Gasdermin offers insight into coral necrotic death


Gasdermin offers insight into coral necrotic death
Cleavage of GSDME by caspase 3. Credit: IOCAS

Pyroptosis is a highly inflammatory form of programmed necrotic cell death that acts as a defense mechanism against the infection of bacterial and viral pathogens. Pyroptosis is executed by gasdermin, a family of pore-forming proteins.

Gasdermin-mediated pyroptosis is characterized by rapid cell swelling, membrane disruption, and massive cytoplasmic content release. To date, pyroptosis-inducing gasdermins have only been reported in vertebrates. It remains unclear whether functional gasdermins exist in invertebrates.

Recently, a research team led by Prof. Sun Li from the Institute of Oceanology of the Chinese Academy of Sciences (IOCAS), in collaboration with Prof. Zhou Zhi from Hainan University, has identified gasdermin E (GSDME) from the reef-building coral Orbicella faveolata and demonstrated that coral GSDME triggers pyroptosis and is involved in pathogen-induced coral death.

Their study was published in Science Immunology on Dec. 4, 2020.

Via biochemical and cellular studies, the researchers revealed that O. faveolata GSDME was activated by caspase 3, which cleaved GSDME at two different sites. This resulted in two forms of the N-terminal domain of GSDME, and both of them were able to induce pyroptosis.

“When co-present with caspase 3, GSDME switched cell fate from caspase 3-induced apoptosis to pyroptosis,” said Dr. Jiang Shuai, the first author of the study.

Gasdermin offers insight into coral necrotic death
GSDME induces pyroptosis. Credit: IOCAS

Vibrio coralliilyticus is a coral pathogen found worldwide. In this study, the researchers demonstrated in a coral death model that V. coralliilyticus infection caused rapid tissue necrosis with activation of caspase 3 and GSDME, as well as subcellular structural damage including disorganization of mitochondria and Golgi apparatus.

Furthermore, inhibition of caspase 3 was found to block GSDME cleavage and protect corals from necrotic death.

The researchers revealed the activation mechanism and pyroptosis-executing capacity of coral GSDME as well as its involvement in pathogen-induced coral necrotic death.

Gasdermin offers insight into coral necrotic death
GSDME is involved in pathogen-induced coral death. Credit: IOCAS

Their findings shed light on the evolution, function, and activation mechanism of gasdermins, and promote our understanding of coral death caused by environmental stress.

This work was supported by the National Natural Science Foundation of China and the National Key Research and Development Project of China.


Insights into a versatile molecular death switch


More information:
S. Jiang el al., “Coral gasdermin triggers pyroptosis,” Science Immunology (2020). immunology.sciencemag.org/look … 6/sciimmunol.abd2591

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TU Graz entwickelt Screeningsystem für Lungengeräuschanalyse

Pneumologie


Ein an der TU Graz entwickeltes Mehrkanal-Aufnahmegerät für krankhafte Lungengeräusche und die dazugehörige automatische Analyse der Geräusche könnten bestehende Screening-Methoden zur Früherkennung zum Beispiel von COVID-19-Infektionen unterstützen. Hierfür benötigt es nun klinische Daten und eine interdisziplinäre Zusammenarbeit.

Es pfeift, es zischt, es rasselt: Unser Körper gibt laufend Geräusche von sich, die (zum Glück) nicht immer mit dem freien Ohr hörbar sind. Das Auftreten bestimmter Geräusche oder Änderungen in den normalen Tönen kann ein Hinweis auf Erkrankungen sein. Am Beispiel der Lunge hat sich ein Forschungsteam der TU Graz intensiv mit der Geräuschaufzeichnung und der Entwicklung von computergestützten Analysemethoden als Ergänzung für die medizinische Diagnose befasst.

Die Arbeiten mündeten vor einigen Monaten in einem Prototyp eines Mehrkanal-Aufnahmegeräts und der laufenden Entwicklung eines dazugehörigen computergestützten Diagnosesystems. Die Gruppe rund um Franz Pernkopf vom Institut für Signalverarbeitung und Sprachkommunikation will das System nun für das Screening von COVID-19-Erkrankten weiterentwickeln. Dafür brauche es Geräuschaufnahmen von COVID-19-positiven Personen in klinischer Behandlung. Aktuell liegt dem FWF ein entsprechender Förderantrag für die Ausschreibung „Akutförderung SARS-CoV-2“ zur Prüfung vor.

Objektive Geräuschbeurteilung als Diagnosehilfe

Akustische Anomalien in der Lunge sind oft schwer von normalen Lungengeräuschen und anderen Körpergeräuschen wie Herz- und Darmgeräuschen, Sprache oder Husten zu unterscheiden. Die kurz andauernden Geräusche haben eine relativ geringe Amplitude und liegen im tiefen Frequenzbereich, wo das menschliche Gehör eine begrenzte Empfindlichkeit hat und anfällig für Lärmartefakte ist. Das traditionelle Abhorchen mit einem Stethoskop hat daher Nachteile: Die Beurteilung der Lungengeräusche ist subjektiv und schwankt je nach Erfahrung des medizinischen Personals. Ein kontinuierliches Monitoring ist mit Stethoskop – ob real oder digital – nicht möglich.

