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.

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.

S-Acylation, the reversible post-translational lipid modification of proteins, is an important mechanism to control the properties and function of ion channels and other polytopic transmembrane proteins. However, although increasing evidence reveals the role of diverse acyl protein transferases (zDHHC) in controlling ion channel S-acylation, the acyl protein thioesterases that control ion channel deacylation are very poorly defined. Here we show that ABHD17a (α/β-hydrolase domain-containing protein 17a) deacylates the stress-regulated exon domain of large conductance voltage- and calcium-activated potassium (BK) channels inhibiting channel activity independently of effects on channel surface expression. Importantly, ABHD17a deacylates BK channels in a site-specific manner because it has no effect on the S-acylated S0–S1 domain conserved in all BK channels that controls membrane trafficking and is deacylated by the acyl protein thioesterase Lypla1. Thus, distinct S-acylated domains in the same polytopic transmembrane protein can be regulated by different acyl protein thioesterases revealing mechanisms for generating both specificity and diversity for these important enzymes to control the properties and functions of ion channels.

Mass spectrometry has become an indispensable tool for the characterization of glycosylation across biological systems. Our ability to generate rich fragmentation of glycopeptides has dramatically improved over the last decade yet our informatic approaches still lag behind. Although glycoproteomic informatics approaches using glycan databases have attracted considerable attention, database independent approaches have not. This has significantly limited high throughput studies of unusual or atypical glycosylation events such as those observed in bacteria. As such, computational approaches to examine bacterial glycosylation and identify chemically diverse glycans are desperately needed. Here we describe the use of wide-tolerance (up to 2000 Da) open searching as a means to rapidly examine bacterial glycoproteomes. We benchmarked this approach using N-linked glycopeptides of Campylobacter fetus subsp. fetus as well as O-linked glycopeptides of Acinetobacter baumannii and Burkholderia cenocepacia revealing glycopeptides modified with a range of glycans can be readily identified without defining the glycan masses before database searching. Using this approach, we demonstrate how wide tolerance searching can be used to compare glycan use across bacterial species by examining the glycoproteomes of eight Burkholderia species (B. pseudomallei; B. multivorans; B. dolosa; B. humptydooensis; B. ubonensis, B. anthina; B. diffusa; B. pseudomultivorans). Finally, we demonstrate how open searching enables the identification of low frequency glycoforms based on shared modified peptides sequences. Combined, these results show that open searching is a robust computational approach for the determination of glycan diversity within bacterial proteomes.

Influenza A virus (IAV) mutates rapidly, resulting in antigenic drift and poor year-to-year vaccine effectiveness. One challenge in designing effective vaccines is that genetic mutations frequently cause amino acid variations in IAV envelope protein hemagglutinin (HA) that create new N-glycosylation sequons; resulting N-glycans cause antigenic shielding, allowing viral escape from adaptive immune responses. Vaccine candidate strain selection currently involves correlating antigenicity with HA protein sequence among circulating strains, but quantitative comparison of site-specific glycosylation information may likely improve the ability to design vaccines with broader effectiveness against evolving strains. However, there is poor understanding of the influence of glycosylation on immunodominance, antigenicity, and immunogenicity of HA, and there are no well-tested methods for comparing glycosylation similarity among virus samples. Here, we present a method for statistically rigorous quantification of similarity between two related virus strains that considers the presence and abundance of glycopeptide glycoforms. We demonstrate the strength of our approach by determining that there was a quantifiable difference in glycosylation at the protein level between WT IAV HA from A/Switzerland/9715293/2013 (SWZ13) and a mutant strain of SWZ13, even though no N-glycosylation sequons were changed. We determined site-specifically that WT and mutant HA have varying similarity at the glycosylation sites of the head domain, reflecting competing pressures to evade host immune response while retaining viral fitness. To our knowledge, our results are the first to quantify changes in glycosylation state that occur in related proteins of considerable glycan heterogeneity. Our results provide a method for understanding how changes in glycosylation state are correlated with variations in protein sequence, which is necessary for improving IAV vaccine strain selection. Understanding glycosylation will be especially important as we find new expression vectors for vaccine production, as glycosylation state depends greatly on the host species.

