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"Nelson, T"
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PIP2: A critical regulator of vascular ion channels hiding in plain sight
SignificancePhosphatidylinositol 4,5-bisphosphate (PIP2), a plasma membrane lipid, is hydrolyzed by Gq-protein–coupled receptor (GqPCR) signaling into inositol 1,4,5-trisphosphate and diacylglycerol—extensively studied second messengers with profound regulatory effects in the vasculature. However, there is extensive evidence that PIP2 directly regulates ion channels, a finding with significant implications for vascular function. Beyond providing a previously unexplored perspective on how vascular GqPCR signaling influences vascular function, the concept of PIP2-mediated ion channel regulation helps to explain how vascular cell excitability is coordinated to support cerebral blood flow control mechanisms. Importantly, the link between the metabolic state of vascular cells and PIP2 content may provide insight into how metabolism affects vascular ion channel activity and, ultimately, vascular function in health and disease.
The phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2), has long been established as a major contributor to intracellular signaling, primarily by virtue of its role as a substrate for phospholipase C (PLC). Signaling by Gq-protein–coupled receptors triggers PLC-mediated hydrolysis of PIP2 into inositol 1,4,5-trisphosphate and diacylglycerol, which are well known to modulate vascular ion channel activity. Often overlooked, however, is the role PIP2 itself plays in this regulation. Although numerous reports have demonstrated that PIP2 is critical for ion channel regulation, how it impacts vascular function has received scant attention. In this review, we focus on PIP2 as a regulator of ion channels in smooth muscle cells and endothelial cells—the two major classes of vascular cells. We further address the concerted effects of such regulation on vascular function and blood flow control. We close with a consideration of current knowledge regarding disruption of PIP2 regulation of vascular ion channels in disease.
Journal Article
Environmental Controls on Simulated Deep Moist Convection Initiation Occurring during RELAMPAGO-CACTI
This study synthesizes the results of 13 high-resolution simulations of deep convective updrafts forming over idealized terrain using environments observed during the RELAMPAGO and CACTI field projects. Using composite soundings from multiple observed cases, and variations upon them, we explore the sensitivity of updraft properties (e.g., size, buoyancy, and vertical pressure gradient forces) to influences of environmental relative humidity, wind shear, and mesoscale orographic forcing that support or suppress deep convection initiation (CI). Emphasis is placed on differentiating physical processes affecting the development of updrafts (e.g., entrainment-driven dilution of updrafts) in environments typifying observed successful and null (i.e., no CI despite affirmative operational forecasts) CI events. Thermally induced mesoscale orographic lift favors the production of deep updrafts originating from ∼1- to 2-km-wide boundary layer thermals. Simulations without terrain forcing required much larger (∼5-km-wide) thermals to yield precipitating convection. CI outcome was quite sensitive to environmental relative humidity; updrafts with increased buoyancy, depth, and intensity thrived in otherwise inhospitable environments by simply increasing the free-tropospheric relative humidity. This implicates the entrainment of free-tropospheric air into updrafts as a prominent governor of CI, consistent with previous studies. Sensitivity of CI to the environmental wind is manifested by 1) low-level flow affecting the strength and depth of mesoscale convergence along the terrain, and 2) clouds encountering updraft-suppressing pressure gradient forces while interacting with vertical wind shear in the free troposphere. Among the ensemble of thermals occurring in each simulation, the widest deep updrafts in each simulation were the most sensitive to environmental influences.
Journal Article
Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow
Longden
et al
. demonstrate that brain capillaries function as a vast sensory web, monitoring neuronal activity by sensing K
+
and translating this into a K
IR
-channel-mediated regenerative retrograde hyperpolarizing signal that propagates to upstream arterioles to drive vasodilation and an increase in blood flow into the capillary bed.
Blood flow into the brain is dynamically regulated to satisfy the changing metabolic requirements of neurons, but how this is accomplished has remained unclear. Here we demonstrate a central role for capillary endothelial cells in sensing neural activity and communicating it to upstream arterioles in the form of an electrical vasodilatory signal. We further demonstrate that this signal is initiated by extracellular K
+
—a byproduct of neural activity—which activates capillary endothelial cell inward-rectifier K
+
(K
IR
2.1) channels to produce a rapidly propagating retrograde hyperpolarization that causes upstream arteriolar dilation, increasing blood flow into the capillary bed. Our results establish brain capillaries as an active sensory web that converts changes in external K
+
into rapid, 'inside-out' electrical signaling to direct blood flow to active brain regions.
Journal Article
Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpn
fl/fl
mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpn
fl/fl/NEXcre
and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.
