Here is a link to the case study Amazon prepared about MediaPlatform's use of the Amazon Elastic Compute Cloud (EC2) and Simple Storage Solution (S3).


http://aws.amazon.com/solutions/case-studies/mediaplatform/

MediaPlatform is the only streaming software solution that allows clients to access the obvious benefits of cloud computing while retaining the ability to maintain security, achieve integrations with Active Directory/LDAP, control remote encoders, etc.

Combined with its groundbreaking approaches to multicasting Flash and leveraging the native caching abilities of WAN acceleration devices to stream HTTP, MediaPlatform's cloud offering represents the most innovative approach to enterprise webcasting available on the market today.

Interactive Media Strategies (IMS) is a market research firm that follows streaming media. They discuss the news of Microsoft’s $8.5 billion acquisition of Skype, and the prospects for Skype to emerge as a viable platform for business video communications. 

Their research compares usage levels for a range of social media and communications applications, including Skype, YouTube and Facebook. Here is a link to the video.

They report that personal use of Facebook and YouTube is relatively high but that has not yet translated into comparable levels of corporate use. They believe this raises the question of whether YouTube and Facebook will be able to outgrow their focus on the consumer side of the business to compete in the enterprise market.

Usage levels for Skype are significantly lower overall, but Skype’s penetration in business communications is higher than they see for other communications apps online among young users most likely to experiment with emerging technologies.

IMS puts forth the opinion that if Microsoft could make it easier for technology laggards to embrace Skype - i.e. integrate Skype with the Microsoft Office suite - then Skype could achieve significant enterprise adoption.

The following article, Unhinged Liberal Women Cry On Social Media Over Trump’s Victory And Falsely Claim They’ve Lost All Their Rights, was first published on Conservative Firing Line.

(Natural News) Liberals have been working hard to portray Trump as a misogynist, and it worked on a lot of women – with some of them buying into the false narrative that he will work against women so wholeheartedly that they are now having very public meltdowns over his victory. Revolver put together some of the …

Continue reading Unhinged Liberal Women Cry On Social Media Over Trump’s Victory And Falsely Claim They’ve Lost All Their Rights ...

President-elect Donald Trump is reportedly considering lawyer Alina Habba to be the White House press secretary. Habba often spoke to the media while she was on the legal team representing […]

The post Report Shows New Front-Runner for Trump's Press Secretary Spot: The Media Should Be Terrified appeared first on The Western Journal.

Numerous iron-sulfur (Fe-S) proteins with diverse functions are present in the matrix and respiratory chain complexes of mitochondria. Although [4Fe-4S] clusters are the most common type of Fe-S cluster in mitochondria, the molecular mechanism of [4Fe-4S] cluster assembly and insertion into target proteins by the mitochondrial iron-sulfur cluster (ISC) maturation system is not well-understood. Here we report a detailed characterization of two late-acting Fe-S cluster-carrier proteins from Arabidopsis thaliana, NFU4 and NFU5. Yeast two-hybrid and bimolecular fluorescence complementation studies demonstrated interaction of both the NFU4 and NFU5 proteins with the ISCA class of Fe-S carrier proteins. Recombinant NFU4 and NFU5 were purified as apo-proteins after expression in Escherichia coli. In vitro Fe-S cluster reconstitution led to the insertion of one [4Fe-4S]2+ cluster per homodimer as determined by UV-visible absorption/CD, resonance Raman and EPR spectroscopy, and analytical studies. Cluster transfer reactions, monitored by UV-visible absorption and CD spectroscopy, showed that a [4Fe-4S]2+ cluster-bound ISCA1a/2 heterodimer is effective in transferring [4Fe-4S]2+ clusters to both NFU4 and NFU5 with negligible back reaction. In addition, [4Fe-4S]2+ cluster-bound ISCA1a/2, NFU4, and NFU5 were all found to be effective [4Fe-4S]2+ cluster donors for maturation of the mitochondrial apo-aconitase 2 as assessed by enzyme activity measurements. The results demonstrate rapid, unidirectional, and quantitative [4Fe-4S]2+ cluster transfer from ISCA1a/2 to NFU4 or NFU5 that further delineates their respective positions in the plant ISC machinery and their contributions to the maturation of client [4Fe-4S] cluster-containing proteins.

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

SNF Dialogues: Social media, social movements and political change 6 July 2022 — 2:30PM TO 3:45PM Anonymous (not verified) 15 June 2022 Online

Experts and activists explore how the digital world has changed the nature of social movements and the impact this has on policymaking.