Communication between individuals via molecules, termed chemosignaling, is widespread among animal and plant species. However, we lack knowledge on the specific functions of the substances involved for most systems. The femoral gland is an organ that secretes a waxy substance involved in chemical communication in lizards. Although the lipids and volatile substances secreted by the femoral glands have been investigated in several biochemical studies, the protein composition and functions of secretions remain completely unknown. Applying a proteomic approach, we provide the first attempt to comprehensively characterize the protein composition of femoral gland secretions from the Galápagos marine iguana. Using samples from several organs, the marine iguana proteome was assembled by next-generation sequencing and MS, resulting in 7513 proteins. Of these, 4305 proteins were present in the femoral gland, including keratins, small serum proteins, and fatty acid-binding proteins. Surprisingly, no proteins with discernible roles in partner recognition or inter-species communication could be identified. However, we did find several proteins with direct associations to the innate immune system, including lysozyme C, antileukoproteinase (ALP), pulmonary surfactant protein (SFTPD), and galectin (LGALS1) suggesting that the femoral glands function as an important barrier to infection. Furthermore, we report several novel anti-microbial peptides from the femoral glands that show similar action against Escherichia coli and Bacillus subtilis such as oncocin, a peptide known for its effectiveness against Gram-negative pathogens. This proteomics data set is a valuable resource for future functional protein analysis and demonstrates that femoral gland secretions also perform functions of the innate immune system.

Synaptic transmission leading to release of neurotransmitters in the nervous system is a fast and highly dynamic process. Previously, protein interaction and phosphorylation have been thought to be the main regulators of synaptic transmission. Here we show that sialylation of N-linked glycosylation is a novel potential modulator of neurotransmitter release mechanisms by investigating depolarization-dependent changes of formerly sialylated N-linked glycopeptides. We suggest that negatively charged sialic acids can be modulated, similarly to phosphorylation, by the action of sialyltransferases and sialidases thereby changing local structure and function of membrane glycoproteins. We characterized site-specific alteration in sialylation on N-linked glycoproteins in isolated rat nerve terminals after brief depolarization using quantitative sialiomics. We identified 1965 formerly sialylated N-linked glycosites in synaptic proteins and found that the abundances of 430 glycosites changed after 5 s depolarization. We observed changes on essential synaptic proteins such as synaptic vesicle proteins, ion channels and transporters, neurotransmitter receptors and cell adhesion molecules. This study is to our knowledge the first to describe ultra-fast site-specific modulation of the sialiome after brief stimulation of a biological system.

Tandem mass tag (TMT) is a multiplexing technology widely-used in proteomic research. It enables relative quantification of proteins from multiple biological samples in a single MS run with high efficiency and high throughput. However, experiments often require more biological replicates or conditions than can be accommodated by a single run, and involve multiple TMT mixtures and multiple runs. Such larger-scale experiments combine sources of biological and technical variation in patterns that are complex, unique to TMT-based workflows, and challenging for the downstream statistical analysis. These patterns cannot be adequately characterized by statistical methods designed for other technologies, such as label-free proteomics or transcriptomics. This manuscript proposes a general statistical approach for relative protein quantification in MS- based experiments with TMT labeling. It is applicable to experiments with multiple conditions, multiple biological replicate runs and multiple technical replicate runs, and unbalanced designs. It is based on a flexible family of linear mixed-effects models that handle complex patterns of technical artifacts and missing values. The approach is implemented in MSstatsTMT, a freely available open-source R/Bioconductor package compatible with data processing tools such as Proteome Discoverer, MaxQuant, OpenMS, and SpectroMine. Evaluation on a controlled mixture, simulated datasets, and three biological investigations with diverse designs demonstrated that MSstatsTMT balanced the sensitivity and the specificity of detecting differentially abundant proteins, in large-scale experiments with multiple biological mixtures.

We performed an in-depth characterization and comparison of the pediatric and adult urinary glycomes using a nanoLC-MS/MS based glycomics method, which included normal healthy pediatric (1–10 years, n = 21) and adult (21–50 years, n = 22) individuals. A total of 116 N-glycan compositions were identified, and 46 of them could be reproducibly quantified. We performed quantitative comparisons of the 46 glycan compositions between different age and sex groups. The results showed significant quantitative changes between the pediatric and adult cohorts. The pediatric urinary N-glycome was found to contain a higher level of high-mannose (HM), asialylated/afucosylated glycans (excluding HM), neutral fucosylated and agalactosylated glycans, and a lower level of trisialylated glycans compared with the adult. We further analyzed gender-associated glycan changes in the pediatric and adult group, respectively. In the pediatric group, there was almost no difference of glycan levels between males and females. In adult, the majority of glycans were more abundant in males than females, except the high-mannose and tetrasialylated glycans. These findings highlight the importance to consider age-matching and adult sex-matching for urinary glycan studies. The identified normal pediatric and adult urinary glycomes can serve as a baseline reference for comparisons to other disease states affected by glycosylation.

