Especially after someone put that giant wooden thing on top.

Avoiding Duplicate URL’s From Being Crawled The canonical tag was introduced in 2007 and tells the search engines what should be indexed. By allowing the search engines to know the preferred page it eliminates duplicate page indexing. E-commerce or large websites usually run into more issue’s surrounding duplicate indexing problems. This is due to multiple […]

Okay, recently there has been some discussion surrounding the Google Authorship and Publisher topic. So I figured what a great time to cover another article for the topic since it has been part of an update being done for some websites I am working on. First off, there has been some more talk about the […]

Anxiety is something most of us are familiar with in one way or another. It can feel like a storm inside your mind, making even simple things feel overwhelming. Anxiety disorders are more common than ever, and while they can feel insurmountable, the right understanding and tools can make all the difference. In this article, ... Read more

The post A Practical Guide to Understanding Anxiety and Managing It Effectively appeared first on LifeHack.

Explores how the Institute for Research and Innovation in Social Services (IRISS) promotes the delivery of cost effective social services in Scotland that will support the achievement of positive outcomes for people accessing support. It identifies a number of principles that underpin the work of IRISS and suggests how these facilitate innovative evidence-informed practice. The approach to evidence-informed practice comprises four pillars of activity. The first pillar focuses on improving awareness and access to evidence and is exemplified by the Learning Exchange, the IRISS Insights series, and audio and video recording. The second pillar refers to strengthening the evidence base and is discussed in the context of work on self-directed support. Improving skills and confidence to use evidence forms the third pillar and is represented by work on data visualisation and peer support for self-evaluation. The final pillar is embedding evidence in organisations, through co-production, creating spaces to test and challenge evidence, and through the development of evidence-based products. Supporting people to share knowledge, learn from each other and to collectively produce new knowledge and solutions is an innovative approach but also one which should be cost-effective. Pre-print. Published in Evidence and Policy, 2014 (10)4 as Embedding research into practice through innovation and creativity: a case study from social services

Side Effects
di: fantasynight

Let’s face it—traditional security training can feel as thrilling as reading the fine print on a software update. It’s routine, predictable, and, let’s be honest, often forgotten the moment it's over. Now, imagine cybersecurity training that’s as unforgettable as your favorite show. Remember how "Hamilton" made history come alive, or how "The Office" taught us CPR (Staying Alive beat, anyone?)?

I completed Mass Effect 2 a couple of days ago for the first time. This article contains spoilers…

The claustrum seems to act as a switchboard, telling different parts of the brain when to turn on and off. But what happens when the switchboard operator steps away?

Warming temperatures are causing extreme weather patterns across the country. But communities are pushing back with solutions old and new.

Do you want more website visitors and customers? Of course you do! Then you need to learn how...

The post How to Write an Effective Call to Action appeared first on Ignition Media.

You’ve probably attended a webinar or two (or more), but are you using them effectively as part of your overall content plan? In this blog post, we teach you the basics of hosting a webinar and how to use them effectively as you build out your content strategy and grow your business.

Over the past decade, parent advocacy groups led a grassroots movement resulting in most states adopting dyslexia-specific legislation, with many states mandating the use of the Orton-Gillingham (OG) approach to reading instruction. Orton-Gillingham is a direct, explicit, multisensory, structured, sequential, diagnostic, and prescriptive approach to reading for students with or at risk for word-level reading disabilities (WLRD). Evidence from a prior synthesis and What Works Clearinghouse reports yielded findings lacking support for the effectiveness of OG interventions.

Michal Bassani-Sternberg
Mar 1, 2015; 14:658-673
Research

Mitsunori Fukuda
Jun 1, 2008; 7:1031-1042
Research

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

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

The trickle-up effect of rights-based climate litigation Expert comment NCapeling 16 November 2021

With governments failing in their pledges and companies accused of ‘green-washing’, human rights-based litigation is increasingly important for accountability.

Tuvalu’s foreign minister addressing COP26 while standing knee-deep in seawater was a stark illustration of how the climate emergency directly and imminently threatens the most basic human rights protected under international law – including to the right to life, self-determination and cultural rights.

Human rights are now a fundamental component of more than 90 per cent of the climate litigation currently taking place outside the US, highlighting the international reach of human rights law and how its emphasis on protecting the most vulnerable helps diverse communities find common arguments for shared goals.

