Estimating intraseasonal intrinsic water-use efficiency from high-resolution tree-ring delta C-13 data in boreal Scots pine forests

Intrinsic water-use efficiency (iWUE), a key index for carbon and water balance, has been widely estimated from tree-ring delta C-13 at annual resolution, but rarely at high-resolution intraseasonal scale. We estimated high-resolution iWUE from laser-ablation delta C-13 analysis of tree-rings (iWUE(iso)) and compared it with iWUE derived from gas exchange (iWUE(gas)) and eddy covariance (iWUE(EC)) data for two Pinus sylvestris forests from 2002 to 2019. By carefully timing iWUE(iso) via modeled tree-ring growth, iWUE(iso) aligned well with iWUE(gas) and iWUE(EC) at intraseasonal scale. However, year-to-year patterns of iWUE(gas), iWUE(iso), and iWUE(EC) were different, possibly due to distinct environmental drivers on iWUE across leaf, tree, and ecosystem scales. We quantified the modification of iWUE(iso) by postphotosynthetic delta C-13 enrichment from leaf sucrose to tree rings and by nonexplicit inclusion of mesophyll and photorespiration terms in photosynthetic discrimination model, which resulted in overestimation of iWUE(iso) by up to 11% and 14%, respectively. We thus extended the application of tree-ring delta C-13 for iWUE estimates to high-resolution intraseasonal scale. The comparison of iWUE(gas), iWUE(iso), and iWUE(EC) provides important insights into physiological acclimation of trees across leaf, tree, and ecosystem scales under climate change and improves the upscaling of ecological models.Peer reviewe

HIMMELI v1.0 : HelsinkI Model of MEthane buiLd-up and emIssion for peatlands

Wetlands are one of the most significant natural sources of methane (CH4) to the atmosphere. They emit CH4 because decomposition of soil organic matter in waterlogged anoxic conditions produces CH4, in addition to carbon dioxide (CO2). Production of CH4 and how much of it escapes to the atmosphere depend on a multitude of environmental drivers. Models simulating the processes leading to CH4 emissions are thus needed for upscaling observations to estimate present CH4 emissions and for producing scenarios of future atmospheric CH4 concentrations. Aiming at a CH4 model that can be added to models describing peatland carbon cycling, we composed a model called HIMMELI that describes CH4 build-up in and emissions from peatland soils. It is not a full peatland carbon cycle model but it requires the rate of anoxic soil respiration as input. Driven by soil temperature, leaf area index (LAI) of aerenchymatous peat-land vegetation, and water table depth (WTD), it simulates the concentrations and transport of CH4, CO2, and oxygen (O-2) in a layered one-dimensional peat column. Here, we present the HIMMELI model structure and results of tests on the model sensitivity to the input data and to the description of the peat column (peat depth and layer thickness), and demonstrate that HIMMELI outputs realistic fluxes by comparing modeled and measured fluxes at two peatland sites. As HIMMELI describes only the CH4-related processes, not the full carbon cycle, our analysis revealed mechanisms and dependencies that may remain hidden when testing CH4 models connected to complete peatland carbon models, which is usually the case. Our results indicated that (1) the model is flexible and robust and thus suitable for different environments; (2) the simulated CH4 emissions largely depend on the prescribed rate of anoxic respiration; (3) the sensitivity of the total CH4 emission to other input variables is mainly mediated via the concentrations of dissolved gases, in particular, the O-2 concentrations that affect the CH4 production and oxidation rates; (4) with given input respiration, the peat column description does not significantly affect the simulated CH4 emissions in this model version.Peer reviewe

Tree organ growth and carbon allocation dynamics impact the magnitude and δ13C signal of stem and soil CO2 fluxes