Over the past decade, modern methods of MS (MS) have emerged that allow reliable, fast and cost-effective identification of pathogenic microorganisms. Although MALDI-TOF MS has already revolutionized the way microorganisms are identified, recent years have witnessed also substantial progress in the development of liquid chromatography (LC)-MS based proteomics for microbiological applications. For example, LC-tandem MS (LC-MS²) has been proposed for microbial characterization by means of multiple discriminative peptides that enable identification at the species, or sometimes at the strain level. However, such investigations can be laborious and time-consuming, especially if the experimental LC-MS² data are tested against sequence databases covering a broad panel of different microbiological taxa. In this proof of concept study, we present an alternative bottom-up proteomics method for microbial identification. The proposed approach involves efficient extraction of proteins from cultivated microbial cells, digestion by trypsin and LC–MS measurements. Peptide masses are then extracted from MS¹ data and systematically tested against an in silico library of all possible peptide mass data compiled in-house. The library has been computed from the UniProt Knowledgebase covering Swiss-Prot and TrEMBL databases and comprises more than 12,000 strain-specific in silico profiles, each containing tens of thousands of peptide mass entries. Identification analysis involves computation of score values derived from correlation coefficients between experimental and strain-specific in silico peptide mass profiles and compilation of score ranking lists. The taxonomic positions of the microbial samples are then determined by using the best-matching database entries. The suggested method is computationally efficient – less than 2 mins per sample - and has been successfully tested by a test set of 39 LC-MS¹ peak lists obtained from 19 different microbial pathogens. The proposed method is rapid, simple and automatable and we foresee wide application potential for future microbiological applications.

Complex protein glycosylation occurs through biosynthetic steps in the secretory pathway that create macro- and microheterogeneity of structure and function.  Required for all life forms, glycosylation diversifies and adapts protein interactions with binding partners that underpin interactions at cell surfaces and pericellular and extracellular environments. Because these biological effects arise from heterogeneity of structure and function, it is necessary to measure their changes as part of the quest to understand nature.  Quite often, however, the assumption behind proteomics that post-translational modifications are discrete additions that can be modeled using the genome as a template does not apply to protein glycosylation.  Rather, it is necessary to quantify the glycosylation distribution at each glycosite and to aggregate this information into a population of mature glycoproteins that exist in a given biological system.  To date, mass spectrometric methods for assigning singly glycosylated peptides are well-established.  But it is necessary to quantify glycosylation heterogeneity accurately in order to gauge the alterations that occur during biological processes.  The task is to quantify the glycosylated peptide forms as accurately as possible and then apply appropriate bioinformatics algorithms to the calculation of micro- and macro-similarities.  In this review, we summarize current approaches for protein quantification as they apply to this glycoprotein similarity problem.

Malaria elimination is still pending on the development of novel tools that rely on a deep understanding of parasite biology. Proteins of all living cells undergo a myriad number of posttranslational modifications (PTMs) that are critical to multifarious life processes. An extensive proteome-wide dissection revealed a fine PTM map of most proteins in both Plasmodium falciparum, the causative agent of severe malaria, and the infected red blood cells. More than two-thirds of proteins of the parasite and its host cell underwent extensive and dynamic modification throughout the erythrocytic developmental stage. PTMs critically modulate the virulence factors involved in the host-parasite interaction and pathogenesis. Furthermore, P. falciparum stabilized the supporting proteins of erythrocyte origin by selective de-modification. Collectively, our multiple omic analyses, apart from having furthered a deep understanding of the systems biology of P. falciparum and malaria pathogenesis, provide a valuable resource for mining new antimalarial targets.

Open searching has proven to be an effective strategy for identifying both known and unknown modifications in shotgun proteomics experiments. Rather than being limited to a small set of user-specified modifications, open searches identify peptides with any mass shift that may correspond to a single modification or a combination of several modifications. Here we present PTM-Shepherd, a bioinformatics tool that automates characterization of PTM profiles detected in open searches based on attributes such as amino acid localization, fragmentation spectra similarity, retention time shifts, and relative modification rates. PTM-Shepherd can also perform multi-experiment comparisons for studying changes in modification profiles, e.g. in data generated in different laboratories or under different conditions. We demonstrate how PTM-Shepherd improves the analysis of data from formalin-fixed paraffin-embedded samples, detects extreme underalkylation of cysteine in some datasets, discovers an artefactual modification introduced during peptide synthesis, and uncovers site-specific biases in sample preparation artifacts in a multi-center proteomics profiling study.

