A Non-amyloid Prion Particle that Activates a Heritable Gene Expression Program.

Spatiotemporal gene regulation is often driven by RNA-binding proteins that harbor long intrinsically disordered regions in addition to folded RNA-binding domains. We report that the disordered region of the evolutionarily ancient developmental regulator Vts1/Smaug drives self-assembly into gel-like condensates. These proteinaceous particles are not composed of amyloid, yet they are infectious, allowing them to act as a protein-based epigenetic element: a prion [SMAUG+]. In contrast to many amyloid prions, condensation of Vts1 enhances its function in mRNA decay, and its self-assembly properties are conserved over large evolutionary distances. Yeast cells harboring [SMAUG+] downregulate a coherent network of mRNAs and exhibit improved growth under nutrient limitation. Vts1 condensates formed from purified protein can transform naive cells to acquire [SMAUG+]. Our data establish that non-amyloid self-assembly of RNA-binding proteins can drive a form of epigenetics beyond the chromosome, instilling adaptive gene expression programs that are heritable over long biological timescales.

Structural implications of amyloidogenic rare variants Ser282Leu and Gln356Arg identified in h-BRCA1.

Preliminary studies have shown BRCA1 (170-1600) residues to be intrinsically disordered with unknown structural details. However, thousands of clinically reported variants have been identified in this central region of BRCA1. Therefore, we aimed to characterize h-BRCA1(260-553) to assess the structural basis for pathogenicity of two rare missense variants Ser282Leu, Gln356Arg identified from the Indian and Russian populations respectively. Small-angle X-ray scattering analysis revealed WT scores Rg -32 Å, Dmax -93 Å, and Rflex-51% which are partially disordered, whereas Ser282Leu variant displayed a higher degree of disorderedness and Gln356Arg was observed to be aggregated. WT protein also possesses an inherent propensity to undergo a disorder-to-order transition in the presence of cruciform DNA and 2,2,2-Trifluoroethanol (TFE). An increased alpha-helical pattern was observed with increasing concentration of TFE for the Gln356Arg mutant whereas Ser282Leu mutant showed significant differences only at the highest TFE concentration. Furthermore, higher thermal shift was observed for WT-DNA complex compared to the Gln356Arg and Ser282Leu protein-DNA complex. Moreover, mature amyloid-like fibrils were observed with 30 µM thioflavin T (ThT) at 37°C for Ser282Leu and Gln356Arg proteins while the WT protein exists in a protofibril state as observed by TEM. Gln356Arg formed higher-order aggregates with amyloidogenesis over time as monitored by ThT fluorescence. In addition, computational analyses confirmed larger conformational fluctuations for Ser282Leu and Gln356Arg mutants than for the WT. The global structural alterations caused by these variants provide a mechanistic approach for further classification of the variants of uncertain clinical significance in BRCA1 into amyloidogenic variants which may have a significant role in disease pathogenesis.

Proteasome activation: A novel strategy for targeting undruggable intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are characterized by their inability to adopt well-defined tertiary structures under physiological conditions. Nonetheless, they often play pivotal roles in the progression of various diseases, including cancer, neurodegenerative disorders, and cardiovascular ailments. Owing to their inherent dynamism, conventional drug design approaches based on structural considerations encounter substantial challenges when applied to IDPs. Consequently, the pursuit of therapeutic interventions directed towards IDPs presents a complex endeavor. While there are indeed existing methodologies for targeting IDPs, they are encumbered by noteworthy constrains. Hence, there exists an imminent imperative to investigate more efficacious and universally applicable strategies for modulating IDPs. Here, we present an overview of the latest advancements in the research pertaining to IDPs, along with the indirect regulation approach involving the modulation of IDP degradation through proteasome. By comprehending these advancements in research, novel insights can be generated to facilitate the development of new drugs targeted at addressing the accumulation of IDPs in diverse pathological conditions.

The dynamic space of aid relations in protracted internal displacement: the case of Sri Lanka's northern Muslims.

