O-GlcNAcylation, the addition of a single N-acetylglucosamine residue to serine and threonine residues of cytoplasmic, nuclear, or mitochondrial proteins, is a widespread regulatory post-translational modification. It is involved in response to nutritional status and stress and its dysregulation is associated with diseases ranging from Alzheimer’s to diabetes.  While the modification was first detected over thirty-five years ago, research into the function of O-GlcNAcylation has accelerated dramatically in the last ten years due to the development of new enrichment and mass spectrometry techniques that facilitate its analysis.  This article summarizes methods for O-GlcNAc enrichment, key mass spectrometry instrumentation advancements, particularly those that allow modification site localization, and software tools that allow analysis of data from O-GlcNAc modified peptides.

The faithful segregation, or “partition,” of many low-copy number bacterial plasmids is driven by plasmid-encoded ATPases that are represented by the P1 plasmid ParA protein. ParA binds to the bacterial nucleoid via an ATP-dependent nonspecific DNA (nsDNA)-binding activity, which is essential for partition. ParA also has a site-specific DNA-binding activity to the par operator (parOP), which requires either ATP or ADP, and which is essential for it to act as a transcriptional repressor but is dispensable for partition. Here we examine how DNA binding by ParA contributes to the relative distribution of its plasmid partition and repressor activities, using a ParA with an alanine substitution at Arg351, a residue previously predicted to participate in site-specific DNA binding. In vivo, the parAR351A allele is compromised for partition, but its repressor activity is dramatically improved so that it behaves as a “super-repressor.” In vitro, ParAR351A binds and hydrolyzes ATP, and undergoes a specific conformational change required for nsDNA binding, but its nsDNA-binding activity is significantly damaged. This defect in turn significantly reduces the assembly and stability of partition complexes formed by the interaction of ParA with ParB, the centromere-binding protein, and DNA. In contrast, the R351A change shows only a mild defect in site-specific DNA binding. We conclude that the partition defect is due to altered nsDNA binding kinetics and affinity for the bacterial chromosome. Furthermore, the super-repressor phenotype is explained by an increased pool of non-nucleoid bound ParA that is competent to bind parOP and repress transcription.

Mine Action in Angola: Clearing the Legacies of Conflict to Harness the Potential of Peace Other resource sysadmin 14 June 2019

This publication draws on and updates the briefing note published following a meeting of the All- Party Parliamentary Group (APPG) on Angola on 26 April 2017. It also incorporates insights from a Chatham House Africa Programme conference session on the legacies of the Angolan Civil War, held on 23 March 2018; and draws on the Africa Programme’s research into conservation-driven development models in Southern Africa.

Almost two decades after the end of its civil war, Angola remains one of the most heavily landmine-contaminated countries in the world. The Angolan government has committed to clearing its landmines by 2025, and there is constructive collaboration between the government and mine clearing agencies in this endeavour, but the target will be achievable only if a decline in funding from international donors is reversed. International funding for mine clearance in Angola fell by more than 80 per cent between 2005 and 2017, and this sharp drop in external support has compounded the impact on domestic funding for national clearance efforts as a result of the downturn in prices for Angola’s main export commodities.

The national mine action agency, the Comissão Nacional Intersectorial de Desminagem e Assistência Humanitária (CNIDAH), is supported by the Mines Advisory Group (MAG), Norwegian People’s Aid (NPA) and the HALO Trust. By 2017, 15 years after the end of the civil war, these organizations had collectively helped clear 56 per cent of known landmine-contaminated land. State-led demining has focused principally on clearing areas designated for infrastructure projects. Now, it is critical that humanitarian demining in largely agricultural and conservation areas is prioritized to bring to an end the daily threat to Angola’s rural poor – as well as to the country’s livestock and wildlife – of injury or death as a result of landmine accidents.

Angola has some of the world’s most important remaining wilderness, including the tributary system for the unique Okavango Delta, and the country has the potential to host one of the most diverse wildlife populations on the continent. However, the presence of landmines and other remnants of the civil war render large areas of the country unsafe both for wildlife and for the local people, whose ability to derive a sustainable livelihood from their natural environment is fundamental to its protection.