The Costs of Fuelling Humanitarian Aid Research paper sysadmin 7 December 2018

As humanitarian crises become more protracted and aid budgets face unprecedented scrutiny, agencies could save millions by switching from diesel and oil fuels to cleaner energy sources.

Download the accompanying toolkit

Most refugee and internal displacement camps are in remote locations, so humanitarian agencies consume large amounts of fuel on the transport of staff, equipment, and goods such as food and water.

Operations tend to rely on on-site electricity generation to power reception centres, clinics, schools, food storage, water-pumping and street lighting. Despite the essential role of energy in humanitarian action, and the UN’s stated commitment to carbon neutrality by 2020, there is no concerted effort to move away from fossil fuel to date.

Summary points

• Agencies are paying too much for the energy they consume. They are overwhelmingly dependent on oil fuel for electricity generation, even though renewable energy solutions are reducing costs for those deploying them in similar conditions. Well-below-optimum standards of efficiency in buildings, generator use and fleet management are also the norm.
• Agencies typically have few incentives to do things better. There is rarely motivation to conserve fuel, nor performance indicators for energy or fuel use. In addition, energy spending and use lacks transparency.
• Few agencies collect and report on energy use. Where numbers are available, they are usually partial and unverified. Energy costs are rarely transparent in budgets; and donors do not know how much is being spent.
• We estimate that around 5 per cent of humanitarian agencies’ expenditure goes on diesel, petrol and associated costs such as fixing generators. That would mean that the sector spent some $1.2 billion on polluting fuel in 2017.
• Based on current best-practice, the sector could save at least 10 per cent of fuel costs on ground transport, 37 per cent through behaviour change and more efficient technologies, and 60 per cent on generation – all using currently available, affordable and proven practice and technology changes.
• At current prices, this could mean operational savings of over $517 million a year for the humanitarian sector, roughly equal to 5 per cent of UNHCR’s funding gap for 2017.
• In Kenya, annual spending on diesel and petrol for the seven agencies surveyed was $6.7 million in 2017. Replacing gensets with solar systems could create significant savings due the costs of diesel, the likelihood of protracted camp situations, and the opportunities that off-grid solar would offer for extending electricity access to refugees and local populations in Garissa and Turkana counties.
• In Jordan, solar energy now powers the majority of camp facilities and many households. However, the use of grid electricity by humanitarian agencies’ large head offices in Amman remains high and expensive. Improving the energy efficiency of buildings is a priority for savings.
• In Burkina Faso’s Goudoubo camp, NGO offices are desperately short of power – they have no computers or air-conditioning. Investment in renewable forms of energy for this and other camp services such as street lighting and water pumping would enable better service provision, and could drive increased rural energy access among host populations across this area of the Sahel.

Toolkit

An accompanying toolkit, Powering Ahead: Improving How We Use and Account for Energy in Humanitarian Operations, provides practical guidance for humanitarian agencies that want to make energy cost savings and reduce their carbon and emissions footprint.

Innovative Financing for Humanitarian Energy Interventions Research paper sysadmin 28 February 2019

This paper explores the increase in resources and funding needed to improve the access of displaced people to modern and sustainable energy services.

Summary

• In settings that host displaced and refugee communities, energy can act as an enabler for improved healthcare, education and access to clean water. More efficient sources of energy can also save money that can be reinvested in life-saving interventions. A range of challenges exist that inhibit the uptake and effective management of cleaner energy solutions in displacement settings. These are magnified by a lack of available and appropriate funding.
• The current funding gap is significant. In many cases, involving the private sector (both enterprises and investors) is viewed as a way to accelerate delivery of sustainable energy solutions, leverage additional capital, efficiency and expertise, and adopt more sustainable and market-based approaches.
• Displacement settings are an extreme example of complex and unpredictable operating environments. Traditional approaches to the financing of energy access will not be supported by the risk/return characteristics of this market opportunity, so alternative structures are needed.
• Such structures can include mechanisms such as grants, guarantees, ‘results-based financing’ and ‘impact bonds’. These blended financial instruments should aim to leverage first losses – whereby, in the case of default, the first loss is taken by the ‘impact-first’ investors, or guarantors, thereby fully or partially protecting ‘finance-first’ investors.
• Given the specific constraints of displacement settings, any financing mechanisms at present are likely to fall between the categories of providing ‘more efficient aid’ and ‘more efficient aid through markets’. They are likely to constitute a transitional step from grant-making towards the use of commercial investment vehicles.
• While a number of financial mechanisms could be applied to attract private-sector engagement, most remain theoretical, with few being implemented extensively or at scale. Where such financial mechanisms have already been used, access to relevant data is poor, especially in circumstances where the desired outcomes were not achieved.
• The Moving Energy Initiative (MEI) completed feasibility work into the concept of an energy humanitarian fund and found that, while a need for this type of facility has emerged, it sits in a difficult position between energy access, climate and humanitarian funding sources. Key donors are needed to drive forward innovative financing vehicles and further testing of these mechanisms, in order to generate market data and evidence for further iterations and additional investments.