Aid relations in protracted displacement comprise a diversity of actors with different influence and involvement over time. Building on the case of Sri Lanka's northern Muslim's expulsion from the north of the country in 1990, this paper investigates the dynamic space of aid relations in their drawn-out internal displacement. The study draws on 38 key informant interviews and 10 focus-group discussions, conducted in Sri Lanka (Jaffna, Mannar, Puttalam, and Colombo) in 2022. The paper contributes new knowledge of the local dynamics of assistance in protracted displacement, by analysing the roles of a wide set of actors within this dynamic space of aid relations over time. The analysis incorporates angles and voices often overlooked in mainstream humanitarian studies, including internally displaced persons, hosts, and Middle Eastern aid funders. The study argues that a long-term perspective and a variety of voices provide foundations for more productive engagement with localisation in humanitarian action in protracted displacement crises.

The Proteomic Analysis of Cancer-Related Alterations in the Human Unfoldome.

Many proteins lack stable 3D structures. These intrinsically disordered proteins (IDPs) or hybrid proteins containing ordered domains with intrinsically disordered protein regions (IDPRs) often carry out regulatory functions related to molecular recognition and signal transduction. IDPs/IDPRs constitute a substantial portion of the human proteome and are termed "the unfoldome". Herein, we probe the human breast cancer unfoldome and investigate relations between IDPs and key disease genes and pathways. We utilized bottom-up proteomics, MudPIT (Multidimensional Protein Identification Technology), to profile differentially expressed IDPs in human normal (MCF-10A) and breast cancer (BT-549) cell lines. Overall, we identified 2271 protein groups in the unfoldome of normal and cancer proteomes, with 148 IDPs found to be significantly differentially expressed in cancer cells. Further analysis produced annotations of 140 IDPs, which were then classified to GO (Gene Ontology) categories and pathways. In total, 65% (91 of 140) IDPs were related to various diseases, and 20% (28 of 140) mapped to cancer terms. A substantial portion of the differentially expressed IDPs contained disordered regions, confirmed by in silico characterization. Overall, our analyses suggest high levels of interactivity in the human cancer unfoldome and a prevalence of moderately and highly disordered proteins in the network.

Protein Disorder in Plant Stress Adaptation: From Late Embryogenesis Abundant to Other Intrinsically Disordered Proteins.

Global climate change has caused severe abiotic and biotic stresses, affecting plant growth and food security. The mechanical understanding of plant stress responses is critical for achieving sustainable agriculture. Intrinsically disordered proteins (IDPs) are a group of proteins without unique three-dimensional structures. The environmental sensitivity and structural flexibility of IDPs contribute to the growth and developmental plasticity for sessile plants to deal with environmental challenges. This article discusses the roles of various disordered proteins in plant stress tolerance and resistance, describes the current mechanistic insights into unstructured proteins such as the disorder-to-order transition for adopting secondary structures to interact with specific partners (i.e., cellular membranes, membrane proteins, metal ions, and DNA), and elucidates the roles of liquid-liquid phase separation driven by protein disorder in stress responses. By comparing IDP studies in animal systems, this article provides conceptual principles of plant protein disorder in stress adaptation, reveals the current research gaps, and advises on the future research direction. The highlighting of relevant unanswered questions in plant protein disorder research aims to encourage more studies on these emerging topics to understand the mechanisms of action behind their stress resistance phenotypes.

Dietary diversity and associated factors among households and children in internally displaced person camps in Southern Somalia: A cross-sectional study.

