Writers and human rights experts call on India to repeal laws that threaten free expression in world’s largest democracyToronto, ON – Earlier this year, India’s Ministry of Home Affairs used an extensive arsenal of vague and overbroad laws to muzzle the world’s largest environmental watchdog, Greenpeace International.  Using seemingly innocuous provisions in the Indian Foreign Contribution (Regulation) Act […]

Toronto, ON – An inefficient legal system and what amounts to unchecked abuse of vague and overbroad legislation have contributed to a chilling effect on free speech within India’s society and throughout its public sphere according to a report released today by PEN International, PEN Canada and International Human Rights Program (IHRP) at the University of […]

SELF EXPRESSION by Hessam is a(n) Limited Edition. The Edition is Limited to Limited Edition pcs

The OSCE Office for Democratic Institutions and Human Rights (ODIHR) joined with other global and regional intergovernmental human rights organizations and experts in issuing a statement condemning the recent evictions of Roma and Sinti, as well as Travellers, in Europe, on 29 June 2016.

Signatories call on national, regional and, in particular, local authorities to find sustainable solutions to the housing problems that many Roma and Sinti face, while condemning forced evictions without due process and provisions of adequate alternative housing. The statement reminds participating States that such evictions violate international human rights obligations and authorities must ensure that everyone subject to eviction is adequately informed of their rights and necessary evictions must be carried out without discrimination or harassment.

The statement highlights the long-term negative implications of eviction that can result in physical and psychological problems, including emotional trauma and lasting social isolation, which particularly affects older people, women, children and people with disabilities.

ODIHR had previously reminded the OSCE participating States that evictions of Roma and Sinti must comply with international standards and provide for adequate housing for those evicted. Furthermore, greater efforts are needed to promote sustainable and non-discriminatory housing solutions. The OSCE Action Plan on Improving the Situation of Roma and Sinti from 2003 additionally calls for mechanisms and procedures to clarify property rights, resolve questions of ownership and regularize the legal status of Roma and Sinti people living in circumstances of unsettled legality.

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• OSCE workshop in Kosovo focuses on improving the recording of hate crimes
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WARSAW, 3 June 2016 – Michael Georg Link, Director of the OSCE Office for Democratic Institutions and Human Rights (ODIHR), expressed concern today over yesterday’s sentencing by a court in Dushanbe of two leaders of the banned Islamic Renaissance Party (IRPT) to life imprisonment, and 11 other high-ranking party officials to jail terms ranging from two to 28 years.

“The harsh sentences handed down yesterday, following the earlier ban of the IRPT and the arrest and harassment of its members and their families and lawyers, raise concerns in relation to the commitments Tajikistan has made as an OSCE participating State to uphold key values of democracy, including political pluralism and political participation,” the ODIHR Director said. “ODIHR has raised this issue with the authorities in the past, and asked for more information on the rationale behind these actions.”

The IRPT party officials were convicted and sentenced by the court on charges that they had conspired in and taken part in the organization of an army coup in the country in September 2015. At that time, the Supreme Court banned the party as an “extremist and terrorist organization”.

The trials leading up to yesterday’s sentences were held behind closed doors, with the proceedings off-limits to the media as well.

“Fair-trial rights are a central element of the rule of law, and measures limiting public scrutiny of and access to criminal proceedings can only undermine confidence that these rights are being upheld,” Director Link said. “ODIHR continues to stand ready to support the Tajik authorities in fulfilling the country’s OSCE commitments in the areas of political pluralism and the rule of law.”

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• ODIHR Director Link welcomes U.S. Supreme Court decision throwing out conviction, death sentence of African-American man from all-white jury

YEREVAN, 30 June 2016 – OSCE Chairperson-in-Office and German Foreign Minister Frank-Walter Steinmeier visited the premises of the OSCE Office in Yerevan on 30 June to discuss its work and activities and to meet with civil society representatives, while in Armenia as part of his official visit to the three countries of the South Caucasus.