Incomplete knowledge of carbon (C) allocation dynamics in trees hinders accurate modeling and future predictions of tree growth. We studied C allocation dynamics in a mature Pinus sylvestris L. dominated forest with a novel analytical approach, allowing the first comparison of: (i) magnitude and delta C-13 of shoot, stem and soil CO2 fluxes (A(shoot), R-stem and R-soil), (ii) concentration and delta C-13 of compound-specific and/or bulk non-structural carbohydrates (NSCs) in phloem and roots and (iii) growth of stem and fine roots. Results showed a significant effect of phloem NSC concentrations on tracheid growth, and both variables significantly impacted R-stem. Also, concentrations of root NSCs, especially starch, had a significant effect on fine root growth, although no effect of root NSC concentrations or root growth was detected on R-soil. Time series analysis between delta C-13 of A(shoot) and delta C-13 of R-stem or delta C-13 of R-soil revealed strengthened C allocation to stem or roots under high C demands. Furthermore, we detected a significant correlation between delta C-13 of R-stem and delta C-13 of phloem sucrose and glucose, but not for starch or water-soluble carbohydrates. Our results indicate the need to include C allocation dynamics into tree growth models. We recommend using compound-specific concentration and delta C-13 analysis to reveal C allocation processes that may not be detected by the conventional approach that utilizes bulk organic matter.Peer reviewe

Change in brain amyloid load and cognition in patients with amnestic mild cognitive impairment: a 3-year follow-up study

Background Our aim was to investigate the discriminative value of F-18-Flutemetamol PET in longitudinal assessment of amyloid beta accumulation in amnestic mild cognitive impairment (aMCI) patients, in relation to longitudinal cognitive changes. Methods We investigated the change in F-18-Flutemetamol uptake and cognitive impairment in aMCI patients over time up to 3 years which enabled us to investigate possible association between changes in brain amyloid load and cognition over time. Thirty-four patients with aMCI (mean age 73.4 years, SD 6.6) were examined with F-18-Flutemetamol PET scan, brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to Alzheimer ' s disease (AD). F-18-Flutemetamol data were analyzed both with automated region-of-interest analysis and voxel-based statistical parametric mapping. Results F-18-flutemetamol uptake increased during the follow-up, and the increase was significantly higher in patients who were amyloid positive at baseline as compared to the amyloid-negative ones. At follow-up, there was a significant association between F-18-Flutemetamol uptake and MMSE, logical memory I (immediate recall), logical memory II (delayed recall) and verbal fluency. An association was seen between the increase in F-18-Flutemetamol uptake and decline in MMSE and logical memory I scores. Conclusions In the early phase of aMCI, presence of amyloid pathology at baseline strongly predicted amyloid accumulation during follow-up, which was further paralleled by cognitive declines. Inversely, some of our patients remained amyloid negative also at the end of the study without significant change in F-18-Flutemetamol uptake or cognition. Future studies with longer follow-up are needed to distinguish whether the underlying pathophysiology of aMCI in such patients is other than AD.</p

TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome"

Under-reported aspects of diagnosis and treatment addressed in the Dutch-Flemish guideline for comprehensive diagnostics in disorders/differences of sex development

We present key points from the updated Dutch-Flemish guideline on comprehensive diagnostics in disorders/differences of sex development (DSD) that have not been widely addressed in the current (inter)national literature. These points are of interest to physicians working in DSD (expert) centres and to professionals who come across persons with a DSD but have no (or limited) experience in this area. The Dutch-Flemish guideline is based on internationally accepted principles. Recent initiatives striving for uniform high-quality care across Europe, and beyond, such as the completed COST action 1303 and the European Reference Network for rare endocrine conditions (EndoERN), have generated several excellent papers covering nearly all aspects of DSD. The Dutch-Flemish guideline follows these international consensus papers and covers a number of other topics relevant to daily practice. For instance, although next-generation sequencing (NGS)-based molecular diagnostics are becoming the gold standard for genetic evaluation, it can be difficult to prove variant causality or relate the genotype to the clinical presentation. Network formation and centralisation are essential to promote functional studies that assess the effects of genetic variants and to the correct histological assessment of gonadal material from DSD patients, as well as allowing for maximisation of expertise and possible cost reductions. The Dutch-Flemish guidelines uniquely address three aspects of DSD. First, we propose an algorithm for counselling and diagnostic evaluation when a DSD is suspected prenatally, a clinical situation that is becoming more common. Referral to ultrasound sonographers and obstetricians who are part of a DSD team is increasingly important here. Second, we pay special attention to healthcare professionals not working within a DSD centre as they are often the first to diagnose or suspect a DSD, but are not regularly exposed to DSDs and may have limited experience. Their thoughtful communication to patients, carers and colleagues, and the accessibility of protocols for first-line management and efficient referral are essential. Careful communication in the prenatal to neonatal period and the adolescent to adult transition are equally important and relatively under-reported in the literature. Third, we discuss the timing of (NGS-based) molecular diagnostics in the initial workup of new patients and in people with a diagnosis made solely on clinical grounds or those who had earlier genetic testing that is not compatible with current state-of-the-art diagnostics