From Extinction Rebellion to Black Lives Matter, social movements are increasingly harnessing social media to project their calls for action. This event, convened in partnership with the SNF Dialogues series, will reflect on the value of social media to social movements and the effects of such digital movements on policymakers. Experts and activists from around the world will explore whether social media is an effective tool for social movements or a distraction, the extent to which digital forms of protest incite social change, and finally if this change has an impact on policy decisions.

The SNF Dialogues, an initiative of the Stavros Niarchos Foundation (SNF), are a series of monthly discussions whose goal is to foster the exchange of ideas, inspire a new way of thinking and acting, and encourage and elevate public discourse across geographic boundaries. The Dialogues discussions are free and open to the public, aiming to bring to light timely questions and developments, share informed reflections and concerns, highlight new data and angles, and present fascinating people, projects and ideas.

The Dialogues are curated and moderated by Anna-Kynthia Bousdoukou and are facilitated by the non-profit journalism organization iMEdD (incubator for Media Education and Development).

The discussion will be conducted in English with simultaneous interpretation into Greek. If you wish to watch the discussion in Greek, tune in here.

JF Oram
Dec 1, 1996; 37:2473-2491
Reviews

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

Selim Esedoḡlu, Jiajia Guo and David Li
Math. Comp. 93 (), 2679-2710.
Abstract, references and article information

Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.

The online media changing African news The World Today mhiggins.drupal 2 August 2022

Africa’s news sites are gripping audiences with digital innovation and bold directions. Helen Fitzwilliam talks to editors at three platforms.

Lydia Namubiru
News editor of ‘The Continent’ (South Africa)

At the start of the pandemic, we realized a lot of fake news was being shared on WhatsApp. So, The Continent chose to launch on that platform to insert some real journalism in a way that could easily be shared. We now have about 100,000 readers across Africa and the rest of the world, but we had to dramatically change the way we write and edit stories: to compete with the likes of Twitter and Instagram, we try to keep stories tight at 300 words. 

There’s a real variety. We can run an investigation into corruption in the Democratic Republic of the Congo a week after a front page on the fashion designer who dresses Africa’s ‘big men’ [powerful leaders]. We cover feminist issues, the backlash against LGBT people in Ghana; we’ve had the Namibian first lady talking to us about misogyny. These are not the sort of topics a typical African newspaper is going to lead with.

With a story such as Ukraine, the war’s impact on the cost of living has been the most obvious angle for us. It has driven countries such as Malawi into crisis, forcing a devaluation of the currency.
 
As for the future, we see two issues looming. Workers’ economic rights and their treatment by multinationals will be a big story. There are refugees in camps in Kenya working in data operations and being paid a pittance to help create huge, potentially multimillion-dollar systems for US companies. 

Second, Africa has the world’s youngest population and the oldest leaders, so this will likely lead to activism and protests. The young are exposed to the global village, so they want different things and have different values. They speak a completely different language their leaders do not understand. It will be an interesting conflict, but could lead to real violence. 

John Githongo
Editor of ‘The Elephant’ (Kenya)

We set up this platform four years ago. Due to political and commercial pressures, mainstream media wasn’t doing much critical reporting. We have between 30,000 and 80,000 readers a week, the majority of them in Africa. 

The digital space reaches a completely different demographic. When The Elephant started, it was 80 per cent male and over 40, but we have gained more younger people and more women. Now it is 60 per cent men, 40 per cent women and that is something we have been working at. 

Our editorial approach is that as long as a piece has a strong argument and fits into our pan-African brief, we will publish it – even if we don’t agree with it.

The conflicts in Ethiopia and parts of the Sahel make the war in Ukraine pale in comparison. So many people have died in Ethiopia or been displaced and now we have the onset of a famine after four years of failed rain. During the 1960s and 1970s, when the Cold War found its way on to African soil, millions of people died – so there is caution about getting involved in a European fight.

There is always a lot of fake news around during elections. But people are beginning to be more sceptical. We go after those who attempt to change the level of debate with reputation-laundering and try to expose their actions. 
 
The future of democracy is going to be a big issue. When Africans were watching the attack on the US Capitol last year, they were hoping it was not a Black Lives Matter protest, which could have resulted in a ‘blackbath’. As soon as they saw the white guys wearing horns, people laughed with relief. 

There is an ongoing recalibration of Africa’s geopolitical relations with the rest of the world. A poll released in June showed China has overtaken the United States as the foreign power having the biggest positive influence in Africa in the eyes of young people across the continent. The younger generation is writing its own narrative. 