Cases are set to continue and to evolve but three types of claim are emerging, each of which is examined in a new Chatham House briefing paper.

1. Enforcing commitments

One category of cases seeks to hold states accountable for pledges they have made on climate change, such as emission reduction targets made under the framework of the 2015 Paris Agreement. Drawing on human rights obligations, governments can be charged with not taking sufficient steps to implement these pledges.

The case of Leghari v Pakistan (2015) concerned the government’s failure to carry out the National Climate Change Policy of 2012 and the Framework for Implementation of Climate Change Policy (2014-2030). The Lahore High Court held that several of the human rights enshrined in Pakistan’s constitution cover climate change and ‘provide the necessary judicial toolkit to address the government’s response to climate change’.

The court ordered the government to carry out measures such as publishing an adaptation action plan realizable within a few months of the order and establishing a Climate Change Commission to monitor progress.

2. Positive duties to mitigate risks

Many rights-based climate cases are being brought to clarify the scope of states’ positive duties under human rights law to take meaningful steps to protect their citizens against foreseeable risks to life and other rights.

This ‘trickle-up’ effect of human rights was prominent in the case of State of the Netherlands vs the Urgenda Foundation (2019) where the Dutch Supreme Court held that reducing emissions with the highest possible level of ambition amounts to a ‘due diligence standard’ for states to comply with their positive duties to adopt adequate measures to address climate change. Human rights law was also used by the court to fill in the content of the due diligence standards.

There is also a growing trend for rights-based actions to be brought against corporations, such as a recent case which drew on the UN Guiding Principles on Business and Human Rights to define the parameters of Shell’s duty of care and due diligence obligations in relation to carbon emissions under Dutch law. The court ordered Shell to reduce emissions by a net rate of 45 per cent by the end of 2030 – relative to 2019 figures – through its group corporate policy.

3. Avoiding harm in climate action

The global human rights regime is also increasingly invoked in litigation concerning states’ negative obligations to ensure that their climate mitigation and adaptation activities do not themselves contribute to human rights violations (including discrimination) and that states prioritize adaptation measures for those most at risk in a just and equitable way.

As Chatham House’s paper makes clear, this kind of litigation ‘puts pressure on governments to expand their approach to tackling climate change beyond purely a regulatory one to a more holistic strategy’.

Closing the climate justice gap

Climate and environmental litigation grounded in human rights is set to continue given the overwhelming scientific evidence of risks associated with human-induced climate change and the limited confidence in pledges made by states and corporations alike – including those made recently at COP26.

A growing collaboration between civil society organizations and vulnerable communities in relation to both the protection of nature and the enjoyment of their land and cultural rights was evident at COP26, and this alliance will add further momentum to the trend for rights-based climate litigation based on the rights of indigenous and other vulnerable communities, especially on issues such as deforestation.

But more challenges are coming. International human rights law recognizes a duty of international cooperation but there remain significant hurdles for climate-vulnerable communities in developing countries to compel action by richer nations despite the vast debts of ‘carbon colonialism.’

One big issue is the problem of extraterritoriality, as the extent to which states owe obligations to individuals outside their territory is contested. Courts in both Germany and the Netherlands have rejected claimants from developing countries in domestic class actions on this basis. But a recent decision of the UN Committee on the Rights of the Child on a complaint brought by Greta Thunberg and other youth activists against five countries opens the door for further litigation.

One of a number of cases being brought by youth claimants across the world, the committee concluded that a state’s human rights duties can – in some instances – extend to children in other countries. This includes any activities on the territory that host states have the power to prevent from causing ‘transboundary harm’ – such as emissions from the territory – where these activities ‘significantly’ impact the enjoyment of human rights of persons outside the territory.

To date, high-profile rights-based cases have argued for policy change and stronger targets underpinned by binding legislation responsive to the science. Claims are set to become more complex and contested. Building on scientific developments in climate attribution, rights-based litigation is now tackling other difficult questions such as apportioning responsibility and remedial action.

These cases examine both historically high emitters and the public and private actors who either continue specific activities or refrains from action in the face of the overwhelming science linking human activities such as extraction and burning of fossil fuels to deforestation and climatic consequences.

Courts are also likely to explore the duties that states and corporations owe to deliver a ‘just transition’ away from carbon-intensive industries, given the benefits of growth and climate action are already unevenly distributed.

