bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the malate–aspartate shuttle in mouse pancreatic islets abolishes glucagon secretion without affecting insulin secretion
Authors: Stamenkovic Jelena A. , Andersson Lotta E. , Adriaenssens Alice E. , Bagge Annika , Sharoyko Vladimir V. , Gribble Fiona , Reimann Frank , Wollheim Claes B. , Mulder Hindrik , Spégel Peter 
Published: March 2015

Altered secretion of insulin as well as glucagon has been implicated in the pathogenesis of Type 2 diabetes (T2D), but the mechanisms controlling glucagon secretion from α-cells largely remain unresolved. Therefore, we studied the regulation of glucagon secretion from αTC1-6 (αTC1 clone 6) cells and compared it with insulin release from INS-1 832/13 cells. We found that INS-1 832/13 and αTC1-6 cells respectively secreted insulin and glucagon concentration-dependently in response to glucose. In contrast, tight coupling of glycolytic and mitochondrial metabolism was observed only in INS-1 832/13 cells. Although glycolytic metabolism was similar in the two cell lines, TCA (tricarboxylic acid) cycle metabolism, respiration and ATP levels were less glucose-responsive in αTC1-6 cells. Inhibition of the malate–aspartate shuttle, using phenyl succinate (PhS), abolished glucose-provoked ATP production and hormone secretion from αTC1-6 but not INS-1 832/13 cells. Blocking the malate–aspartate shuttle increased levels of glycerol 3-phosphate only in INS-1 832/13 cells. Accordingly, relative expression of constituents in the glycerol phosphate shuttle compared with malate–aspartate shuttle was lower in αTC1-6 cells. Our data suggest that the glycerol phosphate shuttle augments the malate–aspartate shuttle in INS-1 832/13 but not αTC1-6 cells. These results were confirmed in mouse islets, where PhS abrogated secretion of glucagon but not insulin. Furthermore, expression of the rate-limiting enzyme of the glycerol phosphate shuttle was higher in sorted primary β- than in α-cells. Thus, suppressed glycerol phosphate shuttle activity in the α-cell may prevent a high rate of glycolysis and consequently glucagon secretion in response to glucose. Accordingly, pyruvate- and lactate-elicited glucagon secretion remains unaffected since their signalling is independent of mitochondrial shuttles.
Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency
Authors: Jin Yi , Chen Mo , Penning Trevor M. , Miller Walter L. 
Published: March 2015

Cytochrome P450 oxidoreductase (POR) is a 2-flavin protein that transfers electrons from NADPH via its FAD and FMN moieties to all microsomal cytochrome P450 enzymes, including steroidogenic and drug-metabolizing P450s. Defects in the POR gene can cause POR deficiency (PORD), manifested clinically by disordered steroidogenesis, genital anomalies and skeletal malformations. We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro. Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting that flavin therapy may be useful for this frequent form of PORD. Transient kinetic dissection of the reaction of POR with NADPH and the reduction in cytochrome c by POR using stopped-flow techniques revealed defects in individual electron transfer steps mediated by A287P. A287P had impaired ability to accept electrons from NADPH, but was capable of a fast FMN → cytochrome c electron donation reaction. Thus the reduced rates of P450 activities with A287P may be due to deficient flavin and impaired electron transfer from NADPH.
Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations
Authors: Kim Tae , Thankachan Stephen , McKenna James T. , McNally James M. , Yang Chun , Choi Jee Hyun , Chen Lichao , Kocsis Bernat , Deisseroth Karl , Strecker Robert E. , Basheer Radhika , Brown Ritchie E. , McCarley Robert W. 
Published: March 2015

Significance
When we are awake, purposeful thinking and behavior require the synchronization of brain cells involved in different aspects of the same task. Cerebral cortex electrical oscillations in the gamma (30–80 Hz) range are particularly important in such synchronization. In this report we identify a particular subcortical cell type which has increased activity during waking and is involved in activating the cerebral cortex and generating gamma oscillations, enabling active cortical processing. Abnormalities of the brain mechanisms controlling gamma oscillations are involved in the disordered thinking typical of neuropsychiatric disorders such as schizophrenia. Thus, these findings may pave the way for targeted therapies to treat schizophrenia and other disorders involving abnormal cortical gamma oscillations.
Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution
Authors: Tzeng Alice , Kwan Byron H. , Opel Cary F. , Navaratna Tejas , Wittrup K. Dane 
Published: March 2015