Wale Lawal
Editor of ‘The Republic’ (Nigeria)

Nigerian audiences are increasingly online and tend to read both local and international publications. They also know that the issues they care about are either under-reported or reported at lower quality levels. 

At The Republic, we provide political journalism that tends to require high levels of expertise. Yet online audiences also prioritize engagement: it is not enough for an issue to be important, it also needs to be interesting.

Some topics we have covered that Western media tend not to include how people experience blackness in different parts of the world; the waves of mostly female-led and youth-led movements rising up against autocratic governments across Africa; and relationships between countries within Africa itself. In the early days of the pandemic, we launched a Covid-19 and Africa series, having noticed a glaring lack of African expert voices in global media.
 
We also cover Africa’s evolving relations with Russia. Whenever we encounter a story like Russia’s invasion of Ukraine, the first thing we always ask ourselves is what missing voice can we add to the current discussion? All we were reading about after the invasion was how neighbouring countries were opening their borders and their homes to Ukrainians. Most people saw only that. 

But we knew that around 15,000 Africans were studying in Ukraine, that Africans routinely face harsh treatment at international borders, and that clearly their voices were missing from the discussion.

With fake news and information gaps on social media, our usual approach is to develop expert-led columns and circulate these as widely as possible.

Our next mission is to think about the role that independent media can play in supporting democracies, such as by increasing voter turnout. During the last election in Nigeria, less than 35 per cent of those who registered to vote eventually did so.

Mouse embryonic stem cells (mESCs) display unique mechanical properties, including low cellular stiffness in contrast to differentiated cells, which are stiffer. We have previously shown that mESCs lacking the clathrin heavy chain (Cltc), an essential component for clathrin-mediated endocytosis (CME), display a loss of pluripotency and an enhanced expression of differentiation markers. However, it is not known whether physical properties such as cellular stiffness also change upon loss of Cltc, similar to what is seen in differentiated cells, and if so, how these altered properties specifically impact pluripotency. Using atomic force microscopy (AFM), we demonstrate that mESCs lacking Cltc display higher Young's modulus, indicative of greater cellular stiffness, compared with WT mESCs. The increase in stiffness was accompanied by the presence of actin stress fibers and accumulation of the inactive, phosphorylated, actin-binding protein cofilin. Treatment of Cltc knockdown mESCs with actin polymerization inhibitors resulted in a decrease in the Young's modulus to values similar to those obtained with WT mESCs. However, a rescue in the expression profile of pluripotency factors was not obtained. Additionally, whereas WT mouse embryonic fibroblasts could be reprogrammed to a state of pluripotency, this was inhibited in the absence of Cltc. This indicates that the presence of active CME is essential for the pluripotency of embryonic stem cells. Additionally, whereas physical properties may serve as a simple readout of the cellular state, they may not always faithfully recapitulate the underlying molecular fate.

The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

Protein biosynthesis is fundamental to cellular life and requires the efficient functioning of the translational machinery. At the center of this machinery is the ribosome, a ribonucleoprotein complex that depends heavily on Mg2+ for structure. Recent work has indicated that other metal cations can substitute for Mg2+, raising questions about the role different metals may play in the maintenance of the ribosome under oxidative stress conditions. Here, we assess ribosomal integrity following oxidative stress both in vitro and in cells to elucidate details of the interactions between Fe2+ and the ribosome and identify Mn2+ as a factor capable of attenuating oxidant-induced Fe2+-mediated degradation of rRNA. We report that Fe2+ promotes degradation of all rRNA species of the yeast ribosome and that it is bound directly to RNA molecules. Furthermore, we demonstrate that Mn2+ competes with Fe2+ for rRNA-binding sites and that protection of ribosomes from Fe2+-mediated rRNA hydrolysis correlates with the restoration of cell viability. Our data, therefore, suggest a relationship between these two transition metals in controlling ribosome stability under oxidative stress.

