The dextransucrase DSR-OK from the Gram-positive bacterium Oenococcus kitaharae DSM17330 produces a dextran of the highest molar mass reported to date (∼109 g/mol). In this study, we selected a recombinant form, DSR-OKΔ1, to identify molecular determinants involved in the sugar polymerization mechanism and that confer its ability to produce a very-high-molar-mass polymer. In domain V of DSR-OK, we identified seven putative sugar-binding pockets characteristic of glycoside hydrolase 70 (GH70) glucansucrases that are known to be involved in glucan binding. We investigated their role in polymer synthesis through several approaches, including monitoring of dextran synthesis, affinity assays, sugar binding pocket deletions, site-directed mutagenesis, and construction of chimeric enzymes. Substitution of only two stacking aromatic residues in two consecutive sugar-binding pockets (variant DSR-OKΔ1-Y1162A-F1228A) induced quasi-complete loss of very-high-molar-mass dextran synthesis, resulting in production of only 10–13 kg/mol polymers. Moreover, the double mutation completely switched the semiprocessive mode of DSR-OKΔ1 toward a distributive one, highlighting the strong influence of these pockets on enzyme processivity. Finally, the position of each pocket relative to the active site also appeared to be important for polymer elongation. We propose that sugar-binding pockets spatially closer to the catalytic domain play a major role in the control of processivity. A deep structural characterization, if possible with large-molar-mass sugar ligands, would allow confirming this hypothesis.

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

There aren’t a ton of synonyms for the word “hypocrisy.” I’ve become aware of this problem ever since I began writing about the Tara Reade–Joe Biden situation. I keep gravitating towards phrases such as “despicable hypocrisy,” or “partisan hypocrisy,” or “unconscionable hypocrisy,” but you can only go to the well so often. Really, though, I’m not sure how else to describe the actions of someone like Senator Dianne Feinstein.You might recall that it was Feinstein, the ranking member of the Judiciary Committee, who withheld Christine Blasey Ford's allegation of sexual misconduct against Supreme Court nominee Brett Kavanaugh from the Senate so that it could not be properly vetted, in a last-ditch effort to sink the nomination.Feinstein knew that Ford's credibility was brittle -- the alleged victim could not tell us where or when the attack occurred, hadn’t mentioned Kavanugh’s name to anyone for over 30 years, and offered nothing approaching a contemporaneous witness.At first, Feinstein did not want to provide Ford’s name, or a place or time of the alleged attack, or allow the accused to see any evidence against him, denying him the ability to answer the charges.Henceforth this brand of justice could be referred to as “The Joe Biden Standard,” since it’s exactly the kind of show trial the presumptive Democratic nominee promises college kids via Title IX rules.When finally asked about Reade yesterday, Feinstein responded: “And I don’t know this person at all who has made the allegations. She came out of nowhere. Where has she been all these years? He was vice president.”To put this in perspective, when Ford came forward “out of nowhere,” Feinstein said: “Victims must be able to come forward only when they are ready.”What’s changed?During the Kavanaugh hearings Feinstein noted that “sharing an experience involving sexual assault — particularly when it involves a politically connected man with influence, authority and power — is extraordinarily difficult.”Is Biden not a politically connected man with influence, authority, and power? Feinstein is now arguing the opposite: She is saying we should dismiss Reade’s allegations because she failed to come forward against a powerful man earlier.But to answer Feinstein’s question about what Reade has been “up to” the past 27 years: Well, she’s been telling people that Biden had engaged in sexual misconduct. She relayed her story to her former neighbor, her brother, her former co-worker, and at least two other friends. It is also likely that her mother called Larry King Live asking for advice for her daughter the year of the alleged attack.Yesterday a document uncovered by local journalists in California -- somehow missed by Barack Obama’s crack vetting team -- shows Reade’s ex-husband bolstering her claim in 1996 divorce proceedings: “On several occasions [Reade] related a problem that she was having at work regarding sexual harassment, in U.S. Senator Joe Biden's office.”The reaction to the divorce papers has been extraordinary. Biden defenders argue that because Reade alleged “sexual harassment” -- a catch-all term used in the 1990s when men were getting away with despicable behavior far more often -- it proves her story has changed. Biden, through his deputy campaign manager Kate Bedingfield, alleges that “more and more inconsistencies” come up every day.Even if Reade didn't tell everyone everything that allegedly happened every time she mentioned the incident, that doesn’t definitively prove anything. If it did, none of us would have ever heard the name Christine Blasey Ford.Indeed, at time of Ford’s evolving story, there was a slew of journalists taking deep dives into the unreliability of memory and trauma and complexities of relaying assault allegations. I assume that science hasn’t changed in two years.Let’s also not forget that, despite Ford’s inconsistencies, Biden still argued that Kavanaugh should be presumed guilty. Why shouldn’t he?It is also quite amazing to see Biden’s defenders implicitly contending that Reade is only credibly claiming that she was sexually harassed for nearly 30 years, so her story must be politically motivated.Even if we concede that Reade is a wily Sanders operative or Putin stooge, what political motive could Reade possibly have had back in 1993 -- after working for Biden -- to smear the senator? What motive did she have to repeat that story to her family before Sanders was a candidate or Putin was running Russia?By the way, liberals have never argued that political motivations should be disqualifying. Ford came forward, by her own admission, because she did not believe the man who had allegedly assaulted her in high school should be given a seat on highest court in the land. Reade says she doesn’t want a man who allegedly assaulted her -- when he was in his 50s -- to hold the most powerful office in the world.Feinstein, of course, isn’t the only one to engage in this kind of transparent double standard. When asked about Reade, the idealist Alexandria Ocasio-Cortez, said, “I’m not sure. Frankly, this is a messy moment, and I think we need to acknowledge that -- that it is not clear-cut.”Where was all this hand-wringing and caution over the messiness of sexual-assault claims when nearly every Democrat and all their allies in the press were spreading Julie Swetnick’s alleged “gang rape” piece? Nowhere.AOC, whose position on Biden has evolved, invited Ana Maria Archila, the women who had famously cornered a weak-kneed senator Jeff Flake in an elevator and yelled at him about Kavanaugh, to the 2019 State of the Union address. Archila now says, “I feel very trapped.”I bet.People point out that there are numerous sexual-misconduct allegations leveled at Donald Trump. Indeed. If they haven’t yet, news outlets should scrutinize and investigate the credibility of those allegations, as they did for Biden but not for Kavanaugh. But it’s important to remember that Trump accuser E. Jean Carroll was given immediate and widespread coverage on cable news, while Reade reportedly wasn’t asked to tell her story by any major network -- save Fox News -- until this week.Of course, most Biden defenders are being purposely obtuse about the debate -- Mona Charen’s recent column is an excellent example. The problem isn’t that Biden is being treated unjustly, or that he should be treated unjustly; it’s that he is being treated justly by the same people who treat others unjustly. Democrats have yet to explain why Biden is afforded every benefit of the doubt but not Kavanaugh, and not millions of college students.Public figures such as Biden have every right to demand fair hearings and due process. Voters have every right to judge the credibility of both accuser and accused. Many women are victims. Many women are victims who are powerless to prove it. And some women are frauds. You can’t keep demanding that our political system adjudicate similar incidents under two completely differ set of rules. It’s untenable.