Significance
Cytokines (potent immunostimulatory proteins) exert powerful antitumor effects but often cause severe whole-body inflammation when used as cancer therapies. Contrary to the current paradigm that fusion to antitumor antibodies can constrain cytokine activity to tumors, we have found that, for some immunocytokines incorporating the cytokine IL-2, the cytokine moiety overrides antibody-mediated targeting, localizing the fusion protein to IL-2 receptor-expressing cells rather than tumor cells. Although the IL-2 immunocytokines did not selectively home to tumors, they persisted longer in circulation than free IL-2, such that a nontoxic immunocytokine dose could synergize with tumor-specific antibody to cure mice with aggressive solid tumors.
Plasmodium falciparumchloroquine resistance transporter is a H+-coupled polyspecific nutrient and drug exporter
Authors: Juge Narinobu , Moriyama Sawako , Miyaji Takaaki , Kawakami Mamiyo , Iwai Haruka , Fukui Tomoya , Nelson Nathan , Omote Hiroshi , Moriyama Yoshinori 
Published: March 2015

SignificanceMalaria caused byPlasmodium falciparumis a severe infectious disease with high mortality and morbidity rates worldwide. Chloroquine (CQ) is a widely used antimalarial agent, but the emergence and spread of CQ-resistant parasites is a growing global health problem. Although its physiological relevance remains unknown,P. falciparumCQ resistance transporter (PfCRT) confers CQ resistance through CQ egress from digestive vacuoles ofP. falciparum. To address this issue, recombinant CQ-sensitive or CQ-resistant PfCRT proteins were purified and their transport activities were assessed. Both CQ-sensitive and CQ-resistant PfCRTs transported CQ, various antimalarial agents, and basic amino acids, indicating that PfCRT is a polyspecific drug and nutrient exporter.
Comprehensive analysis of heterotrimeric G-protein complex diversity and their interactions with GPCRs in solution
Authors: Hillenbrand Matthias , Schori Christian , Schöppe Jendrik , Plückthun Andreas 
Published: March 2015

Significance
G-protein–coupled receptors (GPCRs) are the target of 30% of all drugs on the market. Nevertheless, the lack of detailed knowledge of GPCR signaling impedes the development of highly specific drugs. In this respect, additional structures of GPCR/G-protein complexes could greatly enhance our knowledge on how to design specific drugs. Unfortunately, the nature of the GPCR/G-protein complex is characterized by a transient interaction and an intrinsic instability, thereby hampering structure determination. In our study, we show—besides new insights into the combinatorial diversity of heterotrimeric G proteins—that the combination of evolved, stable GPCR mutants and G-protein combinations selected from the natural pool of G proteins yields promisingly stable GPCR/G-protein complexes.
Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance
Authors: Conde João , Oliva Nuria , Artzi Natalie 
Published: March 2015

Significance
The integration of biomaterials science, innovative imaging, and cancer biology now enables the design of smart responsive material platforms for cancer theranostics. We show herein that our developed nanovehicle is able to sense and silence a multidrug resistance gene based on its expression in the tumor microenvironment, followed by local chemotherapeutic drug release, with a significant tumor regression not achieved otherwise. This ON/OFF molecular nanoswitch approach can be used to reverse the resistance to many other chemotherapeutic drugs and can serve as a universal gene therapy and drug delivery vehicle for cancer therapy. This disease-responsive platform can revolutionize clinical outcome and cancer patients’ point of care.
Four basic residues critical for the ion selectivity and pore blocker sensitivity of TMEM16A calcium-activated chloride channels
Authors: Peters Christian J. , Yu Haibo , Tien Jason , Jan Yuh Nung , Li Min , Jan Lily Yeh 
Published: March 2015

