Abstract
The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular ...mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4
R269C
) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4
R269C
triggers increased intracellular Ca
2+
through a Ca
2+
/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca
2+
and neurotoxicity in
Drosophila
and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca
2+
-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca
2+
responses, the importance of tightly regulated Ca
2+
dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.
Presynaptic resting Ca2+ influences synaptic vesicle (SV) release probability. Here, we report that a TRPV channel, Inactive (Iav), maintains presynaptic resting Ca2+ by promoting Ca2+ release from ...the endoplasmic reticulum in Drosophila motor neurons, and is required for both synapse development and neurotransmission. We find that Iav activates the Ca2+/calmodulin-dependent protein phosphatase calcineurin, which is essential for presynaptic microtubule stabilization at the neuromuscular junction. Thus, loss of Iav induces destabilization of presynaptic microtubules, resulting in diminished synaptic growth. Interestingly, expression of human TRPV1 in Iav-deficient motor neurons rescues these defects. We also show that the absence of Iav causes lower SV release probability and diminished synaptic transmission, whereas Iav overexpression elevates these synaptic parameters. Together, our findings indicate that Iav acts as a key regulator of synaptic development and function by influencing presynaptic resting Ca2+.
•Iav-dependent ER Ca2+ release promotes NMJ synapse development by regulating the activity of calcineurin, which dephosphorylates presynaptic microtubule-associated proteins•Expression of human TRPV1, but not TRPV4, rescues the synaptic growth defects observed in the iav mutants•Iav plays a dose-dependent role in maintaining presynaptic resting Ca2+ levels and synaptic transmission
Wong et al. demonstrate that the Drosophila TRPV channel, Inactive (Iav), functions cell autonomously in motor neurons to promote Ca2+ release from the endoplasmic reticulum (ER), which is required for neuromuscular junction (NMJ) synapse development and function.
TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of TRPV4 cause distinct, ...tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to the intracellular N-terminal domain whereas skeletal dysplasia mutations are in multiple domains. Using an unbiased screen, we identified the cytoskeletal remodeling GTPase RhoA as a TRPV4 interactor. TRPV4-RhoA binding occurs via the TRPV4 N-terminal domain, resulting in suppression of TRPV4 channel activity, inhibition of RhoA activation, and extension of neurites in vitro. Neuropathy but not skeletal dysplasia mutations disrupt TRPV4-RhoA binding and cytoskeletal outgrowth. However, inhibition of RhoA restores neurite length in vitro and in a fly model of TRPV4 neuropathy. Together these results identify RhoA as a critical mediator of TRPV4-induced cell structure changes and suggest that disruption of TRPV4-RhoA binding may contribute to tissue-specific toxicity of TRPV4 neuropathy mutations.
Patients with intestinal failure often need long-term home parenteral support (PS). We aimed to determine how the underlying diagnosis, complications and survival had changed over the last 36 years ...in the UK's largest IF centre.
978 adult home PS patient records were analysed from January 1979 until October 2016. The age, sex, underlying aetiology, complications and survival was compared over 5-year periods.
Pre-1990 to 2011–2016, numbers increased from 29 to 451, the mean age of patients increased from 31 ± 16.5 to 52 ± 17.6 years. The percentage of patients with IF due to surgical complications increased (3.4%–28.8%, p < 0.001)), while those with inflammatory bowel disease decreased (37.9%–22.6%, p < 0.001). Complication of home PS reduced: catheter related blood stream infections (CRBSI) 71.4% to 42,2%, CVC thrombosis 34.5%–5.3%. Intestinal failure associated liver disease (IFLAD) 10.3%–1.8%. Patients with dysmotility, scleroderma and a congenital aetiology had the highest incidence of CRBSI and CVC Thrombosis. Overall survival was greater pre-1995 HR 0.2–0.4 (p = 0.02) most likely associated with an increase in mean age. Survival for patients without malignancy was 90%, 66%, 55%, 45%, 33% and 25% at 1,5, 10, 15, 20 and 30 years respectively. Multivariate analysis demonstrated a relationship between survival and age of starting home PS; type of home PS; presence or absence of the colon in continuity; and underlying aetiology.