Samuel W Entwisle
Apr 6, 2020; 0:RA120.001946v2-mcp.RA120.001946
Research

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

Björn Morén
Apr 15, 2020; 0:jlr.ILR120000808v1-jlr.ILR120000808
Images in Lipid Research

Stimulating brown adipose tissue (BAT) activity represents a promising therapy for overcoming metabolic diseases. mTORC2 is important for regulating BAT metabolism, but its downstream targets have not been fully characterized. In this study, we apply proteomics and phosphoproteomics to investigate the downstream effectors of mTORC2 in brown adipocytes. We compare wild-type controls to isogenic cells with an induced knockout of the mTORC2 subunit RICTOR (Rictor-iKO) by stimulating each with insulin for a 30-minute time course. In Rictor-iKO cells, we identify decreases to the abundance of glycolytic and de novo lipogenesis enzymes, and increases to mitochondrial proteins as well as a set of proteins known to increase upon interferon stimulation. We also observe significant differences to basal phosphorylation due to chronic RICTOR loss including decreased phosphorylation of the lipid droplet protein perilipin-1 in Rictor-iKO cells, suggesting that RICTOR could be involved with regulating basal lipolysis or droplet dynamics. Finally, we observe mild dampening of acute insulin signaling response in Rictor-iKO cells, and a subset of AKT substrates exhibiting statistically significant dependence on RICTOR.

7 May 2020 , Volume 96, Number 3

Colin Poche's fastball won't light up the radar gun, but it proved to be one of the most effective pitches in the Minors last season.

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance.

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using ²H₂O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of ¹³C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

WASHINGTON – A pesar de que los gobiernos de América Latina y el Caribe han tomado medidas generosas e innovadoras para lidiar con el desplazamiento forzado desde Venezuela y más recientemente desde Nicaragua, la cálida bienvenida se ha enfriado en algunos lugares a medida que el número de entradas, la presión sobre los servicios públicos y la preocupación del público aumenta.

Catholic Church -- Clergy -- Sexual behavior.

19th century.

Paris : Germer-Bailliere, 1856-1857.

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Although the etiology of schizophrenia is still unknown, it is accepted to be a neurodevelopmental disorder that results from the interaction of genetic vulnerabilities and environmental insults. Although schizophrenia's pathophysiology is still unclear, postmortem studies point toward a dysfunction of cortical interneurons as a central element. It has been suggested that alterations in parvalbumin-positive interneurons in schizophrenia are the consequence of a deficient signaling through NMDARs. Animal studies demonstrated that early postnatal ablation of the NMDAR in corticolimbic interneurons induces neurobiochemical, physiological, behavioral, and epidemiological phenotypes related to schizophrenia. Notably, the behavioral abnormalities emerge only after animals complete their maturation during adolescence and are absent if the NMDAR is deleted during adulthood. This suggests that interneuron dysfunction must interact with development to impact on behavior. Here, we assess in vivo how an early NMDAR ablation in corticolimbic interneurons impacts on mPFC and ventral hippocampus functional connectivity before and after adolescence. In juvenile male mice, NMDAR ablation results in several pathophysiological traits, including increased cortical activity and decreased entrainment to local gamma and distal hippocampal theta rhythms. In addition, adult male KO mice showed reduced ventral hippocampus-mPFC-evoked potentials and an augmented low-frequency stimulation LTD of the pathway, suggesting that there is a functional disconnection between both structures in adult KO mice. Our results demonstrate that early genetic abnormalities in interneurons can interact with postnatal development during adolescence, triggering pathophysiological mechanisms related to schizophrenia that exceed those caused by NMDAR interneuron hypofunction alone.