Significance
TMEM16A is a calcium-activated chloride channel, meaning that it is a protein found at the surface of a variety of cells that permits chloride to enter when internal calcium levels rise. TMEM16A has been implicated in a variety of biological processes, including epithelial fluid secretion, smooth muscle contraction, neuron firing, and cancer cell proliferation. However, it is unclear how chloride ions are guided across the cell membrane by this protein. Here, we have modified and tested positively charged amino acids of TMEM16A and found four that modify chloride flux. We also tested potential blockers from a high-throughput screen and describe two that appear to block chloride’s path, which should contribute to future studies attempting to further analyze TMEM16A’s function.
Ultrasonographic comparison of two landmarks for the internal jugular vein: high versus conventional approach
Authors: Hwang Jin-Young , Ju Jae-Woo , Min Seong-Won , Do Sang-Hwan , Ryu Jung-Hee 
Published: March 2015

Objective
We assessed and compared two landmarks (conventional vs. high approach) used in internal jugular vein (IJV) cannulation with respect to the degree of overlap with the carotid artery (CA) and the cross-sectional area (CSA) of the IJV using ultrasonography.

Patients and methods
Forty-eight adult patients were included. Using ultrasonography, the percentage overlaps with the CA and the CSA of both IJVs were measured in the supine and Trendelenburg positions using conventional and high approaches. With the conventional approach, the IJV is penetrated at the apex of Sedillot’s triangle, formed by the clavicle and the sternal and clavicular heads of the sternocleidomastoid muscle. The high approach involves the midpoint between the sternal notch and the mastoid process.

Results
The degree of overlap with the CA was 30.5 (7.5–69.4)% [median (interquartile range)] and 0.0 (0.0–25.4)% with the conventional and high approaches, respectively, for the right IJV (P<0.001) in the Trendelenburg position with 30° head rotation. The CSA of the right IJV was 1.22 (0.92–2.01) and 0.98 (0.79–1.72) cm2 with the conventional and high approaches, respectively (P<0.001), in the Trendelenburg position with 30° head rotation. IJV was more deeply positioned using the high approach than the conventional approach (P<0.001).

Conclusion
The high approach for IJV cannulation decreased both the degree of overlap with the CA and CSA of the IJV and increased the depth of the IJV from the skin compared with the conventional approach.
WRKY42 Modulates Phosphate Homeostasis through Regulating Phosphate Translocation and Acquisition in Arabidopsis
Authors: Su Tong , Xu Qian , Zhang Fei-Cui , Chen Yun , Li Li-Qin , Wu Wei-Hua , Chen Yi-Fang 
Published: March 2015

Abstract
The Arabidopsis (Arabidopsis thaliana) WRKY transcription factor family has more than 70 members, and some of them have been reported to play important roles in plant response to biotic and abiotic stresses. This study shows that WRKY42 regulated phosphate homeostasis in Arabidopsis. The WRKY42-overexpressing lines, similar to the phosphate1 (pho1) mutant, were more sensitive to low-inorganic phosphate (Pi) stress and had lower shoot Pi content compared with wild-type plants. The PHO1 expression was repressed in WRKY42-overexpressing lines and enhanced in the wrky42 wrky6 double mutant. The WRKY42 protein bound to the PHO1 promoter under Pi-sufficient condition, and this binding was abrogated during Pi starvation. These data indicate that WRKY42 modulated Pi translocation by regulating PHO1 expression. Furthermore, overexpression of WRKY42 increased root Pi content and Pi uptake, whereas the wrky42 mutant had lower root Pi content and Pi uptake rate compared with wild-type plants. Under Pi-sufficient condition, WRKY42 positively regulated PHOSPHATE TRANSPORTER1;1 (PHT1;1) expression by binding to the PHT1;1 promoter, and this binding was abolished by low-Pi stress. During Pi starvation, the WRKY42 protein was degraded through the 26S proteasome pathway. Our results showed that AtWRKY42 modulated Pi homeostasis by regulating the expression of PHO1 and PHT1;1 to adapt to environmental changes in Pi availability.
MIDCOM: a strategic initiative in the Middle East and Africa
Authors: Jham Vimi , Van Genderen Eric 
Published: March 2015

Subject area
Marketing Strategy, International Marketing.