Der an der TU Graz entwickelte Prototyp erlaubt hingegen qualitativ hochwertige Aufzeichnungen von Lungengeräuschen, anhand derer Lungenkrankheiten und pathologische Lungenzustände objektiver beurteilt werden können. Das ermöglicht eindeutigere Untersuchungsergebnisse und dadurch optimalere Therapien. Pernkopf erklärt die Technik dahinter: „Das Lungengeräusch-Aufzeichnungssystem (lung sound recording system; LSRS) ist mehrkanalig und mit sehr leistungsstarken mikro-elektromechanischen Mikrofonen (MEMS) ausgestattet. Die Aufzeichnung der Lungengeräusche erfolgt nicht-invasiv: Der Patient oder die Patientin legt sich einfach in Rückenlage auf das Gerät.“ Dieses zeichnet in insgesamt 16 Kanälen die Lungengeräusche während der Atmung auf. Ganz entscheidend sind die Dämpfung von Umgebungs- und anderweitiger Körpergeräuschen und die Qualität der aufgezeichneten Lungensignale.

Datensammlung für automatische Diagnose

Das LSRS erfasst Lungengeräusche in einer derart guten Tonqualität, dass die Forschenden an einer computergestützten automatischen Lungengeräuschanalyse arbeiten können. Dafür braucht es zunächst eine Menge Daten, anhand derer das System lernen kann. Eine klinische Studie soll zu entsprechend großen Datensätzen gesunder und pathologischer Lungenaufnahmen verhelfen. „Vorrangig konzentrieren wir uns auf die Lungengeräusche, die mit Lungenentzündungen, Bronchitis, Rippenfellentzündungen, idiopathischen Lungenfibrosen und systolischer Herzinsuffizienz einhergehen“, sagt Pernkopf und führt weiter aus: „Dabei brauchen wir Lungengeräusch-Aufnahmen von Menschen aller Geschlechter, verschiedener Altersgruppen und mit unterschiedlichem Body-Mass-Index.“ Derzeit ist für die Datensammlung eine klinische Studie in Zusammenarbeit mit der Medizinischen und Pharmazeutischen Universität in Ho-Chi-Mhin-Stadt in Vorbereitung. Eine Vorstudie zu Geräuschen, die mit der Idiopatischen Lungenfibrose einhergehen, hat bereits in Zusammenarbeit mit der Med Uni Graz stattgefunden (Freyja Smolle-Jüttner, Klinische Abteilung für Thorax- und hyperbare Chirurgie und Horst Olschewski, Klinische Abteilung für Pulmonologie).

Eine Anpassung des Systems an COVID-19-typische Lungengeräusche benötigt entsprechende Aufnahmemöglichkeiten bei infizierten Personen. „Da sind wir freilich nicht an Aufzeichnungen von Lungengeräuschen aus dem Vietnam gebunden. Es ist aber eine Kostenfrage, wie schnell wir hier weiterkommen. Wir hoffen daher sehr auf die Mittel aus dem FWF-Topf und sind zuversichtlich, dass wir unseren kostengünstigen Screening-Ansatz für Lungenkrankheiten – auch für jene im Zuge von COVID-19-Erkrankungen – anbieten können“, sagt Pernkopf.

Ergänzungstool im Pre-Screening

Ursprünglich wurde das System mit Blick auf geografische Gebiete mit fehlendem Zugang teuren Diagnoseverfahren wie MR oder CT entwickelt. „Aber auch in Ländern mit grundsätzlich gut ausgestatteten klinischen Umgebungen wie wir sie hierzulande haben, kann das System eine große Erleichterung sein: nämlich im Pre-Screening. Am Beispiel der aktuellen COVID-19-Pandemie könnte das heißen, dass im Zuge von Massentests auch die Lungengeräusche analysiert werden. „Es ist eine Frage der Ausreifung des gesamten Systems und der Verfügbarkeit von Referenzdaten. Ist beides gegeben, ließe sich unser System auf mehrere Lungenerkrankungen hin adaptieren“, so Pernkopf, der gleichzeitig betont: „Idealerweise geschieht dies in Zusammenarbeit mit interdisziplinären Forschungsgruppen aus den Bereichen Medizin und Technik, deren Arbeit in eine ähnliche Richtung geht. Wir sind dankbar für ergänzende Inputs und offen für mögliche Kooperationen“.

Diese Forschung ist an der TU Graz in den Fields of Expertise „Information, Communication and Computing“ und „Human & Biotechnology“ angesiedelt, zwei von fünf strategischen Schwerpunktfeldern.