Demand for home PS is increasing in particular for advanced malignancy, post-surgical complications and older more co-morbid patients. Complications of home PS are reducing over the last 30 years and 10-year survival for non-malignant aetiologies improving. Survival and changes in aetiology in intestinal failure.
ABSTRACT
A sediment core from the salt marsh fringing Loch Duart, NW Scotland, UK, containing Lateglacial to Holocene sediments, was analysed using a multi‐element geochemical approach to elucidate ...the relative sea level (RSL) and palaeoenvironmental changes associated with the deglaciation of the British and Irish Ice Sheet. Elemental and isotopic measurements of rhenium, osmium, carbon and nitrogen, X‐ray fluorescence scanning, radiocarbon dating, and foraminiferal analysis produced a suite of data that complements the existing biostratigraphic framework. This suite of bio‐, litho‐ and chemostratigraphic analyses permits discussion of RSL changes that reflect the interplay between post‐glacial eustatic rise and glacio‐isostatic adjustment. The osmium‐isotope (187Os/188Os) data, coupled with a new age–depth model, depict an RSL fall between 16.8 and 14.1 ka cal
bp at an average rate of 2 mm a−1. Falling RSL culminates in basin isolation and is followed by subsequent marine inundation from 11.6 ka cal
bp. This RSL record preserves the local interaction between glacial isostatic adjustment and glacio‐eustatic sea‐level change, a relationship that is reflected in the sediment's 187Os/188Os signature. This is the first known application of the osmium isotope system in an isolation basin that is shown to be a viable proxy for RSL change, a technique that could be applied to glacially influenced isolation basins globally.
During the past four decades significant decrease in Arctic sea ice and a dramatic ice mass loss of the Greenland Ice Sheet (GIS) has been coincident with global warming and an increase in ...atmospheric CO2. In Northeast Greenland significant mass loss from the outlet glaciers Nioghalvfjerdsbræ (79NG) and Zachariæ Isstrøm (ZI) and intensive seasonal breakup of the local Norske Øer Ice Barrier (NØIB) have also been observed since 2000. In order to better understand the processes driving these modern changes, studies of paleoclimate records are important and of major societal relevance. A multiproxy study including organic‐biogeochemical and micropaleontological proxies was carried out on a marine sediment core recovered directly in front of 79NG. Data from Core PS100/270 evidenced a strong inflow of warm recirculating Atlantic Water across the Northeast Greenland shelf from the early Holocene between ~10 and 7.5 ka. An overall high in phytoplankton productivity occurred within a stable sea ice margin regime, accompanied by 79NG retreat most probably triggered by peak solar insolation and changes in the local ocean circulation. Enhanced basal melt of the underside of 79NG at ~7.5 ka then led to the total disintegration of the ice shelf. The released freshwater would have driven water column stratification and promoted the formation of the local landfast ice barrier, which is shown by lowered biomarker values and foraminifera abundances toward the end of the early Holocene. Near perennial sea ice conditions with short summers and 79NG retreat to the inner fjord then prevailed from ~7.5 to ~0.8 ka.