Study level/applicability
MBA Course Core course of Marketing Management. Specialization courses in Services marketing, Marketing Management, Retail Management. Executive training workshops on strategy formulations. Faculty development workshops on teaching pedagogy through cases. Capstone courses.

Case overview
The case talks about the declining share of Nokia globally, which affected Midcom's business. Despite this downfall, Midcom had maintained a majority share in the market. For now, the Middle East and Africa region was least effected by the global market share drop of Nokia, but Nokia's dropping market share was one of the threats Midcom might face in Africa. The segment where Android and BlackBerry Messenger (BBM) had hit Nokia was a minority stake holder in Nokia's share in Africa. The market itself was growing, but there was stiff competition from brands such as Samsung, Tecno, HTC, Apple and other Chinese brands. The case revolves around the strategies adopted by Midcom to maintain its leadership in the market to avoid the threats from its competitors.

Expected learning outcomes
The case seeks an intensive reading, research and a stimulating in-class discussion on implementing marketing strategy mixed with creating experience in the service industry with special focus on the telecom industry. The case is also open to other angles as per the other intents and context of the course and course instructor. Some of the learning outcomes from the case will be in the area of: customer satisfaction, distribution management, market leadership, retailing, competitive strategies in marketing and international marketing.

Supplementary materials
Teaching notes are available for educators only. Please contact your library to gain login details or e-mail support@emeraldinsight.com to request teaching notes.

Subject code
CSS 8: Marketing
Intrim Business Associates: taking on global consulting goliaths
Authors: Rastogi Parag , Sharma Radharani 
Published: March 2015

Subject area
Entrepreneurship, Strategic Marketing, Retail Management.

Study level/applicability
It may be used in marketing/strategy/organisation behaviour courses of MBA programmes as well as in specific executive education programmes dealing with business strategy, sales and marketing, entrepreneurship and organisation behaviour.

Case overview
In 2002, Rajan Chhibba co-founded Intrim Business Associates (IBA), a niche strategy consulting firm in India. IBA pitched for a consulting assignment for retail strategy/implementation with a steel manufacturer in India, where they were pitched against a large global consulting firm. After conducting a diagnostic study and reaching a stage where IBA had almost got the project, the client put forth a demand which was make-or-break for IBA. The case puts forth the questions faced by Rajan Chhibba at the time of replying to the client: How was IBA different from global consulting firms? Was IBA willing to compromise on quality of the project to reduce costs? Was reduction of price the only option for getting the project? What factors should Rajan Chhibba consider before making his final pitch?

Expected learning outcomes
This case may help students to: appreciate an entrepreneur's smart strategy up against formidable competition, analyse the resources crunch an entrepreneur faces and how he overcomes them, understand how organisations learn from their experience and appreciate the challenges in a competitive environment.

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.
Maruti Suzuki India Limited: the Celerio
Authors: Kumar Vinod , Gautam Vivek 
Published: March 2015

Subject area
Marketing, new product launch and innovations.

Study level/applicability
Postgraduate students.

Case overview
Maruti Suzuki India Ltd. (MSIL), established in February 1981, formerly known as MarutiUdyog Limited, is a subsidiary of Japanese automobile Manufacturer Suzuki. It has a market share of 37 per cent in passenger car segment in India. Its product portfolio ranges from entry-level Alto to hatchbacks like A-Star, Zen Estilo, etc. to sedans like SX 4 to sports utility vehicles like Grand Vitara. MSIL is always known for delivering value on these lines – low cost of acquisition, high fuel economy, less maintenance hassles and wide service network. MSIL is planning to launch its much awaited hatchback Celerio with revolutionary auto gear shift technology for the first time in India at an affordable price. Promotional campaign is yet to be completed. Online trends reflect the consumer trends of any country. During the Auto Expo Week, Maruti Suzuki Celerio became the most searched hatchback on Google in the subcontinent according to a report published by the Indian Express citing the Google Trends Report. One of the key success factor is communicating the right message to the customers so as to attract them. So, MSIL's challenge is to plan a product launch so as to spread awareness.