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Iraqi activists go underground after wave of attacks by pro-Iran militias


There has been a wave of kidnappings, torture and killings of high-profile anti-government activists in Iraq in recent months. Protesters and experts blame pro-Iran militias within the Popular Mobilisation Forces, a paramilitary organisation created in 2014 to combat the Islamic State group. The Popular Mobilisation Forces have been accused of numerous instances of violence against civilians. At least seven activists have narrowly survived assassination attempts since November 20. Others have spoken out about the terror they must live with every day.

A group made mostly of students began a protest movement in Iraq on October 25, 2019, calling for both an end to corruption and the political system that allocates government roles depending on religion and ethnic group. The protestors were also calling for an end to Iran’s influence in the country. Security forces carried out a bloody crackdown on the movement, firing bullets to disperse protests in locations like Baghdad’s iconic Tahrir Square. An estimated 600 people were killed in the period between October 2019 and January 2020, according to reports by Amnesty International

Activists have also faced the terror of kidnappings and targeted assassinations. Whether they are students, journalists or intellectuals, if they are active on social media or in the public eye during protests, they run the risk of being targeted by armed men waiting for them at the edge of a protest, hidden in a side street or in front of their homes.

The FRANCE 24 Observers team has recorded seven assassination attempts against activists since November 20.   

One assassination attempt after another 

Akram Aadab, one of the most prominent figures in the protest movement, survived an assassination attempt on the evening of November 25. He was standing with a friend outside of his home when two hooded men carrying guns with silencers burst out of a white car, shot at him and chased him into a supermarket where he sought refuge. 

A video shared on Twitter shows neighbours carrying the activist towards a hospital.

Screengrab of a video showing activist Akram Aadab being taken to the hospital.
Screengrab of a video showing activist Akram Aadab being taken to the hospital. © Twitter

       

The next day, he was able to walk again after doctors removed three bullets, as shown by a video posted on Twitter.

A few days later, on the night of November 22, unknown men fired shots at the front of the home of Ammar al-Halafi, an activist in Basra. No one was injured. Al-Halafi shared surveillance footage showing shots being fired from a car stopped in front of his home. 

A week later, al-Halafi shared more surveillance footage, this time showing six armed individuals breaking into his apartment building on November 28. In the comments section on the post, he said that they had again tried to kill him, without providing more details.

On the same day, in Al-Diwaniyah, a town to the south of Baghdad, a bomb exploded outside of the home of Ammar al-Khazali, another activist. His home was damaged. 

On November 20, Bashar al-Naïmi, an activist from Baghdad, was shot at by men armed with a pistol and a silencer, a common method according to Iraqi media outlets. Al-Naïmi was getting ready to leave Tahrir Square after having participated in a ceremony honouring a fallen comrade several days prior. He escaped with just a shoulder wound.  

In late October, Iraqi Prime Minister Mustafa al-Kadhimi ordered the tearing down of the tents that protesters have maintained since the very start of the protest movement. Even so, activists continued to take to the streets, including our Observer Zouhair (not his real name). He protests regularly in Basra and is politically active on Instagram, where he has several thousand followers. Zouhair was kidnapped several months ago. He shared a video with our team showing the signs of torture on his body. 

‘They subjected me to electrical shocks, hit me with a baton and shaved my head’

“It happened during a protest in late 2019 [Editor’s note: we aren’t giving any more details in order to protect our Observer’s safety]. When I was leaving the gathering in the morning, men in civilian clothes kidnapped me and tortured me for two days. They subjected me to electrical shocks, hit me with a baton and forcibly shaved my head. They told me if I didn’t stop protesting and sharing images online, they’d kill me. But I decided to continue until the people who assassinated other activists are arrested and tried.”

Fearing for their lives, some activists decided to stay away from both the protests and social media. Ammar (not his real name) gave up his job as a journalist because he feared for his life. 

‘I haven’t seen my parents in eight months, but it is the price to pay to stay alive’

One day when I was covering the protests, I was kidnapped by four hooded men wearing black. They forced me into a black Chevrolet SUV before covering my eyes. They locked me up somewhere for four days without giving me any food. One of them burned my right leg with some kind of metal cylindrical object and said to me, “This way, you’ll repent and you won’t go to the protests anymore.”

When they let me go, I was in a terrible state. One of my jailers had violently kicked me in the stomach and so I had internal bleeding. I spent several days in a hospital, where I had serious surgery.  

I am still terrified, even today, especially when I see friends assassinated every day. I haven’t seen my parents for eight months. I don’t dare to visit them for fear that I will be recognised.

 

Ammar (not his real name) shared photos of his hospital stay with the Observers. One shows stitches across his abdomen. Another shows a circular burn on his leg.

Threatened by a battalion of trolls on social media

After taking office on May 7, PM al-Kadhimi announced that he would set up a special commission to investigate the murders of activists. But many activists and analysts believe that this is just an attempt to quiet the demonstrations and that the Iraqi government doesn’t have enough power to properly investigate militias supported by Iran. 

