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Endolysosomal phosphoinositides PI3P and PI(3,5)P2 regulate mammalian lysosomal V-ATPases containing the V0 a1-isoform
No full textLysosomal acidification is critical for maintaining luminal acidic pH─ requirement for lysosome function in macromolecule processing, metabolite transport, and trafficking. Conversely, impaired acidification of lysosomes is associated with a wide array of diseases, including lysosomal storage disorders (LSDs) and multiple neurological disorders. The multi-subunit vacuolar-ATPase (V-ATPase) enzyme is the key player in acidifying lysosomes. V-ATPase, an ATP-dependent proton translocating pump, causes the lumenal acidification of lysosomes by proton translocation across the lysosomal membrane, emphasizing the importance of regulating V-ATPase function in lysosomes. The regulation of V-ATPase proton pump is multifaceted. The multi-subunit V-ATPase has a membrane-embedded V0 sub-complex, where the V0 a-subunit dictates organelle-specific distribution and assembly of V-ATPases. The V0 a-subunit has four isoforms (a1-a4) in mammals, whereas the a1 and a3 isoforms both localize to endolysosomal compartments and are involved in lysosomal acidification in many cells. However, the a-isoform-specific regulation of lysosomal V-ATPase function is not completely understood. Here, we used 4T1 mouse breast cancer cell line and it's a1-isoform knockout and partial a3-knockdown counterparts to unveil a-isoform-specific regulation and function of V-ATPases in lysosomes. Pulse-chase endocytosis of FITC-Dextran revealed that V-ATPase-mediated lysosomal acidification still occurs both in a1KO and a3KO cell lines as well as wild-type (WT) 4T1 cells. Regardless of the complete loss of a1 or partial expression of a3; the lysosomal pH, luminal proteolytic activity remain unperturbed in a1KO and a3KD cells. Partial overlapping of V0a1 and V0a3 antigen under immunofluorescence microscopy corroborates the redundant functions of both isoforms and suggests the rescue of lysosomal pH and function by the alternative a-isoform in case any one a-isoform is lost or partially expressed. Interestingly, lysosome-containing cell lysates from 4T1-a1KO and 4T1-a3KD cell lines fail to re-establish the pH gradient in vitro, indicating a possibility of different regulatory mechanisms for a1- and a3-containing lysosomes. Removal of PI3P and PI(3,5)P2 from WT and mutant cells unveiled that endolysosomal PIP removal reduces only the a1-containing V-ATPase proton pumping activity. We previously reported that the N-terminal cytosolic domain (NT) of endolysosomal V0 a1 binds specifically to endolysosomal phosphoinositides (PIPs) ─ PI3P and PI(3,5)P2. A potential PIP binding site was identified in a1 isoform. Mutation in this site abolishes the interaction with these PIPs in vitro. Given this finding, we exploited a CRISPR-Cas9-based homology-directed repair approach (HDR) to introduce this specific mutation into genomic V0 a1 of 4T1 cells. We noticed no notable changes in lysosomal acidification, pH and cathepsin B protease activity in the a1-PIP binding mutant. However, due to the Y214VH>AVA mutation in a1NT, the resulting a1-PIP mutant displayed significantly reduced proton pumping activity, a similar pattern noted in the untreated a1KO cell lysate. Endolysosomal PIPs removal and generation of a1-PIP binding mutant cells confirmed the endolysosomal PIP-dependent regulation of a1- containing V-ATPase activity in lysosomes, where PI3P and PI(3,5)P2 interacts with the 'Y214VH' residue of a1NT. Altogether, the findings of our study elucidates an unresolved mechanisms of V-ATPase regulation and provide new insight for target-based development of therapeutics to treat lysosomal disorders caused by V-ATPase dysregulation and dysfunction.NAUpstate Medical UniversityBiochemistry & Molecular BiologyMaster of ScienceKane, Patrici
Rational expectations in housing markets: the case of survey forecasts
Full text linkThis paper examines the rational expectations hypothesis within the U.S. housing market using econometric methods to evaluate forecast efficiency and bias. The study focuses on five key housing indicators—building permits, construction spending, existing home sales, new home sales, and housing starts—spanning both pre- and post-2006 housing boom periods. By employing methods such as Augmented Dickey-Fuller (ADF) tests, Dynamic Ordinary Least Squares (DOLS) cointegration regressions, Mincer-Zarnowitz (MZ) bias tests, and anchoring bias tests, the research uncovers varying degrees of stationarity and cointegration across indicators, revealing inefficiencies in forecast accuracy. Results show significant biases in some forecast series, indicating that housing market expectations may not fully reflect all available information. This work provides critical insights into the complex dynamics of housing market forecasts and contributes to improving predictive models. These findings are valuable for policymakers and economists seeking to enhance forecasting methodologies, especially in markets prone to volatility and speculative bubbles.