A holistic human-rights based approach

Several states together with civil society are leading the charge for global recognition of the right to a healthy, clean, and sustainable environment in the United Nations (UN) Human Rights Council, and multi-stakeholder processes are defining what effective corporate due diligence looks like.

In addition, UN-appointed special rapporteurs are delivering practical guidance on how to devise solutions which are fair, non-discriminatory, participatory, and climate-resilient without exacerbating inequality – including difficult issues of planned relocation – and UN Human Rights Treaty Bodies are unpacking the duty of international cooperation to act in good faith to address loss and damage.

Recently the Committee on the Elimination of Discrimination Against Women recommended the Marshall Islands, in order to meet its duty to its citizens, should actively seek international cooperation and assistance – including climate change financing – from other countries but in particular the US, whose ‘extraterritorial nuclear testing activities have exacerbated the adverse effects of climate change and natural disasters’ in the islands.

Pierre Lairez, Eric Pichon-Pharabod and Pierre Vanhove
Math. Comp. 93 (), 2985-3025.
Abstract, references and article information

Laura F Fielden
Nov 11, 2020; 0:RA120.002370v1-mcp.RA120.002370
Research

Diana Samodova
Dec 1, 2020; 19:2139-2156
Technological Innovation and Resources

Akemi Kakino
Nov 3, 2020; 0:jlr.RA120000767v1-jlr.RA120000767
Research Articles

The cornea is densely innervated, mainly by sensory nerves of the ophthalmic branch of the trigeminal ganglia (TG). These nerves  are important to maintain corneal homeostasis, and nerve damage can lead to a decrease in wound healing, an increase in corneal ulceration and dry eye disease (DED), and neuropathic pain. Pathologies, such as diabetes, aging, viral and bacterial infection, as well as  prolonged use of contact lenses and surgeries to correct vision can produce nerve damage. There are no effective therapies to alleviate DED (a multifunctional disease) and several clinical trials using -3 supplementation show unclear and sometimes negative results. Using animal models of corneal nerve damage, we show that treating corneas with pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) increases nerve regeneration, wound healing, and tear secretion. The mechanism involves the activation of a calcium-independent phospholipase A2 (iPLA2) that releases the incorporated DHA from phospholipids and enhances the synthesis of docosanoids neuroprotectin D1 (NPD1) and a new resolvin stereoisomer  RvD6i. NPD1 stimulates the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and of semaphorin 7A (Sema7A).  RvD6i treatment of injured corneas modulates gene expression in the TG resulting in enhanced neurogenesis; decreased neuropathic pain and increased sensitivity. Taken together, these results represent a promising therapeutic option to re-establish the homeostasis of the cornea.

Adiponectin, an adipocyte-derived protein, has anti-atherogenic and anti-diabetic effects, but how it confers the anti-atherogenic effects is not well understood. To study the anti-atherogenic mechanisms of adiponectin, we examined whether it interacts with atherogenic low-density lipoprotein (LDL) to attenuate LDL’s atherogenicity. L5, the most electronegative subfraction of LDL, induces atherogenic responses similarly to copper-oxidized LDL (oxLDL). Unlike native LDL endocytosed via the LDL receptor, L5 and oxLDL are internalized by cells via the lectin-like oxidized LDL receptor-1 (LOX-1). Using enzyme-linked immunosorbent assays (ELISAs), we showed that adiponectin preferentially bound oxLDL but not native LDL. In Chinese hamster ovary (CHO) cells transfected with LOX-1 or LDL receptor, adiponectin selectively inhibited the uptake of oxLDL but not of native LDL, respectively. Furthermore, adiponectin suppressed the internalization of oxLDL in human coronary artery endothelial cells (HCAECs) and THP-1–derived macrophages. Western blot analysis of human plasma showed that adiponectin was abundant in L5 but not in L1, the least electronegative subfraction of LDL. Sandwich ELISAs with anti-adiponectin and anti–apolipoprotein B antibodies confirmed the binding of adiponectin to L5 and oxLDL. In LOX-1–expressing CHO cells, adiponectin inhibited cellular responses to oxLDL and L5, including nuclear factor-B activation and ERK phosphorylation. In HCAECs, adiponectin inhibited oxLDL-induced endothelin-1 secretion and ERK phosphorylation. Conversely, oxLDL suppressed the adiponectin-induced activation of adenosine monophosphate–activated protein kinase in COS-7 cells expressing adiponectin receptor AdipoR1. Our findings suggest that adiponectin binds and inactivates atherogenic LDL, providing novel insight into the anti-atherogenic mechanisms of adiponectin.