The study aimed to assess household and child dietary diversity in Southern Somalia by identifying determinants of adequate dietary diversity in three internally displaced person (IDP) camps in Baidoa, Dayniile and Dharkanley. A total of 1655 female main caregivers with 2370 children (6-59 months old) were included. Data on household dietary diversity score and child dietary diversity score indicators were collected from all households. The questionnaire was read face-to-face to the female main caregivers. Multivariate logistic regression analysis was performed to identify factors associated with adequate dietary diversity, which was defined as the consumption of at least four food groups within 24 h before the survey. The proportion of households achieving adequate HDDS was high in all locations 95.8%, 96.9% and 89.0% in Baidoa, Dharkanley and Dayniile, respectively, and the total adequate household dietary diversity score (AHDDS) was 95.6%. The proportion of adequate child dietary diversity score (ACDDS) was achieved in 63.5%, 8.5% and 38.3%. The main factors associated with AHDDS were larger household size, greater wealth, attendance of antenatal care (ANC) and joint decision-making between husband and wife, while factors associated with ACDDS included ANC attendance, age, the consumption of ready-to-use therapeutic food and deworming tablets. These findings can guide future programmes and policies aimed at improving maternal and child nutrition in IDP camps in Somalia. By tackling these diverse factors, a promising pathway emerges to enhance the nutritional welfare of both households and children in IDP camps.

A sequence-based foldability score combined with AlphaFold2 predictions to disentangle the protein order/disorder continuum.

Order and disorder govern protein functions, but there is a great diversity in disorder, from regions that are-and stay-fully disordered to conditional order. This diversity is still difficult to decipher even though it is encoded in the amino acid sequences. Here, we developed an analytic Python package, named pyHCA, to estimate the foldability of a protein segment from the only information of its amino acid sequence and based on a measure of its density in regular secondary structures associated with hydrophobic clusters, as defined by the hydrophobic cluster analysis (HCA) approach. The tool was designed by optimizing the separation between foldable segments from databases of disorder (DisProt) and order (SCOPe [soluble domains] and OPM [transmembrane domains]). It allows to specify the ratio between order, embodied by regular secondary structures (either participating in the hydrophobic core of well-folded 3D structures or conditionally formed in intrinsically disordered regions) and disorder. We illustrated the relevance of pyHCA with several examples and applied it to the sequences of the proteomes of 21 species ranging from prokaryotes and archaea to unicellular and multicellular eukaryotes, for which structure models are provided in the AlphaFold protein structure database. Cases of low-confidence scores related to disorder were distinguished from those of sequences that we identified as foldable but are still excluded from accurate modeling by AlphaFold2 due to a lack of sequence homologs or to compositional biases. Overall, our approach is complementary to AlphaFold2, providing guides to map structural innovations through evolutionary processes, at proteome and gene scales.

Intrinsically disordered proteins and liquid-liquid phase separation in SARS-CoV-2 interactomes.

This paper discusses the properties of proteins and their relations in the interactomes of the selected subsets of SARS-CoV-2 proteome-the membrane protein, nonstructural proteins, and, finally, full proteome. Protein disorder according to several measures, liquid-liquid phase separation probabilities, and protein node degrees in the interaction networks were singled out as the features of interest. Additionally, viral interactomes were combined with the interactome of human lung tissue so as to examine if the new connections in the resulting viral-host interactome are linked to protein disorder. Correlation analysis shows that there is no clear relationship between raw features of interest, whereas there is a positive correlation between the protein disorder and its neighborhood mean disorder. There are also indications that highly connected viral hubs tend to be on average more ordered than proteins with a small number of connections. This is in contrast to previous similar studies conducted on eukaryotic interactomes and possibly raises new questions in research on viral interactomes.

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.

BACKGROUND: Stroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain. METHODS: We performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used. RESULTS: Forward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10-12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW ß = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10-7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR. CONCLUSIONS: We identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.

A simple method to purify intrinsically disordered proteins by adjusting trichloroacetic acid concentration.

Late embryogenic abundant proteins (LEA) are a group of proteins that accumulate during the desiccation phase of the seed and in response to water deficit in the plant. Most LEA proteins are highly hydrophilic and have physicochemical characteristics similar to those of intrinsically disordered proteins (IDPs). Although the function of LEA proteins is not fully understood, there is evidence indicating that these proteins have an important role in reducing the effects caused by water limitation. The analysis of the biochemical and physicochemical characteristics of LEA proteins is crucial to determine their function, for which it is necessary to obtain large amounts of pure protein. Within this current work, we have improved our previous TCA purification method used for basic recombinant LEA proteins to obtain acidic IDPs, the method reported here is fast and simple and is based on the enrichment of the protein of interest by boiling of the bacterial extract followed by a precipitation with different concentrations of TCA and salt. This protocol was applied to acidic and basic IDPs, represented by eight recombinant LEAs, resulting in milligram quantities of highly enriched proteins, which keep their in vitro functionality.

