Multiple endocrine neoplasia type 4: a new member of the MEN family.

Objective: Multiple endocrine neoplasia type 4 (MEN4) is caused by a CDKN1B germline mutation first described in 2006. Its estimated prevalence is less than one per million. The aim of this study was to define the disease characteristics. Methods: A systematic review was performed according to the PRISMA 2020 criteria. A literature search from January 2006 to August 2022 was done using MEDLINE® and Web of ScienceTM. Results: Forty-eight symptomatic patients fulfilled the pre-defined eligibility criteria. Twenty-eight different CDKN1B variants, mostly missense (21/48, 44%) and frameshift mutations (17/48, 35%), were reported. The majority of patients were women (36/48, 75%). Men became symptomatic at a median age of 32.5 years (range 10-68, mean 33.7 ± 23), whereas the same event was recorded for women at a median age of 49.5 years (range 5-76, mean 44.8 ± 19.9) (P = 0.25). The most frequently affected endocrine organ was the parathyroid gland (36/48, 75%; uniglandular disease 31/36, 86%), followed by the pituitary gland (21/48, 44%; hormone-secreting 16/21, 76%), the endocrine pancreas (7/48, 15%), and the thyroid gland (4/48, 8%). Tumors of the adrenal glands and thymus were found in three and two patients, respectively. The presenting first endocrine pathology concerned the parathyroid (27/48, 56%) and the pituitary gland (11/48, 23%). There were one (27/48, 56%), two (13/48, 27%), three (3/48, 6%), or four (5/48, 10%) syn- or metachronously affected endocrine organs in a single patient, respectively. Conclusion: MEN4 is an extremely rare disease, which most frequently affects women around 50 years of age. Primary hyperparathyroidism as a uniglandular disease is the leading pathology.

Root exudates increase soil respiration and alter microbial community structure in alpine permafrost and active layer soils.

Due to climate warming, alpine ecosystems are changing rapidly. Ongoing upward migrations of plants and thus an increase of easily decomposable substrates will strongly affect the soil microbiome. To understand how belowground communities will respond to such changes, we set up an incubation experiment with permafrost and active soil layers from northern (NW) and southern (SE) slopes of a mountain ridge on Muot da Barba Peider in the Swiss Alps and incubated them with or without artificial root exudates (AREs) at two temperatures, 4°C or 15°C. The addition of AREs resulted in elevated respiration across all soil types. Bacterial and fungal alpha diversity decreased significantly, coinciding with strong shifts in microbial community structure in ARE-treated soils. These shifts in bacterial community structure were driven by an increased abundance of fast-growing copiotrophic taxa. Fungal communities were predominantly affected by AREs in SE active layer soils and shifted towards fast-growing opportunistic yeast. In contrast, in the colder NW facing active layer and permafrost soils fungal communities were more influenced by temperature changes. These findings demonstrate the sensitivity of soil microbial communities in high alpine ecosystems to climate change and how shifts in these communities may lead to functional changes impacting biogeochemical processes.

The Soil Microbiome of GLORIA Mountain Summits in the Swiss Alps.

While vegetation has intensively been surveyed on mountain summits, limited knowledge exists about the diversity and community structure of soil biota. Here, we study how climatic variables, vegetation, parent material, soil properties, and slope aspect affect the soil microbiome on 10 GLORIA (Global Observation Research Initiative in Alpine environments) mountain summits ranging from the lower alpine to the nival zone in Switzerland. At these summits we sampled soils from all four aspects and examined how the bacterial and fungal communities vary by using Illumina MiSeq sequencing. We found that mountain summit soils contain highly diverse microbial communities with a total of 10,406 bacterial and 6,291 fungal taxa. Bacterial α-diversity increased with increasing soil pH and decreased with increasing elevation, whereas fungal α-diversity did not change significantly. Soil pH was the strongest predictor for microbial ß-diversity. Bacterial and fungal community structures exhibited a significant positive relationship with plant communities, indicating that summits with a more distinct plant composition also revealed more distinct microbial communities. The influence of elevation was stronger than aspect on the soil microbiome. Several microbial taxa responded to elevation and soil pH. Chloroflexi and Mucoromycota were significantly more abundant on summits at higher elevations, whereas the relative abundance of Basidiomycota and Agaricomycetes decreased with elevation. Most bacterial OTUs belonging to the phylum Acidobacteria were indicators for siliceous parent material and several OTUs belonging to the phylum Planctomycetes were associated with calcareous soils. The trends for fungi were less clear. Indicator OTUs belonging to the genera Mortierella and Naganishia showed a mixed response to parent material, demonstrating their ubiquitous and opportunistic behaviour in soils. Overall, fungal communities responded weakly to abiotic and biotic factors. In contrast, bacterial communities were strongly influenced by environmental changes suggesting they will be strongly affected by future climate change and associated temperature increase and an upward migration of vegetation. Our results provide the first insights into the soil microbiome of mountain summits in the European Alps that are shaped as a result of highly variable local environmental conditions and may help to predict responses of the soil biota to global climate change.

Cell-cycle regulation of NOTCH signaling during C. elegans vulval development.

C. elegans vulval development is one of the best-characterized systems to study cell fate specification during organogenesis. The detailed knowledge of the signaling pathways determining vulval precursor cell (VPC) fates permitted us to create a computational model based on the antagonistic interactions between the epidermal growth factor receptor (EGFR)/RAS/MAPK and the NOTCH pathways that specify the primary and secondary fates, respectively. A key notion of our model is called bounded asynchrony, which predicts that a limited degree of asynchrony in the progression of the VPCs is necessary to break their equivalence. While searching for a molecular mechanism underlying bounded asynchrony, we discovered that the termination of NOTCH signaling is tightly linked to cell-cycle progression. When single VPCs were arrested in the G1 phase, intracellular NOTCH failed to be degraded, resulting in a mixed primary/secondary cell fate. Moreover, the G1 cyclins CYD-1 and CYE-1 stabilize NOTCH, while the G2 cyclin CYB-3 promotes NOTCH degradation. Our findings reveal a synchronization mechanism that coordinates NOTCH signaling with cell-cycle progression and thus permits the formation of a stable cell fate pattern.