Omar Farhane, an activist exiled in Jordan, is the director of an independent NGO called the Iraqi Center for the Documentation of War Crimes. He told the FRANCE 24 Observers team that the assassins are part of a paramilitary group known as the Popular Mobilization Forces, which is made up of more than 60 brigades. Some groups are Sunni Muslim, Christian or Yazidi, but the vast majority are Shia Muslim.

There is no concrete proof for now because the investigations aren’t going anywhere. But we spoke with the victims of attempted assassinations and kidnappings, and the names of certain militias came up frequently, including Iraqi Hezbollah [Editor’s note: This is considered to be the most powerful pro-Iranian militia and is included on the list of terrorist organisations drafted by the US State Department], Asa’ib Ahl al-Haq [Editor’s note: This brigade is accused of carrying out numerous extrajudicial killings of Sunnis in Iraq, including executing 50 people in Babil Province in July 2014],  Moqtada al-Sadr’s Blue Helmets, Saraya al-Salam and others.

The aim of these atrocities is to shut up the protest movement that is aiming to reduce Iran’s influence. Since the very start of the protest, we’ve heard accounts of men in civilian clothing infiltrating crowds of protesters, filming them and sometimes even stabbing them in the middle of the crowd. And that’s not to mention those who are shot point blank in front of their homes or in the street.

The online landscape can also be hazardous. Trolls with links to pro-Iranian militias attack the protesters online, claiming that they are “pro-American” or traitors, says Omar Farhane:

In order to scare the activists, they invested massively in social media. Batallions of trolls managed to shut down numerous accounts by reporting them. They shut down the Facebook account of the Iraqi Center for War Crimes. Lots of activists, including those who received death threats, created accounts under false names so they could keep communicating with each other.

Prime Minister Al-Kadhimi ordered on June 26 the arrest of 13 members of the Iraqi Hezbollah, accusing them of planning an attack against the US Embassy. This was the first such action against an armed faction of the powerful Popular Mobilization Forces. 

“Al-Kadhimi went after a pro-Iranian militia to save the US Embassy. When will he dare to do it to save the Iraqi people from assassinations?” said an activist who asked for anonymity.





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Baricitinib, a Covid-19 Drug from Eli Lilly, Is Expensive And Doesn’t Do Much


In mid-November, an arthritis drug with a tricky name hit a pandemic milestone — then slipped back into relative obscurity.

The drug, baricitinib, was granted an emergency authorization by the Food and Drug Administration to treat a subset of hospitalized Covid-19 patients in combination with another medication, the antiviral remdesivir. It is one of only a handful of treatments to have earned the agency’s green light.

But baricitinib’s reception by the medical community has been lukewarm. It doesn’t work all that well, for one thing, and comes with side effects, such as blood clots. And at a cost of roughly $1,500 per patient, many doctors don’t know when it would make sense to use the drug, which might have overlapping roles with cheap and widely available steroids like dexamethasone.

In a clinical trial sponsored by the National Institutes of Health, hospitalized Covid-19 patients treated with baricitinib and remdesivir recovered one day faster than patients who had received remdesivir alone.

“I think it’s really a nothing burger,” said Dr. Ilan Schwartz, an infectious disease physician at the University of Alberta. “We’re talking about adding a drug that reduces the time to clinical improvement by one day, in a disease that takes weeks to recover.”

These results, which were announced through a series of news releases by drugmaker Eli Lilly, have yet to be published in a peer-reviewed scientific journal. Kristen Porter Basu, a spokeswoman for the company, wrote in an email that a “more detailed analysis” would be published “very soon.”

When an emergency authorization has been released but the data have not, doctors are caught “in a difficult place,” said Dr. Manuela Cernadas, a critical care physician at Brigham and Women’s Hospital in Boston. “It’s not entirely clear where this drug fits in our armamentarium of drugs we’re comfortable using.”

Baricitinib is a repurposed arthritis treatment that, like a steroid, dampens inflammation, which, in severe cases of Covid-19, can spiral out of control and destroy healthy tissues. The drug acts like a molecular muffler, preventing the cells from responding to alarm signals that could make the body’s immune response spiral out of control.

The N.I.H. trial was designed to test whether baricitinib could boost the benefits of remdesivir, now the standard of care for Covid-19 patients. Remdesivir by itself speeds recovery by several days. The researchers found that the addition of baricitinib clipped an additional day off a patient’s recovery time and kept a few extra people off ventilators. But these and other results largely failed to impress experts, many of whom said the drug would need to have far bigger benefits to outweigh its price tag and potential harms.

“It seems more incremental than blockbuster,” said Dr. Taison Bell, a critical care physician at the University of Virginia, who was involved in the clinical trial. Although Dr. Bell described baricitinib as a reasonable addition to the Covid treatment toolbox, and even deserving of an emergency approval, “I don’t think it’s a game changer,” he said.

Still, the findings were enough to convince the F.D.A., which issued an emergency authorization on Nov. 19. The drug is now allowed to be paired with remdesivir, but only to hospitalized patients who need supplemental oxygen, mechanical ventilation or other breathing support.