South Africa's Land Reform Quandary: Scenarios and Policy 10 July 2018 — 10:00AM TO 11:00AM Anonymous (not verified) 13 June 2018 Chatham House, London

Slow delivery on expectations of land redistribution in South Africa has once again put the issue at the forefront of political debate in the country. A parliamentary public consultation process will consider whether constitutional change is required to accelerate expropriation without compensation. Policymakers face dual - often opposing - pressures due to investors’ fears of negative economic impacts as well as citizens’ frustrations over persistent inequality and hardship. State land and tribal trust land remain contentious issues for rural economic development, but with two thirds of the population now living in urban areas policy responses must be as cognizant of the country’s future as it is of its past.

At this meeting, Terence Corrigan, project manager at the South African Institute of Race Relations, will discuss the current debates on expropriation and present the institute’s latest research on future scenarios of land reform in South Africa.

Attendance at this event is by invitation only.

Mine Action in Angola: Clearing the Legacies of Conflict to Harness the Potential of Peace Other resource sysadmin 14 June 2019

This publication draws on and updates the briefing note published following a meeting of the All- Party Parliamentary Group (APPG) on Angola on 26 April 2017. It also incorporates insights from a Chatham House Africa Programme conference session on the legacies of the Angolan Civil War, held on 23 March 2018; and draws on the Africa Programme’s research into conservation-driven development models in Southern Africa.

Almost two decades after the end of its civil war, Angola remains one of the most heavily landmine-contaminated countries in the world. The Angolan government has committed to clearing its landmines by 2025, and there is constructive collaboration between the government and mine clearing agencies in this endeavour, but the target will be achievable only if a decline in funding from international donors is reversed. International funding for mine clearance in Angola fell by more than 80 per cent between 2005 and 2017, and this sharp drop in external support has compounded the impact on domestic funding for national clearance efforts as a result of the downturn in prices for Angola’s main export commodities.

The national mine action agency, the Comissão Nacional Intersectorial de Desminagem e Assistência Humanitária (CNIDAH), is supported by the Mines Advisory Group (MAG), Norwegian People’s Aid (NPA) and the HALO Trust. By 2017, 15 years after the end of the civil war, these organizations had collectively helped clear 56 per cent of known landmine-contaminated land. State-led demining has focused principally on clearing areas designated for infrastructure projects. Now, it is critical that humanitarian demining in largely agricultural and conservation areas is prioritized to bring to an end the daily threat to Angola’s rural poor – as well as to the country’s livestock and wildlife – of injury or death as a result of landmine accidents.

Angola has some of the world’s most important remaining wilderness, including the tributary system for the unique Okavango Delta, and the country has the potential to host one of the most diverse wildlife populations on the continent. However, the presence of landmines and other remnants of the civil war render large areas of the country unsafe both for wildlife and for the local people, whose ability to derive a sustainable livelihood from their natural environment is fundamental to its protection.

Wildlife and tourism provide important economic opportunities for diversification beyond an oil-dominated economy. Critically, Angola’s economic diversification and development objectives can only be achieved if the landmines that prohibit access to land for agriculture, mining, tourism and wildlife are cleared.

There are economic opportunities for released land in the most heavily mined provinces of Cuando Cubango and Moxico. Already, some new funding for mine action in Angola, if upscaled or matched by international donors, could be transformative for its people, and for the conservation of the region’s vital biodiversity.

Q&A: Maria Kolesnikova The World Today rescobales.drupal 29 September 2021

The jailed Belarusian opposition activist says: ‘It’s worth it’

Earlier this month, the Belarusian opposition activists, Maria Kolesnikova and Maxim Znak, were sentenced to long prison terms on charges of conspiring to seize power and crimes against national security. Both Kolesnikova, a prominent musician, and Znak, a lawyer, are supporters of Sviatlana Tsikhanouskaya, who ran against President Alexander Lukashenka in last year’s election and is now in exile in Lithuania. European Union countries have called for all political detainees, including Kolesnikova, to be released, but so far these calls have fallen on deaf ears. Alistair Burnett interviewed Maria Kolesnikova.

