Combinatorial Complexity and Compositional Drift in Protein Interaction Networks

The assembly of molecular machines and transient signaling complexes does not typically occur under circumstances in which the appropriate proteins are isolated from all others present in the cell. Rather, assembly must proceed in the context of large-scale protein-protein interaction (PPI) networks that are characterized both by conflict and combinatorial complexity. Conflict refers to the fact that protein interfaces can often bind many different partners in a mutually exclusive way, while combinatorial complexity refers to the explosion in the number of distinct complexes that can be formed by a network of binding possibilities. Using computational models, we explore the consequences of these characteristics for the global dynamics of a PPI network based on highly curated yeast two-hybrid data. The limited molecular context represented in this data-type translates formally into an assumption of independent binding sites for each protein. The challenge of avoiding the explicit enumeration of the astronomically many possibilities for complex formation is met by a rule-based approach to kinetic modeling. Despite imposing global biophysical constraints, we find that initially identical simulations rapidly diverge in the space of molecular possibilities, eventually sampling disjoint sets of large complexes. We refer to this phenomenon as “compositional drift”. Since interaction data in PPI networks lack detailed information about geometric and biological constraints, our study does not represent a quantitative description of cellular dynamics. Rather, our work brings to light a fundamental problem (the control of compositional drift) that must be solved by mechanisms of assembly in the context of large networks. In cases where drift is not (or cannot be) completely controlled by the cell, this phenomenon could constitute a novel source of phenotypic heterogeneity in cell populations

ASSESSMENT OF CHLORIDE LEVELS ON RENAL FUNCTION AFTER CARDIAC ARREST

SCOPUS: no.jinfo:eu-repo/semantics/publishe

Health-seeking behaviors and self-care practices of Dominican women with lymphoedema of the leg: implications for lymphoedema management programs

BACKGROUND: In the Dominican Republic, a Latin American country with filariasis-endemic areas, more than 63,000 people have lymphatic filariasis and more than 400,000 people are at risk of future infection. In this paper, we explore the health beliefs, health-seeking behaviors and self-care practices of women with lymphoedema in filariasis-endemic areas to better understand the needs of women when developing lymphoedema morbidity control programs. METHODS: Qualitative data were collected through semi-structured interviews of 28 women, 3 focus group discussions with 28 women, field notes and photographs. RESULTS: Women described exhaustive and expensive attempts at seeking a cure for their lymphoedema. Family members were influential in providing women with initial care seeking referrals to indigenous healers credited with influence over physical, mental, spiritual and supernatural properties of illness. When indigenous treatments proved to be ineffectual, the women sought care from trained healthcare providers. Most healthcare providers incorrectly diagnosed the edema, failed to adequately treat and meet the needs of women and were viewed as expensive. Most women resorted to self-prescribing injectable, oral, or topical antibiotics along with oral analgesics as a standard practice of self-care. CONCLUSION: Healthcare providers must understand a woman's cultural perspectives of illness, her natural networks of support and referral, her behavioural practices of care-seeking and self-care and the financial burden of seeking care. In the culture of the Dominican Republic family members and traditional healthcare providers are influential advisors on initial health-seeking behaviors and self-care practices. For this reason family-oriented interventions, support groups for women and their families, community education and training on simple, low cost lymphoedema management techniques for indigenous healers are viable ways to influence the early detection, diagnosis and treatment of women with lymphoedema. The extensive use of injectable, oral and topical antibiotics by indigenous healers and women without medical supervision suggests a need for health education messages related to the risks of such practices

The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch\u27s APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch\u27s data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch\u27s analytic tools by developing a customized plugin for OpenAI\u27s ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app

Use of an innovative model to evaluate mobility in seniors with lower-limb amputations of vascular origin: a pilot study

<p>Abstract</p> <p>Background</p> <p>The mobility of older individuals has often been only partially assessed, without considering all important aspects such as potential (available) versus effective (used) mobilities and the physical and psychosocial factors that modulate them. This study proposes a new model for evaluating mobility that considers all important aspects, applied here to lower-limb amputees with vascular origin. This model integrates the concepts of potential mobility (e.g. balance, speed of movement), effective mobility (e.g. life habits, movements in living areas) and factors that modulate these two types of mobility (e.g. strength, sensitivity, social support, depression). The main objective was to characterize potential and effective mobility as well as mobility modulators in a small sample of people with lower-limb amputations of vascular origin with different characteristics. The second objective of this pilot study was to assess the feasibility of measuring all variables in the model in a residential context.</p> <p>Methods</p> <p>An observational and transversal design was used with a heterogeneous sample of 10 participants with a lower-limb amputation of vascular origin, aged 51 to 83, assessed between eight and 18 months after discharge from an acute care hospital. A questionnaire of participant characteristics and 16 reliable and valid measurements were used.</p> <p>Results</p> <p>The results show that the potential mobility indicators do not accurately predict effective mobility, i.e., participants who perform well on traditional measures done in the laboratory or clinic are not always those who perform well in the real world. The model generated 4 different profiles (categories) of participants ranging from reduced to excellent potential mobility and low to excellent effective mobility, and characterized the modulating factors. The evaluations were acceptable in terms of the time taken (three hours) and the overall measurements, with a few exceptions, which were modified to optimize the data collected and the classification of the participants. For the population assessed, the results showed that some of the negative modulators (particularly living alone, no rehabilitation, pain, limited social support, poor muscle strength) played an important role in reducing effective mobility.</p> <p>Conclusion</p> <p>The first use of the model revealed interesting data that add to our understanding of important aspects linked to potential and effective mobility as well as modulators. The feasibility of measuring all variables in the model in a residential context was demonstrated. A study with a large number of participants is now warranted to rigorously characterize mobility levels of lower-limb amputees with vascular origin.</p

Carnosine:can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?

The dipeptide carnosine (β-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells. © 2013 Hipkiss et al.; licensee Chemistry Central Ltd

Overview of the TCV tokamak experimental programme

The tokamak a configuration variable (TCV) continues to leverage its unique shaping capabilities, flexible heating systems and modern control system to address critical issues in preparation for ITER and a fusion power plant. For the 2019-20 campaign its configurational flexibility has been enhanced with the installation of removable divertor gas baffles, its diagnostic capabilities with an extensive set of upgrades and its heating systems with new dual frequency gyrotrons. The gas baffles reduce coupling between the divertor and the main chamber and allow for detailed investigations on the role of fuelling in general and, together with upgraded boundary diagnostics, test divertor and edge models in particular. The increased heating capabilities broaden the operational regime to include T (e)/T (i) similar to 1 and have stimulated refocussing studies from L-mode to H-mode across a range of research topics. ITER baseline parameters were reached in type-I ELMy H-modes and alternative regimes with \u27small\u27 (or no) ELMs explored. Most prominently, negative triangularity was investigated in detail and confirmed as an attractive scenario with H-mode level core confinement but an L-mode edge. Emphasis was also placed on control, where an increased number of observers, actuators and control solutions became available and are now integrated into a generic control framework as will be needed in future devices. The quantity and quality of results of the 2019-20 TCV campaign are a testament to its successful integration within the European research effort alongside a vibrant domestic programme and international collaborations