Rapid whole exome sequencing in pregnancies to identify the underlying genetic cause in fetuses with congenital anomalies detected by ultrasound imaging

Objective: The purpose of this study was to explore the diagnostic yield and clinical utility of trio-based rapid whole exome sequencing (rWES) in pregnancies of fetuses with a wide range of congenital anomalies detected by ultrasound imaging. Methods: In this observational study, we analyzed the first 54 cases referred to our laboratory for prenatal rWES to support clinical decision making, after the sonographic detection of fetal congenital anomalies. The most common identified congenital anomalies were skeletal dysplasia (n = 20), multiple major fetal congenital anomalies (n = 17) and intracerebral structural anomalies (n = 7). Results: A conclusive diagnosis was identified in 18 of the 54 cases (33%). Pathogenic variants were detected most often in fetuses with skeletal dysplasia (n = 11) followed by fetuses with multiple major fetal congenital anomalies (n = 4) and intracerebral structural anomalies (n = 3). A survey, completed by the physicians for 37 of 54 cases, indicated that the rWES results impacted clinical decision making in 68% of cases. Conclusions: These results suggest that rWES improves prenatal diagnosis of fetuses with congenital anomalies, and has an important impact on prenatal and peripartum parental and clinical decision making

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

Purpose De novovariants inCUL3(Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants inCUL3,describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.MethodsGenetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells.ResultsWe assembled a cohort of 35 individuals with heterozygousCUL3variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants.CUL3LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugatesin vitro. Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells.ConclusionOur study further refines the clinical and mutational spectrum ofCUL3-associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism

Familial Male-Limited Precocious Puberty (FMPP) and Testicular Germ Cell Tumors

OBJECTIVE: The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty (FMPP) because of LHCGR pathogenic variants in 2 families. Secondarily, to study the possible relation between FMPP and testicular tumors and to investigate whether FMPP might predispose to development of malignant testicular tumors in adulthood a literature review is conducted. METHODS: Data on 6 cases in 2 families are obtained from the available medical records. In addition, a database search is performed in Cochrane, PubMed, and Embase for studies that report on a possible link between FMPP and testicular tumors. RESULTS: The characteristics of 6 males with FMPP based on activating LH receptor (LHCGR) germline pathogenic variants are described, as are details of the testicular GCTs. Furthermore, a literature review identified 4 more patients with signs of FMPP and a (precursor of) testicular GCT in adolescence or adulthood (age 15-35 years). Additionally, 12 patients with signs of precocious puberty and, simultaneously, occurrence of a Leydig cell adenoma or Leydig cell hyperplasia are reported. CONCLUSION: There is a strong suggestion that FMPP might increase the risk of development of testicular GCTs in early adulthood compared with the risk in the general population. Therefore, prolonged patient monitoring from mid-pubertal age onward including instruction for self-examination and periodic testicular ultrasound investigation in patients with a germline LHCGR pathogenic variant might contribute to early detection and thus early treatment of testicular GCT

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8: NM_000498.3: c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the biochemical and genetic work-up performed and describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1