Electronic reporting of rare endocrine conditions within a clinical network: results from the EuRRECa project.

Objective: The European Registries for Rare Endocrine Conditions (EuRRECa, eurreb.eu) includes an e-reporting registry (e-REC) used to perform surveillance of conditions within the European Reference Network (ERN) for rare endocrine conditions (Endo-ERN). The aim of this study was to report the experience of e-REC over the 3.5 years since its launch in 2018. Methods: Electronic reporting capturing new encounters of Endo-ERN conditions was performed monthly through a bespoke platform by clinicians registered to participate in e-REC from July 2018 to December 2021. Results: The number of centres reporting on e-REC increased to a total of 61 centres from 22 countries. A median of 29 (range 11, 45) paediatric and 32 (14, 51) adult centres had reported cases monthly. A total of 9715 and 4243 new cases were reported in adults (age ≥18 years) and children, respectively. In children, sex development conditions comprised 40% of all reported conditions and transgender cases were most frequently reported, comprising 58% of sex development conditions. The median number of sex development cases reported per centre per month was 0.6 (0, 38). Amongst adults, pituitary conditions comprised 44% of reported conditions and pituitary adenomas (69% of cases) were most commonly reported. The median number of pituitary cases reported per centre per month was 4 (0.4, 33). Conclusions: e-REC has gained increasing acceptability over the last 3.5 years for capturing brief information on new encounters of rare conditions and shows wide variations in the rate of presentation of these conditions to centres within a reference network. Significance statement Endocrinology includes a very wide range of rare conditions and their occurrence is often difficult to measure. By using an electronic platform that allowed monthly reporting of new clinical encounters of several rare endocrine conditions within a defined network that consisted of several reference centres in Europe, the EuRRECa project shows that a programme of e-surveillance is feasible and acceptable. The data that have been collected by the e-reporting of rare endocrine conditions (e-REC) can allow the continuous monitoring of rare conditions and may be used for clinical benchmarking, designing new studies or recruiting to clinical trials.

The genetic origin of Huns, Avars, and conquering Hungarians.

Huns, Avars, and conquering Hungarians were migration-period nomadic tribal confederations that arrived in three successive waves in the Carpathian Basin between the 5th and 9th centuries. Based on the historical data, each of these groups are thought to have arrived from Asia, although their exact origin and relation to other ancient and modern populations have been debated. Recently, hundreds of ancient genomes were analyzed from Central Asia, Mongolia, and China, from which we aimed to identify putative source populations for the above-mentioned groups. In this study, we have sequenced 9 Hun, 143 Avar, and 113 Hungarian conquest period samples and identified three core populations, representing immigrants from each period with no recent European ancestry. Our results reveal that this "immigrant core" of both Huns and Avars likely originated in present day Mongolia, and their origin can be traced back to Xiongnus (Asian Huns), as suggested by several historians. On the other hand, the "immigrant core" of the conquering Hungarians derived from an earlier admixture of Mansis, early Sarmatians, and descendants of late Xiongnus. We have also shown that a common "proto-Ugric" gene pool appeared in the Bronze Age from the admixture of Mezhovskaya and Nganasan people, supporting genetic and linguistic data. In addition, we detected shared Hun-related ancestry in numerous Avar and Hungarian conquest period genetic outliers, indicating a genetic link between these successive nomadic groups. Aside from the immigrant core groups, we identified that the majority of the individuals from each period were local residents harboring "native European" ancestry.

Maternal Lineages of Gepids from Transylvania.

