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Background: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations.Objective: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations.Design: Multicenter, descriptive study.Setting: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology.Participants: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring.Measurements: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results.Results: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients.Limitations: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations.Conclusions: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present. [ABSTRACT FROM AUTHOR]

Reports on the study conducted on the maturity-onset diabetes of the young 5 (MODY5). Reduction in insulin production due to mutation in the hepatocyte nuclear factor-1 (HNF-1) gene; Methodology of the study being use of ultrasounds, tomography scans and DNA analysis; Suggestion of MODY5 being an uncommon disease with diverse clinical and genetic findings.

Objective: Lipoprotein (a) [Lp(a)] is an LDL-like particle constituted by lipids, apolipoprotein B100 and apolipoprotein (a) [apo(a)], a multidomain glycoprotein whose molecular mass is dependent on the genetically encoded number of Kringle IV type 2 (KIV-2) repeats. Because Lp(a) isoforms have been associated with cardiovascular risk (CVR), we have investigated if their interfacial properties can contribute to distinguish between low and high-risk groups and thus be used as a new CVR indicator., Methods: Four Lp(a) variants, each carrying a different apo(a) isoform (K20, K24, K25, and K29), were purified from plasma of homozygous donors and their interfacial properties characterized using ellipsometry and surface pressure techniques., Results: Ellipsometry measurements revealed that these isoforms had a similar propensity to form adsorbed layers at hydrophobic-hydrophilic interfaces, but surface pressure enabled to clearly separate them into two groups: K20 and K24 on one side, and K25 and K29 on the other side., Conclusion: Though K24 and K25 differ only by a single KIV-2 domain, their sharp difference in surface pressure suggests a critical threshold between the two Lp(a) forms, providing insights into the use of condensed matter approaches to monitor CVR. Our findings may represent a new laboratory window to assist medical decisions and to develop precision medicine treatments, practices, and products for CVR, which can be extended to other cardiovascular disease conditions., (© 2021 by the Association of Clinical Scientists, Inc.)

The formation of dense protein interfacial layers at a free air-water interface is known to result from both diffusion and advection. Furthermore, protein interactions in concentrated phases are strongly dependent on their overall positive or negative net charge, which is controlled by the solution pH. As a consequence, an interesting question is whether the presence of an advection flow of water toward the interface during protein adsorption produces different kinetics and interfacial structure of the adsorbed layer, depending on the net charge of the involved proteins and, possibly, on the sign of this charge. Here we test a combination of the following parameters using ovalbumin and lysozyme as model proteins: positive or negative net charge and the presence or absence of advection flow. The formation and the organization of the interfacial layers are studied by neutron reflectivity and null-ellipsometry measurements. We show that the combined effect of a positive charge of lysozyme and ovalbumin and the presence of advection flow does induce the formation of interfacial multilayers. Conversely, negatively charged ovalbumin forms monolayers, whether advection flow is present or not. We show that an advection/diffusion model cannot correctly describe the adsorption kinetics of multilayers, even in the hypothesis of a concentration-dependent diffusion coefficient as in colloidal filtration, for instance. Still, it is clear that advection is a necessary condition for making multilayers through a mechanism that remains to be determined, which paves the way for future research.