Understanding multilevel barriers to childhood vaccination uptake among Internally Displaced Populations (IDPs) in Mogadishu, Somalia: a qualitative study.

BACKGROUND: Disparities in vaccination coverage exist in Somalia with Internally Displaced Persons (IDPs) being among the groups with the lowest coverage. We implemented an adapted Participatory Learning and Action (PLA) intervention, which focused on routine vaccinations among displaced populations living in Mogadishu IDP camps. The intervention was successful in improving maternal knowledge and vaccination coverage but unsuccessful in improving timely vaccination. We conducted a qualitative study to understand this result and analyze the multi-level barriers to routine childhood immunization uptake. METHOD: In this qualitative study we used observation data from 40 PLA group discussions with female caregivers and purposively sampled nine vaccination service providers and six policy makers for interview. We also reviewed national-level vaccine policy documents and assessed the quality of health facilities in the study area. We used the socioecological framework to structure our analysis and analyzed the data in NVivo. RESULTS: The barriers to childhood vaccination among IDPs at the individual level were fear due to lack of knowledge, mistrust of vaccines, concerns about side effects and misinformation; opportunity costs; and costs of transportation. At the interpersonal level, family members played an important role as did the extent of decision-making autonomy. Community factors such as cultural practices, gender roles, and household evictions influenced vaccination. Organizational issues at health facilities such as waiting times, vaccine stock-outs, distance to the facility, language differences, and hesitancy of health workers to open multi-dose vials affected vaccination. At the policy level, confusion about the eligible age for routine vaccination and age restrictions for catch-up vaccination and certain antigens such as BCG were important barriers. CONCLUSION: Complex and interrelated factors affect childhood vaccination uptake among IDPs in Somalia. Interventions that address multiple barriers simultaneously will have the greatest impact given the complex nature of vulnerabilities in this population. There is a need to strengthen the health system and connect it with existing community structures to increase demand for services. Our research highlights the importance of formative research before implementing interventions. Further research on the integration of health service strengthening with PLA to improve childhood vaccination among IDPs is recommended. TRIAL REGISTRATION NUMBER: ISRCTN-83,172,390. Date of registration: 03/08/2021.

Health aid displacement during a decade of conflict (2011-19) in Syria: an exploratory analysis.

BACKGROUND: Syria has been in continuous conflict since 2011, resulting in more than 874,000 deaths and 13.7 million internally displaced people (IDPs) and refugees. The health and humanitarian sectors have been severely affected by the protracted, complex conflict and have relied heavily on donor aid in the last decade. This study examines the extent and implications of health aid displacement in Syria during acute humanitarian health crises from 2011 to 2019. METHODS: We conducted a trend analysis on data related to humanitarian and health aid for Syria between 2011 and 2019 from the OECD's Creditor Reporting System. We linked the data obtained for health aid displacement to four key dimensions of the Syrian conflict. The data were compared with other fragile states. We conducted a workshop in Turkey and key informants with experts, policy makers and aid practitioners involved in the humanitarian and health response in Syria between August and October 2021 to corroborate the quantitative data obtained by analysing aid repository data. RESULTS: The findings suggest that there was health aid displacement in Syria during key periods of crisis by a few key donors, such as the EU, Germany, Norway and Canada supporting responses to certain humanitarian crises. However, considering that the value of humanitarian aid is 50 times that of health aid, this displacement cannot be considered as critical. Also, there was insufficient evidence of health displacement across all donors. The results also showed that the value of health aid as a proportion of aggregate health and humanitarian aid is only 2% in Syria, compared to 22% for the combined average of fragile states, which further indicates the predominance of humanitarian aid over health aid in the Syrian crisis context. CONCLUSION: This study highlights that in very complex conflict-affected contexts such as Syria, it is difficult to suggest the use of health aid displacement as an effective tool for aid-effectiveness for donors as it does not reflect domestic needs and priorities. Yet there seems to be evidence of slight displacement for individual donors. However, we can suggest that donors vastly prefer to focus their investment in the humanitarian sector rather than the health sector in conflict-affected areas. There is an urgent need to increase donors' focus on Syria's health development aid and adopt the humanitarian-development-peace nexus to improve aid effectiveness that aligns with the increasing health needs of local communities, including IDPs, in this protracted conflict.