Steinmeier was welcomed by Ambassador Argo Avakov, Head of the OSCE Office in Yerevan.  “The Office in Yerevan is closely co-operating with state structures and civil society in Armenia and welcomes this visit by the Chairperson-in-Office,” said Avakov. “Civil society plays an important role in enhancing public confidence in the electoral process, improving police-public partnership as well as promoting women and youth engagement and the freedom of the media in Armenia.”

The Chairperson-in-Office underlined his appreciation for the Office’s activities in all three dimensions and commended its good co-operation with Armenian institutions.

The OSCE Office in Yerevan works closely with government partners, civil society and other actors in Armenia to support activities in a variety of areas including legislative and criminal justice reform, anti-corruption, migration policy, economic integration, environmental activities, raising awareness on human rights, media freedom, access to information, gender equality, assistance to police and security sector reform.  

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PRISHTINË/PRIŠTINA, 9 May 2016 – A ten-day school of journalism organized by the OSCE Mission for around 20 young people from northern Kosovo started today in Mitrovica/Mitrovicё North.

In the course of the programme, led by Davor Glavaš, a renowned journalist and lecturer at the University of Zagreb, participants will gain practical knowledge in reporting, writing skills and the use of social media and new technologies, such as blogs and web portals. Enhancing these skills will help them in their careers as well as contribute to media pluralism in Kosovo.

“For democratic societies it is crucial to have well educated journalists able to report in an objective, factual and independent manner. It is also important to provide aspiring young people with education opportunities to pursue a career in journalism,” said Christopher Tuetsch, Director of the OSCE Mission in Kosovo Democratization Department. “With this activity the OSCE Mission aims to help media outlets in northern Kosovo strengthen their human capacities and enhance information pluralism offered to the public.”

Following the successful completion of the programme, the top four candidates will be selected to participate in a six-month apprenticeship programme, to be implemented jointly with four media outlets in northern Kosovo: TV Mir, Radio Kosovska Mitrovica, Radio Kontakt Plus and the KoSSev web portal.

The OSCE Mission in Kosovo is mandated with human rights protection and promotion, democratization and public safety sector development. It helps safeguard freedom of the media and freedom of expression, and supports media development.

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VIENNA, 16 July 2016 – OSCE media freedom representative Dunja Mijatović today said she was deeply saddened upon learning of the death of photojournalist Mustafa Cambaz in Turkey, and worried about the state of media freedom in the country.

“I was deeply saddened to learn about Cambaz’ death,” Mijatović said. “The authorities must do their utmost to ensure journalists’ safety and free flow of information during times of crisis.”

Cambaz, a photojournalist with the media outlet Yeni Safak, was shot last night during the unrest in Turkey. Reportedly, a number of members of the media were detained last night for a short period of time. Some journalists were also injured, including Reporters Without Borders correspondent Selçuk Şamiloğlu who was beaten when reporting from the Bosphorus Bridge in Istanbul.

“Journalists continue to put themselves in great danger in order to provide information to the public,” Mijatović said. “They must be able to report freely and safely.”

Further, Mijatović noted reports that the editorial offices of several newspapers, including the Hürriyet newspaper, Hürriyet Daily News, and broadcaster CNNTürk, were raided and taken over for a few hours by a group of soldiers in Istanbul.

The Representative also welcomed the attention attributed to journalists’ safety by Prime Minister Binali Yildirim in his public remarks today, expressing regret for any harm that media workers might have suffered during the events.

Mijatović said she will continue to follow and closely monitor all issues related to media freedom and safety of journalists in the country.

The OSCE Representative on Freedom of the Media observes media developments in all 57 OSCE participating States. She provides early warning on violations of freedom of expression and media freedom and promotes full compliance with OSCE media freedom commitments. Learn more at www.osce.org/fom, Twitter: www.twitter.com/osce_rfom and on www.facebook.com/osce.rfom. 

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Back with another negotiated deal and this time it's on the 8Bitdo Ultimate 2C Black Myth: Wukong Limited Edition in both the wired and wireless variants. It beats the previous deal, still beats $69.95 at EB Games and ships from 8BitDo's official store.

