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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases genetically characterised by the expansion of the hexanucleotide repeat (GGGGCC)n. Here we investigated the formation of nucleic-acid secondary structures in the expansion repeats, and their role in generating aggregates that are characteristic of ALS/FDT. We observed significant aggregation of DNA (GGGGCC)n, which we ascribe to the formation of multimolecular G-quadruplexes (G4s), as confirmed with G4-selective fluorescent staining. Exposing the aggregates to G4-unfolding conditions, such as photo-oxidation of guanines, led to prompt disassembly, suggesting an essential role of G4s in the aggregation process. We then characterised aggregation in RNA (GGGGCC)nrepeats, which are directly relevant to ALS/FTD pathology. We observed that the RNA repeats aggregate at significantly lower concentrations compared to DNA, strengthening the hypothesis that nucleic acids may play a structural role in pathological aggregation at physiological concentrations. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free aggregates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for ALS and FTD.Abstract Figure

Unprecedented bacterial targets are urgently needed to overcome the resistance crisis. Herein we systematically mine pyridoxal phosphate-dependent enzymes (PLP-DEs) in bacteria to focus on a target class which is involved in crucial metabolic processes. For this, we tailored eight pyridoxal (PL) probes bearing modifications at various positions. Overall, the probes exceeded the performance of a previous generation and provided a detailed map of PLP-DEs in clinically relevant pathogens including challenging Gram-negative strains. Putative PLP-DEs with unknown function were exemplarily characterized via in-depth enzymatic assays. Finally, we screened a panel of PLP binders for antibiotic activity and unravelled the targets of hit molecules. Here, an uncharacterized enzyme, essential for bacterial growth, was assigned as PLP-dependent cysteine desulfurase and confirmed to be inhibited by the marketed drug phenelzine. Our approach provides a basis for deciphering novel PLP-DEs as essential antibiotic targets along with corresponding ways to decipher small molecule inhibitors.

Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.

The transfer of technology from the foreign partner to the domestic partner has been a problem for international joint ventures throughout the world, but particularly in China. Because of the nature of organisational learning, especially in its tacit forms, such transfers can occur quite subtly without the foreign partner realising what has transpired until it is too late. The problem is complicated by the fact that technology is short‐lived and must be exploited within narrow time frames, the fact that the Chinese partner’s primary interest is in acquiring the foreign partner’s technology, and the fact that the foreign partner typically shows little interest in obtaining the Chinese partner’s unique non‐technical knowledge as an offset. This article attempts to show how technology transfers can be controlled in the first place and how the foreign partner’s competitive advantage can be preserved by acquiring the domestic partner’s unique knowledge of host country circumstances.

The seconf of two articles on the transfer from foreign companies to affiliates in China. Addresses wholly owned subsidiaries. Tries to determine strategic management know‐how and if it is currently being transferred. Attempts to forecast the likelihood of access to China’s domestic market and if this will grow.

Briefly outlines the development and attraction of the “joint venture” approach to foreign investment in China. Provides a number of in‐depth interviews with top management personnel of five well‐known international joint ventures. Attempts to discover what strategic management knowledge was transferred from the Western partner. Finds only limited evidence to suggest such a transfer was taking place but suggests that these ventures are still relatively new. Points to China’s likely entry into the World Trade Organisation as an opportunity for change.

States that competitive advantage is like a moving target, changing over time as market conditions, consumer demand and resource availability vary. Provides a case study of Taiwan’s present advantages within the heights of the Asian economic growth and the recent economic crisis. Considers the ability of the country to sustain its remarkable growth rate and ask whether it needs to develop a new set of advantages. Uses Porter’s Diamond model in the “Competitive Advantage of Nations” (1990) to examine this issue. Concludes that the biggest threat is that of China’s claim to Taiwan’s territory.

Looks at the problems of logistics in military operations and today’s commercial businesses. Traces the development of logistics management from a subordinate activity within a product producing entity to its performance by a separate entity which specializes in this area and requires a strategic alliance. Looks at this issue from the perspective of the outsourcing company and the logistical company. Considers what happens when this process is reversed and provides implications for the future.

Assesses the effects of the Asian economic crisis on Taiwan and identifies some reasons why it has been less dramatically affected than other Asian countries. Discusses its actual and planned policies aimed at strengthening the economy further by maintaining currency stability, improving competitive strengths in both hi‐tech industries and manufacturing, entering new export markets, stimulating domestic demand and reforming financial institutions and regulations. Recognizes the political threats it faces but believes that increasing trade with and investment in China has reduced them.

Outlines the Japanese system of protectionism as a global barrier and focuses on the rice markets as one of the first markets to be opened up. Analyses the reasons for this and offers strategies for overseas companies to take advantage of this opportunity. Suggest that these examples can then be applied to other markets.

Warns against expecting the Japanese and Chinese to behave similarly, despite common features of their national cultures and geographical proximity. Points out that China follows Confucian‐based business ethics based on connections, mutual trust and under the table dealings, whereas Japan subscribes to Shinto‐based business ethics, depending on perfection, product superiority, obligation, personal honesty and self‐sacrifice. Provides a brief historical overview of each country’s cultural and political dynamics, then draws attention to some of the important differences between China and Japan – China preferring a command culture, pragmatism, centred on the family and using punishment as a means of ensuring conformity, whereas Japan prefers a consensus culture, sentimentality, has a strong sense of nationhood and relies on praise to achieve required performance. Suggests that western businesses keep this in mind if they are to conduct business successfully in either or both of these two countries.

Explores Chinese culture and the problems foreign firms and governments encounter when dealing with China. Emphasizes Confucianism’s dominant cultural tradition in China and attempts to explain it to improve foreign firms’ chances of success. Describes Confucianism as a way of living, incorporating the principles of humanism and the notion of filial piety. Mentions the five cardinal relations, harmony and Neo‐Confucianism’s “Principle of universal truth, order, law, production and reproduction”. Assesses the implications of social inequality, social ritual, familism, guan xi (connections), face, and sun yung (mutual trust) for foreign firms. Concludes that foreign firms wishing to do business with China need to understand the labyrinth of Confucianism.

Strategic management thinking emerged in the 1930s (Steiner, 1969), and developed significantly in the 1940s. An identifiable body of literature began to appear in the 1950s and increased significantly, so much so that strategic management became a separate discipline in the 1970s. Over these years, two main themes were pursued: (1) process and (2) content. A third theme, structure (sometimes referred to as “organisation”), received less attention, probably because of its overlap with process and content, and because its parameters have been difficult to identify.

The textile and apparel industries of certain Pacific Rim countries have posed a serious threat to their counterparts in the United States. Competition from those countries has forced the closure of major segments of the US textile and apparel industries and has placed heavy negative pressure on the United States balance of payments account. Yet, those industries remain a $50 billion giant in the US economy, provide over 2.4 million jobs at lower levels of the wage spectrum (United States Bureau of the Census, 1989), and are consequently a force to be reckoned with.

Before endowing lifetime employment with magical powers and importing it to solve America's problems, we should take a good look at what it is and the culture in which it has evolved.