What is your response to the verdict and the 11-year sentence handed down to you?

My conscience is clear. We didn’t break the law. We followed the law at all the stages of the electoral campaign.

After the verdict, we applauded when the judges left the courtroom. They fulfilled their despicable role in this historical process – now this decision is on their conscience.

It is impossible to take the court and the verdict in any way seriously. This is not a verdict on Maxim and me but on the authorities themselves, on the system itself.

It is evidence not only of a legal default, but of a system-wide default. I feel sorry for those who did not understand what happened and did not learn history’s lessons.

Your trial was held behind closed doors and you were charged with conspiring to seize power and crimes against national security. What can you tell us about the prosecution’s case against you?

If there had been any evidence against us, the trial would have been open.

The very existence of accusations like this denies people the potential to participate in election campaigning and in political activity generally. It also prohibits public criticism of the authorities.

Such a judgment and verdict is a Pandora’s box with far-reaching negative consequences.

After the crackdown over last year’s protests and now your sentencing, what is the state of the opposition within Belarus?

I am in prison, so it is hard for me to judge objectively people’s attempts to fight for their freedom and basic human rights. According to what I see on TV, as well as the mood of those few people I have had a chance to talk to, I can say that the authorities are scared by the people’s activism.

They understand that though they can put down protests, they can’t change people’s mindsets. I see the fear in their eyes. I also believe that even those outside of Belarus can do a lot, and it’s important to continue opposition activity both inside and outside the country.

Sviatlana Tsikhanouskaya has been visiting European countries and the United States to maintain their support. Has international pressure, including from human rights groups, had any effect on the Lukashenka government?

I will use this opportunity to say hi to Sviatlana: ‘You are amazing. Keep it up.’

I’m sure Lukashenka is scared. He turned from a person who meets presidents to talk about Ukraine into an outcast no one wants to shake hands with.

It is traumatic for him, but the fear will pass. He will get used to it.

That is why it’s important to think about the next step, to understand what American and European partners are ready to offer Lukashenka in return for him to change course. If they aren’t ready to offer him anything – it’s important to know how long they are ready to maintain the pressure.

It concerns Russia as well. Maybe they simply don’t understand that Lukashenka and his government are in a bad way.

To what extent do you believe the futures of the Lukashenka and Russian President Vladimir Putin are now intertwined?

Lukashenka is a famous manipulator. Almost 30 years in power has made his self-preservation instincts automatic. It’s a tactical choice. There’s nothing behind it besides the willingness to stay in power till he dies.

But a trapped person is a dangerous and unreliable partner. It won’t remain like this for a long time. His partners will sooner or later face unpleasant surprises.

What can the international community do?

Hundreds of political prisoners, thousands in exile, tens of thousands arrested, fined, subjected to violence, and the media and businesses are being destroyed. The authorities are at war with their own people and leading the country into an abyss.

The support of the international community is very important for Belarusians. We need to look for an opportunity to start a dialogue, both within the country and with international partners.

Why did last year’s protests last as long as they did? Was it the relative youth of the protesters; the use of social media; the prominence of women; and did COVID restrictions play any part?

For me, the protests aren’t the main thing. The transformation of Belarusian society is the most important thing.

Most Belarusians decided what they want to see in their county: Belarus as a free, democratic, sovereign country. And the current authorities aren’t able to provide that.

Regarding new technology, of course, it gives more opportunities for people to organize, however, social media users are still the minority in Belarus. Everything happened on a deeper level after being built up over time through people’s real-life experience.

Throughout the campaign, I have been surprised by the fact that most of the activists are middle-aged people from different professions. There were plenty of women who expressed their objection first.

Through the situation with COVID, we gained a new experience of solidarity and mutual assistance, so when the government turned against the people, we realized then how many we were.

Looking back now at the protests, would you do anything differently and have you learned lessons for the future?

We definitely have more appreciation for what we already have. We appreciate our amazing journalists, our civil society, and private businesses. And, of course, our upcoming victory.

What could we have done differently? We could have been more consistent in terms of our willingness to resolve the crisis quickly and painlessly for the country. We were calling for dialogue in August, and then we had this unfortunate period of ultimatums that damaged both sides.

The situation is different now, and everything is more complicated. The moment has gone, and I don’t think that negotiation or national dialogue in the form we expected a year ago is possible anymore.

We had to make very hard choices many times, but the most important thing is that we never deviated from our principles and values - the fairness of the law, kindness, respect and love. I believe it is the only right way.

How can you now achieve your goal of removing President Lukashenka from power?

To be a politician in Belarus nowadays means to be in prison. In this way, I can contribute to the common endeavor. It’s not our objective, though.