Properties of protein unfolded states suggest broad selection for expanded conformational ensembles.

Much attention is being paid to conformational biases in the ensembles of intrinsically disordered proteins. However, it is currently unknown whether or how conformational biases within the disordered ensembles of foldable proteins affect function in vivo. Recently, we demonstrated that water can be a good solvent for unfolded polypeptide chains, even those with a hydrophobic and charged sequence composition typical of folded proteins. These results run counter to the generally accepted model that protein folding begins with hydrophobicity-driven chain collapse. Here we investigate what other features, beyond amino acid composition, govern chain collapse. We found that local clustering of hydrophobic and/or charged residues leads to significant collapse of the unfolded ensemble of pertactin, a secreted autotransporter virulence protein from Bordetella pertussis, as measured by small angle X-ray scattering (SAXS). Sequence patterns that lead to collapse also correlate with increased intermolecular polypeptide chain association and aggregation. Crucially, sequence patterns that support an expanded conformational ensemble enhance pertactin secretion to the bacterial cell surface. Similar sequence pattern features are enriched across the large and diverse family of autotransporter virulence proteins, suggesting sequence patterns that favor an expanded conformational ensemble are under selection for efficient autotransporter protein secretion, a necessary prerequisite for virulence. More broadly, we found that sequence patterns that lead to more expanded conformational ensembles are enriched across water-soluble proteins in general, suggesting protein sequences are under selection to regulate collapse and minimize protein aggregation, in addition to their roles in stabilizing folded protein structures.

Insights into the Cellular Localization and Functional Properties of TSPYL5 Protein.

In recent years, the role of liquid-liquid phase separation (LLPS) and intrinsically disordered proteins (IDPs) in cellular molecular processes has received increasing attention from researchers. One such intrinsically disordered protein is TSPYL5, considered both as a marker and a potential therapeutic target for various oncological diseases. However, the role of TSPYL5 in intracellular processes remains unknown, and there is no clarity even in its intracellular localization. In this study, we characterized the intracellular localization and exchange dynamics with intracellular contents of TSPYL5 and its parts, utilizing TSPYL5 fusion proteins with EGFP. Our findings reveal that TSPYL5 can be localized in both the cytoplasm and nucleoplasm, including the nucleolus. The nuclear (nucleolar) localization of TSPYL5 is mediated by the nuclear/nucleolar localization sequences (NLS/NoLS) identified in the N-terminal intrinsically disordered region (4-27 aa), while its cytoplasmic localization is regulated by the ordered NAP-like domain (198-382 aa). Furthermore, our results underscore the significant role of the TSPYL5 N-terminal disordered region (1-198 aa) in the exchange dynamics with the nucleoplasm and its potential ability for phase separation. Bioinformatics analysis of the TSPYL5 interactome indicates its potential function as a histone and ribosomal protein chaperone. Taken together, these findings suggest a significant contribution of liquid-liquid phase separation to the processes involving TSPYL5, providing new insights into the role of this protein in the cell's molecular life.