According to the written historical sources, the Gepids were a Germanic tribe that settled in the Carpathian Basin during the Migration Period. They were allies of the Huns, and an independent Gepid Kingdom arose after the collapse of the Hun Empire. In this period, the Carpathian Basin was characterized by so-called row-grave cemeteries. Due to the scarcity of historical and archaeological data, we have a poor knowledge of the origin and composition of these barbarian populations, and this is still a subject of debate. To better understand the genetic legacy of migration period societies, we obtained 46 full mitogenome sequences from three Gepid cemeteries located in Transylvania, Romania. The studied samples represent the Classical Gepidic period and illustrate the genetic make-up of this group from the late 5th and early 6th centuries AD, which is characterized by cultural markers associated with the Gepid culture in Transylvania. The genetic structure of the Gepid people is explored for the first time, providing new insights into the genetic makeup of this archaic group. The retrieved genetic data showed mainly the presence of Northwestern European mitochondrial ancient lineages in the Gepid group and all population genetic analyses reiterated the same genetic structure, showing that early ancient mitogenomes from Europe were the major contributors to the Gepid maternal genetic pool.

Wavelength-dependent orientation of the principal axes of photonic crystal fibers measured by windowed Fourier-transform spectral interferometry.

We present a novel polarization alignment technique based on windowed Fourier-transform (WFT) spectral interferometry to determine the wavelength-dependent orientation of the principal polarization axes of photonic crystal fibers (PCFs). To test the technique, a commercially available, 82.5-cm-long HC-800-02 type hollow-core PCF was measured. The angles belonging to the fast and the slow principal axes of the fiber were determined from the peak intensity values of the ridges in the WFT map at different wavelengths. We demonstrate that the orientation of the principal polarization axes of the tested PCF is wavelength-dependent. The precision of the angle measurement was better than 0.3°.

Chromatic dispersion measurement along both polarization directions of a birefringent hollow-core photonic crystal fiber using spectral interferometry.

Applications based on photonic crystal fibers depend strongly on their dispersion properties that might differ from the desired specifications due to deficiencies in the manufacturing process. Since dispersion characteristics might also be affected by the placement of the fiber, in this paper the effect of various placements on the chromatic dispersion properties of a commercially available HC-800-02 photonic crystal fiber was investigated between 760 and 870 nm with Fourier-transform spectral interferometry. To test the scaling of dispersion with fiber length, samples of different lengths ranging from 10 to 97 cm were used in the measurements. It was found that the dispersion properties of the orthogonal directions were different. The dispersion parameter showed small dependence on the placement and fiber length. The polarization-mode dispersion (PMD) of the fiber was measured using an indirect and a direct technique. To retrieve the PMD directly in the case of the shorter fibers where the fringes were too sparse for the Fourier method, the so-called minima-maxima method was employed. The precision was comparable with both techniques; however, the direct approach proved to be more accurate when longer samples were measured, and the indirect method seemed to be more reliable in the case of shorter fibers.

Carrier-envelope phase changes in the focal region: propagation effects measured by spectral interferometry.

Spectral interferometric measurements are presented that show how wave propagation affects the carrier-envelope phase (CEP) of an ultrashort pulse in the focal region and results in variations that are different from the Gouy phase shift. Wavelength-dependent properties of the input beam are investigated and are seen to influence how the CEP is altered. The measured CEP changes show characteristics similar to the variations predicted by theory.

A dimerization hierarchy in the transmembrane domains of the HER receptor family.

Bitopic membrane proteins offer an opportunity for studying transmembrane domain interactions without the structural complexity inherent to multitopic integral membrane proteins. To date, only homomeric associations have been extensively studied quantitatively. Here we propose to assess the thermodynamics of heteromeric associations, which opens the way to investigating specificity and selectivity. A very interesting system of biological relevance with single transmembrane domains possibly involved in interactions with different partners is the EGFR receptor family. The four members, all tyrosine kinase receptors, are involved in an interaction network that potentially leads to a complete set of homo- and heterodimers, ideally suited to such a study. Furthermore, the transmembrane domains of these receptors have been previously implicated in their function in the past by mutations in the transmembrane domain leading to constitutive activation. We demonstrate, using a fluorescence-based measurement of interaction energies, a hierarchy of transmembrane domain interactions ranging from a noninteractive pair to strong dimerization. We propose a structural model based on the crystal structure of the EGFR dimer, to show how the dimeric structure favors these interactions. The correlation we observe between transmembrane domain and whole receptor interaction hierarchies opens a new perspective, suggesting a role for transmembrane receptor domains in the modulation of receptor signaling.