Our objective is a country free of current and future forms of authoritarianism.

How to free the country? On the one hand, we all have to maintain our effort, cohesion and solidarity. We should try not to lose that. On the other hand, we should focus on limiting the political space for the government. We should show that the system will have to deal with us, the Belarusians.

Thirdly, we have to think about the future of Belarus. We have to dream about it, believe in it and stay active. Everything is up to us.

You were a musician before becoming active in politics. Has music shaped your approach to political activism and have you had the chance to continue playing in detention?

The artistic path shapes the personality. Of course, teamwork, looking for unusual solutions, and the ability to stay concentrated and work for a long time in critical situations, as well as performing in public, is what I’ve been learning my whole life as a musician.

Management of contemporary art projects and partnerships with businesses, like with Viktar Babaryka, the former presidential candidate, for example, gave me even more experience.

I miss music a lot, but in Belarusian prisons, even books aren’t really allowed. I don’t have an opportunity to play.

Do you have any regrets about your decision to become involved in opposition politics?

I consider my decision to participate in the campaign the most important and responsible one of my life. I knew it would be hard, but the future of the nation is at stake. So it’s worth it. My love for Belarus and Belarusian people didn’t allow me to stay aloof.

War on Ukraine: Exploring the humanitarian response to the conflict 12 April 2022 — 12:00PM TO 1:00PM Anonymous (not verified) 6 April 2022 Online

This event explores the implications of the humanitarian realities from Russia’s invasion of Ukraine, the largest ground campaign in Europe since World War Two.

Reports from humanitarian organizations working in Ukraine are dire and reveal that a humanitarian disaster on an epic scale is unfolding.

The United Nations (UN) and other organizations estimate 12 million of Ukraine’s population are in need of assistance, 4.1 million have been displaced to neighbouring countries, and 6.4 million have become internally displaced.

Gillian Triggs, the assistant secretary-general and assistant high commissioner for protection at the UNHCR, joins other experts to discuss the humanitarian situation in Ukraine.

The panel considers:

• What are the greatest needs in Ukraine now?
• How can aid agencies meet those needs?
• What are the short and long-term implications of the crisis for Ukraine and Europe?
• How do international organizations work with local NGOs to provide food, medical aid and shelter?

This event is part of a regular series of events offering insight and analysis from experts and policymakers on how the war is affecting Ukraine, the region and the world.

This event is part of Chatham House’s ongoing work on the future of conflict.

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Neoadjuvant therapy in patients with locally advanced rectal cancer (LARC) has achieved good pathologic complete response (pCR) rates, potentially eliminating the need for surgical intervention. This study investigated preoperative methods for predicting pCR after neoadjuvant short-course radiotherapy (SCRT) combined with immunochemotherapy. Methods: Treatment-naïve patients with histologically confirmed LARC were enrolled from February 2023 to July 2023. Before surgery, the patients received neoadjuvant SCRT followed by 2 cycles of capecitabine and oxaliplatin plus camrelizumab. ⁶⁸Ga-labeled fibroblast activation protein inhibitor ([⁶⁸Ga]Ga-FAPI-04) PET/MRI, [¹⁸F]FDG PET/CT, and contrast-enhanced MRI were performed before treatment initiation and before surgery in each patient. PET and MRI features and the size and number of lesions were also collected from each scan. Each parameter’s sensitivity, specificity, and diagnostic cutoff were derived via receiver-operating-characteristic curve analysis. Results: Twenty eligible patients (13 men, 7 women; mean age, 60.2 y) were enrolled and completed the entire trial, and all patients had proficient mismatch repair or microsatellite-stable LARC. A postoperative pCR was achieved in 9 patients (45.0%). In the visual evaluation, both [⁶⁸Ga]Ga-FAPI-04 PET/MRI and [¹⁸F]FDG PET/CT were limited to forecasting pCR. Contrast-enhanced MRI had a low sensitivity of 55.56% to predict pCR. In the quantitative evaluation, [⁶⁸Ga]Ga-FAPI-04 change in SUL_peak percentage, where SUL_peak is SUV_peak standardized by lean body mass, had the largest area under the curve (0.929) with high specificity (sensitivity, 77.78%; specificity, 100.0%; cutoff, 63.92%). Conclusion: [⁶⁸Ga]Ga-FAPI-04 PET/MRI is a promising imaging modality for predicting pCR after SCRT combined with immunochemotherapy. The SUL_peak decrease exceeding 63.92% may provide valuable guidance in selecting patients who can forgo surgery after neoadjuvant therapy.