The divalent anion sodium symporter (DASS) family (SLC13) plays critical roles in metabolic homeostasis, influencing many processes, including fatty acid synthesis, insulin resistance, and adiposity. DASS transporters catalyze the Na+-driven concentrative uptake of Krebs cycle intermediates and sulfate into cells; disrupting their function can protect against age-related metabolic diseases and can extend lifespan. An inward-facing crystal structure and an outward-facing model of a bacterial DASS family member, VcINDY from Vibrio cholerae, predict an elevator-like transport mechanism involving a large rigid body movement of the substrate-binding site. How substrate binding influences the conformational state of VcINDY is currently unknown. Here, we probe the interaction between substrate binding and protein conformation by monitoring substrate-induced solvent accessibility changes of broadly distributed positions in VcINDY using a site-specific alkylation strategy. Our findings reveal that accessibility to all positions tested is modulated by the presence of substrates, with the majority becoming less accessible in the presence of saturating concentrations of both Na+ and succinate. We also observe separable effects of Na+ and succinate binding at several positions suggesting distinct effects of the two substrates. Furthermore, accessibility changes to a solely succinate-sensitive position suggests that substrate binding is a low-affinity, ordered process. Mapping these accessibility changes onto the structures of VcINDY suggests that Na+ binding drives the transporter into an as-yet-unidentified conformational state, involving rearrangement of the substrate-binding site–associated re-entrant hairpin loops. These findings provide insight into the mechanism of VcINDY, which is currently the only structurally characterized representative of the entire DASS family.

Trypsin is the protease of choice in bottom-up proteomics. However, its application can be limited by the amino acid composition of target proteins and the pH of the digestion solution. In this study we characterize ProAlanase, a protease from the fungus Aspergillus niger that cleaves primarily on the C-terminal side of proline and alanine residues. ProAlanase achieves high proteolytic activity and specificity when digestion is carried out at acidic pH (1.5) for relatively short (2 h) time periods. To elucidate the potential of ProAlanase in proteomics applications, we conducted a series of investigations comprising comparative multi-enzymatic profiling of a human cell line proteome, histone PTM analysis, ancient bone protein identification, phosphosite mapping and de novo sequencing of a proline-rich protein and disulfide bond mapping in mAb. The results demonstrate that ProAlanase is highly suitable for proteomics analysis of the arginine- and lysine-rich histones, enabling high sequence coverage of multiple histone family members. It also facilitates an efficient digestion of bone collagen thanks to the cleavage at the C terminus of hydroxyproline which is highly prevalent in collagen. This allows to identify complementary proteins in ProAlanase- and trypsin-digested ancient bone samples, as well as to increase sequence coverage of noncollagenous proteins. Moreover, digestion with ProAlanase improves protein sequence coverage and phosphosite localization for the proline-rich protein Notch3 intracellular domain (N3ICD). Furthermore, we achieve a nearly complete coverage of N3ICD protein by de novo sequencing using the combination of ProAlanase and tryptic peptides. Finally, we demonstrate that ProAlanase is efficient in disulfide bond mapping, showing high coverage of disulfide-containing regions in a nonreduced mAb.

Thermal proteome profiling (TPP) allows for the unbiased detection of drug – target protein engagements in vivo. Traditionally, one cell type is used for TPP studies, with the risk of missing important differentially expressed target proteins. The use of whole organisms would circumvent this problem. Zebrafish embryos are amenable to such an approach. Here, we used TPP on whole zebrafish embryo lysate to identify protein targets of napabucasin, a compound that may affect Signal transducer and activator of transcription 3 (Stat3) signaling through an ill-understood mechanism. In zebrafish embryos, napabucasin induced developmental defects consistent with inhibition of Stat3 signaling. TPP profiling showed no distinct shift in Stat3 upon napabucasin treatment, but effects were detected on the oxidoreductase, Pora, which might explain effects on Stat3 signaling. Interestingly, thermal stability of several aldehyde dehydrogenases (Aldhs) was affected. Moreover, napabucasin activated ALDH enzymatic activity in vitro. Aldhs have crucial roles in retinoic acid metabolism and functionally we validated napabucasin-mediated activation of the retinoic acid pathway in zebrafish in vivo. We conclude that TPP profiling in whole zebrafish embryo lysate is feasible and facilitates direct correlation of in vivo effects of small molecule drugs with their protein targets.