Wildlife and tourism provide important economic opportunities for diversification beyond an oil-dominated economy. Critically, Angola’s economic diversification and development objectives can only be achieved if the landmines that prohibit access to land for agriculture, mining, tourism and wildlife are cleared.

There are economic opportunities for released land in the most heavily mined provinces of Cuando Cubango and Moxico. Already, some new funding for mine action in Angola, if upscaled or matched by international donors, could be transformative for its people, and for the conservation of the region’s vital biodiversity.

A boom in AI has created a problem for the organizers of the NeurIPS conference, which is considered an essential machine-learning research conference. The sheer number of registrations has overwhelmed […]

The post Lottery to Determine Major AI Conference Attendees Amid Registration Boom appeared first on HPCwire.

Governors' races in Kentucky and Mississippi took center stage, testing the political muscle of teacher activists and yielding possible policy implications for everything from public employee pensions to teacher pay.

Governors' races in Kentucky and Mississippi took center stage, testing the political muscle of teacher activists and yielding possible policy implications for everything from public employee pensions to teacher pay.

Nora D. Volkow
Dec 1, 2001; 21:9414-9418
Behavioral

Danilo De Gregorio
Feb 3, 2021; 41:891-900
Symposium and Mini-Symposium

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration–exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration–exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration–exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

In his address to the Joint Meeting of the Finance and Programme Committees this morning, the Director-General assured Members of the determination and commitment to delivery of the current Programme [...]

The food security situation in Gaza is catastrophic. Famine is imminent in the Northern Governorates and there is a risk of famine across the rest of the Gaza Strip, according [...]

More on Kathleen Turner and her show at Arena Stage: http://j.mp/T0IkkZ Before taking the stage in "Red Hot Patriot: The Kick-Ass Wit of Molly Ivins," Academy Award nominee Kathleen Turner discusses the woman who inspired the show.

Discover the incredible ways in which living organisms illuminate the darkness of the deep sea, lush forests, and even our own backyards. --- For more videos from Smithsonian Magazine: https://www.smithsonianmag.com/videos/ Digital Editorial Director: Brian Wolly Director of Programming: Nicki Marko Supervising Producer & Scriptwriter: Michelle Mehrtens Video Editor: Sierra Theobald

The small town of Spruce Pine, North Carolina, is one of the only sources of high-purity quartz on Earth, but it has been left battered by the storm's heavy rains

The Manhattan district attorney's office has obtained an arrest warrant for Edoardo Almagià, who has been accused of working with looters and dealing stolen artifacts for years

To understand the circuitry of the brain, it is often advantageous to visualize the processes of a single neuron or population of neurons. Identifying sites where a neuron, or neurons, originates and where it projects can allow a researcher to begin to map the circuitry underlying various processes, including sensory-guided behaviors. Furthermore, neural tracing allows one to map locations where processes terminate onto regions of the brain that may have known functions and sometimes to identify candidate upstream or downstream connections, based on proximity. Many methods of neural tracing are available; here, we focus on loading fluorescent dyes into a neuron (fluorescent dye filling). Different options for dyes exist to label neurites. Among the most versatile and easy to use are dextran amine–conjugated dyes. They fill neurons bidirectionally, not discriminating between anterograde or retrograde loading direction. Dye filling must be done in unfixed tissue, as the dye needs to move through the neurons; however, dextran amine conjugates are aldehyde-fixable and once cells have been fully loaded with dye the tissue can be fixed and subjected to immunostaining. Coupling neural tracing with immunofluorescence is a useful way to determine specific brain or ventral nerve cord (VNC) regions where a neuron projects. This protocol describes methods for loading dextran amine conjugated dyes into a sensory tissue in the mosquito to visualize sites of sensory neuron innervation in the central nervous system, as well as efferent projections to these structures. This protocol is described for Aedes aegypti, for which it was optimized, but it also works across a variety of insects.

Water quality guidelines for mercury are 0.02 micrograms per litre of water. Several results show that levels at four sites are far above that threshold. During the second week of October, one value close to the mine was more than seven times the acceptable level.