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Acute lung injury (ALI), is a rapidly progressing heterogenous pulmonary disorder that possesses a high risk of mortality. Accumulating evidence has implicated the activation of the p65 subunit of NF-κB [NF-κB(p65)] activation in the pathological process of ALI. microRNAs (miRNAs), a group of small RNA molecules, have emerged as major governors due to their post-transcriptional regulation of gene expression in a wide array of pathological processes, including ALI. The dysregulation of miRNAs and NF-κB activation has been implicated in human diseases. In the current study, we set out to decipher the convergence of miR-99b and p65 NF-κB activation in ALI pathology. We measured the release of pro-inflammatory cytokines (IL-1β, IL-6, and TNFα) in bronchoalveolar lavage fluid using ELISA. MH-S cells were cultured and their viability were detected with cell counting kit 8 (CCK8) assays. The results showed that miR-99b was up-regulated, while PRDM1 was down-regulated in a lipopolysaccharide (LPS)-induced murine model of ALI. Mechanistic investigations showed that NF-κB(p65) was enriched at the miR-99b promoter region, and further promoted its transcriptional activity. Furthermore, miR-99b targeted PRDM1 by binding to its 3'UTR, causing its down-regulation. This in-creased lung injury, as evidenced by increased wet/dry ratio of mouse lung, myeloperoxidase activity and pro-inflammatory cytokine secretion, and enhanced infiltration of inflammatory cells in lung tissues. Together, our findings indicate that NF-κB(p65) promotion of miR-99b can aggravate ALI in mice by down-regulating the expression of PRDM1.

Type I and III interferons induce expression of the “myxovirus resistance proteins” MxA in human cells and its ortholog Mx1 in murine cells. Human MxA forms cytoplasmic structures, whereas murine Mx1 forms nuclear bodies. Whereas both HuMxA and MuMx1 are antiviral toward influenza A virus (FLUAV) (an orthomyxovirus), only HuMxA is considered antiviral toward vesicular stomatitis virus (VSV) (a rhabdovirus). We previously reported that the cytoplasmic human GFP-MxA structures were phase-separated membraneless organelles (“biomolecular condensates”). In the present study, we investigated whether nuclear murine Mx1 structures might also represent phase-separated biomolecular condensates. The transient expression of murine GFP-Mx1 in human Huh7 hepatoma, human Mich-2H6 melanoma, and murine NIH 3T3 cells led to the appearance of Mx1 nuclear bodies. These GFP-MuMx1 nuclear bodies were rapidly disassembled by exposing cells to 1,6-hexanediol (5%, w/v), or to hypotonic buffer (40–50 mosm), consistent with properties of membraneless phase-separated condensates. Fluorescence recovery after photobleaching (FRAP) assays revealed that the GFP-MuMx1 nuclear bodies upon photobleaching showed a slow partial recovery (mobile fraction: ∼18%) suggestive of a gel-like consistency. Surprisingly, expression of GFP-MuMx1 in Huh7 cells also led to the appearance of GFP-MuMx1 in 20–30% of transfected cells in a novel cytoplasmic giantin-based intermediate filament meshwork and in cytoplasmic bodies. Remarkably, Huh7 cells with cytoplasmic murine GFP-MuMx1 filaments, but not those with only nuclear bodies, showed antiviral activity toward VSV. Thus, GFP-MuMx1 nuclear bodies comprised phase-separated condensates. Unexpectedly, GFP-MuMx1 in Huh7 cells also associated with cytoplasmic giantin-based intermediate filaments, and such cells showed antiviral activity toward VSV.

Daphne E.C. Boer
Dec 23, 2020; 0:jlr.RA120001043v1-jlr.RA120001043
Research Articles

Natalie Bruiners
Dec 1, 2020; 61:1617-1628
Research Articles

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

Deficiency of glucocerebrosidase (GBA), a lysosomal β-glucosidase, causes Gaucher disease. The enzyme hydrolyzes β-glucosidic substrates and transglucosylates cholesterol to cholesterol-β-glucoside. Here we show that recombinant human GBA also cleaves β-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as acceptor for subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced β-glucosidase activity were similarly impaired in β-xylosidase, transglucosidase and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from Gaucher disease patients. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous β-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing β-glucosidase GBA2. We later sought an endogenous β-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyse formation of XylCer. Thus, food-derived β-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

The adipocyte-derived hormone leptin increases trafficking of KATP and Kv2.1 channels to the pancreatic β-cell surface, resulting in membrane hyperpolarization and suppression of insulin secretion. We have previously shown that this effect of leptin is mediated by the NMDA subtype of glutamate receptors (NMDARs). It does so by potentiating NMDAR activity, thus enhancing Ca2+ influx and the ensuing downstream signaling events that drive channel trafficking to the cell surface. However, the molecular mechanism by which leptin potentiates NMDARs in β-cells remains unknown. Here, we report that leptin augments NMDAR function via Src kinase–mediated phosphorylation of the GluN2A subunit. Leptin-induced membrane hyperpolarization diminished upon pharmacological inhibition of GluN2A but not GluN2B, indicating involvement of GluN2A-containing NMDARs. GluN2A harbors tyrosine residues that, when phosphorylated by Src family kinases, potentiate NMDAR activity. We found that leptin increases phosphorylation of Tyr-418 in Src, an indicator of kinase activation. Pharmacological inhibition of Src or overexpression of a kinase-dead Src mutant prevented the effect of leptin, whereas a Src kinase activator peptide mimicked it. Using mutant GluN2A overexpression, we show that Tyr-1292 and Tyr-1387 but not Tyr-1325 are responsible for the effect of leptin. Importantly, β-cells from db/db mice, a type 2 diabetes mouse model lacking functional leptin receptors, or from obese diabetic human donors failed to respond to leptin but hyperpolarized in response to NMDA. Our study reveals a signaling pathway wherein leptin modulates NMDARs via Src to regulate β-cell excitability and suggests NMDARs as a potential target to overcome leptin resistance.