Keywords: finance, business analytics, rational expectations, housing market, forecast bias, Mincer-Zarnowitz regression, anchoring bias, DOLS regression.NASUNY College at New PaltzHonorsN/AForest, JamesLi, Ta
DevATLAS: A novel tool to monitor the sequence of neural circuit development and study neurodevelopmental disorders
Full text linkEarly postnatal brain development is the critical stage when the symptoms of many neurodevelopment disorders (NDDs) start manifesting. These functional deficits are often caused by abnormal neural circuit maturation without accompanying gross alteration to brain architecture, making it challenging to pinpoint disruptions in these NDD models. There is an urgent need for genetic tools to track the neural circuit maturation sequence on the whole brain level during the early postnatal period. One of the key driving factors of neural circuit maturation is neuronal activity. Our lab has developed DevATLAS, the Developmental Activation Timing-based Longitudinal Acquisition System, to overcome this challenge based on the immediate early gene Npas4 expression. Npas4 is selectively induced by neuronal activity, and its activation during development triggers activity-dependent synapse development, which is a critical step during the functional maturation of neural circuits. DevATLAS permanently labels neurons with tdTomato (tdT) as they are activated by neuronal activity to express Npas4. We demonstrate that DevATLAS captures the functional neural circuit maturation sequence across the whole brain during the early postnatal period. We also demonstrate that early environmental enrichment (EE) intervention can accelerate functional neural circuit development in the granule cells (GC) of the dentate gyrus (DG). Finally, we combine DevATLAS with the NDD model of Fragile-X Syndrome (FXS) and observe significant developmental perturbations in neural circuit maturation in multiple ASD-associated regions, including the dorsal striatum, primary motor cortex, medial prefrontal cortex, which can be associated with perturbed behaviors in juvenile FXS mice. Within the DG of FXS mice, we use DevATLAS to track perturbed neural circuit maturation with delayed emergence of contextual learning and memory with altered development of granule cell dendritic arbors and spines, as well as demonstrate how early EE can ameliorate. Our results indicate that DevATLAS can study neural circuit maturation in NDD models, enable researchers to gain an improved underlying NDD etiology, and ultimately help derive new therapeutic interventions to ameliorate NDD deficits.NAUpstate Medical UniversityNeurosciencePhDLin, Yingx
Language and Control: The Way You’re Allowed to Talk Is the Way You’re Allowed to Act
No full textSUNY OswegoEnglish and Creative Writin
Effect of phospholipid transfer protein and apolipoprotein M in sphingosine-1-phosphate and chylomicron metabolism
No full textPhospholipid transfer protein (PLTP) is a monomeric protein primarily responsible for the
transfer of hydrophobic molecules, including phospholipids, cholesterol, triglycerides from
apolipoprotein B containing particles to high-density lipoprotein (HDL). Shingosine-1-phoshate
is a lipid mediator which acts on five unique receptors expressed in various tissues. Both PLTP
and S1P have been implicated in cardio-related disease. Germline PLTP KO studies reveal
plasma S1P decreases without affected apoM, a major carrier of S1P which is bound to HDL
particles. From this data, we hypothesize that PLTP could be a carrier for S1P in circulation and
that its carrier function is independent of the apoM-S1P axis. We, therefore, developed single
apoM and inducible PLTP KO lines as well as a double PLTP/apoM KO mice model and
compared plasma changes for S1P. Our theory was that if our hypothesis was correct, double
PLTP/apoM KO should decrease plasma S1P more than single KO models suggesting an
additive or synergetic effect. We observed that single apoM KO reduced plasma S1P roughly
50% and single PLTP KO reduced plasma S1P roughly 40%; however, double KO did not reduce
plasma S1P more than 50%. In addition, we found that PLTP KO also reduced plasma HDL,
suggesting that the S1P reduction observed in this inducible KO model was due to HDL
reduction in circulation. Further, we found that KO of albumin, which has long been thought to
be a non-apoM-related S1P carrier, had no effect on S1P levels suggesting that although PLTP
may not be an independent carrier of S1P, neither is albumin.