Hydrogen bonding in a model bacteriochlorophyll-binding site drives assembly of light harvesting complex.

In this study, the contribution of intramembrane hydrogen bonding at the interface between polypeptide and cofactor is explored in the native lipid environment by use of model bacteriochlorophyll proteins. In the peripheral antenna complex, LH2, large portions of the transmembrane helices, which make up the dimeric bacteriochlorophyll-binding site, are replaced by simplified, alternating alanine-leucine stretches. Replacement of either one of the two helices with the helices containing the model sequence at a time results in the assembly of complexes with nearly native light harvesting properties. In contrast, replacement of both helices results in the loss of antenna complexes from the membrane. The assembly of such doubly modified complexes is restored by a single intramembrane serine residue at position -4 relative to the liganding histidine of the alpha-subunit. In situ analysis of the spectral properties in a series of site-directed mutants reveals a critical dependence of the model complex assembly on the side chain of the residue at this position in the helix. A hydrogen bond between the hydroxy group of the serine and the 13(1) keto group of one of the central bacteriochlorophylls of the complexes is identified by Raman spectroscopy in the model antenna complex containing one of the alanine-leucine helices. The additional OH group of the serine residue, which participates in hydrogen bonding, increases the thermal stability of the model complexes in the native membrane. Intramembrane hydrogen bonding is thus shown to be a key factor for the binding of bacteriochlorophyll and assembly of this model cofactor-polypeptide site.

Spectroscopic characterisation of a tetrameric subunit form of the core antenna protein from Rhodospirillum rubrum.

The core light-harvesting complex (LH1) of Rhodospirillum rubrum is constituted of multiple heterodimeric subunits, each containing two transmembrane polypeptides, alpha and beta. The detergent octylglucoside induces the stepwise dissociation of LH1 into B820 (an alphabeta dimer) and B777 (monomeric polypeptides), both of which still retain their bound bacteriochlorophyll molecules. We have investigated the absorption properties of B820 as a function of temperature, whereby a spectral population called 'B851' has been characterised. We show evidence that it is a dimer of the B820 complex. This may represent an intermediate oligomeric form in the process of the LH1 ring formation, as its existence was predicted from global analysis of the absorption spectra of the LH1/B820 equilibrium [Pandit et al. (2001) Biochemistry 40, 12913-12924]. Stabilisation of this dissociated form of LH1 may help in understanding both the electronic properties and the association process of these integral membrane proteins.

The fall of homovanillic acid and 5-hydroxyindoleacetic acid concentrations in brains of mice withdrawn from repeated morphine treatment and their restoration by acute morphine administration.

The striatal homovanillic acid (HVA) and cerebral 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were estimated in male mice withdrawn from 3- to 5-day morphine treatment (total dose: 1,100-2,350 mg/kg). All mice were given probenecid (200 mg/kg, 2 hours). The HVA concentration was decreased (by 26%) in mice withdrawn from 3-day treatment, but the 5-HIAA concentration fell (by 22%) only after 4-day treatment. An acute morphine dose (30 mg/kg, 2 hours) clearly elevated the HVA concentration in mice withdrawn from 4-day treatment, but mice withdrawn from 3-day treatment tended to be tolerant to the HVA concentration elevating effect of morphine. The acute dose increased the 5-HIAA concentration in mice withdrawn from 4-day treatment, by 20-40%, but the mice withdrawn from 3-day treatment were clearly tolerant to this effect of morphine. These results suggest that endogenous activities of dopaminergic and 5-HTergic neurons are attenuated by repeated morphine treatment. However, such attenuation seems to reactivate these neurons to respond to acute morphine administration nearly normally.