The agency’s limited clearance aligns with the subset of patients in the N.I.H. trial who benefited the most from the dual drug combo, said Dr. Andre Kalil, an infectious disease physician at the University of Nebraska Medical Center and one of the lead researchers on the trial.

But this same population of patients — people sick enough to need some form of breathing support — would also be great candidates for steroids like dexamethasone, said Dr. Phyllis Tien, an infectious disease physician at the University of California, San Francisco.

Dexamethasone, unlike baricitinib, has been shown in studies to curb mortality in severely sick Covid-19 patients. A generic drug, it’s also cheap, costing cents or dollars per day of treatment, and has for months been a part of the coronavirus treatment playbook.

“I’m asking myself, ‘Who would I think about using baricitinib in, over dexamethasone?’” Dr. Tien said.

But Dr. Boghuma Kabisen Titanji, an infectious disease physician at Emory University who pioneered early studies of baricitinib against the coronavirus, offered a more sobering perspective on dexamethasone. Steroids are “blunt knives,” she said, quashing inflammation on a broader scale than drugs like baricitinib do. That’s why steroids come with a host of unwanted side effects, including exacerbating conditions like diabetes or osteoporosis, she said.

The family of drugs that includes baricitinib, on the other hand, may offer more therapeutic precision, Dr. Titanji said. There’s also been some evidence that baricitinib might be able to block the coronavirus from entering cells.

Still, baricitinib comes with its own problems, such as raising the risk of blood clots — already an issue in many cases of Covid-19. “That does give you pause,” Dr. Cernadas said.

Both baricitinib and dexamethasone also blunt immune function, increasing the likelihood that other viruses or bacteria might infiltrate the bodies of the people they’re used in. But of the two, dexamethasone is “the devil you know,” said Dr. Lauren Henderson, a pediatric rheumatologist at Boston Children’s Hospital. “I would probably not turn to baricitinib as a first line.”

Dr. Tien and other experts echoed this sentiment, saying they would be likely to choose dexamethasone over baricitinib when treating someone with a serious case of Covid-19, unless there was an obvious reason their patient might respond poorly to steroids.

A head-to-head comparison between baricitinib and dexamethasone might clarify which patients would be better off taking one drug over another. At the end of November, the N.I.H. announced a trial that will compare outcomes between hospitalized Covid-19 patients who receive either a combination of remdesivir and dexamethasone, or a combination of remdesivir and baricitinib. But Dr. Schwartz and others raised ethical concerns about this trial, which he said would by definition deprive some patients of a lifesaving steroid therapy.

Eli Lilly is also running a trial to study the effects of baricitinib on its own in hospitalized patients. In this study, which isn’t likely to finish until next summer, all participants will receive dexamethasone.



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Erdogan expresses hope that France will ‘get rid of Macron’ as soon as possible



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Turkish President Recep Tayyip Erdogan said on Friday he hopes France will get rid of Emmanuel Macron as soon as possible, the latest salvo in an escalating war of words between the two leaders.

Turkey is embroiled in a series of disputes with France and its EU partners, from tensions in the eastern Mediterranean to the contested Nagorno-Karabakh region.

The spat has risen to new levels in recent months as France has moved to crack down on Islamist extremism after several attacks on its soil.

Macron is trouble for France. With Macron, France is passing through a very, very dangerous period. I hope that France will get rid of Macron trouble as soon as possible,” Erdogan told reporters after Friday prayers in Istanbul.

He said the French should dump their leader “otherwise they will not be able to get rid of yellow vests“, referring to the protest movement that erupted in France in 2018.

“Yellow vests could later turn into red vests,” Erdogan said, without elaborating.

The Turkish leader has repeatedly suggested that Macron get “mental checks” and urged the Turkish people to boycott French-labelled products.

Erdogan’s diatribe came as the European Union weighs imposing sanctions against Turkey at a December 10 summit, largely over its standoff with EU member Greece in the eastern Mediterranean.

Diplomats have said that Paris is pressing for such punitive measures against Ankara even if some key EU members — notably Germany — are more circumspect and want a diplomatic approach.

“We are ready to use the means at our disposal,” said European Council chief Charles Michel, expressing dismay over Ankara’s “unilateral acts” and “hostile rhetoric”.

In a televised interview Friday, Macron appeared unwilling to be drawn into a new round of insults with Erdogan.

“I believe in respect… I think invective between political leaders is not a good method,” said Macron.

‘Give Marseille to Armenians’

Turkey and France are also at odds over Nagorno-Karabakh, a region of Azerbaijan populated by ethnic Armenians that broke away from Baku’s control in a 1990s post-Soviet war.

Fresh fighting broke out in September, leaving several thousand people dead, until a Russian-brokered ceasefire deal was sealed last month.

Turkey is a staunch ally of Azerbaijan and Macron — whose country has a large Armenian community — repeatedly accused Ankara of sending Syrian militia to fight for Baku.

Last month, the French Senate adopted a non-binding resolution calling on France to recognise Nagorno-Karabakh as an independent state.