SIGNIFICANCE STATEMENT NMDAR hypofunction in cortical interneurons has been linked to schizophrenia pathophysiology. How a dysfunction of GABAergic cortical interneurons interacts with maturation during adolescence has not been clarified yet. Here, we demonstrate in vivo that early postnatal ablation of the NMDAR in corticolimbic interneurons results in an overactive but desynchronized PFC before adolescence. Final postnatal maturation during this stage outspreads the impact of the genetic manipulation toward a functional disconnection of the ventral hippocampal-prefrontal pathway, probably as a consequence of an exacerbated propensity toward hippocampal-evoked depotentiation plasticity. Our results demonstrate a complex interaction between genetic and developmental factors affecting cortical interneurons and PFC function.

The PFC, through its high degree of interconnectivity with cortical and subcortical brain areas, mediates cognitive and emotional processes in support of adaptive behaviors. This includes the formation of fear memories when the anticipation of threat demands learning about temporal or contextual cues, as in trace fear conditioning. In this variant of fear learning, the association of a cue and shock across an empty trace interval of several seconds requires sustained cue-elicited firing in the prelimbic cortex (PL). However, it is unknown how and when distinct PL afferents contribute to different associative components of memory. Among the prominent inputs to PL, the hippocampus shares with PL a role in both working memory and contextual processing. Here we tested the necessity of direct hippocampal input to the PL for the acquisition of trace-cued fear memory and the simultaneously acquired contextual fear association. Optogenetic silencing of ventral hippocampal (VH) terminals in the PL of adult male Long-Evans rats selectively during paired trials revealed that direct communication between the VH and PL during training is necessary for contextual fear memory, but not for trace-cued fear acquisition. The pattern of the contextual memory deficit and the disruption of local PL firing during optogenetic silencing of VH-PL suggest that the VH continuously updates the PL with the current contextual state of the animal, which, when disrupted during memory acquisition, is detrimental to the subsequent rapid retrieval of aversive contextual associations.

SIGNIFICANCE STATEMENT Learning to anticipate threat from available contextual and discrete cues is crucial for survival. The prelimbic cortex is required for forming fear memories when temporal or contextual complexity is involved, as in trace fear conditioning. However, the respective contribution of distinct prelimbic afferents to the temporal and contextual components of memory is not known. We report that direct input from the ventral hippocampus enables the formation of the contextual, but not trace-cued, fear memory necessary for the subsequent rapid expression of a fear response. This finding dissociates the contextual and working-memory contributions of prelimbic cortex to the formation of a fear memory and demonstrates the crucial role for hippocampal input in contextual fear learning.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5–72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M₂ or M₄ receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.

SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M₂ and M₄ receptors.

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Na_v1.6 and K_v7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.

SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.

The findings further refute the outdated notion that humans' capacity for complex artistic expression evolved exclusively in Europe

Late-onset hypocalcemia is common in neonates, often presents with seizures or tetany, and is often attributed to transient hypoparathyroidism.

Late-onset hypocalcemia in neonates is often a sign of coexisting vitamin D deficiency and hypomagnesemia and is readily managed with therapy of limited duration, and neonates presenting with tetany or seizures due to hypocalcemia are unlikely to benefit from neuroimaging studies. (Read the full article)

The end of the year is a propitious time to take a closer look at the proposal that teachers should be paid like workers in business because it's when bonuses are handed out. In this regard, no group is more fitting to examine than executives, whose pay is ostensibly based on company performance. Bu

Corporate reformers speak with forked tongue about performance pay for teachers.

It only weighs 235 grams, runs for two hours on a full charge, offers a screen size of up to 84-inches, and doubles as a mobile charger.

Our mission is to solve boredom. There are now 500 million Indians who have an internet connection, and are spending nearly five hours a day on social media and entertainment.

This modified Suzuki Jimny is the pocket rocket you never know you wanted. With 200hp at the disposal of your right foot, this is probably the fastest Jimny on the road today.

The steep hikes on auto fuel taxes - Rs 10/litre on petrol and Rs 13/litre on diesel – announced by the Centre late Tuesday won’t inflate the retail prices of these fuels immediately.

This is the sixteenth issue of POC || GTFO.

This is the seventeenth issue of POC || GTFO.

The Information Commissioner’s Office (“ICO”) has asked to be given the ability to exercise various powers (and gain access to investigation) under the Proceeds of Crime Act 2002 (“POCA”), and has opened a consultation ...