The EGFR tyrosine kinase inhibitor gefitinib is commonly used for lung cancer patients. However, some patients eventually become resistant to gefitinib and develop progressive disease. Here, we indicate that ecto-ATP synthase, which ectopically translocated from mitochondrial inner membrane to plasma membrane, is considered as a potential therapeutic target for drug-resistant cells. Quantitative multi-omics profiling reveals that ecto-ATP synthase inhibitor mediates CK2-dependent phosphorylation of DNA topoisomerase IIα (topo IIα) at serine 1106 and subsequently increases the expression of long noncoding RNA, GAS5. Additionally, we also determine that downstream of GAS5, p53 pathway, is activated by ecto-ATP synthase inhibitor for regulation of programed cell death. Interestingly, GAS5-proteins interactomic profiling elucidates that GAS5 associates with topo IIα and subsequently enhancing the phosphorylation level of topo IIα. Taken together, our findings suggest that ecto-ATP synthase blockade is an effective therapeutic strategy via regulation of CK2/phospho-topo IIα/GAS5 network in gefitinib-resistant lung cancer cells.

Oxidative stress has been implicated in aging and many human diseases, notably neurodegenerative disorders and various cancers. The reactive oxygen species that are generated by aerobic metabolism and environmental stressors can chemically modify proteins and alter their biological functions. Cells possess protein repair pathways to rescue oxidized proteins and restore their functions. If these repair processes fail, oxidized proteins may become cytotoxic. Cell homeostasis and viability are therefore dependent on the removal of oxidatively damaged proteins. Numerous studies have demonstrated that the proteasome plays a pivotal role in the selective recognition and degradation of oxidized proteins. Despite extensive research, oxidative stress-triggered regulation of proteasome complexes remains poorly defined. Better understanding of molecular mechanisms underlying proteasome function in response to oxidative stress will provide a basis for developing new strategies aimed at improving cell viability and recovery as well as attenuating oxidation-induced cytotoxicity associated with aging and disease. Here we highlight recent advances in the understanding of proteasome structure and function during oxidative stress and describe how cells cope with oxidative stress through proteasome-dependent degradation pathways.

AI-driven Personalization in Digital Media: Political and Societal Implications Research paper sysadmin 2 December 2019

The fallout from disinformation and online manipulation strategies have alerted Western democracies to the novel, nuanced vulnerabilities of our information society. This paper outlines the implications of the adoption of AI by the the legacy media, as well as by the new media, focusing on personalization.

Summary

• Machine learning (ML)-driven personalization is fast expanding from social media to the wider information space, encompassing legacy media, multinational conglomerates and digital-native publishers: however, this is happening within a regulatory and oversight vacuum that needs to be addressed as a matter of urgency.
• Mass-scale adoption of personalization in communication has serious implications for human rights, societal resilience and political security. Data protection, privacy and wrongful discrimination, as well as freedom of opinion and of expression, are some of the areas impacted by this technological transformation.
• Artificial intelligence (AI) and its ML subset are novel technologies that demand novel ways of approaching oversight, monitoring and analysis. Policymakers, regulators, media professionals and engineers need to be able to conceptualize issues in an interdisciplinary way that is appropriate for sociotechnical systems.
• Funding needs to be allocated to research into human–computer interaction in information environments, data infrastructure, technology market trends, and the broader impact of ML systems within the communication sector.
• Although global, high-level ethical frameworks for AI are welcome, they are no substitute for domain- and context-specific codes of ethics. Legacy media and digital-native publishers need to overhaul their editorial codes to make them fit for purpose in a digital ecosystem transformed by ML. Journalistic principles need to be reformulated and refined in the current informational context in order to efficiently inform the ML models built for personalized communication.
• Codes of ethics will not by themselves be enough, so current regulatory and legislative frameworks as they relate to media need to be reassessed. Media regulators need to develop their in-house capacity for thorough research and monitoring into ML systems, and – when appropriate –proportionate sanctions for actors found to be employing such systems towards malign ends. Collaboration with data protection authorities, competition authorities and national electoral commissions is paramount for preserving the integrity of elections and of a political discourse grounded on democratic principles.
• Upskilling senior managers and editorial teams is fundamental if media professionals are to be able to engage meaningfully and effectively with data scientists and AI engineers.

