Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. ...Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCKLPBN) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1VMH) are the specific target of CCKLPBN glucoregulatory neurons. This discrete CCKLPBN→SF1VMH neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCKLPBN neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.
Display omitted
•CCKLPBN neurons are glucose inhibited and activated by hypoglycemia•CCKLPBN neurons are necessary and sufficient for counterregulatory (CR)-responses•CCK neuropeptide is the key mediator of CCKLPBN neuron-mediated CR-responses•CCKLPBN neuron-induced CR-responses require downstream SF1VMH neurons
The counterregulatory response (CRR) to hypoglycemia is critical for the maintenance of normoglycemia and governed by the brain. Garfield et al. identify a population of brainstem CCK neurons that directly sense extracellular glucose concentrations and, via their connection to SF1 hypothalamic neurons, promote CRR.
Vestibular schwannomas (VS) account for approximately 85% of tumors in the cerebello-pontine angle, with a lifetime incidence of approximately 1 in 1000. Most are sporadic, with approximately 5% ...related to the tumor predisposition syndrome Neurofibromatosis Type 2 (NF2). The mainstays of management strategies are: observation, surgery, radiosurgery/radiotherapy and, for patients with NF2 and rapidly growing tumors or deteriorating neurologic function the targeted therapy bevacizumab. While morbidity and mortality rates related to treatment of VS have improved dramatically over the last decades, there are still significant improvements that could be made, in particular with regards to long-term facial nerve and hearing outcomes. Areas covered: The epidemiology and diagnosis of VS are discussed, followed by the different management strategies and outcomes of those for both sporadic and NF2 related tumors. An extensive literature review has been performed to inform this review article using PubMed and Google Scholar. Expert commentary: The future direction of VS management lies in obtaining longer-term follow-up data for patients with treated VS, and in improved understanding of cellular pathways and targeted therapies.
ABSTRACT
Fens represent a large array of ecosystem services, including the highest biodiversity found among wetlands, hydrological services, water purification and carbon sequestration. Land‐use ...change and drainage has severely damaged or annihilated these services in many parts of North America and Europe; restoration plans are urgently needed at the landscape level. We review the major constraints on the restoration of rich fens and fen water bodies in agricultural areas in Europe and disturbed landscapes in North America: (i) habitat quality problems: drought, eutrophication, acidification, and toxicity, and (ii) recolonization problems: species pools, ecosystem fragmentation and connectivity, genetic variability, and invasive species; and here provide possible solutions. We discuss both positive and negative consequences of restoration measures, and their causes. The restoration of wetland ecosystem functioning and services has, for a long time, been based on a trial‐and‐error approach. By presenting research and practice on the restoration of rich fen ecosystems within agricultural areas, we demonstrate the importance of biogeochemical and ecological knowledge at different spatial scales for the management and restoration of biodiversity, water quality, carbon sequestration and other ecosystem services, especially in a changing climate. We define target processes that enable scientists, nature managers, water managers and policy makers to choose between different measures and to predict restoration prospects for different types of deteriorated fens and their starting conditions.
Heterozygous germline PTCH1 mutations are causative of Gorlin syndrome (naevoid basal cell carcinoma), but detection rates > 70% have rarely been reported. We aimed to define the causative mutations ...in individuals with Gorlin syndrome without PTCH1 mutations.
We undertook exome sequencing on lymphocyte DNA from four unrelated individuals from families with Gorlin syndrome with no PTCH1 mutations found by Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or RNA analysis.
A germline heterozygous nonsense mutation in SUFU was identified in one of four exomes. Sanger sequencing of SUFU in 23 additional PTCH1-negative Gorlin syndrome families identified a SUFU mutation in a second family. Copy-number analysis of SUFU by MLPA revealed a large heterozygous deletion in a third family. All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts. Each SUFU-positive family included a single case of medulloblastoma, whereas only two (1.7%) of 115 individuals with Gorlin syndrome and a PTCH1 mutation developed medulloblastoma.
We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. Our study redefines the risk of medulloblastoma in Gorlin syndrome, dependent on the underlying causative gene. Previous reports have found a 5% risk of medulloblastoma in Gorlin syndrome. We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals. Our data suggest childhood brain magnetic resonance imaging surveillance is justified in SUFU-related, but not PTCH1-related, Gorlin syndrome.
