The lipocalin protein family is a large group of small extracellular proteins. The family demonstrates great diversity at the sequence level; however, most lipocalins share three characteristic conserved sequence motifs, the kernel lipocalins, while a group of more divergent family members, the outlier lipocalins, share only one. Belying this sequence dissimilarity, lipocalin crystal structures are highly conserved and comprise a single eight-stranded continuously hydrogen-bonded antiparallel beta-barrel, which encloses an internal ligand-binding site. Together with two other families of ligand-binding proteins, the fatty-acid-binding proteins (FABPs) and the avidins, the lipocalins form part of an overall structural superfamily: the calycins. Members of the lipocalin family are characterized by several common molecular-recognition properties: the ability to bind a range of small hydrophobic molecules, binding to specific cell-surface receptors and the formation of complexes with soluble macromolecules. The varied biological functions of the lipocalins are mediated by one or more of these properties. In the past, the lipocalins have been classified as transport proteins; however, it is now clear that the lipocalins exhibit great functional diversity, with roles in retinol transport, invertebrate cryptic coloration, olfaction and pheromone transport, and prostaglandin synthesis. The lipocalins have also been implicated in the regulation of cell homoeostasis and the modulation of the immune response, and, as carrier proteins, to act in the general clearance of endogenous and exogenous compounds.

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The lipocalin protein family: structure and function

Intrinsically disordered proteins (IDPs) lack stable tertiary and/or secondary structures under physiological conditions in vitro. They are highly abundant in nature and their functional repertoire complements the functions of ordered proteins. IDPs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Functions of IDPs are tuned via alternative splicing and posttranslational modifications. Intrinsic disorder is a unique structural feature that enables IDPs to participate in both one-to-many and many-toone signaling. Numerous IDPs are associated with human diseases, including cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, and diabetes. Overall, intriguing interconnections among intrinsic disorder, cell signaling, and human diseases suggest that protein conformational diseases may result not only from protein misfolding, but also from misidentification, missignaling, and unnatural or nonnative folding. IDPs, such as α-synuclein, tau protein, p53, and BRCA1, are attractive targets for drugs modulating protein-protein interactions. From these and other examples, novel strategies for drug discovery based on IDPs have been developed. To summarize work in this area, we are introducing the D 2 (disorder in disorders) concept.

Intrinsically Disordered Proteins in Human Diseases: Introducing the D2 Concept

Dietary sources of conjugated dienoic isomers of linoleic acid, a newly recognized class of anticarcinogens

Nomenclature of the Proteins of Cows’ Milk—Sixth Revision

Essential fatty acids in growth and development

Lactoferrin is an iron-binding protein closely related in structure to the serum iron transport protein transferrin. Unlike transferrin, only traces are normally present in serum, and it is instead found mainly in milk and other external secretions, and in the secondary granules of neutrophils. Although lactoferrin was first isolated 30 years ago, its biological role remains unclear. Some aspects of its function were discussed about 12 years ago in this journal,' and this review will attempt to reassess the function of lactoferrin in the light of the large amount of new information that has accrued since then. Knowledge of the structure of lactoferrin has been advanced by recent x ray crystallographic studies, and the structure and iron binding properties of lactoferrin are reviewed in detail elsewhere.2 Briefly lactoferrin, like transferrin, reversibly binds two ferric ions, for which synergistic binding of an anion, usually bicarbonate or carbonate, is necessary. However, its affinity constant for iron is 300 times greater than that of transferrin, and even in the presence of a competing iron chelator such as citrate it can retain iron down to pH 3 or less while transferrin loses it at pH 5. Unlike transferrin, lactoferrin is strongly basic. Human lactoferrin has been cloned and sequenced4 and the recombinant protein expressed in baby hamster kidney cells.5 bearing in mind when considering its possible biological function. Human milk contains 3-6-12-5 ,umol/l of iron, and of this only 60-70% is in the whey fraction, the remainder being in the lipid fraction (11-20%) or bound to casein (2-14%). " As a consequence, milk lactoferrin is only 6-8% saturated with iron, presumably because of the difficulty in gaining access to iron in the lipid fraction or casein micelles.

https://adc.bmj.com/content/archdischild/67/5/657.full.pdf

Biological role of lactoferrin.