Expected learning outcomes
To discuss the ways in which the product may be differentiated, to acquaint students with the process of developing a slogan for the introduction of Celerio to the existing market, to explain the concept of segmentation to the students, to familiarize students with communication mix and to give the students an idea about need of digital communication to promote the product.

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.
Mastering the art of managing a conglomerate business empire in Myanmar
Authors: Goh Jenson Chong-Leng , Sabnani Manohar P. , Tan Gee Kwang Randolph , Tan Siew Peng 
Published: March 2015

Subject area
Strategy.

Study level/applicability
Undergraduate final year or MBA.

Case overview
This teaching case describes the journey undertaken by Yoma Strategic Holdings (YSH) Ltd, a Singapore-listed company that operates predominately in Myanmar, to become a successful and highly profitable conglomerate business empire in Myanmar. The case provides a rich contextual description of how YSH leveraged upon its partnerships and capabilities, especially with its parent and sister companies, to pursue its conglomerate business model. To facilitate the discussion that this teaching case aims to generate among lecturers and students, we have provided a summary of the latest developments in Myanmar since the 2010 general election. This helps to give students an appreciation of the challenges involved in creating a successful business in Myanmar.

Expected learning outcomes
The learning outcomes that this teaching case hopes to achieve in students are as follows: Understand the concept of “economies of scope” in corporate strategy; identify and explain the various corporate strategies (i.e. diversification and vertical integration) that can be implemented to develop a conglomerate business model; recognize the organizational and managerial issues arising from implementing these corporate strategies and understand the circumstances that influence its success; and assess the relative advantages of managing a business in a conglomerate business model and advise a company on whether a particular activity should be undertaken internally or outsourced.

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.
Fastrack: pushing the boundaries of brand extension
Authors: Prabhakar Shekar , Lokhande Madhavi 
Published: March 2015

Subject area
Marketing.

Study level/applicability
MBA students.

Case overview
Titan Industries Limited is the world's fifth-largest wristwatch manufacturer and India's leading producer of watches under the Titan, Fastrack, Sonata, Nebula, Raga, Regalia, Octane and Xylys brand names. When a joint venture with Timex came to an end, Titan found themselves without a range of watches for the youth, a growing segment with significant disposable incomes. To serve that segment, they launched a range of “cool” casual watches under the Fastrack from Titan sub-brand in 1998. Sunglasses were also launched but under the Accessories division of the company. In 2003, a decision was taken to combine the watches and sunglasses and spin it off under a new group called “Fastrack and New Brands”. Post this spin-off, Fastrack was launched as a standalone brand with the vision of becoming the most iconic and exciting fashion brand for youth. The overarching strategy was to bring affordable fashion to the youth and bridging the gap between the unorganized market and international brands. The product strategy was to extend the brand rapidly into other accessories such as belts, wallets, bags and wristbands. The brand personality was to be irreverent and comfortable with impropriety. Their communications reflected the brand attitude with edgy advertising. The distribution model adopted was to have their own branded stores. The brand grew from a mere INR30 crores in 2003 to INR770 crores in 2013. As the brand grew largely from moving into adjacent product categories, Fastrack managers were always looking for the next product category to enter and dominate. In 2013-2014, the product category seriously being looked at was two-wheeler helmets – a category dominated largely by the unorganized sector with low quality. The challenge was to take a product category that existed mainly due to safety regulations and turn it into a personal, fashion accessory. Was it a large enough market to penetrate and dominate? Would they be able to change consumer perception of helmets being a necessary evil to being a fashion accessory proudly displayed? Can they change consumer purchase behavior to go shopping for helmets instead ofjust buying the cheapest, comfortable helmet? Would the brand extension into helmets strengthen or dilute brand equity? These were the questions that faced Ronnie Talati, the Chief Marketing Officer.

Expected learning outcomes
Understand how to go about creating a brand strategy when re-launching it as a standalone brand without the support of the corporate umbrella brand; analyze different product markets to enter and how to arrive at a go/no-go decision; comprehend the challenges of extending the brand into different and sometimes unrelated product categories.

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.