Key Points
Multiproxy record allowed reconstruction of NEG ice sheet retreat and sea ice history from the last deglaciation to the late Holocene
Increased inflow of warm recirculating Atlantic Water linked to retreat and disintegration of the 79NG between 10 and 7.5 ka
Extended to even perennial sea ice conditions were predominant on the inner NE Greenland shelf since 7.5 ka
High-resolution Os isotope stratigraphy can aid in reconstructing Pleistocene ice sheet fluctuation and elucidating the role of local and regional weathering fluxes on the marine Os residence time. ...This paper presents new Os isotope data from ocean cores adjacent to the West Greenland ice sheet that have excellent chronological controls. Cores MSM-520 and DA00-06 represent distal to proximal sites adjacent to two West Greenland ice streams. Core MSM-520 has a steadily decreasing Os signal over the last 10 kyr (187Os/188Os = 1.35–0.81). In contrast, Os isotopes from core DA00-06 (proximal to the calving front of Jakobshavn Isbræ) highlight four stages of ice stream retreat and advance over the past 10 kyr (187Os/188Os = 2.31; 1.68; 2.09; 1.47). Our high-resolution chemostratigraphic records provide vital benchmarks for ice-sheet modelers as we attempt to better constrain the future response of major ice sheets to climate change. Variations in Os isotope composition from sediment and macro-algae (seaweed) sourced from regional and global settings serve to emphasize the overwhelming effect weathering sources have on seawater Os isotope composition. Further, these findings demonstrate that the residence time of Os is shorter than previous estimates of ∼104 yr.
•Here we present new Holocene Os isotope data from distal and proximal sediment cores from West Greenland.•These data can be correlated to ice stream activity and document ice stream retreat and advance over the past 10 kyr.•The global sample suite highlights considerable variations in seawater Os isotope composition in well-mixed ocean basins.•The data presented here confirms that the marine residence time of Os is shorter than previously thought.
In Svalbard, the rapid glacier retreat observed since the end of the Little Ice Age (LIA) has transformed the geomorphology and sediment budgets of glacial forelands, river valleys, and slope ...systems. To date, relatively little information exists regarding the impact of such a profound glacial landscape degradation on the evolution of coastal environment. This paper addresses this deficiency by detailing the post‐LIA sediment fluxes to the coastal zone in Billefjorden, central Spitsbergen (Svalbard). We analysed the response of the gravel‐dominated barrier coast to the decay of Ferdinandbreen, one of the fastest retreating glaciers in the region. Glacier retreat resulted in the development of paraglacial sediment cascade where eroded and reworked glacigenic sediments progressed through alluvial fans to the coast, thus feeding gravel‐dominated spit systems in Petuniabukta. We demonstrated that the coastal systems in central Spitsbergen responded abruptly to post‐LIA climatic changes. The acceleration of coastal erosion and associated spit development was coincident with rapid climate warming that dates from the 1980s and has been associated with longer ice‐free periods and activation of multiple sediment supply sources from the deglaciated landscape. In colder phases of post‐LIA period, coastal zone development was subdued and strongly dependent on the efficiency of sediment transport via in a longshore drift. Finally, we discuss the differences in the post‐LIA coastal responses between central Spitsbergen and western Spitsbergen highlighting the efficiency of paraglacial sediment delivery from land to the coast controlled by the state of glacial systems, bedrock topography, and development of river channels.
The structure of the canted antiferromagnet β‐p‐NCC6F4CNSSN (1) was determined from synchrotron powder‐diffraction studies in the pressure range 0–21.6 kbar. Radical 1 crystallizes in the ...orthorhombic space group Fdd2, but undergoes an asymmetric contraction of the unit‐cell size with increasing pressure. At the molecular level, this contraction of the unit cell is simultaneously accommodated by: 1) an increase in twist angle between aryl and heterocyclic rings; and 2) a shortening of the intermolecular S⋅⋅⋅N contacts, which propagate the magnetic‐exchange pathway. DFT calculations based on the structures in this pressure range revealed an increase in the magnetic‐exchange interaction (J) with increasing pressure, and an excellent correlation was observed between J and the magnetic‐ordering temperature, which increased from 36 K at ambient pressure up to 70 K at 16 kbar.
Squeeze me! The organic magnet p‐NCC6F4CNSSN revealed a dramatic increase in the magnetic‐ordering temperature under pressure reaching 70 K at 16 kbar. Structure determination from powder X‐ray diffraction (PXRD) data coupled with DFT calculations revealed that this is associated with a shortening of the intermolecular S⋅⋅⋅N contacts (see figure).
We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of ...the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.
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