Journal Article
Accelerating ethics, empathy, and equity in geographic information science
Science has traditionally been driven by curiosity and followed one goal: the pursuit of truth and the advancement of knowledge. Recently, ethics, empathy, and equity, which we term “the 3Es,” are emerging as new drivers of research and disrupting established practices. Drawing on our own field of GIScience (geographic information science), our goal is to use the geographic approach to accelerate the response to the 3Es by identifying priority issues and research needs that, if addressed, will advance ethical, empathic, and equitable GIScience. We also aim to stimulate similar responses in other disciplines. Organized around the 3Es we discuss ethical issues arising from locational privacy and cartographic integrity, how our ability to build knowledge that will lead to empathy can be curbed by data that lack representativeness and by inadvertent inferential error, and how GIScientists can lead toward equity by supporting social justice efforts and democratizing access to spatial science and its tools. We conclude with a call to action and invite all scientists to join in a fundamentally different science that responds to the 3Es and mobilizes for change by engaging in humility, broadening measures of excellences and success, diversifying our networks, and creating pathways to inclusive education. Science united around the 3Es is the right response to this unique moment where society and the planet are facing a vast array of challenges that require knowledge, truth, and action.
Journal Article
Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE): Clinical and Neuropathological Associations
Abstract
Recently, a consensus working group provided new terminology for a common disease entity, limbic predominant age-related TDP-43 encephalopathy (LATE), and its neuropathological substrate (LATE-NC). LATE-NC not only often co-occurs with Alzheimer disease neuropathological change (ADNC), but also may present in isolation. The present study aimed to investigate potential risk factors and neuropathological characteristics associated with LATE-NC. A sample of 616 autopsied participants (>75 years at death), with TDP-43 immunohistochemical studies performed, was obtained from the National Alzheimer’s Coordinating Center. Logistic regression analyses examined associations between demographic, clinical and neuropathological characteristics and LATE-NC (TDP-43 in amygdala, hippocampus, or entorhinal/inferior temporal cortex) (alpha = 0.05). Adjusted models indicated that ADNC, hippocampal sclerosis (HS), arteriolosclerosis, and limbic or amygdala-predominant Lewy body disease (LBD), but not other LBD subtypes, were associated with higher odds of LATE-NC, whereas congestive heart failure (CHF) and motor problems as first predominant symptom were associated with lower odds of LATE-NC. Our findings corroborate previous studies indicating associations between LATE-NC and ADNC, HS, and arteriolosclerosis. Novel findings suggest the association with LATE-NC is restricted to amygdala/limbic-predominant subtype of LBD, and a possible protective (or competing risk) association with CHF. This study may inform future hypothesis-driven research on LATE-NC, a common brain disease of aging.
Journal Article
ATGL is a biosynthetic enzyme for fatty acid esters of hydroxy fatty acids
Branched fatty acid (FA) esters of hydroxy FAs (HFAs; FAHFAs) are recently discovered lipids that are conserved from yeast to mammals
1
,
2
. A subfamily, palmitic acid esters of hydroxy stearic acids (PAHSAs), are anti-inflammatory and anti-diabetic
1
,
3
. Humans and mice with insulin resistance have lower PAHSA levels in subcutaneous adipose tissue and serum
1
. PAHSA administration improves glucose tolerance and insulin sensitivity and reduces inflammation in obesity, diabetes and immune-mediated diseases
1
,
4
–
7
. The enzyme(s) responsible for FAHFA biosynthesis in vivo remains unknown. Here we identified adipose triglyceride lipase (ATGL, also known as patatin-like phospholipase domain containing 2 (PNPLA2)) as a candidate biosynthetic enzyme for FAHFAs using chemical biology and proteomics. We discovered that recombinant ATGL uses a transacylation reaction that esterifies an HFA with a FA from triglyceride (TG) or diglyceride to produce FAHFAs. Overexpression of wild-type, but not catalytically dead, ATGL increases FAHFA biosynthesis. Chemical inhibition of ATGL or genetic deletion of
Atgl
inhibits FAHFA biosynthesis and reduces the levels of FAHFA and FAHFA-TG. Levels of endogenous and nascent FAHFAs and FAHFA-TGs are 80–90 per cent lower in adipose tissue of mice in which
Atgl
is knocked out specifically in the adipose tissue. Increasing TG levels by upregulating diacylglycerol acyltransferase (DGAT) activity promotes FAHFA biosynthesis, and decreasing DGAT activity inhibits it, reinforcing TGs as FAHFA precursors. ATGL biosynthetic transacylase activity is present in human adipose tissue underscoring its potential clinical relevance. In summary, we discovered the first, to our knowledge, biosynthetic enzyme that catalyses the formation of the FAHFA ester bond in mammals. Whereas ATGL lipase activity is well known, our data establish a paradigm shift demonstrating that ATGL transacylase activity is biologically important.
A study in mammals identifies a new role for adipose triglyceride lipase in catalysing the esterification of hydroxyl fatty acids to produce biologically active fatty acid esters of hydroxy fatty acids.
Journal Article
Observation of room-temperature polar skyrmions
Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO
3
)
n
/(SrTiO
3
)
n
suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses
1
–
3
. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.
Chiral polar-skyrmion bubbles are observed in superlattices of titanium-based perovskite oxides at room temperature.
Journal Article