Hydroxyapatite (HA) has received much interest for being used as bone substitutes because of its similarity with bioapatites. In form of nanowires or nanotubes, HA would offer more advantages such as better biological and mechanical properties than conventional particles (spherical). To date, no study had allowed the isolated nanowires production with simultaneously well-controlled morphology and size, narrow size distribution and high aspect ratio (length on diameter ratio). So, it is impossible to determine exactly the real impact of particles' size and aspect ratio on healing responses of bone substitutes and characteristics of these ones; their biological and mechanical effects can never be reproducible. By the template-assisted pulsed electrodeposition method, we have for the first time succeeded to obtain such calcium-deficient hydroxyapatite (CDHA) particles in aqueous baths with hydrogen peroxide by both applying pulsed current density and pulsed potential in cathodic electrodeposition. After determining the best conditions for CDHA synthesis on gold substrate in thin films by X-ray diffraction (XRD) and Energy dispersive X-ray spectroscopy (EDX), we have transferred those conditions to the nanowires and nanotubes synthesis with high aspect ratio going until 71 and 25 respectively. Polycrystalline CDHA nanowires and nanotubes were characterized by Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). At the same time, this study enabled to understand the mechanism of nanopores filling in gold covered polycarbonate membrane: here a preferential nucleation on gold in membranes with 100 and 200 nm nanopores diameters forming nanowires whereas a preferential and randomly nucleation on nanopores walls in membranes with 400 nm nanopores diameter forming nanotubes., (Copyright © 2018. Published by Elsevier B.V.)

Hypothesis: The effective contribution of interfacial properties to the rheology of foams is a source of many open questions. Film dynamics during topological T1 changes in foams, essentially studied for low molecular weight surfactants, and scarcely for proteins, could connect interfacial properties to protein foam rheology., Experiments: We modified whey protein isolate (WPI), and its purified major protein β-lactoglobulin (β-lg) by powder pre-conditioning and dry-heating in order to obtain a broad variety of interfacial properties. We measured interfacial properties, film relaxation duration after a T1 event and bulk foam rheology., Findings: We found that, for β-lg, considered as a model protein, the higher the interfacial elastic modulus, the longer the duration of topological T1 changes and the greater the foam storage and loss moduli and the yield stress. However, in the case of the more complex WPI, these correlations were less clear. We propose that the presence in WPI of other proteins, lactose and minerals modify the impact of pre-conditioning and dry-heating on proteins and thereby, their behaviour at the interface and inside the liquid film., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We obtained osmotic pressure data of lysozyme solutions, describing their physical states over a wide concentration range, using osmotic stress for pressures between 0.05 bar and about 40 bar and volume fractions between 0.01 and 0.61. The osmotic pressure vs. volume fraction data consist of a dilute, gas-phase regime, a transition regime with a high-compressibility plateau, and a concentrated regime where the system is nearly incompressible. The first two regimes are shifted towards a higher protein volume fraction upon decreasing the strength or the range of electrostatic interactions. We describe this shift and the overall shape of the experimental data in these two regimes through a model accounting for a steric repulsion, a short-range van der Waals attraction and a screened electrostatic repulsion. The transition is caused by crystallization, as shown by small-angle X-ray scattering. We verified that our data points correspond to thermodynamic equilibria, and thus that they consist of the reference experimental counterpart of a thermodynamic equation of state.

We have compared the behavior of ovotransferrin at the air-solution interface in the presence of a monovalent ion (acetate), or a divalent ion (citrate), the latter being known to induce conformational changes of this protein upon interaction with its iron-binding sites. We have characterised the adsorption layer at the air-water interface in terms of homogeneity, surface concentration excess and rheological properties at pH 4.0. Besides we have investigated the bulk conformation in the presence of the two anions. In the presence of citrate only, interfacial layers display well-defined domains of higher overall surface concentration suggesting multilayers adsorption. Citrate also induces higher helical content and stabilizes the protein against thermal denaturation. Hence we propose that these changes are involved in the propensity of ovotransferrin to self-assemble at the air-water interface resulting in thick and heterogeneous interfacial layer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France., Study Design: Two pedigrees were identified from the French registry., Results: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation., Conclusions: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein., (© 2014 Wiley Periodicals, Inc.)