The Ultimate 2C improves upon the original by introducing Bluetooth connectivity alongside 2.4G wireless, hall effect joysticks/triggers, customisable R4/L4 buttons and tactile switches. Comparison here.

• Apply the coupons 8BITDOVIPAU and AU1132

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For those paying in USD this is how you get the correct exchange rate in PayPal:

Setting overseas websites to AUD or letting PayPal do the currency conversion results in an inflated rate. To get the correct rate you need a card without international fees and do the following:

• Set the website currency to USD
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Now you'll get the correct MasterCard or VISA exchange rate depending on the card.

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The Eastern & Oriental Express is back on the rails in Southeast Asia after a long hiatus.

Use cases for structured threat information expression

In the last eight years, my posting habits have become pretty sparse, to say the least. Starting and running a school…it’s a lot. It keeps me busy and thoroughly exhausted. I miss it. I miss the cadence of posting regularly and interacting with my education friends virtually. I miss swapping ideas and being thoroughly steeped...

Library - Art Library, Location - LIB, Call number - NA1085 .L44 2016

I have a website The site has a button that is programmed in HTML which has a design of the button, image, and link.I am interested in an application that will pull the images from AliExpress with the option of selecting an image, and automatically insert the image and the link into the code on the website

EU expresses ‘profound concern’ over violence towards Christians

DHL recently expanded its vast network of U.S. retail locations by introducing a new company owned and operated retail shipping store in Fairfax, Virginia. The 1,152 sq. ft. store is the sixth DHL Service Point in Virginia, offering convenient access to its industry-leading shipping services in the D.C. area. 

DHL has recently expanded its vast network of U.S. retail locations with a new company owned and operated retail shipping store in Bellaire, Texas

Copyright 2020 NPR. To see more, visit SARAH MCCAMMON, HOST: School - parents, students and teachers are wondering, what will it look like this year? Will doors actually open, or will students be back on their computers for classes or a mix of both? In North Carolina, Gov. Roy Cooper says he'll make an announcement this week about what his state's schools should do. Teachers like Tamika Walker Kelly are waiting. She teaches elementary school music in Fayetteville, and she's also the president of the North Carolina Association of Educators. She joins us now. Thanks for joining us. TAMIKA WALKER KELLY: Thank you for having me. MCCAMMON: I'd like to start with what you and other teachers in the state are hoping for. What do you want to see happen this fall? WALKER KELLY: So many educators around our state - and, I would say, nationwide - are really concerned about re-entering schools in a safe way. Our safety of our educators and our student is the No. 1 priority of many of us. And so we

Publisher urgently seeking songs for film and television placement. All styles. No demos. No samples. Must control composition and master rights. If your song is selected you will be offered an exclusive publishing agreement. Please submit through Music Xray.

Expressive Artists is a music publishing company with an emphasis on film and television placement. In the past year we've placed hundreds of songs in feature films, major network TV shows including, "S.W.A.T.," "No Activity," "What We Do In The Shadows", documentaries, podcasts and apps. Two of our Music Xray artists songs are featured in the upcoming major motion picture, "The Comeback Trail," starring Robert De Niro, Morgan Freeman and Tommy Lee Jones.

The Ministry of Health has set Flu Express dates for October 19, 22, and 23, offering free shots for seniors and $20 for others. A Government spokesperson said, “The Ministry of Health announces new Flu Express dates. The Hamilton Health Centre is on Saturday, October 19th, from 10 am—2 pm [for seniors 65 and older]; […]

- Scarper; British slang for 'run away'. From Scapa Flow - Go. 

- Grass; as in informant. From Grasshopper - copper (and from there to copper's nark) 

- Dukes; slang for fists, as in 'duking it out'. From Duke of York - Fork. ('Forks' being now-forgotten slang for hands.) 

- Donkey's years; a long time. From Donkey's Ears, rhyming slang for Years... but then the Y crept back in. 