VOLUME 289 (2014) PAGES 6604–6618In Fig. 4G, in the foxi1 panel, the images in Fig. 4G, i and l, corresponding to “smad1 MO” and “smad5 MO + samd1/9 mRNA” samples, respectively, were inadvertently reused during figure preparation. This error has now been corrected using images pertaining to each treatment and sample. This correction does not affect the results or conclusions of the work.jbc;295/52/18650/F4F1F4Figure 4G.

Rebuilding Zimbabwe's Economy: Emmerson Mnangagwa’s Immediate Priorities Expert comment sysadmin 13 December 2017

Zimbabwe cannot expect to rebuild in the same economic model that brought previous prosperity.

Returning to Harare as Zimbabwe’s president-designate Emmerson Mnangagwa declared, ‘We want to grow our economy, we want peace, we want jobs, jobs, jobs.’

Robert Mugabe leaves a legacy of an independent Zimbabwe in a deep economic crisis. Much remains uncertain as to what a new government in Zimbabwe will look like, and there is sure to be continuity as well as considerable change.

What is clear is that a new administration under Mnangagwa will need to turn the economy around to garner support and legitimacy from the Zimbabwean people. Zimbabwe’s economic output halved over the period 1997–2008, and it has not recovered. With more than 80 per cent of Zimbabweans in the informal economy, and with social and economic resilience undermined by previous crises and decades of mismanagement, the stakes for the new leader are very high.

Reform will be difficult particularly because politically connected elites have acquired businesses through uncompetitive means. They will be reluctant to see significantly more competition. But they will also want an improved economic environment. And there is scope for the people of Zimbabwe to benefit from this.

An important change will be in the prioritization of economic stability. Mugabe demonstrated that he was willing to make political decisions irrespective of the economic consequences. Mnangagwa is thought to be less ideological and more of a pragmatist. For him, delivering economic recovery will be crucial to building political support.

The most pressing fiscal priority is the public wage bill. Employment costs account for over 80 per cent of government expenditure, crowding out spending on social programmes, health and education. But the fragility of the economy means that reform cannot be fast-tracked. The public wage bill accounts for over 20 per cent of GDP and is an essential driver of demand. Public sector workers are also politically influential. Another further priority is the reform of state-owned enterprises that are pressuring the fiscus.

A new administration will need to rebuild confidence. Policymakers have been operating in a low-confidence environment for a long time, but for any meaningful change to take root there has to be trust between the government, businesses and the people of Zimbabwe. Businesses and citizens will want to see a plan of action for remonetizing the economy. Zimbabwe faces an acute liquidity crisis. A shortage of US dollars and a lack of confidence in government-issued bond notes are testing resilience.

The financial system has recovered from a crisis of nonperforming loans – triggered by high debt amassed during the post-dollarization boom, and weak corporate governance. But the system remains highly fragile and swamped with government debt. Hard cash US dollar deposits fell from 49 per cent ($582 million) in 2009 to just six per cent ($269 million) in 2016. In 2015, industrial utilization stood at just 34.3 per cent of installed capacity, and it was estimated that just five per cent of the country’s businesses were viable.

The crux of the Zimbabwean economy is the linkage between agriculture and manufacturing. Commercial agriculture contributes approximately 12 per cent of the country’s GDP, and more than 60 per cent of inputs into the manufacturing sector. Tobacco in particular is a vital earner of much needed foreign exchange. Policies to support mid-scale farmers will have multiplier effects. They drive agricultural growth and generate jobs throughout the supply chain.

Zimbabwe also has world-class natural resource endowments including ferrochrome, gold, copper, iron ore, lithium, diamonds and platinum group metals. But longer investment-gestation periods and industry risk adversity will mean that payoffs from fresh investments in this sector will take longer to materialize.

Domestic finance will need to be mobilized to generate recovery, and this will need to be supported by international investment. But international investors entering the country must be cognizant of Zimbabwean’s expectations and also historical perceptions – especially around the scepticism of neoliberal economics as a result of failed structural adjustment programmes in the 1990s.