“You are a mediator but on the other side, you have passed a resolution in your parliament… about a region on which you are supposed to be a mediator,” Erdogan charged.

France along with Russia and the United States co-chairs the Minsk Group, which has led talks seeking a solution to the conflict for decades but has failed to reach a lasting agreement.

Erdogan also repeated comments by Azerbaijani President Ilham Aliyev that France should concede the Mediterranean port city of Marseille — home to one of France’s biggest Armenian communities — to Armenia if it wanted to establish a state for the Armenians of Karabakh.

“I am giving the same advice: if they are so keen, they should give Marseille to Armenians,” Erdogan said.

In September, Macron’s comments on the simmering eastern Mediterranean standoff, which has pitted Turkey against Greece and the rest of the EU, drew Ankara’s wrath.

“The people of Turkey, who are a great people, deserve something else,” Macron said in comments slammed by Ankara as meddling in domestic politics.

Macron told Al-Jazeera in October France wanted things to “calm down” but it was essential first that the “Turkish president respects France, respects the European Union, respects its values, does not tell lies and does not utter insults”.

(AFP)



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New pathway in Alzheimer’s disease provides earlier target for potential therapies


dementia
Credit: CC0 Public Domain

Researchers at the Case Western Reserve University School of Medicine have identified a new target in development of Alzheimer’s disease (AD) that could lead to therapies focused on treating the neurodegenerative condition early in its progression.

The discovery helps bolster a promising approach to AD research: finding and manipulating processes earlier in the disease’s development with hopes of slowing its advance.

“This is a missing part of the puzzle,” said Xin Qi, a professor in the Department of Physiology and Biophysics at the School of Medicine and lead researcher of the study, just published in the journal Science Advances. “We’ve discovered a pathway that is accessible to detection and potential treatment, prior to much of the disease’s damage and well before clinical symptoms appear.”

First identified more than 100 years ago, AD is an age-related neurodegenerative disorder that is associated with deposits of plaques of amyloid beta protein and tangles of tau protein in the brain, along with progressive nerve cell death. The cause of AD is not known, and the greatest risk factors for developing AD are age, genetics, and a previous traumatic brain injury.

Before the defining pathological characteristics of the disease are in place, the new pathway identified by Case Western Reserve researchers can be targeted by potential therapeutics that aim to mitigate the degeneration of white matter that impairs the normal functions of brain circuitry.

“There is a growing body of evidence in the field that AD develops much earlier than previously thought, most likely decades before our current ability to clinically diagnose the condition,” said study co-author Andrew A. Pieper, the Morley-Mather Chair in Neuropsychiatry in the School of Medicine, Director of the Harrington Discovery Institute Neurotherapeutics Center at University Hospitals.

“Detecting the disease—and potentially treating it—at earlier stages will be critical to our battle against its devastating effects. The new pathway uncovered by Dr. Qi’s laboratory could be targeted for therapy before the disease has progressed to the point of causing cognitive problems,” said Pieper, also a psychiatrist at the Louis Stokes Cleveland VA Medical Center Geriatrics Research Education and Clinical Center (GRECC).

The Drp1 pathway

Researchers found that the pathway—known as Drp1-HK1-NLRP3—plays a key role in disrupting normal function of brain cells that produce the protective white matter sheathing for nerves, known as myelin.

The dysfunction and eventual death of these myelin-producing cells—called oligodendrocytes (OLs)—are well-established early events in AD that lead to cognitive deficits.

The new findings illuminate how OLs start to go awry: the overexpression of a certain protein (Drp1) within the recently discovered pathway.

It’s the hyperactivation of Drp1 protein that triggers inflammation and injury to OLs, culminating in a reduction of myelin—slowing communication in the brain—which leads to the degeneration of white matter and significant cognitive impairment.

What’s next—targeting with therapeutics

A near total degeneration of OLs occurs before common symptoms of AD become apparent in most patients.

As such, researchers hope to target and manipulate the pathway with therapeutics that regulate the expression of Drp1, thereby slowing or reducing damage to myelin-producing OLs.

In fact, Qi’s lab has patented a small molecule, known as a peptide inhibitor, that regulates the expression of Drp1—putting the brakes on degeneration of brain cells.

In the study published by Science Advances, researchers found that eliminating Drp1 expression in mouse models corrected the energy-related defect in OLs associated with the hyperexpression of that protein; this approach also reduced the activation of inflammation OLs, lessened tissue damage at those brain sites and improved cognitive performance.

“Our results show promise that targeting the Drp1-HK1-NLRP3 pathway and reducing the expression of the Drp1 protein could help reduce the downstream cascade of abnormal brain functions associated with the progression of AD,” said Qi, whose lab has studied Drp1 for a decade, mostly in Parkinson’s and Huntington’s diseases.”

“If therapies targeting this pathway can slow, stop or even reverse early stage AD progression, then possibly there can be a reduction or delay to later stage damage and impairments,” Qi said.

