Project description:BackgroundThe need to execute a sequence of events in an orderly and timely manner is central to many biological processes, including cell cycle progression and cell differentiation. For self-perpetuating systems, such as the cell cycle oscillator, delay times between events are defined by the network of interacting proteins that propagates the system. However, protein levels inside cells are subject to genetic and environmental fluctuations, raising the question of how reliable timing is maintained.ResultsWe compared the robustness of different mechanisms for encoding delay times to fluctuations in protein expression levels. Gradual accumulation and gradual decay of a regulatory protein have an equivalent capacity for defining delay times. Yet, we find that the former is highly sensitive to fluctuations in gene dosage, while the latter can buffer such perturbations. In particular, a positive feedback where the degrading protein auto-enhances its own degradation may render delay times practically insensitive to gene dosage.ConclusionWhile our understanding of biological timing mechanisms is still rudimentary, it is clear that there is an ample use of degradation as well as self-enhanced degradation in processes such as cell cycle and circadian clocks. We propose that degradation processes, and specifically self-enhanced degradation, will be preferred in processes where maintaining the robustness of timing is important.
Project description:Studies of past sea-level markers are commonly used to unveil the tectonic history and seismic behavior of subduction zones. We present new evidence on vertical motions of the Hellenic subduction zone as resulting from a suite of Late Pleistocene - Holocene shorelines in western Crete (Greece). Shoreline ages obtained by AMS radiocarbon dating of seashells, together with the reappraisal of shoreline ages from previous works, testify a long-term uplift rate of 2.5-2.7 mm/y. This average value, however, includes periods in which the vertical motions vary significantly: 2.6-3.2 mm/y subsidence rate from 42 ka to 23 ka, followed by ~7.7 mm/y sustained uplift rate from 23 ka to present. The last ~5 ky shows a relatively slower uplift rate of 3.0-3.3 mm/y, yet slightly higher than the long-term average. A preliminary tectonic model attempts at explaining these up and down motions by across-strike partitioning of fault activity in the subduction zone.
Project description:Sputum retention is a very common problem in comatose and postoperative patients. The biochemical changes of hypoxia and hypercarbia associated with it ultimately lead to respiratory failure. Tracheobronchial toilet can be achieved by various methods all of which have their disadvantages. Minitracheostomy has been suggested as the best available method for tracheobronchial toilet Nineteen patients in our series underwent minitracheostomy for tracheobronchial toilet Fifteen patients showed full recovery. The oxygen saturation improved from 85.47% to 98.53%. There were very few complications and the procedure was comfortable and acceptable to patients.
Project description:Recent genome-wide analyses have uncovered a high accumulation of RNA polymerase II (Pol II) at the 5' end of genes. This elevated Pol II presence at promoters, referred to here as Poll II poising, is mainly (but not exclusively) attributed to temporal pausing of transcription during early elongation which, in turn, has been proposed to be a regulatory step for processes that need to be activated "on demand". Yet, the full genome-wide regulatory role of Pol II poising is yet to be delineated. To elucidate the role of Pol II poising in B cell activation, we compared Pol II profiles in resting and activated B cells. We found that while Pol II poised genes generally overlap functionally among different B cell states and correspond to the functional groups previously identified for other cell types, non-poised genes are B cell state specific. Focusing on the changes in transcription activity upon B cell activation, we found that the majority of such changes were from poised to non-poised state. The genes showing this type of transition were functionally enriched in translation, RNA processing and mRNA metabolic process. Interestingly, we also observed a transition from non-poised to poised state. Within this set of genes we identified several Immediate Early Genes (IEG), which were highly expressed in resting B cell and shifted from non-poised to poised state after B cell activation. Thus Pol II poising does not only mark genes for rapid expression in the future, but it is also associated with genes that are silenced after a burst of their expression. Finally, we performed comparative analysis of the presence of G4 motifs in the context of poised versus non-poised but active genes. Interestingly we observed a differential enrichment of these motifs upstream versus downstream of TSS depending on poising status. The enrichment of G4 sequence motifs upstream of TSS of non-poised active genes suggests a potential role of quadruplexes in expression regulation.