The kinetics of adsorption of solubilized spider major ampullate (MA) silk fibers at the air-water interface and the molecular structure and mechanical properties of the interfacial films formed have been studied using various physical techniques. The data show that Nephila clavipes MA proteins progressively adsorb at the interface and ultimately form a highly cohesive thin film. In situ infrared spectroscopy shows that as soon as they reach the interface the proteins predominantly form β sheets. The protein secondary structure does not change significantly as the film grows, and the amount of β sheet is the same as that of the natural fiber. This suggests that the final β-sheet content is mainly dictated by the primary structure and not by the underlying formation process. The measure of the shear elastic constant at low strain reveals a very strong, viscous, cohesive assembly. The β sheets seem to form cross-links dispersed within an intermolecular network, thus probably playing a major role in the film strength. More importantly, the molecular weight seems to be a crucial factor because interfacial films made from the natural proteins are ~7 times stronger and ~3 times more viscous than those obtained previously with shorter recombinant proteins. Brewster angle microscopy at the air-water interface and transmission electron microscopy of transferred films have revealed a homogeneous organization on the micrometer scale. The images suggest that the structural assembly at the air-water interface leads to the formation of macroscopically solid and highly cohesive networks. Overall, the results suggest that natural spider silk proteins, although sharing similarities with recombinant proteins, have the particular ability to self-assemble into ordered materials with exceptional mechanical properties.

Translocator protein TSPO is a membrane protein highly conserved in evolution which does not belong to any structural known family. TSPO is involved in physiological functions among which transport of molecules such as cholesterol to form steroids and bile salts in mammalian cells. Membrane protein structure determination remains a difficult task and needs concomitant approaches (for instance X-ray- or Electron-crystallography and NMR). Electron microscopy and two-dimensional crystallization under functionalized monolayers have been successfully developed for recombinant tagged proteins. The difficulty comes from the detergent carried by membrane proteins that disrupt the lipid monolayer. We identified the best conditions for injecting the histidine tagged recombinant TSPO in detergent in the subphase and to keep the protein stable. Reconstituted recombinant protein into a lipid bilayer favors its adsorption to functionalized monolayers and limits the disruption of the monolayer by reducing the amount of detergent. Finally, we obtained the first transmission electron microscopy images of recombinant mouse TSPO negatively stained bound to the lipid monolayer after injection into the subphase of pre-reconstituted TSPO in lipids. Image analysis reveals that circular objects could correspond to an association of at least four monomers of mouse TSPO. The different amino acid compositions and the location of the polyhistidine tag between bacterial and mouse TSPO could account for the formation of dimer versus tetramer, respectively. The difference in the loop between the first and second putative transmembrane domain may contribute to distinct monomer interaction, this is supported by differences in ligand binding parameters and biological functions of both proteins., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Exchangeable apolipoproteins A-I and A-II play distinct roles in reverse cholesterol transport. ApoA-I interacts with phospholipids and cholesterol of the cell membrane to make high density lipoprotein particles whereas apolipoprotein A-II interacts with high density lipoprotein particles to release apolipoprotein A-I. The two proteins show a high activity at the aqueous solution/lipid interface and are characterized by a high content of amphipathic α-helices built upon repetition of the same structural motif. We set out to investigate to what extent the number of α-helix repeats of this structural motif modulates the affinity of the protein for lipids and the sensitivity to lipid packing. To this aim we have compared the insertion of apolipoproteins A-I and A-II in phospholipid monolayers formed on a Langmuir trough in conditions where lipid packing, surface pressure and charge were controlled. We also used atomic force microscopy to obtain high resolution topographic images of the surface at a resolution of several nanometers and performed statistical image analysis to calculate the spatial distribution and geometrical shape of apolipoproteins A-I and A-II clusters. Our data indicate that apolipoprotein A-I is sensitive to packing of zwitterionic lipids but insensitive to the packing of negatively charged lipids. Interestingly, apolipoprotein A-II proved to be insensitive to the packing of zwitterionic lipids. The different sensitivity to lipid packing provides clues as to why apolipoprotein A-II barely forms nascent high density lipoprotein particles while apolipoprotein A-I promotes their formation. We conclude that the different interfacial behaviors of apolipoprotein A-I and apolipoprotein A-II in lipidic monolayers are important determinants of their distinctive roles in lipid metabolism., (Copyright © 2012 Elsevier B.V. All rights reserved.)