The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

OBJECTIVE. Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias. DESIGN AND METHODS. Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network. RESULTS. Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients. CONCLUSIONS. SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common

Multicentric Castleman's disease as a cause for unclear febrile episodes in a 55-year-old HIV-infected man

Our case illustrates the difficulties involved in diagnosing multicentric Castleman's disease (MCD) in a human immunodeficiency virus-infected man with febrile episodes and malaise. In the absence of well-established treatment protocols, we have chosen a new treatment algorithm with rituximab, etoposide, and valganciclovir, which led to the remission of clinical symptoms. Yet, we advocate focused exploration for MCD in immunosuppressed patients with unclear febrile episodes, as recent advances in treatment are promisin

Testosterone production during puberty in two 46,XY patients with disorders of sex development and novel NR5A1 (SF-1) mutations

BACKGROUND: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of many genes involved in the hypothalamic–pituitary–gonadal axis and mutations in NR5A1 can result in 46,XY disorders of sex development (DSD). Patients with this condition typically present with ambiguous genitalia, partial gonadal dysgenesis, and absent/rudimentary Müllerian structures. In these cases, testosterone is usually low in early infancy, indicating significantly impaired androgen synthesis. Further, Sertoli cell dysfunction is seen (low inhibin B, anti-Müllerian hormone). However, gonadal function at puberty in patients with NR5A1 mutations is unknown. SUBJECTS AND METHODS: Clinical assessment, endocrine evaluation, and genetic analysis were performed in one female and one male with 46,XY DSD who showed spontaneous virilization during puberty. The female patient presented at adolescence with clitoral hypertrophy, whereas the male patient presented at birth with severe hypospadias and entered puberty spontaneously. Molecular analysis of NR5A1 was performed followed by in vitro functional analysis of the two novel mutations detected. RESULTS: Testosterone levels were normal during puberty in both patients. Analysis of NR5A1 revealed two novel heterozygous missense mutations in the ligand-binding domain of SF-1 (patient 1: p.L376F; patient 2: p.G328V). The mutant proteins showed reduced transactivation of the CYP11A promoter in vitro. CONCLUSION: Patients with 46,XY DSD and NR5A1 mutations can produce sufficient testosterone for spontaneous virilization during puberty. Phenotypic females (46,XY) with NR5A1 mutations can present with clitoromegaly at puberty, a phenotype similar to other partial defects of androgen synthesis or action. Testosterone production in 46,XY males with NR5A1 mutations can be sufficient for virilization at puberty. As progressive gonadal dysgenesis is likely, gonadal function should be monitored in adolescence and adulthood, and early sperm cryopreservation considered in male patients if possible

Highly Efficient Year-Round Energy and Comfort Optimization of HVAC Systems in Electric City Buses

In this paper, we present a novel approach to perform highly efficient numerical simulations of the heating, ventilation, and air-conditioning (HVAC) system of an electric city bus. The models for this simulation are based on the assumption of a steady-state operation. We show two approaches to obtain the minimum energy requirement for a certain thermal comfort criterion under specific ambient conditions. Due to the computationally efficient approach developed, we can evaluate the model on a large dataset of 7500 scenarios in various ambient conditions to estimate the year-round performance of the system subject to different comfort requirements. Compared to a heating strategy based on positive temperature coefficient (PTC) elements, we can thus show that a heat pump (HP) can reduce the annual mean power consumption by up to 60%. Ceiling-mounted radiant heating elements complementing a PTC heating system can reduce the annual mean power consumption by up to 10%, while they cannot improve the energy efficiency when used in conjunction with a HP. Finally, a broad sensitivity study reveals the fact that improving the HP's heating-mode coefficient of performance (COP) manifests the largest leverage in terms of mean annual power consumption. Moreover, the annual energy expenditure for cooling are around eight times smaller than those for heating. The case study considered thus reveals that the advantages of improving the COP of the cooling mode are significantly lower.Comment: This work has been accepted to IFAC for publication under a Creative Commons Licence CC-BY-NC-N

ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland

The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland

Multiexcitons confined within a sub-excitonic volume: Spectroscopic and dynamical signatures of neutral and charged biexcitons in ultrasmall semiconductor nanocrystals

The use of ultrafast gating techniques allows us to resolve both spectrally and temporally the emission from short-lived neutral and negatively charged biexcitons in ultrasmall (sub-10 nm) CdSe nanocrystals (nanocrystal quantum dots). Because of forced overlap of electronic wave functions and reduced dielectric screening, these states are characterized by giant interaction energies of tens (neutral biexcitons) to hundreds (charged biexcitons) of meV. Both types of biexcitons show extremely short lifetimes (from sub-100 picoseconds to sub-picosecond time scales) that rapidly shorten with decreasing nanocrystal size. These ultrafast relaxation dynamics are explained in terms of highly efficient nonradiative Auger recombination.Comment: 5 pages, 4 figures, to be published in Phys. Rev.

Spatio-temporal dynamics of quantum-well excitons

We investigate the lateral transport of excitons in ZnSe quantum wells by using time-resolved micro-photoluminescence enhanced by the introduction of a solid immersion lens. The spatial and temporal resolutions are 200 nm and 5 ps, respectively. Strong deviation from classical diffusion is observed up to 400 ps. This feature is attributed to the hot-exciton effects, consistent with previous experiments under cw excitation. The coupled transport-relaxation process of hot excitons is modelled by Monte Carlo simulation. We prove that two basic assumptions typically accepted in photoluminescence investigations on excitonic transport, namely (i) the classical diffusion model as well as (ii) the equivalence between the temporal and spatial evolution of the exciton population and of the measured photoluminescence, are not valid for low-temperature experiments.Comment: 8 pages, 6 figure

Photothermal Absorption Spectroscopy of Individual Semiconductor Nanocrystals

Photothermal heterodyne detection is used to record the first room-temperature absorption spectra of single CdSe/ZnS semiconductor nanocrystals. These spectra are recorded in the high cw excitation regime, and the observed bands are assigned to transitions involving biexciton and trion states. Comparison with the single nanocrystals photoluminescence spectra leads to the measurement of spectral Stokes shifts free from ensemble averaging

Molecular spintronics: Coherent spin transfer in coupled quantum dots

Time-resolved Faraday rotation has recently demonstrated coherent transfer of electron spin between quantum dots coupled by conjugated molecules. Using a transfer Hamiltonian ansatz for the coupled quantum dots, we calculate the Faraday rotation signal as a function of the probe frequency in a pump-probe setup using neutral quantum dots. Additionally, we study the signal of one spin-polarized excess electron in the coupled dots. We show that, in both cases, the Faraday rotation angle is determined by the spin transfer probabilities and the Heisenberg spin exchange energy. By comparison of our results with experimental data, we find that the transfer matrix element for electrons in the conduction band is of order 0.08 eV and the spin transfer probabilities are of order 10%.Comment: 13 pages, 6 figures; minor change

The effect of Auger heating on intraband carrier relaxation in semiconductor quantumrods

The rate at which excited charge carriers relax to their equilibrium state affects many aspects of the performance of nanoscale devices, including switching speed, carrier mobility and luminescent efficiency. Better understanding of the processes that govern carrier relaxation therefore has important technological implications. A significant increase in carrier-carrier interactions caused by strong spatial confinement of electronic excitations in semiconductor nanostructures leads to a considerable enhancement of Auger effects, which can further result in unusual, Auger-process-controlled recombination and energy-relaxation regimes. Here, we report the first experimental observation of efficient Auger heating in CdSe quantum rods at high pump intensities, leading to a strong reduction of carrier cooling rates. In this regime, the carrier temperature is determined by the balance between energy outflow through phonon emission and energy inflow because of Auger heating. This equilibrium results in peculiar carrier cooling dynamics that closely correlate with recombination dynamics, an effect never before seen in bulk or nanoscale semiconductors.Comment: 7 pages, 4 figure