Most AD diagnoses are in patients 65 or older, so identifying the disease in younger patients can be difficult. Many patients experience a significant loss in their brain’s white matter—central to cognition, emotion and consciousness—before receiving a diagnosis.

“Identifying how AD unfolds in its earliest processes will help scientists better understand how to focus research into potential solutions for patients,” said Pieper. “The Qi lab’s findings may help in targeting AD earlier, potentially leading to better management of its symptoms and progression.

“There have still been only a very small number of approved medications for AD since its discovery in 1907. While these medicines augment neurotransmission to provide temporary symptomatic benefit, they do nothing to slow disease progression,” said Pieper. “Identification of earlier approaches to treating AD—such as this research—is critical for society as the magnitude of AD is growing explosively with our aging population.”

Researchers validated the discovery of the pathway using mouse models and post-mortem brain samples of AD patients.


Researchers discover neuroprotective treatment for chronic traumatic brain injury


More information:
“Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease” Science Advances (2020). DOI: 10.1126/sciadv.abb8680

Citation:
New pathway in Alzheimer’s disease provides earlier target for potential therapies (2020, December 4)
retrieved 4 December 2020
from https://medicalxpress.com/news/2020-12-pathway-alzheimer-disease-earlier-potential.html

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Neue Erkenntnisse zur Regulation der Leberfibrose und Leberregeneration

Gastroenterologie


Was genau sind die Prozesse, die aus einer gesunden Leber eine fibrotische Leber machen? Finden sich dort gegebenenfalls Ansatzpunkte für die Therapie von Lebererkrankungen?

Um diese Fragen beantworten zu können, haben Wissenschaftler der Klinik für Dermatologie, Venerologie und Allergologie der Universitätsmedizin Mannheim (UMM) die Rolle der Blutgefäße bei der Entstehung der Leberfibrose untersucht. Dabei gewannen sie nicht nur ein besseres Verständnis der der Fibrose zugrundeliegenden Krankheitsprozesse, sondern sehen ebenso die neuere Erkenntnis bestätigt, dass Blutgefäße die Organfunktion kontrollieren können.

Parallel zur steigenden Zahl der Übergewichtigen in Deutschland – laut Adipositas Gesellschaft zwei Drittel der Männer und die Hälfte der Frauen – hat in den vergangenen Jahren auch die Häufigkeit der nicht alkoholischen Fettlebererkrankungen (NAFLD) zugenommen. Sie übersteigt inzwischen deutlich die der durch Alkohol verursachten Fettlebererkrankungen.

Die meist durch ungesunden Lebensstil verursachte „Wohlstandserkrankung“ kann im Verlauf zu einer Leberfibrose führen, bei der durch Umbauprozesse zunehmend Lebergewebe durch Bindegewebe ersetzt wird. Dies geht mit einer verringerten Leberfunktion einher. Schreitet diese Entwicklung fort, kann es zu einer nicht alkoholische Steatohepatitis (NASH) und bis hin zu einer nicht mehr heilbaren Leberzirrhose oder Leberkrebs kommen.

Das Forscherteam der UMM um Prof. Sergij Goerdt, PD Dr. Philipp Reiners-Koch und Prof. Cyrill Géraud widmet sich speziell den Lebersinusoiden, den kleinsten und hoch spezialisierten Blutgefäßen der Leber. In vorangegangenen Arbeiten hatten sie bereits zeigen können, dass der Transkriptionsfaktor GATA4 wichtig für die korrekte Entwicklung dieser Blutgefäße ist.

Transkriptionsfaktoren erkennen bestimmte DNA-Strukturen, binden daran und regulieren so, ob von einem Genabschnitt die Information für ein neues Protein abgelesen wird oder nicht. Wird ein solcher Transkriptionsfaktor in einem Modellsystem ausgeschaltet, können aus möglichen Veränderungen oder Ausfällen Rückschlüsse auf dessen Funktion gezogen werden.

In der aktuell veröffentlichen Arbeit konnten die Wissenschaftler zeigen, dass der Verlust von GATA4 in dem die Lebersinusoiden auskleidenden Endothel ausreicht, um eine Leberfibrose zu verursachen, was mit einer gestörten Funktion und Regenerationsfähigkeit des gesamten Organs einhergeht.

Darüber hinaus konnten die Forscher nachweisen, dass angiokrine Faktoren die Fibrose der Leber vermitteln. Dazu gehört beispielsweise der Wachstumsfaktor PDGFB (Platelet-derived growth facor B). Und auch ein Großteil der Genexpression in den Blutgefäßen der Leber ist verändert. Dadurch ändern sich Struktur und Funktion der Lebersinusoide, sodass diese zunehmend Blutgefäßen ähneln, wie sie in anderen Organen, etwa der Lunge, zu finden sind. Diese Beobachtungen wurden sowohl in Modellsystemen der Leberfibrose, als auch bei Patienten mit Leberzirrhose gemacht.