Modulation of the host cell is integral to the survival and replication of microbial pathogens. Several intracellular bacterial pathogens deliver bacterial proteins, termed ‘effector proteins’ into the host cell during infection by sophisticated protein translocation systems, which manipulate cellular processes and functions. The functional contribution of individual effectors is poorly characterised, particularly in intracellular bacterial pathogens with large effector protein repertoires. Technical caveats have limited the capacity to study these proteins during a native infection, with many effector proteins having only been demonstrated to be translocated during over-expression of tagged versions. Here we developed a novel strategy to examine effector proteins in the context of infection. We coupled a broad, unbiased proteomics-based screen with organelle purification to study the host-pathogen interactions occurring between the host cell mitochondrion and the Gram-negative, Q fever pathogen Coxiella burnetii. We identify 4 novel mitochondrially-targeted C. burnetii effector proteins, renamed Mitochondrial Coxiella effector protein (Mce) B to E. Examination of the subcellular localisation of ectopically expressed proteins confirmed their mitochondrial localisation, demonstrating the robustness of our approach. Subsequent biochemical analysis and affinity enrichment proteomics of one of these effector proteins, MceC, revealed the protein localises to the inner membrane and can interact with components of the mitochondrial quality control machinery. Our study adapts high-sensitivity proteomics to study intracellular host-pathogen interactions, providing a robust strategy to examine the sub-cellular localisation of effector proteins during native infection. This approach could be applied to a range of pathogens and host cell compartments to provide a rich map of effector dynamics throughout infection.

The U.S. Food and Drug Administration has determined commonly used oral phenylephrine is "not effective" and has proposed its removal from over-the-counter nasal decongestants.

The U.S. Food and Drug Administration has determined commonly used oral phenylephrine is "not effective" and has proposed its removal from over-the-counter nasal decongestants.

The therapy helps the brain work more efficiently and lifts depression.

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?.

Two infectious disease experts weigh in on how a COVID-19 vaccine that’s 90 percent effective, as early results are showing, could change school health and safety protocols.

The principal of a school in Washington, DC, describes a shift toward equity, diversity, and inclusion.

Yasmin L. Hurd
Oct 16, 2019; 39:8250-8258
Symposium and Mini-Symposium

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.

Key event-related potentials (ERPs) of perceptual decision-making such as centroparietal positivity (CPP) elucidate how evidence is accumulated toward a given choice. Furthermore, this accumulation can be impacted by visual target selection signals such as the N2 contralateral (N2c). How these underlying neural mechanisms of perceptual decision-making are influenced by the spatial congruence of distractors relative to target stimuli remains unclear. Here, we used electroencephalography (EEG) in humans of both sexes to investigate the effect of distractor spatial congruency (same vs different hemifield relative to targets) on perceptual decision-making. We confirmed that responses for perceptual decisions were slower for spatially incongruent versus congruent distractors of high salience. Similarly, markers of target selection (N2c peak amplitude) and evidence accumulation (CPP slope) were found to be lower when distractors were spatially incongruent versus congruent. To evaluate the effects of congruency further, we applied drift diffusion modeling to participant responses, which showed that larger amplitudes of both ERPs were correlated with shorter nondecision times when considering the effect of congruency. The modeling also suggested that congruency's effect on behavior occurred prior to and during evidence accumulation when considering the effects of the N2c peak and CPP slope. These findings point to spatially incongruent distractors, relative to congruent distractors, influencing decisions as early as the initial sensory processing phase and then continuing to exert an effect as evidence is accumulated throughout the decision-making process. Overall, our findings highlight how key electrophysiological signals of perceptual decision-making are influenced by the spatial congruence of target and distractor.

Washington, 15 September 2016 - The recent entry into force of a ground-breaking international accord on illegal fishing is a welcome development but it now requires "strong and effective implementation", FAO [...]

Sharing Information Between Design and Production Eliminates Budget Overruns That Erode Customers’ Profits