Internally displaced persons in Mali facing the COVID 19 pandemic: A qualitative study / Les personnes déplacées internes au Mali face à la COVID-19 : une étude qualitative

Introduction: The COVID-19 pandemic has exacerbated an already existing security crisis leading to massive population displacements that have been taking place since 2012. Purpose of research: This study aims to explore the representations of internally displaced persons (IDPs) about the existence of COVID-19 and their knowledge about its signs, symptoms, modes of transmission and prevention measures. Methods: The study was qualitative and exploratory. Individual and group interviews were used to collect data from 52 IDPs in six sites in Bamako and Segou. All interviews were recorded and transcribed. Thematic content analysis and N-Vivo software were used. Results: The majority of IDPs believed in the existence of COVID-19 and had good knowledge of the signs, symptoms, modes of transmission and prevention measures against the disease. However, this was not sufficient for the adoption of public health measures. Among those who believed in its existence, some thought that it was a disease of the white and rich. Finally, a group of participants believed in conspiracy theories and claimed that the government and humanitarian organizations were only trying to make money through these campaigns. Conclusion: To our knowledge, this is the first study in Mali to explore IDPs' beliefs and knowledge about COVID-19. These results could inform policies, strategies, and interventions to combat COVID-19 in IDP sites and in the general population.

Introduction: Le Mali fait face depuis 2012 à une crise sécuritaire qui a entraîné des déplacements massifs des populations à laquelle s'est greffée la pandémie de la COVID-19. But de l'étude: Cette étude vise à explorer les représentations des personnes « déplacées internes ¼ (PDIs), c'est-à-dire des personnes forcées de fuir leur lieu d'origine, sur l'existence de la COVID-19 ainsi que leurs connaissances sur ses signes, ses symptômes, les modes de transmission et les mesures de prévention. Méthodes: L'étude est qualitative et exploratoire. Des entretiens individuels et en groupes ont permis de collecter les données auprès de 52 PDIs de six sites de Bamako et Ségou. Tous les entretiens ont été enregistrés et transcrits. L'analyse de contenu thématique et le logiciel NVivo ont été utilisés. Résultats: Dans leur majorité, les PDIs croyaient en l'existence de la COVID-19 et avaient de bonnes connaissances sur les signes, les symptômes, les modes de transmission et les mesures de prévention contre la maladie. Toutefois, cela n'a pas été suffisant pour l'adoption des mesures de santé publique. Parmi ceux qui croient en son existence, certains pensent que c'est toutefois une maladie des blancs et des riches. Enfin, un groupe de participants croyait plutôt en des théories du complot selon lesquelles le gouvernement et les organisations humanitaires ne chercheraient qu'à gagner de l'argent à travers ces campagnes. Conclusions: Il s'agit à notre connaissance de la première étude au Mali explorant les représentations et les connaissances des PDIs sur la COVID-19. Ces résultats pourraient éclairer les politiques, stratégies et interventions de lutte contre la COVID-19 dans les sites PDI et dans la population générale.

Pure shift amide detection in conventional and TROSY-type experiments of 13C,15N-labeled proteins.

Large coupling networks in uniformly 13C,15N-labeled biomolecules induce broad multiplets that even in flexible proteins are frequently not recognized as such. The reason is that given multiplets typically consist of a large number of individual resonances that result in a single broad line, in which individual components are no longer resolved. We here introduce a real-time pure shift acquisition scheme for the detection of amide protons which is based on 13C-BIRDr,X. As a result the full homo- and heteronuclear coupling network can be suppressed at low power leading to real singlets at substantially improved resolution and uncompromised sensitivity. The method is tested on a small globular and an intrinsically disordered protein (IDP) where the average spectral resolution is increased by a factor of ~ 2 and higher. Equally important, the approach works without saturation of water magnetization for solvent suppression and exchanging amide protons are not affected by saturation transfer.

Self-assembling systems comprising intrinsically disordered protein polymers like elastin-like recombinamers.

