Prognostic Value for Mortality of Plasma Bioactive Adrenomedullin in Patients with Pulmonary Arterial Hypertension: A Sub Analysis of the Biomarker Study in the COHARD-PH Registry.

The adrenomedullin level increases in pulmonary arterial hypertension (PAH, and correlates with a high mortality rate. Its active form, bioactive adrenomedullin (bio-ADM), has been recently developed and has significant prognostic applications in acute clinical settings. Aside from idiopathic/hereditary PAH (I/H-PAH), atrial septal defects-associated pulmonary artery hypertension (ASD-PAH) is still prevalent in developing countries and associated with increased mortality. This study aimed to investigate the mortality-wise prognostic value of the plasma bio-ADM level by comparing subjects with ASD-PAH and I/H-PAH with ASD patients without pulmonary hypertension (PH) as a control group. This was a retrospective, observational cohort study. The subjects were Indonesian adult patients who were recruited from the Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry and divided into three groups: (1) ASD without PH (control group), (2) ASD-PAH and (3) I/H-PAH. During right-heart catheterization at the time of diagnosis, a plasma sample was taken and assayed for bio-ADM using a chemiluminescence immunoassay. Follow-up was performed as a part of the COHARD-PH registry protocol in order to evaluate the mortality rate. Among the 120 subjects enrolled: 20 turned out to have ASD without PH, 85 had ASD-PAH and 15 had I/H-PAH. Compared to the control group (5.15 (3.0-7.95 pg/mL)) and ASD-PAH group (7.30 (4.10-13.50 pg/mL)), bio-ADM levels were significantly higher in the I/H-PAH group (median (interquartile range (IQR)): 15.50 (7.50-24.10 pg/mL)). Moreover, plasma bio-ADM levels were significantly higher in subjects who died (n = 21, 17.5%) compared to those who survived (median (IQR): 11.70 (7.20-16.40 pg/mL) vs. 6.90 (4.10-10.20 pg/mL), p = 0.031). There was a tendency toward higher bio-ADM levels in those who died among the PAH subjects, in both ASD-PAH and I/H-PAH groups. In conclusion, the plasma bio-ADM level is elevated in subjects with PAH from both ASD-PAH and I/H-PAH origins, reaching the highest levels in subjects with the I/H-PAH form. A high bio-ADM level tended to be associated with a high mortality rate in all subjects with PAH, indicating a relevant prognostic value for this biomarker. In patients with I/H-PAH, monitoring bio-ADM could represent a valid tool for predicting outcomes, allowing more appropriate therapeutical choices.

Comparison of the distribution and phenology of Arctic Mountain plants between the early 20th and 21st centuries.

Arctic plants are adapted to climatic variability, but their long-term responses to warming remain unclear. Responses may occur by range shifts, phenological adjustments in growth and reproduction, or both. Here, we compare distribution and phenology of 83 arctic and boreal mountain species, sampled identically in the early 20th (1917-1919) and 21st centuries (2017-2018) from a region of northern Sweden that has warmed significantly. We test two compensatory hypotheses to high-latitude warming-upward shifts in distribution, and earlier or extended growth and reproduction. For distribution, we show dramatic upward migration by 69% of species, averaging 6.1 m per decade, especially boreal woodland taxa whose upward expansion has reduced arctic montane habitat by 30%. Twenty percent of summit species showed distributional shifts but downward, especially moisture-associated snowbed flora. For phenology, we detected wide inter-annual variability in the onset of leafing and flowering in both eras. However, there was no detectable change in growing-season length, relating to two mechanisms. First, plot-level snow melt data starting in 1917 demonstrated that melt date, rather than vernal temperatures, better predicts plant emergence, with snow melt influenced by warmer years having greater snowfall-warmer springs did not always result in earlier emergence because snowbeds can persist longer. Second, the onset of reproductive senescence between eras was similar, even when plant emergence was earlier by a month, possibly due to intensified summer heat stress or hard-wired 'canalization' where senescence occurs regardless of summer temperature. Migrations in this system have possibly buffered arctic species against displacement by boreal expansion and warming, but ongoing temperature increases, woody plant invasion, and a potential lack of flexibility in timing of senescence may foreshadow challenges.

Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. As CAKUT is a genetically heterogeneous disorder and most cases are genetically unexplained, we aimed to identify new CAKUT causing genes. Using whole-exome sequencing and trio-based de novo analysis, we identified a novel heterozygous de novo frameshift variant in the leukemia inhibitory factor receptor (LIFR) gene causing instability of the mRNA in a patient presenting with bilateral CAKUT and requiring kidney transplantation at one year of age. LIFR encodes a transmembrane receptor utilized by IL-6 family cytokines, mainly by the leukemia inhibitory factor (LIF). Mutational analysis of 121 further patients with severe CAKUT yielded two rare heterozygous LIFR missense variants predicted to be pathogenic in three unrelated patients. LIFR mutants showed decreased half-life and cell membrane localization resulting in reduced LIF-stimulated STAT3 phosphorylation. LIFR showed high expression in human fetal kidney and the human ureter, and was also expressed in the developing murine urogenital system. Lifr knockout mice displayed urinary tract malformations including hydronephrosis, hydroureter, ureter ectopia, and, consistently, reduced ureteral lumen and muscular hypertrophy, similar to the phenotypes observed in patients carrying LIFR variants. Additionally, a form of cryptorchidism was detected in all Lifr-/- mice and the patient carrying the LIFR frameshift mutation. Altogether, we demonstrate heterozygous novel or rare LIFR mutations in 3.3% of CAKUT patients, and provide evidence that Lifr deficiency and deactivating LIFR mutations cause highly similar anomalies of the urogenital tract in mice and humans.

Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT).

Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent-trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation. Sequence analysis of 100 further CAKUT cases yielded three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237-phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. The patient with the truncating TBC1D1 mutation showed evidence for insulin resistance. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis.

Bithorax-complex genes sculpt the pattern of leucokinergic neurons in the Drosophila central nervous system.

Although the Hox genes are the main factors involved in the generation of diversity along the anterior/posterior body axis of segmented organisms, it is still largely unknown how these genes act in single cells to determine specific traits at precise developmental stages. The aim of this study was to understand the mechanisms by which Hox genes of the Bithorax complex (Bx-C) of Drosophila act to define segmental differences in the ventral nerve cord of the central nervous system. To achieve this, we have focused on the specification of the leucokinin-expressing neurons. We find that these neurons are specified from the same progenitor neuroblast at two different developmental stages: embryonic and larval neurogenesis. We show that genes of the Bx-C acted in postmitotic cells to specify the segment-specific appearance of leucokinergic cells in the larval and adult ventral nerve cord.

Low-frequency magnetic fields do not aggravate disease in mouse models of Alzheimer's disease and amyotrophic lateral sclerosis.

Low-frequency magnetic fields (LF-MF) generated by power lines represent a potential environmental health risk and are classified as possibly carcinogenic by the World Health Organization. Epidemiological studies indicate that LF-MF might propagate neurodegenerative diseases like Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS). We conducted a comprehensive analysis to determine whether long-term exposure to LF-MF (50 Hz, 1 mT) interferes with disease development in established mouse models for AD and ALS, namely APP23 mice and mice expressing mutant Cu/Zn-superoxide dismutase (SOD1), respectively. Exposure for 16 months did not aggravate learning deficit of APP23 mice. Likewise, disease onset and survival of SOD1(G85R) or SOD1(G93A) mice were not altered upon LF-MF exposure for ten or eight months, respectively. These results and an extended biochemical analysis of protein aggregation, glial activation and levels of toxic protein species suggests that LF-MF do not affect cellular processes involved in the pathogenesis of AD or ALS.