Zimbabweans have high social expectations for international investors. Educated, tech-savvy, internationally connected youth are at the core of the consumer class that investors will be targeting, to both sell products to but also to staff offices in country. But this cohort also has a greater expectation of international companies to adhere to the norms and standards that they abide by at home and not take advantage of weak governance or poor regulation to exploit citizens.

Investors in Zimbabwe must also recognize that behind the controversial Mugabe policies of land reform and indigenization – the empowerment of local citizens through shared ownership – was a popular desire for postcolonial economic transformation. This sentiment remains. Working in partnership with local entities and communicating the economic contribution made to society will be necessary to build a long-term presence in Zimbabwe, and reap the dividend of what many hope to be a new start for the country.

Fresh thinking is required from domestic policymakers and international partners. A skilled population and estimated 3-5 million-strong diaspora will bring international experience and make a considerable contribution to this process. Some of this thinking has been done. The Lima process of re-engagement with international financial institutions that was agreed at the end of 2015 has laid some of the groundwork, especially around international expectations regarding both economic and governance reform – the substance of which was analysed in a 2016 Chatham House paper. The implementation of recommendations of the well-regarded auditor-general’s report on SOE reform will also be a key prerequisite for long-term reform.

Zimbabweans are not alone in processing what has happened and how to react. Investors have long been poised to capitalize on what is perceived to be one of the continent’s best long-term prospects. A lot will remain unchanged following the transition. But significantly, for the first time in decades, there is a real opportunity to effect positive change and improve the livelihoods of millions of Zimbabweans.

This article was originally published at the Huffington Post.

Chatham House Primer: Social media and democracy 21 March 2023 — 6:00PM TO 6:45PM Anonymous (not verified) 23 February 2023 Chatham House

From the Arab Spring to the 2016 Trump election win, how have democracies benefited and suffered from the impact of social media? 

With social media now a well-entrenched, yet still recent, component of societies, democracies are still grappling with the impact bought about by this new form of communication and promotion.

For all that social media has bought people closer together and brought government, business and civic leaders, it has also been said to have fuelled divisions and hate. Governments and businesses are now drawing battle lines on the legal responsibilities required of social media platforms as we slowly determine the role they play in our society.

This Primer will discuss key questions including:

• What are the current legal responsibilities of social media companies? What sort of laws and regulations must they abide by?
• How are governments looking to change to this?
• How have some countries manipulated social media to monitor and censor their populations?
• Can social media truly tackle harmful and dangerous content?
• Is it possible to combat disinformation and what role should social media platforms play?
• How can we make social media best fit our society in the future?
• How should we govern online space?

A drinks reception will follow this event.

As with all member events, questions from the audience drive the conversation.

Trump Media and Technology Group shares rose 15% in value on Tuesday as voters cast ballots on Election Day.

Australian Prime Minister Anthony Albanese said Thursday his government will introduce legislation to ban children under 16 years of age from social media.

President-elect Donald Trump wants legal authorities to investigate what he said were possibly illegal rumors he is going to sell his majority stock stake in Trump Media. He claims he won't sell.

Did you grow up in a world void of social media platforms? Then, you’re probably the last ‘lucky’ generation. A part of Generation Y and most of Generation Z have been raised alongside the internet and social media. Individuals belonging to the latter have practically been raised by such platforms, as they interact with strangers […]

The post Sacrificing the Human Psyche at the Altar of Social Media? 4 Concerning Ill-Effects to Know first appeared on What is Psychology?.

Texas Longhorns fans were very happy after the second edition of the College Football Playoff rankings were released Tuesday.

Tsuneya Ikezu
Oct 2, 2024; 44:e1170242024-e1170242024
Symposium

Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, are thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knock-out (KO) mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin KO mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of neuritin was decreased by unpredictable chronic stress in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves fibroblast growth factor (FGF) signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.

Reelin, a secreted glycoprotein, plays a crucial role in guiding neocortical neuronal migration, dendritic outgrowth and arborization, and synaptic plasticity in the adult brain. Reelin primarily operates through the canonical lipoprotein receptors apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr). Reelin also engages with noncanonical receptors and unidentified coreceptors; however, the effects of which are less understood. Using high-throughput tandem mass tag (TMT) liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics and gene set enrichment analysis (GSEA), we identified both shared and unique intracellular pathways activated by Reelin through its canonical and noncanonical signaling in primary murine neurons of either sex during dendritic growth and arborization. We observed pathway cross talk related to regulation of cytoskeleton, neuron projection development, protein transport, and actin filament-based process. We also found enriched gene sets exclusively by the noncanonical Reelin pathway including protein translation, mRNA metabolic process, and ribonucleoprotein complex biogenesis suggesting Reelin fine-tunes neuronal structure through distinct signaling pathways. A key discovery is the identification of aldolase A, a glycolytic enzyme and actin-binding protein, as a novel effector of Reelin signaling. Reelin induced de novo translation and mobilization of aldolase A from the actin cytoskeleton. We demonstrated that aldolase A is necessary for Reelin-mediated dendrite growth and arborization in primary murine neurons and mouse brain cortical neurons. Interestingly, the function of aldolase A in dendrite development is independent of its known role in glycolysis. Altogether, our findings provide new insights into the Reelin-dependent signaling pathways and effector proteins that are crucial for dendritic development.