The U.S. Navy conducted a two-missile test flight of unarmed life-extended Trident II-D5LE missiles from the USS Wyoming in the Eastern Test Range off the coast of Cape Canaveral, Fla, the Navy announced.

U.S. Space Force has made public the prototypes of its new uniforms, which immediately drew comparisons to those worn in Star Trek and other science fiction franchises.

The USNS Choctaw County has arrived in Beirut, Lebanon, to participate in a first-of-its-kind mission intended to strengthen military ties between the countries, the U.S. Navy said Tuesday.

Four U.S. Marines remain hospitalized after an attack near Hamid Karzai International Airport in Kabul, Afghanistan, last month as service members were evacuating foreign nationals and refugees.

COLUMBUS, Ohio, Nov. 7, 2024 — Alexander Hoover, an assistant professor in the Department of Mathematics and Statistics at Cleveland State University, has always been fascinated by marine organisms—the way […]

The post OSC Advances Marine Movement Research with Computational Tools for Bio-Inspired Robotics appeared first on HPCwire.

Democratic Rep. Ruben Gallego was poised Monday night to defeat election denier and President-elect Donald Trump ally Kari Lake in a closely watched Senate race in Arizona.

Not only does hearing this statement lower IQ, it also makes people more aggressive, other studies have shown.

Schools are putting in place or considering measures such as extending holiday breaks or shifting back to full-time remote learning.

Two lawsuits were filed Monday challenging a proposition that Arizona voters approved to impose an additional 3.5% tax on individuals earning above $250,000 to pay school teacher salaries and training.

It's possible there could be an eight-way tie atop the SEC standings at the end of the regular season. Then what will the College Football Playoff committee do?

Sharon G. Kujawa
Nov 11, 2009; 29:14077-14085
BehavioralSystemsCognitive

Yang Hu
Feb 24, 2021; 41:1699-1715
BehavioralSystemsCognitive

Michele Deodato
Oct 2, 2024; 44:e2308232024-e2308232024
BehavioralSystemsCognitive

Hannah Grotzinger
May 29, 2024; 44:e1856232024-e1856232024
BehavioralSystemsCognitive

During adolescence, cannabis experimentation is common, and its association with interindividual variations in brain maturation well studied. Cellular and molecular underpinnings of these system-level relationships are, however, unclear. We thus conducted a three-step study. First, we exposed adolescent male mice to -9-tetrahydrocannabinol (THC) or a synthetic cannabinoid WIN 55,212-2 (WIN) and assessed differentially expressed genes (DEGs), spine numbers, and dendritic complexity in their frontal cortex. Second, in human (male) adolescents, we examined group differences in cortical thickness in 34 brain regions, using magnetic resonance imaging, between those who experimented with cannabis before age 16 (n = 140) and those who did not (n = 327). Finally, we correlated spatially these group differences with gene expression of human homologs of mouse-identified DEGs. The spatial expression of 13 THC-related human homologs of DEGs correlated with cannabis-related variations in cortical thickness, and virtual histology revealed coexpression patterns of these 13 genes with cell-specific markers of astrocytes, microglia, and a type of pyramidal cells enriched in dendrite-regulating genes. Similarly, the spatial expression of 18 WIN-related human homologs of DEGs correlated with group differences in cortical thickness and showed coexpression patterns with the same three cell types. Gene ontology analysis indicated that 37 THC-related human homologs are enriched in neuron projection development, while 33 WIN-related homologs are enriched in processes associated with learning and memory. In mice, we observed spine loss and lower dendritic complexity in pyramidal cells of THC-exposed animals (vs controls). Experimentation with cannabis during adolescence may influence cortical thickness by impacting glutamatergic synapses and dendritic arborization.

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage–inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage–induced cell death and hearing loss.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b^M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone–shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b^M220T mice. At 24 h post-trauma, Pde4b^M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b^M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Representatives of all countries in Latin America and the Caribbean have gathered here this week to agree on the actions needed to definitively eradicate hunger in the region before 2025. [...]

South-South Cooperation is the mutual sharing and exchange of development solutions - knowledge, experiences and good practices, policies, technology and resources - between and among countries in the global [...]

MANUEL PLANELLES, EL PAÍS, Paris- “Agriculture is seen as a threat in the fight against climate change,” Maria Helena Semedo warns. The Deputy Director-General of the Food and Agriculture Organization [...]

Mr Chairman,

I wish to convey, through you, to the Committee on Fisheries, the considered views of the FAO Secretariat on the item on the proposed Fisheries University.  

So far, the [...]