Essayist Phil Klay says Trump tried to use the military to push his partisan agenda before, and may further erode norms around the military as he looks for those willing to "go with his whims."

1. Trump taps Marco Rubio & Michael Waltz, known to be pro-India and tough on China, for top jobs  The Indian Express
2. Donald Trump Sets 'Existential' Battle Against China With Cabinet Picks  NDTV
3. Trump's NSA pick Mike Waltz's pro-India stand in 5 quotes  Firstpost
4. Trump's incoming NSA Mike Waltz wants US to dance cheek-to-check with India  The Times of India
5. Who is Mike Waltz, Donald Trump’s pick for national security adviser?  The Hindu

1. PM Modi’s Rs 12,100 crore infrastructure push to transform Bihar’s railways and roadways – Here’s all you need to know  The Financial Express
2. PM Modi to visit Bihar on Wednesday, inaugurate projects worth Rs 12,100 Cr  Deccan Herald
3. PM Modi lays foundation stone for AIIMS Darbhanga, says NDA Govt committed to welfare of people  The Hindu
4. PM Modi Bihar Visit Live: Nitish Kumar removed 'jungle raj' in Bihar, says PM Modi in Darbhanga  Moneycontrol
5. Politics News Today Live Updates on November 13, 2024: ‘BJP trying to create controversy’: Karnataka Deputy CM Shivakumar on ‘Kaalia’ remark against Kumaraswamy  Mint

Tamar Geiger
Mar 1, 2012; 11:M111.014050-M111.014050
Special Issue: Prospects in Space and Time

Timothy J. Griffin
Apr 1, 2002; 1:323-333
Research

Guoan Chen
Apr 1, 2002; 1:304-313
Research

Qiang Tian
Oct 1, 2004; 3:960-969
Research

Linn Fagerberg
Feb 1, 2014; 13:397-406
Research

Shao-En Ong
May 1, 2002; 1:376-386
Research

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews

DL Brasaemle
Nov 1, 1997; 38:2249-2263
Articles

K Schoonjans
May 1, 1996; 37:907-925
Reviews

The regional and international implications of restrictions to online freedom of expression in Asia 25 March 2021 — 12:30PM TO 1:30PM Anonymous (not verified) 12 March 2021 Online

Panellists discuss the latest developments affecting online freedom of expression in the Asia region.

Please note this is an online event. Please register using the link below to finalize your registration.

In recent years, state-led clampdowns on online freedom of expression have become widespread in several countries across Asia, further intensified by the COVID-19 crisis.

The reasons for this are complex and diverse – drawing upon history, culture and politics, in addition to external influences. Across the region, governments have been accused of silencing online criticism and failing to uphold rights to free speech.

Individuals have been arrested, fined or attacked for the alleged spread of ‘fake news’, raising concern among human rights organizations. In some countries, this has culminated in the imposition of new social media rules, which could require social media companies to censor posts and share decrypted messages.

In China, the government’s restrictive online regime has relied on a combination of legal, technical and manipulation tactics to manage control of the internet, and now includes attempts at censorship beyond its borders.

Panellists will discuss the latest regional developments affecting online freedom of expression in the Asia region, and will consider the broader regional and international implications for technology governance.

This webinar launches the publication Restrictions on online freedom of expression in China: The domestic, regional and international implications of China’s policies and practices.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.