Simulations of photosynthesis by terrestrial biosphere models typically need a specification of the maximum carboxylation rate (V
cmax). Estimating this parameter using A–C
i curves (net ...photosynthesis, A, vs intercellular CO2 concentration, C
i) is laborious, which limits availability of V
cmax data. However, many multispecies field datasets include net photosynthetic rate at saturating irradiance and at ambient atmospheric CO2 concentration (A
sat) measurements, from which V
cmax can be extracted using a ‘one-point method’.
We used a global dataset of A–C
i curves (564 species from 46 field sites, covering a range of plant functional types) to test the validity of an alternative approach to estimate V
cmax from A
sat via this ‘one-point method’.
If leaf respiration during the day (R
day) is known exactly, V
cmax can be estimated with an r
2 value of 0.98 and a root-mean-squared error (RMSE) of 8.19 μmolm−2 s−1. However, R
day typically must be estimated. Estimating R
day as 1.5% of V
cmax, we found that V
cmax could be estimated with an r
2 of 0.95 and an RMSE of 17.1 μmolm−2 s−1.
The one-point method provides a robust means to expand current databases of fieldmeasured V
cmax, giving new potential to improve vegetation models and quantify the environmental drivers of V
cmax variation.
Restoration of eroded blanket peatlands through revegetation and gully blocking is observed to also deliver significant natural flood management (NFM) benefits (reduce and delay floodpeaks). But ...there is a lack of clear understanding regarding how different catchment processes interact/counteract under each intervention scenario. We seek to provide more insight by rigorously calibrating TOPMODEL rainfall‐runoff model to different experimental catchments each representing an intervention scenario. Through numerical experimentation with the calibrated parameters, we estimate the impact‐magnitude of different processes. Our findings confirm the NFM benefits of these restoration‐focused interventions. In both interventions and in our largest storms, both the delay and reduced floodpeaks are primarily due to surface roughness reducing the floodwave speed thus thickening the overland flow; we conceptualize this as an increase in a “kinematic storage.” Impact of gully blocking in increasing kinematic storage is very significant and comparable to that of revegetation alone. Interventions' impact on “static storage” (interception + ponding + evapotranspiration) becomes important for smaller storms. Although interventions always increase lag times, they can be less effective in reducing peak magnitude when maximum rainfall intensity is sustained for durations longer than mean catchment delay. We propose two approaches to further increase catchment's static and kinematic storage. Finally, while our field‐scale numerical study contributes to the evidence‐base for NFM's effectiveness, it also provides a basis for modeling these interventions in the future. Such catchment‐scale numerical studies are necessary to extend our findings to spatial scales where flooding can cause socioeconomic damage, and to provide a tool for optimizing the distributed configuration of these interventions.
Key Points
Blanket peat restoration interventions significantly reduce flood risk to the downstream communities at risk
Revegetation and gully blocking of eroded blanket peat reduces flood risk primarily through increased surface roughness and not storage
Impact of gully blocking in reducing increasing “kinematic” surface storage is very significant and equivalent to revegetation alone
Mesophyll conductance (gm) is known to affect plant photosynthesis. However, gm is rarely explicitly considered in land surface models (LSMs), with the consequence that its role in ecosystem and ...large‐scale carbon and water fluxes is poorly understood. In particular, the different magnitudes of gm across plant functional types (PFTs) are expected to cause spatially divergent vegetation responses to elevated CO2 concentrations. Here, an extensive literature compilation of gm across major vegetation types is used to parameterize an empirical model of gm in the LSM JSBACH and to adjust photosynthetic parameters based on simulated An − Ci curves. We demonstrate that an explicit representation of gm changes the response of photosynthesis to environmental factors, which cannot be entirely compensated by adjusting photosynthetic parameters. These altered responses lead to changes in the photosynthetic sensitivity to atmospheric CO2 concentrations which depend both on the magnitude of gm and the climatic conditions, particularly temperature. We then conducted simulations under ambient and elevated (ambient + 200 μmol/mol) CO2 concentrations for contrasting ecosystems and for historical and anticipated future climate conditions (representative concentration pathways; RCPs) globally. The gm‐explicit simulations using the RCP8.5 scenario resulted in significantly higher increases in gross primary productivity (GPP) in high latitudes (+10% to + 25%), intermediate increases in temperate regions (+5% to + 15%), and slightly lower to moderately higher responses in tropical regions (−2% to +5%), which summed up to moderate GPP increases globally. Similar patterns were found for transpiration, but with a lower magnitude. Our results suggest that the effect of an explicit representation of gm is most important for simulated carbon and water fluxes in the boreal zone, where a cold climate coincides with evergreen vegetation.