A federal audit of Canada’s strategy to promote the extraction of critical minerals says the government isn’t giving due consideration to the potential impact of mining on the environment, biodiversity and Indigenous people.

Waterloo region’s food landscape is more than farm stands and restaurants. There's a vast array of food producers, food makers and organizations that make up the food scene. And now, a new directory aims to make them easier to find. CBC KW's food columnist Jasmine Mangalaseril explored the directory.

SOLIDWORKS 3D CAD software ensures 23-ton vehicle used to maintain troop and civilian safety around the world is 'more than meets the eye'

Equipment Designed and Modified With SolidWorks Software Located Miners and Helped Drill Escape Shaft Weeks Sooner Than Predicted

Wastewater contains nutrients that can overfeed algae, leading to harmful algal blooms and pollution issues in the ocean and other waterways. A new study by researchers at Penn State tracked how these nutrients migrate from disposal sites in the Florida Keys, and the results have already informed wastewater practices in the region.

Mining expert Barbara Arnold, professor of practice in mining engineering, joined a panel of experts to discuss how the United States will need to make dramatic advances to increase its technical- and skilled-labor workforce to power its green energy future and to become less reliant on foreign nations for securing materials used in both everyday devices and critical national security applications.

The Riverboat community sailed from port-to-port to mobilise believers into missions and share the Hope of God together. How is life after the Riverboat?

In a political twist almost no one saw coming, on the morning of November 23, 2019, Devendra Fadnavis took oath as the Maharashtra Chief Minister for a second term.

The government on Wednesday said 125 new projects have been taken up in the current financial year for exploration of critical minerals.

DEPARTMENT OF STATE: Division of Professional Regulation

DEPARTMENT OF STATE: Division of Professional Regulation

A controversy over a WhatsApp group named 'Mallu Hindu Officers', allegedly administered by Kerala Industry and Commerce Department Director K. Gopalakrishnan, is in the spotlight.

Tanzania's economy is booming and its tourism sector is thriving. However, concerns about the president's strong-arm tactics and delays in the completion of key infrastructure projects are threatening this growth.

London has retained its position as fDi’s European City of the Future, while Paris has climbed to second place, knocking Dublin into the third spot. 

Australia’s proud mining history, the quality of its workers and high working standards were instrumental in bringing Canadian mining and exploration company Kirkland Lake Gold to the Victorian gold fields.

Check here each week to keep up with the latest from John MacArthur's pulpit at Grace Community Church.

The Federal Government, through the Ministry of Solid Minerals Development, has formalised the activities of 250 small and artisanal miners into cooperatives as part of efforts to help artisanal miners transition away from illegal mining. The Minister of Solid Minerals Development, Dele Alake, disclosed this on Tuesday at a briefing to announce the 9th edition

An experiment with a robot and gelatine determined that 65-micrometre-thick paper is the most prone to slicing our skin – but it can also make for a handy recyclable knife

Companies are searching all over the world for deposits of geologic hydrogen that could be used as clean fuel, and a mine in Albania could give them clues about where to look

Amazing images of an open-air library, underground lab and design museum show the reincarnation of dead mines, captured in a new book, 102 Things to Do With a Hole in the Ground

Title: Vitamins, Minerals May Help Older Men's Sperm Stay Healthy
Category: Health News
Created: 8/28/2012 4:05:00 PM
Last Editorial Review: 8/29/2012 12:00:00 AM

Title: Amphetamines Polluting Some Urban Streams: Study
Category: Health News
Created: 8/25/2016 12:00:00 AM
Last Editorial Review: 8/26/2016 12:00:00 AM

Title: Ondansetron (Zofran) vs. Dramamine
Category: Medications
Created: 7/24/2019 12:00:00 AM
Last Editorial Review: 8/2/2022 12:00:00 AM

In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection was used. The results showed rapid clearance from plasma (0.5 to 1.5 hours of half-life) and predominant distribution to the liver and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 hours was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration.

Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, , and ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ~100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system.

Le texte complet de l’article est aussi disponible en français.