Programmed ribosomal frameshifting (PRF) is a mechanism used by arteriviruses like porcine reproductive and respiratory syndrome virus (PRRSV) to generate multiple proteins from overlapping reading frames within its RNA genome. PRRSV employs −1 PRF directed by RNA secondary and tertiary structures within its viral genome (canonical PRF), as well as a noncanonical −1 and −2 PRF that are stimulated by the interactions of PRRSV nonstructural protein 1β (nsp1β) and host protein poly(C)-binding protein (PCBP) 1 or 2 with the viral genome. Together, nsp1β and one of the PCBPs act as transactivators that bind a C-rich motif near the shift site to stimulate −1 and −2 PRF, thereby enabling the ribosome to generate two frameshift products that are implicated in viral immune evasion. How nsp1β and PCBP associate with the viral RNA genome remains unclear. Here, we describe the purification of the nsp1β:PCBP2:viral RNA complex on a scale sufficient for structural analysis using small-angle X-ray scattering and stochiometric analysis by analytical ultracentrifugation. The proteins associate with the RNA C-rich motif as a 1:1:1 complex. The monomeric form of nsp1β within the complex differs from previously reported homodimer identified by X-ray crystallography. Functional analysis of the complex via mutational analysis combined with RNA-binding assays and cell-based frameshifting reporter assays reveal a number of key residues within nsp1β and PCBP2 that are involved in complex formation and function. Our results suggest that nsp1β and PCBP2 both interact directly with viral RNA during formation of the complex to coordinate this unusual PRF mechanism.

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

Visual Abstract

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.

Tuberculosis (TB), caused by the infection of Mycobacterium tuberculosis (MTB), is one of the leading causes of death worldwide, especially in children. However, the mechanisms by which MTB infects its cellular host, activates an immune response, and triggers inflammation remain unknown. Mitochondria play important roles in the initiation and activation of the nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) inflammasome, where mitochondria-associated endoplasmic reticulum membranes (MAMs) may serve as the platform for inflammasome assembly and activation. Additionally, mitofusin 2 (MFN2) is implicated in the formation of MAMs, but, the roles of mitochondria and MFN2 in MTB infection have not been elucidated. Using mircroarry profiling of TB patients and in vitro MTB stimulation of macrophages, we observed an up-regulation of MFN2 in the peripheral blood mononuclear cells of active TB patients. Furthermore, we found that MTB stimulation by MTB-specific antigen ESAT-6 or lysate of MTB promoted MFN2 interaction with NLRP3 inflammasomes, resulting in the assembly and activation of the inflammasome and, subsequently, IL-1β secretion. These findings suggest that MFN2 and mitochondria play important role in the pathogen-host interaction during MTB infection.

Akt3 regulates mitochondrial content in endothelial cells through the inhibition of PGC-1α nuclear localization and is also required for angiogenesis. However, whether there is a direct link between mitochondrial function and angiogenesis is unknown. Here we show that Akt3 depletion in primary endothelial cells results in decreased uncoupled oxygen consumption, increased fission, decreased membrane potential, and increased expression of the mitochondria-specific protein chaperones, HSP60 and HSP10, suggesting that Akt3 is required for mitochondrial homeostasis. Direct inhibition of mitochondrial homeostasis by the model oxidant paraquat results in decreased angiogenesis, showing a direct link between angiogenesis and mitochondrial function. Next, in exploring functional links to PGC-1α, the master regulator of mitochondrial biogenesis, we searched for compounds that induce this process. We found that, sildenafil, a phosphodiesterase 5 inhibitor, induced mitochondrial biogenesis as measured by increased uncoupled oxygen consumption, mitochondrial DNA content, and voltage-dependent anion channel protein expression. Sildenafil rescued the effects on mitochondria by Akt3 depletion or pharmacological inhibition and promoted angiogenesis, further supporting that mitochondrial homeostasis is required for angiogenesis. Sildenafil also induces the expression of PGC-1 family member PRC and can compensate for PGC-1α activity during mitochondrial stress by an Akt3-independent mechanism. The induction of PRC by sildenafil depends upon cAMP and the transcription factor CREB. Thus, PRC can functionally substitute during Akt3 depletion for absent PGC-1α activity to restore mitochondrial homeostasis and promote angiogenesis. These findings show that mitochondrial homeostasis as controlled by the PGC family of transcriptional activators is required for angiogenic responses.

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and the enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (Lipin^NLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic but not nuclear gene regulatory activity of Lipin is essential for survival. Notably, adult Lipin^NLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were misregulated in Lipin^NLS flies. Altogether, our data suggest that the nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.