We make use of an extensive literature compilation of gm across major vegetation types to implement an empirical representation of gm into the land surface model JSBACH and investigate its effects on carbon and water fluxes at the leaf to global scales. We show that gm changes the response of photosynthesis to environmental factors, which leads to an altered photosynthetic sensitivity to CO2 depending on both the magnitude of gm and climatic conditions. Globally, gm caused considerable increases in gross primary productivity of +5% to +15% in the boreal zone, but only minor changes (−2% to +5%) in the tropics.
Candidate genes have been identified for both reading and language, but most of the heritable variance in these traits remains unexplained. Here, we report a genome‐wide association meta‐analysis of ...two large cohorts: population samples of Australian twins and siblings aged 12–25 years (n = 1177 from 538 families), and a younger cohort of children of the UK Avon Longitudinal Study of Parents and their Children (aged 8 and 9 years; maximum n = 5472). Suggestive association was indicated for reading measures and non‐word repetition (NWR), with the greatest support found for single nucleotide polymorphisms (SNPs) in the pseudogene, ABCC13 (P = 7.34 × 10−8), and the gene, DAZAP1 (P = 1.32 × 10−6). Gene‐based analyses showed significant association (P < 2.8 × 10−6) for reading and spelling with genes CD2L1, CDC2L2 and RCAN3 in two loci on chromosome 1. Some support was found for the same SNPs having effects on both reading skill and NWR, which is compatible with behavior genetic evidence for influences of reading acquisition on phonological‐task performance. The results implicate novel candidates for study in additional cohorts for reading and language abilities.
Genome‐wide association analysis implicates loci involved in reading and language skills in the general population.
Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with ...androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone.
Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m
body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS).
In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89
0.84, respectively; 95% CI for the difference, -0.01 to 0.11;
= .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio HR, 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone.
The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.
This study evaluated whether apraxia can be understood as due to impaired motor representations or motor imagery necessary for appropriate object-use, imitation, and pantomime. The causal role of the ...left inferior parietal lobe (IPL), which is heavily implicated in apraxia, is also evaluated. These processes are appraised in light of the proposed ventro-dorsal sub-stream of the classic two visual pathway model, where perceptual information from the ventral stream and the dorsal action stream are integrated and essential for object manipulation. Using a task assessing object-use perception, stroke patients with apraxia demonstrated a selective deficit during perceptual decisions reliant on the integration of visible and known object properties to select the appropriate grasp for object-use. This deficit increased with apraxia severity. A dissociation was evident in these patients showing intact non-motoric perceptual decisions regarding the functional semantic relationship between two objects in the absence of the actor (e.g. how a hammer hits a nail). Converging evidence was found using a modified version of the same task in a neuromodulation study that directly targeted the left IPL in healthy participants using transcranial direct current stimulation (tDCS). Application of inhibitory stimulation over the left IPL reduced performance during perceptual decisions regarding object manipulation whilst performance was unaffected during functional semantic decisions. Excitatory stimulation of the left IPL did not affect performance in either task. Combined, these results suggest that the left inferior parietal lobe is critical for motor imagery, and that apraxia may be caused by an inability to use internal motor representations of object manipulation. These results are discussed in terms of motoric and non-motoric perceptual processes and the proposal of an additional ventro-dorsal sub-stream within the dorsal and ventral visual pathways model.
•Apraxia is associated with deficits in motor imagery.•Stimulation of the left IPL compromises motoric perceptual decisions of object-use.•The left IPL may be a critical region in apraxia and motor imagery.•Motoric and semantic representations of object-use are independent.•Motor representations are implicated in the ventro-dorsal sub-stream.
PDF