Interaction of β-Lactoglobulin with Retinol and Fatty Acids and Its Role as a Possible Biological Function for This Protein: A Review

This letter analyzes the phase noise effects on an orthogonal frequency division multiplexing (OFDM) signal and its dependence with the sub-carrier spacing. Pilot-based channel estimation, which has been suggested as a means of combating the channel effects, can also correct the phase noise effects under some circumstances, which are investigated.

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Phase noise and sub-carrier spacing effects on the performance of an OFDM communication system

OBJECTIVES To assess the risk factors, antibiotic therapy and outcomes of multidrug-resistant Gram-negative bacilli (MDRGNB) bacteraemia in hospitalized patients with cancer. METHODS Episodes of MDRGNB bacteraemia were compared with a susceptible control group in a 4 year prospective study. RESULTS Of 747 bacteraemias, 372 (49.7%) were caused by a Gram-negative bacilli (GNB). Fifty-one of these (13.7%) were caused by a multidrug-resistant (MDR) strain. Previous antibiotics [odds ratio (OR) 3.57; 95% confidence interval (CI) 1.63-7.80] and urinary catheter (OR 2.41; 95% CI 1.01-5.74) were identified as independent risk factors for MDRGNB acquisition. The most frequent mechanism of resistance was extended-spectrum β-lactamase (ESBL) production (45%), mainly by Escherichia coli, followed by Amp-C cephalosporinase hyperproduction (24%). Patients with MDRGNB bacteraemia more frequently received inadequate initial antibiotic therapy (69% versus 9%; P < 0.001) and time to adequate therapy was longer in this group (41% versus 4%; P < 0.001). Patients in the resistant group more frequently required intensive care unit (ICU) admission (14% versus 5%; P = 0.023), had greater need for mechanical ventilation (14% versus 3%; P = 0.005) and had a higher overall case-fatality rate (41% versus 21%; P = 0.003). Risk factors for mortality were solid tumour (OR 5.04; 95% CI 2.49-10.19), current corticosteroid use (OR 4.38; 95% CI 2.39-8.05), ICU admission (OR 11.40; 95% CI 3.19-40.74) and MDRGNB bacteraemia (OR 3.52; 95% CI 1.36-9.09). CONCLUSIONS MDRGNB bacteraemia was common among cancer patients, especially in those exposed to antibiotics and urinary catheter. The most frequent mechanism of resistance was ESBL production. Patients with MDRGNB more frequently received inadequate empirical antibiotic therapy and presented poorer outcomes with a higher overall case-fatality rate (within 30 days).

Bacteraemia due to multidrug-resistant Gram-negative bacilli in cancer patients: risk factors, antibiotic therapy and outcomes

Lactoferrin (LF) is an iron-binding glycoprotein found in different biological fluids of mammals and in neutrophils. It has been proposed to be involved in many functions, including protection from pathogens. In this work, purification of lactoferrin using an ion-exchange chromatography (SP-Sepharose) was attempted for the milk of the following animals: sheep (Ovis aries), goat (Capra hircus), camel (Camelus bactrianus), alpaca (Lama pacos), elephant (Elephas maximus) and grey seal (Halichoerus grypus), as well as human (Homo sapiens). Lactoferrin was identified in all the milks apart from that from grey seal. The thermal stability of the purified lactoferrins, in their native and iron-saturated forms, was studied by differential scanning calorimetry (DSC). Maximum temperature, onset temperature and enthalpy change of denaturation were higher when lactoferrins were saturated with iron than in their native form, indicating an increase in the stability of the protein structure upon iron-binding. Human lactoferrin was found to be the most heat-resistant and the other lactoferrins presented different degrees of thermoresistance, that of elephant being the least resistant. The antimicrobial activity of the different isolated lactoferrins was investigated against Escherichia coli 0157:H7. The minimal inhibitory concentrations (MICs) were determined by measuring the absorbance at 620 nm. The minimum bactericidal concentrations (MBCs) were also measured and it was found that camel lactoferrin was the most active lactoferrin against E. coli 0157:H7, whereas alpaca and human lactoferrins were the least active.

Miguel Calvo

Papers

Biological role of lactoferrin.

Interaction of β-Lactoglobulin with Retinol and Fatty Acids and Its Role as a Possible Biological Function for This Protein: A Review

Phase noise and sub-carrier spacing effects on the performance of an OFDM communication system

Bacteraemia due to multidrug-resistant Gram-negative bacilli in cancer patients: risk factors, antibiotic therapy and outcomes

Isolation of lactoferrin from milk of different species: calorimetric and antimicrobial studies