Despite lacking cooperatively folded structures under native conditions, numerous intrinsically disordered proteins (IDPs) nevertheless have great functional importance. These IDPs are hybrids containing both ordered and intrinsically disordered protein regions (IDPRs), the structure of which is highly flexible in this unfolded state. The conformational flexibility of these disordered systems favors transitions between disordered and ordered states triggered by intrinsic and extrinsic factors, folding into different dynamic molecular assemblies to enable proper protein functions. Indeed, prokaryotic enzymes present less disorder than eukaryotic enzymes, thus showing that this disorder is related to functional and structural complexity. Protein-based polymers that mimic these IDPs include the so-called elastin-like polypeptides (ELPs), which are inspired by the composition of natural elastin. Elastin-like recombinamers (ELRs) are ELPs produced using recombinant techniques and which can therefore be tailored for a specific application. One of the most widely used and studied characteristic structures in this field is the pentapeptide (VPGXG)n . The structural disorder in ELRs probably arises due to the high content of proline and glycine in the ELR backbone, because both these amino acids help to keep the polypeptide structure of elastomers disordered and hydrated. Moreover, the recombinant nature of these systems means that different sequences can be designed, including bioactive domains, to obtain specific structures for each application. Some of these structures, along with their applications as IDPs that self-assemble into functional vesicles or micelles from diblock copolymer ELRs, will be studied in the following sections. The incorporation of additional order- and disorder-promoting peptide/protein domains, such as α-helical coils or ß-strands, in the ELR sequence, and their influence on self-assembly, will also be reviewed. In addition, chemically cross-linked systems with controllable order-disorder balance, and their role in biomineralization, will be discussed. Finally, we will review different multivalent IDPs-based coatings and films for different biomedical applications, such as spatially controlled cell adhesion, osseointegration, or biomaterial-associated infection (BAI).

Intrinsically disordered features of carbonic anhydrase IX proteoglycan-like domain.

hCA IX is a multi-domain protein belonging to the family of hCAs which are ubiquitous zinc enzymes that catalyze the reversible hydration of CO2 to HCO3- and H+. hCA IX is a tumor-associated enzyme with a limited distribution in normal tissues, but over-expressed in many tumors, and is a promising drug target. Although many studies concerning the CA IX catalytic domain were performed, little is known about the proteoglycan-like (PG-like) domain of hCA IX which has been poorly investigated so far. Here we attempt to fill this gap by providing an overview on the functional, structural and therapeutic studies of the PG-like domain of hCA IX which represents a unique feature within the CA family. The main studies and recent advances concerning PG role in modulating hCA IX catalytic activity as well as in tumor spreading and migration are here reported. Special attention has been paid to the newly discovered disordered features of the PG domain which open new perspectives about its molecular mechanisms of action under physiological and pathological conditions, since disorder is likely involved in mediating interactions with partner proteins. The emerged disordered features of PG domain will be explored for putative diagnostic and therapeutic applications involving CA IX targeting in tumors.

Piloting of a suicide first aid gatekeeper training (online) for children and young people in conflict affected areas in Syria.

Suicide among internally displaced people remains an under-researched public health issue especially in conflict affected countries. Given the limited and sometimes inaccessible mental health services, there is a need for scalable evidence-based suicide prevention programmes that could be delivered by trained and supervised non-specialists. The Suicide First Aid Guidelines approach aims to support humanitarian workers who deal directly with children and families with the appropriate knowledge and skills to identify and support those at risk of suicide until they can access further specialized support services or until the crisis passes.This paper presents the findings of an online pilot training of 56 humanitarian workers from different sectors (e.g. Child Protection, Nutrition and Mental Health and Psychosocial Support) in conflict affected areas in Syria. The quantitative and qualitative evaluations were based on pre- and post-training questionnaires and revision journals completed between training sessions. Suggestions and examples provided in the journals and during the trainings were incorporated into the succeeding trainings. This was to contextualize and modify the gatekeeper training to fit the Syrian context and provide adaptations for future research and suicide prevention guidelines. Overall, the evaluation indicated that the pilot training raised awareness and improved participants' knowledge on how to assist a suicidal person, including warning signs. It also contributed to a positive change in attitude or beliefs towards suicide. Although the pilot training was considered adequate for the Syrian context some improvements were suggested.