Die vorliegende Arbeit trägt zu einem besseren Verständnis der Krankheitsprozesse bei der Leberfibrose bei. „Dass Funktionsstörungen der Blutgefäße der Leber direkt zu einer gestörten Funktion des gesamten Organs führen, bestätigt, dass die Blutgefäße die Organfunktion – und damit auch Krankheitsprozesse – kontrollieren können“ erklärt Reiners-Koch. „Darüber hinaus ist mit der Achse GATA4/PDGFB ein potenzieller neuer Angriffspunkt für eine mögliche Therapie identifiziert worden“ ergänzt Erstautor Dr. Manuel Winkler, auch stellvertretend für seine Co-Erstautoren Theresa Staniczek, Sina Kürschner und Dr. Christian Schmid.

Die wissenschaftliche Arbeit ist im Rahmen des an der Universitätsmedizin Mannheim angesiedelten Sonderforschungsbereichs 1366 „Vaskuläre Kontrolle der Organfunktion“ der Deutschen Forschungsgemeinschaft (DFG) in Kooperation zwischen Arbeitsgruppen des European Center for Angioscience (ECAS) der Medizinischen Fakultät Mannheim der Universität Heidelberg, des Deutschen Krebsforschungszentrums (DKFZ), des Zentrums für Molekulare Biologie der Universität Heidelberg (ZMBH) sowie der Technischen Universität München (TUM) entstanden. Zudem wird Winkler durch das von der DFG unterstütze Clinician-Scientist-Programm der Fakultät „Interfaces and Interventions in Complex Chronic Conditions (ICON)“ gefördert.

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What Hearing Loss Feels Like in ‘Sound of Metal’


Creating an audioscape for a movie about a musician losing his hearing is more complicated than it may seem. The filmmakers behind the new drama “Sound of Metal” wanted to take audiences into the experience of its lead character, Ruben (Riz Ahmed), a punk-metal drummer who is forced to look at his life differently as he goes deaf.

Judging by the overwhelmingly positive reviews, the filmmakers pulled off that difficult feat. In The New York Times, Jeannette Catsoulis raved about “an extraordinarily intricate sound design that allows us to borrow Ruben’s ears.”

The film (streaming on Amazon) often places us in Ruben’s aural perspective as he navigates his new reality. (It’s worth watching with headphones or a good sound system.) “I had many conversations with people who have lost their hearing and not two people’s experience is the same,” said Darius Marder, the film’s co-writer and director. “But one thing that’s pretty much true for all people who are deaf is that they don’t lose sound entirely. It isn’t silence.”

Instead, Marder and his sound designer, Nicolas Becker, wanted to capture those low-frequency vibrations and other tones. The approach was adjusted for different moments in Ruben’s experience. In separate Zoom interviews, Marder and Becker focused on three scenes as they spoke about some of the techniques and ideas they used to tap into Ruben’s aural experience, including putting microphones inside skulls and mouths.

One of the first times there’s a notable change in Ruben’s hearing comes before a show, as he is setting up the merchandise table with his bandmate and girlfriend, Lou (Olivia Cooke). At one point, he experiences a high-pitched ringing, then voices are muffled.

Ahmed’s response in that moment isn’t just acting. The filmmakers had custom-fit earpieces made for the actor so they could feed him a high-frequency sound they had created.

“He’s reacting to a very physical process,” Marder said. “And that process gives way to a white noise in Riz’s ears in real time that doesn’t allow him to even hear his own voice, which is a very specific experience, to not be able to hear your own voice. It’s what gives rise to a loss of balance and a real loss of control.”

This moment signals to the audience that the movie will be taking a much more first-person approach, that we will often be listening through Ruben’s ears. The sequence continues with the band’s performance, when Ruben is sitting at the drum kit, the loud beats slowly fading into low, distant tones.

In the next sequence, Ruben gets up in the morning to realize his hearing loss has become more pronounced. The sound here comes off as low and rumbly, somewhat cavernous and very internal.

That internal feeling is a specialty for Becker, who has created immersive, personalized sound experiences on many projects, from the astronaut drama “Gravity,” for which he put on a spacesuit to understand the sound inside it, to the deep-sea disaster film “The Command,” for which he spent two weeks recording underwater in a submarine.

“If I can put people in a real ambient sonic environment, I can create something very specific,” he explained. “It’s about how you relate sound to your body memory.”

Becker said that a year before filming “The Sound of Metal,” he invited Marder to Paris to visit an anechoic chamber. The room is designed to get rid of sound and reverberations.

“After 10 minutes, you can hear your tendons, the pressure of your blood,” Becker said. “You reach the physiological limit of your hearing system.”

Going deeper into this body-sound connection and conjuring up Ruben’s aural experience involved what Marder called a “real experimentation of muffledness.” Becker mic’d the insides of preserved skulls and helmets to get at that feeling of being enveloped. He also used stethoscope-style microphones, along with mics that go inside a performer’s mouth to create a mix of audio illustrating how Ruben experiences sound from the inside out.