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A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism]

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.




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The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1 [Metabolism]

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.




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Targeting the polyamine pathway—“a means” to overcome chemoresistance in triple-negative breast cancer [Cell Biology]

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.




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'Public servants should get off social media': warning after Islamic State hack

Terrorists and criminals are looking for people to blackmail or seduce into stealing data.




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Australian Federal Police walk away from $145 million Israeli crime-fighting software deal

Police walk away from deal with contractor, conceding numerous issues have put project beyond rescue.




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The NBN satellite Malcolm Turnbull never wanted prepares for liftoff

In 34 days and counting down, Australia is set to blast a satellite weighing as much as an elephant one-tenth of the way to the moon.




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Human Services' computers keep disabled out of work

Disabled workers are caught in bureaucratic limbo by problematic computer systems.




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Malcolm Turnbull visits Sunshine Coast to view proposal for new undersea communications cable

A plan to make the Sunshine Coast a vital internet gateway is luring Communications Minister Malcolm Turnbull to the area on Friday to view the proposal in person.




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Public servants warned off internet sex and cheating sites after Ashley Madison hack

Marriage vows are one thing, but the public service Code of Conduct, that's serious.




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What Uber tells us about disruption

Uber's digital component is only part of it's success and there are other important lessons for any business.




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Why we need to stop car crash 'women in tech' panels and actually break the glass ceiling

Women in tech panels seldom have anything to offer besides fortune-cookie wisdom and repackaged logic.




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Digital Transformation Office chief executive Paul Shetler announces public service work schedule

Paul Shetler reveals the digital projects about to hit the federal bureaucracy. Starting with Canberra.




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How Australian public service's digital reforms will happen, according to the Digital Transformation Office

The millions of customers, the short deadline: how the public service's digital revolution will start.




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What it's like to be Australia's top tech talent

They're highly mobile, highly sought after, and tend to "upskill" off their own bat. The ball is most definitely in their court.




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StartupWeek Sydney readies for launch

StartupWeek Sydney 2015 starts on Friday, and 5000 people are expected to attend more than 50 events to celebrate and strengthen the city's thriving start-up community.




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Cyber security expert issues dire warning over vulnerability of key infrastructure

Data theft and cybercrime is a major source of funding for Islamic State which is likely to have secretly planted insiders "around the world" in positions where critical data could be extracted and exploited, a leading cyber security expert has warned.




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Public service to ban paper in boxes: New digital policy to make sweeping reforms across APS

One powerful agency head warns against "tyranny of small person" as sweeping reforms released for public service.




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Australian public service's 'gap in capability' to deal with digital revolution

State of the Service report outlines the major hurdle to digital reform.




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Open government data to public use, and Australia may start to catch up with the world

Public servants need to ditch the control and encourage entrepreneurship.




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Victorian Premier Daniel Andrews announces 175 new tech jobs for Melbourne

State government commits to five-year funding round as software company launches community centre and new jobs.




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From AFL star to Big Apple start-up, Swift's Joel MacDonald is kicking goals

Two years ago Joel MacDonald was in Melbourne playing in the AFL; now he's kicking goals in New York.




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Taxpayer records exposed by serious ATO, myGov security flaw

Taxpayer says he was hung up on twice by call centre staff when trying to report the issue.




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New website allows youth to report cyber bullying at ACT libraries

A new pilot website will also make it easier for material to be taken off the internet.




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Centrelink apologises for web welfare shutdown

Centrelink clients around Australia are furious over missing payments.




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Centrelink's IT meltdown hits the disability pension

Centrelink's tech woes disrupts Disability Pension medical crackdown.




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ACT Health bogged down by outdated faxes

Archaic technology wasting time for Canberrans is in the target of new federal agency.




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Centrelink wrongly hits 70,000 families with bills for up to $726

Computer glitch blamed as welfare agency hits tens of thousands with bills for money that is not owed.




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Troubled myGov website to be taken from Human Services and given to Digital Transformation Office for streamlining

Malcolm Turnbull's DTO has been critical of myGov, now it has the chance to show it can do better.




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Ricochet uses power of the dark web to help journalists, sources dodge metadata laws

A new internet messaging tool that sidesteps the federal government's metadata collection regime to help journalists protect whistle blowers and assists human rights activists has received a tick of approval from security experts.




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Why Hollywood animation powerhouses are resisting the cloud

Despite new performance bottlenecks, the digital animation and visual effects industry is very reluctant to move their productions to the cloud, according to Sydney's Animal Logic.




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MyGov to feel the audit blowtorch

Human Service to face National Audit Office scrutiny. Again.




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Apple v FBI: what the fight is about and why you should care

Apple is in the middle of a legal fight with the FBI over creating a 'back door' to unlock a terrorist's iPhone.




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Government acknowledges poor internet in Canberra's south but sticks to NBN plan

Minister for Communications acknowledges some areas of Canberra's southern suburbs have poor internet access.




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Branching out after death: where next for the 'Internet of Things'?

It turns out that even death needs the internet.




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Slack's secret sauce: how it became the fastest growing business app ever

Slack has launched its Asia-Pacific headquarters in Melbourne. We caught up with Ali Rayl, head of customer experience.




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Recruitment drive for cyber security specialists will bring challenges for government

Fear government's cyber security recruitment drive will lead to job cuts.




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Government agencies name cybercrime as their top fraud risk: PwC

The 'typical' corrupt bureaucrat is a male, university-educated middle manager, aged 41 to 50.




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Digital public service means ditching control and embracing 'we'

Collaborating with the public is the key for a more engaging government experience.




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Centrelink apologises for new privacy breach

Rookie email error shares hundred of email addresses – twice.




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Is the Australian government agile and innovative? Not to those in the start-ups world

Public service departments "too nervous" to innovate, say start-ups.




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Digital government could become just more cost cutting, warns Internet Australia

Revolving door at digital agency must stop, says Labor.




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Can the government really protect your privacy when it 'de-identifies' public data?

We don't really know to how to use big data and protect personal information at the same time.




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$212,000 per public service IT contractor, and we're hiring more of them

Contractors cost 80 grand more than public servants, Finance Departments says, and the public service hires more of them.




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Brisbane City Council IT contract faces potential $60 million blow-out

A $122 million Brisbane City Council IT contract will be renegotiated after a systems replacement program was delayed by 18 months, with a potential cost blow-out of up to $60 million.




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Centrelink debt debacle shows government is unprepared for digital revolution

The public service needs to embrace partnerships if it's to harvest big data's massive yields.




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Tax time in danger from ATO's tech wreck

IT projects thrown overboard as ATO orders all hands to keep tax time afloat.




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Auditor-general exposes weaknesses in ACT government's IT systems

Electronic sexual health records and the births, deaths and marriages registry have been left exposed.




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How federal government departments are protecting Australians' data against cyber hack

Cyber Security Minister Dan Tehan says the government can't rule out vulnerabilities to cyber threats.




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Australia's Cyber Security Strategy: weaknesses, yes, but we're improving

The online world changes so fast it was always going to be tough to design a four-year strategy.




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Medicare details available on dark web is just tip of data breach iceberg

The next wave of government reform will have to focus on data management.