Our focus on HDL in this set of experiments also lead us to studying apoM more closely. A
previous report detailed that apoM deficiency led to decreased circulating triglyceride (TG)
levels. In the liver, very low-density lipoproteins (VLDL) are produced; however, in the small
intestine chylomicron (CM) are produced. CM production only happens postprandially or after
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fat loading. These two particles are mostly responsible for the circulation of TG and both contain
apolipoprotein B (apoB) – VLDL has apoB-100 and CM has apoB-48 as their main structural
proteins. After confirming the previously observed apoM deficiency phenotype, we measured
small intestinal as well as liver proteins related to the formation and secretion of apoB-containing
particles. Although the liver and the small intestine have a similar set of proteins responsible for
apoB-containing particle secretion, we found that in the small intestine but not the liver of apoM
KO mice, levels of microsomal triglyceride transfer protein (MTP) and Sar1B are decreased.
Both these proteins are necessary components in the formation and secretion. In addition to this,
we found accumulation of lipids confirmed by Oil Red O Staining in small intestinal cells of
apoM KO mice. To confirm this observation, we conducted electron microscopy of the intestinal
cells using apoM KO mice which showed increased ER lipid accumulation as well as increased
cytosolic lipid droplet accumulation as compared to WT mice. We also observed dysfunction in
the transport of vesicles from the ER to the Golgi in apoM KO mice as compared to WT mice.
Coat protein complex II are the group of proteins responsible for this transfer, one of which is
Sar1B. Other proteins in this complex include Sec12, 23, 24, 13, and 31. We measured protein
levels of Sec 12, 23, and 24 and found they were significantly decreased in the small intestine of
apoM KO mice but not in the liver. In addition to this, we measure the mRNA levels of Sar1B
and MTP in both the liver and small intestines of WT and apoM KO mice. There was no
difference between the two tissues in terms of mRNA for these proteins which indicates that the
effect of apoM deficiency is at the protein level. Together, our data suggests a novel role of apoM
in postprandial TG metabolism. Using apoM as a target may give a method to explore the role of
dietary fat intake in lipid metabolism.VoRSUNY DownstateCell BiologyN/AJiang, Xian-ChengGeraghty, PatrickGarcia-Arcos, ItsasoHuan, ChongminKollmar, RichardPremsrirut, Pre
ANALYSIS OF GLIA CHARACTERISTICS IN THE RD10 RETINITIS PIGMENTOSA MOUSE IN COMPARISON TO THE MÜLLER GLIA DICER-CKO MOUSE, TWO MODELS OF RETINAL DEGENERATION
Full text link"Purpose
The retinal degeneration (RD) 10 mouse is a well-studied animal model that develops Retinitis Pigmentosa (RP) due to a mutation in rod photoreceptors. Müller glia (MG) are the predominant glia in the retina, have essential roles in the healthy retina, but become reactive in response to retinal damage and contribute to secondary neuronal loss. An in-depth characterization of MG in the RD mouse has not reported yet. Furthermore, molecular alterations in MG, i.e., the depletion of the enzyme Dicer1, results in photoreceptor loss resembling the phenotype of RP. Therefore, similarities in the molecular profile of MG in both models could suggest a putative common regulatory mechanism of glial alteration. The aim of this study was to characterize and compare MG in the central and peripheral retina in the RD10 mouse and the MG-specific Dicer1 conditional knock-out mouse.