Previous studies demonstrated that sigma receptor (R) antagonists alone fail to alter cocaine self-administration despite blocking various other effects of cocaine. However, R antagonists when combined with dopamine transporter (DAT) inhibitors substantially decrease cocaine self-administration. To better understand the effects of this combination, the present study examined the effects of R antagonist and DAT inhibitor combinations in male rats discriminating cocaine (10 mg/kg, i.p.) from saline injections. The DAT inhibitors alone [(–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate monohydrate (WIN 35,428) and methylphenidate] at low (0.1-mg/kg) doses that were minimally active failed to shift the dose-effect function for discriminative-stimulus effects of cocaine to the left more than 2-fold. At 0.32 mg/kg the DAT inhibitors alone shifted the cocaine dose-effect function leftward 24- or 6.6-fold, respectively. The R antagonists (BD1008, BD1047, and BD1063) failed to fully substitute for cocaine, although BD1008 and BD1047 substituted partially. At 10 mg/kg, BD1008, BD1047, or BD1063 alone shifted the cocaine dose-effect function leftward less than 6.0-fold. In combination with 0.1 mg/kg WIN 35,428, the 10 mg/kg doses of R antagonists shifted the cocaine dose-effect function from 12.3- to 36.7-fold leftward, and with 0.32 mg/kg WIN 35,428 from 14.3- to 440-fold leftward. In combination with 0.1 mg/kg methylphenidate, those R antagonist doses shifted the cocaine dose-effect function from 5.5- to 55.0-fold leftward, and with 0.32 mg/kg methylphenidate from 10.5- to 48.1-fold leftward. The present results suggest that dual DAT/R inhibition produces agonist-like subjective effects that may promote decreases in self-administration obtained in previous studies.

Intrapatient intermetastatic heterogeneity (IIH) has been demonstrated in metastatic castration-resistant prostate cancer (mCRPC) patients and is of the utmost importance for radiopharmaceutical therapy (RPT) eligibility. This study was designed to determine the prevalence of IIH and RPT eligibility in mCRPC patients through a triple-tracer PET imaging strategy. Methods: This was a multisite prospective observational study in which mCRPC patients underwent both ¹⁸F-FDG and ⁶⁸Ga-prostate-specific membrane antigen (PSMA)–617 PET/CT scans. A third scan with ⁶⁸Ga-DOTATATE, a potential biomarker of neuroendocrine differentiation, was performed if an ¹⁸F-FDG–positive/⁶⁸Ga-PSMA–negative lesion was found. Per-tracer lesion positivity was defined as having an uptake at least 50% above that of the liver. IIH prevalence was defined as the percentage of participants having at least 2 lesions with discordant features on multitracer PET. Results: IIH was observed in 81 patients (82.7%), and at least 1 ¹⁸F-FDG–positive/⁶⁸Ga-PSMA–negative lesion was found in 45 patients (45.9%). Of the 37 participants who also underwent ⁶⁸Ga-DOTATATE PET/CT, 6 (16.2%) had at least 1 ⁶⁸Ga-DOTATATE–positive lesion. In total, 12 different combinations of lesion imaging phenotypes were observed. On the basis of our prespecified criteria, 52 (53.1%) participants were determined to be eligible for PSMA RPT, but none for DOTATATE RPT. Patients with IIH had a significantly shorter median overall survival than patients without IIH (9.5 mo vs. not reached; log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1–6.8). Conclusion: Most mCRPC patients showed IIH, which was associated with shorter overall survival. On the basis of a triple-tracer PET approach, multiple phenotypic combinations were found. Correlation of these imaging phenotypes with genomics and treatment response will be relevant for precision medicine.

What's the podcast trio been up to this week? Chris is now a punchy demi-fiend, Kelley muses if Scamper is part plumber, and Anna Marie campaigns on Hades for everyone. Also, stoats continue to be extremely cute.

The post RPG Cast – Episode 598: “I Want an Ermine With Angry Eyebrows” appeared first on RPGamer.

EA FC 25 players can snag some big freebies this week, with EA Sports celebrating the Ballon d'Or in style for all Ultimate Team players with some of the best players around.