5AC were increased (P = .001). The decreased expression of MUC5AC was associated with aggressive tumour characteristics, such as TNM stage (P = .023), histologic type (P = .012) and lymph node metastasis (P = .001). High expression of Oct‐4 was detected in 24 tumour tissues (60%), while 16 cases (40%) showed low expression level. Increased Oct‐4 expression was correlated with clinicopathological characteristics such TNM stage (P = .002), histologic type (P = .008) and lymph node metastasis (P = .001). Our results showed that high Oct‐4 expression and the reduction of MUC5AC expression may be involved in the progression and an unfavorable prognosis of GC.
Associations between systemic bone mineral density, knee cartilage defects and bone marrow lesions in patients with knee osteoarthritis
Authors: Zhu Qicui , Xu Jianhua , Wang Kang , Cai Jingyu , Wu Juan , Ren Jiale , Zheng Shuang , Ding Changhai 
Published: August 2017

AbstractAimThe relationship between bone mineral density (BMD) and osteoarthritis (OA) remains controversial. This study aimed to explore the cross‐sectional associations between BMD at the total body, hip and spine and joint structural abnormalities including cartilage defects and bone marrow lesions (BMLs) in patients with knee OA.MethodOne hundred and eight‐five subjects with symptomatic knee OA were included in this study. T2‐weighted fast spin echo magnetic resonance imaging was used to assess knee cartilage defects and BMLs. Total body, hip and spine BMD were measured using dual‐energy X‐ray absorptiometry.ResultsAfter adjustment for potential confounders, total hip BMD was negatively associated with medial tibial cartilage defects, lateral femoral cartilage defects, medial tibial BMLs and lateral tibial BMLs. Spine and total body BMD were negatively associated with lateral femoral cartilage defects, but not with BMLs.ConclusionWe concluded that BMD particularly at the hip was negatively associated with knee cartilage defects and BMLs.
Effect of pre existing respiratory conditions on survival of lung cancer patients: A nationwide population‐based cohort study
Authors: Hong Seri , Park Eun‐Cheol , Kim Tae Hyun , Kwon Jeoung A , Yoo Ki‐Bong , Han Kyu‐Tae , Yoo Ji Won , Kim Sun Jung 
Published: August 2017

AbstractBackgroundCommon diseases with potential to increase the risk of death from lung cancer have so far not been studied in large populations.MethodsWe did a population‐based retrospective cohort study using nationwide health insurance claims data from 2005 to 2012 in Korea including 205 403 lung cancer patients. Multivariate‐adjusted hazard ratios (aHRs) of lung cancer mortality by presence, time intervals with lung cancer diagnosis and combinations of pre‐existing chronic obstructive pulmonary disease (COPD), pneumonia, asthma and tuberculosis were calculated using the Cox‐proportional hazards model.ResultsThe total number of person‐years of follow‐up was 397 780 and 60.2% of patients died (mean survival 23.2 months after lung cancer diagnosis). Lung cancer patients with previous respiratory disease had increased aHR for mortality (COPD, hazard ratio [HR] = 1.32, CI 1.29–1.35; pneumonia, HR = 1.14, CI 1.08–1.19; and asthma, HR = 1.11, CI 1.06–1.16). Risks were positively associated with longer duration of pre‐existing disease diagnosis; cases with >5 years since diagnosis compared to <2 years: COPD, HR = 2.91, CI 2.82–3.00; pneumonia, HR = 1.67, CI 1.51–1.85; asthma, HR = 1.56, CI 1.45–1.68; and tuberculosis, HR = 2.03, CI 1.90–2.17. Furthermore, elevated HRs of death were found among patients with multiple pre‐existing co‐morbidities.ConclusionHazards of death from lung cancer are significantly increased in cases with pre‐existing lung disease, and worse with longer durations, and with multiple combinations before cancer diagnosis. Patients and physicians should be aware of these meaningful risk/prognostic factors for lung cancer when identifying high‐risk patient groups.
Medical travel facilitators, private hospitals and international medical travel in assemblage
Authors: Chee Heng Leng , Whittaker Andrea , Por Heong Hong 
Published: August 2017

AbstractInternational medical travel may be viewed as an ‘assemblage’ of various components such as infrastructure, hospitals, finance, transport, technologies, staff, facilitators and patients. In this paper, we focus on the articulations of medical travel facilitators (MTFs) and private hospitals in producing international medical travel in the context of the neoliberalising processes that had led to the rise of corporate hospital care in Malaysia in the 1990s. We draw from three hospital case studies for a comparative perspective. We highlight the shifting, unstable and contingent relations and interactions of the MTFs, as one component of the assemblage of international medical travel, with hospitals and medical travellers. We identify the practices of MTFs in providing patients with information and advice about hospitals and doctors as efforts to shape patients' choices in the selection of health‐care providers and in decision‐making. The assemblage approach allows us to see how the MTFs emerge and stabilise as a collective identity for individuals and companies performing particular functions through their multifarious articulations with other components in various sites of assemblage.