Methods
To visualize MG in both degeneration models a MG-specific reporter mouse (Rlbp1-CreER:tdTomatostop flox/flox) was crossed with the RD10 or the Dicerflox/flox mouse (Dicer knock-out, referred to as cKO). Histological analysis was performed by means of immunofluorescence staining and confocal microscopy imaging. Retinal cross sections of 1-, 3-, and 6-months old mice were evaluated with regard to overall retinal histology, MG number and their glial protein expression pattern in both the center and periphery.
Results
The RD10 mouse displayed retinal thinning as early as one month of age with proliferating MG at the early phase and degenerating MG at later phases. These MG were glial fibrillary acidic protein (GFAP) positive and vimentin positive at all time points analyzed. The Dicer-cKO mouse displayed proliferating MG at early stages but not obvious degeneration was found at this time. At later stages, MG number declined in central retinal areas which were also significantly degenerated. GFAP and vimentin upregulation was not found in Dicer-cKO MG.
Conclusion
The MG reporter mouse is a very useful tool to study MG number and behavior in models of retinal degeneration including the RD10 mouse and the Dicer-cKO mouse. Moreover, it appears that the deletion of Dicer1 prevents MG from becoming reactive and initiating gliosis. This suggests that molecular manipulation of MG could be utilized to attenuate gliosis and subsequent degenerative events in retinal diseases."NASUNY College of OptometryM
Beyond the eye: effect of guilt and redemption on hidden self-harm
Full text linkSelf-harm is traditionally viewed as a physical manifestation. This study aims to broaden the
scope of what constitutes self-harming behavior and the role that guilt, and redemption can play
on it. The study explores non-traditional forms of self-harm, termed as culturally acceptable
forms of self-harm, like over-working, procrastination, intentional absence of self-care etc.
Specifically, it examines the role of guilt and redemption in motivating individuals to engage in
aversive experiences (aversive sound). Participants underwent a guilt-inducing manipulation and
were subsequently asked to listen to an unpleasant audio stimulus. It was hypothesized that (1)
participants offered a chance for redemption would endure the aversive sound for a shorter
duration than those not offered redemption, and (2) engaging in the aversive task would reduce
feelings of guilt across all participants. Guilt was measured using the Guilt and Shame
Questionnaire (GSQ-8) twice, before the guilt-inducing manipulation, and post the aversive
audio phase. A t-test indicated that participants who were given a chance for redemption listened
to the aversive audio for a significantly shorter duration than those who were not given a chance
for redemption. An ANCOVA analysis, controlling for initial guilt scores showed a significant
effect of condition on final guilt, with participants in both conditions reporting reduced guilt
levels post-task, and those in the neutral condition reporting a greater reduction. These findings
suggest that engaging in culturally acceptable aversive behaviors may serve a guilt-alleviating
function, and that perceived opportunities for redemption may modulate the extent of such selfdirected
harm.NASUNY College at New PaltzPsychologyMSGeher, GlennHolmes, TabithaWice, Matthe
Weaving the past into the future: integrating historical data into science education to foster sustainable fashion practices
Full text linkInstead of a paper, I created and hosted four interactive
workshops at New Paltz middle school.
Using historical and climate data, my goal was to teach and
promote sustainable fashion in a school setting.
These workshops blend climate data, sustainability, and
hands-on clothing repair to inspire eco-conscious thinking in
younger generations.NASUNY College at New PaltzHonorsN/AVarga, Andre
Monitoring consumption in a materialistic society; the environmental impacts of the packaging industry
No full textNASUNY College at New PaltzHonorsN/AVarga, AndreaPilek, Matthe