A structural comparison of human serum transferrin and human lactoferrin

The transferrins are a family of proteins that bind free iron in the blood and bodily fluids. Serum transferrins function to deliver iron to cells via a receptor-mediated endocytotic process as well as to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment. Lactoferrins (found in bodily secretions such as milk) are only known to have an anti-bacterial function, via their ability to tightly bind free iron even at low pH, and have no known transport function. Though these proteins keep the level of free iron low, pathogenic bacteria are able to thrive by obtaining iron from their host via expression of outer membrane proteins that can bind to and remove iron from host proteins, including both serum transferrin and lactoferrin. Furthermore, even though human serum transferrin and lactoferrin are quite similar in sequence and structure, and coordinate iron in the same manner, they differ in their affinities for iron as well as their receptor binding properties: the human transferrin receptor only binds serum transferrin, and two distinct bacterial transport systems are used to capture iron from serum transferrin and lactoferrin. Comparison of the recently solved crystal structure of iron-free human serum transferrin to that of human lactoferrin provides insight into these differences

CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN–associated ID

Navigating conflicts of interest: Ethical policies of 12 exemplary Asian media organisations

While research into non-Western media systems and professional norms are growth areas in journalism studies, little is known about the policies of news organisations beyond a few celebrated global brands. This exploratory study is situated in that gap. It examines 12 reputable media organisations in seven territories – China, India, Indonesia, Malaysia, Pakistan, Philippines and Taiwan. Through interviews with top-level editors and executives, the study analyses their stated policies with regard to commercial conflicts of interest. In particular, how they deal with pressures from owners and advertisers who want favourable news coverage and how they respond to the demand for commercial deals that blur the boundaries between editorial and advertising. The study responds to recent calls in media ethics scholarship for critical-empiricist research on the ‘possible’ world, focusing on actually existing exemplars rather than abstract ideals. The 12 organisations have adopted a range of responses to these pressures. In general, most have policies aimed at preserving their editorial integrity even as they become more accommodating to the market. Our interviewees point to the importance of organisational culture, more than written policies, in maintaining professionalism: most of the organisations were founded by journalist-publishers whose ethos continues to exert a strong influence. While these organisations have lessons for others, it may be unrealistic to expect their culture of journalistic independence to diffuse beyond a small set of principled media outlets