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.

The precise regulation of Ca²⁺ signals plays a crucial role in the physiological functions of neurons. Here, we investigated the rapid effect of glucocorticoids on Ca²⁺ signals in cultured hippocampal neurons from both female and male rats. In cultured hippocampal neurons, glucocorticoids inhibited the spontaneous somatic Ca²⁺ spikes generated by Kv2.1-organized Ca²⁺ microdomains. Furthermore, glucocorticoids rapidly reduced the cell surface expressions of Kv2.1 and Ca_V1.2 channels in hippocampal neurons. In HEK293 cells transfected with Kv2.1 alone, glucocorticoids significantly reduced the surface expression of Kv2.1 with little effect on K⁺ currents. In HEK293 cells transfected with Ca_V1.2 alone, glucocorticoids inhibited Ca_V1.2 currents but had no effect on the cell surface expression of Ca_V1.2. Notably, in the presence of wild-type Kv2.1, glucocorticoids caused a decrease in the surface expression of Ca_V1.2 channels in HEK293 cells. However, this effect was not observed in the presence of nonclustering Kv2.1S586A mutant channels. Live-cell imaging showed that glucocorticoids rapidly decreased Kv2.1 clusters on the plasma membrane. Correspondingly, Western blot results indicated a significant increase in the cytoplasmic level of Kv2.1, suggesting the endocytosis of Kv2.1 clusters. Glucocorticoids rapidly decreased the intracellular cAMP concentration and the phosphorylation level of PKA in hippocampal neurons. The PKA inhibitor H89 mimicked the effect of glucocorticoids on Kv2.1, while the PKA agonist forskolin abrogated the effect. In conclusion, glucocorticoids rapidly suppress Ca_V1.2-mediated Ca²⁺ signals in hippocampal neurons by promoting the endocytosis of Kv2.1 channel clusters through reducing PKA activity.

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch–clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV->PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV->PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development.

Read more about SONG 1: http://j.mp/GTZ0Ru & http://j.mp/GVlcMx Watch how artist Doug Aitken transforms the outside of the art museum into a panoramic movie screen

Transposon-mediated transgenesis has revolutionized both basic and applied studies of mosquito vectors of disease. Currently, techniques such as enhancer traps and transposon tagging, which rely on remobilizable insertional mutagenesis, are only possible with transposon-based vector systems. Here, we provide general descriptions of methods and applications of transposon-based mosquito transgenesis. The exact procedures must be adapted to each mosquito species and comparisons of some differences among different mosquito species are outlined. A number of excellent publications showing detailed and specific protocols and methods are featured and referenced.

The mayor of the eastern P.E.I. town of Three Rivers says comments on social media have become so 'aggressive' that council has decided to hold Tuesday night’s meeting virtually instead of in-person out of concerns for their own safety.

Transposon-mediated transgenesis of mosquito vectors of disease pathogens followed the early success of transgenesis in the vinegar fly, Drosophila melanogaster. The P transposable element used in Drosophila does not function canonically in mosquitoes, and repeatable, routine transgenesis in mosquitoes was not accomplished until new transposable elements were discovered and validated. A number of distinct transposons were subsequently identified that mediate the introduction of exogenous DNA in a stable and heritable manner in mosquito species, including members of the genera Aedes, Anopheles, and Culex. The most versatile element, piggyBac, is functional in all of these mosquito genera, as well as in many other insects in diverse orders, and has been used extensively outside the class. Transposon-mediated transgenesis of recessive and dominant marker genes and reporter systems has been used to define functional fragments of gene control sequences, introduce exogenous DNA encoding products beneficial to medical interests, and act as "enhancer traps" to identify endogenous genes with specific expression characteristics.

Eliminates the Cost and Complexity of Maintaining Online Parts Catalogs; Improves Search, Navigation, and Communication for Engineers Seeking 3D Part Models