Project description:Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases.
Project description:BACKGROUND:According to recent studies, the number of women drug users is dramatically increasing. However, the information on the issue of drug rehab in women is not sufficient, and there are numerous traditional, organizational, political and cultural barriers to the provision of relevant information in this regard in Iran. This study, thus, aimed to explain the factors influencing the decision of these women to stop drug use. METHODS:This qualitative study was conducted in two rehab camps of Isfahan (in Iran) on July to October 2017. Thirty participants (women drug users) were selected through purposive and theoretical sampling until data saturation was reached. Data collection was conducted through semi-structured interviews. The transcribed interviews were analyzed using conventional content analysis. RESULTS:Based on the analysis of the obtained results, the women's experience of the ups and downs of stopping drug use yielded two themes and nine sub-themes. The themes were "the need for emancipation (the deviated path, being abused, compulsive drug use, acquaintance with God, a supportive family)" and "Sinking factors (non-assisting mates, pro-addictive family, unawareness of assisting official organization and non-government organization, woman's lack of authority, ineffective opportunities)". CONCLUSIONS:It was concluded that addiction rehab strategies can lead to a brighter life for women drug users only when they are coupled with open-hearted assistance of the families and women specific rehab centers are established to help them meet their specific needs.
Project description:Recent years have been turbulent ones for the Huntington's disease (HD) community. Three clinical trials for HD, including the first Phase 3 trial of a potentially disease modifying genetic therapy for HD, were all brought to a halt in March of 2021. 2022 brought more study roadblocks and an additional trial termination. As HD science progresses and larger scale trials become more frequent in the community, HD families are faced with the difficult reality that clinical research rarely results in a new drug hitting the market. To better understand how the HD community can be prepared for the ups and downs that accompany an expanding clinical research pipeline, the Huntington's Disease Society of America (HDSA) spoke with members of the Huntington's Disease Coalition for Patient Engagement (HD-COPE). This group of global advocates led by HDSA and the Huntington's Society of Canada (HSC) collaborates with pharmaceutical companies to ensure that HD voices are represented in the planning of clinical trials. These conversations allowed HDSA to summarize how the HD community can be best supported through the clinical research process in three key areas: engagement, support, and education.
Project description:Calcium ions function as intracellular second messengers in regulating a plethora of cellular processes from acclimative stress responses to survival and programmed cell death. The generation of specificity in Ca2+ signals is dependent on influx and efflux from the extracellular milieu, cytosol and intracellular organelles. One aspect of plant Ca2+ signalling that is currently attracting a great deal of interest is how 'Ca2+-signatures', specific spatio-temporal changes in cytosolic-free Ca2+, encode the necessary information to bring about this range of physiological responses. Here, current information is reviewed on how Ca2+-signatures are generated in plant cells and how stimulus-specific information can be encoded in the form of Ca2+-signatures.
Project description:ObjectivesResponse time inconsistency (RTI)-or trial-to-trial variability in speeded performance-is increasingly recognized as an indicator of transient lapses of attention, cognitive health status, and central nervous system integrity, as well as a potential early indicator of normal and pathological cognitive aging. Comparatively, little research has examined personality predictors of RTI across adulthood.MethodsWe evaluated the association between the personality trait neuroticism and RTI in a community-dwelling sample of 317 adults between the ages of 19-83 and tested for two indirect pathways through negative affect (NA) and cognitive interference (CI).ResultsThe personality trait neuroticism predicted greater RTI independent of mean response time performance and demographic covariates; the results were age-invariant. Furthermore, NA (but not CI) accounted for this association and moderated mediation model results indicated that older adults were more vulnerable to the adverse effects of NA.DiscussionNeuroticism predicts greater RTI irrespective of mean performance and this effect is driven largely by heightened negative emotionality that may be particularly detrimental for older adults.