DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage ...by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage.
The notion that civil society and democracy go hand in hand has been a cornerstone of modernization theory. The formation of civil society, so the argument went, contributed to the democratization of ...society and provided the backbone of democracy. If one follows such an interpretation of modernization and of modern society, monarchic systems should be void of civil society. And yet, the case of Germany shows that civil society developed and even flourished within a monarchic society. The Kingdom of Prussia in 1865 was the home to an extensive network of civil society organizations that included associations, endowments, and foundations. These organizations provided services in the fields of education, social welfare, and supported all kinds of cultural institutions. These organizations were essential for the functioning of Prussia’s public institutions. Donors who created these institutions had a voice in the shaping of monarchic society, and the visions of donors often coincided with the visions put forward by monarchical rulers. The number of Prussians involved in giving, the number of organizations created, and the amount of money given were truly astonishing. Between 2 and 3% of Prussia’s population was involved in civil society organizations. The funds provided by these organizations accounted for 20–30% of public-school funding. And the number of organizations created a tight network that spanned across the entire country. Nineteenth-century monarchic Prussia was not void of civil society as it should have been if American social scientists are correct. Instead, Prussia provided the home to a vibrant civil society. Civil society emerges when societies move from an agrarian and organized system of social hierarchies to an industrial, and traditional social hierarchies destroying system. The destruction of established social hierarchies, the creation and accumulation of wealth, and the emergence of social inequality provided powerful incentives for the formation of civil society. Since this economic modernization and transformation occurred not only within democratic societies such as the USA but also within monarchic societies such as Prussia, civil society developed in both types of political system
The cellular outcomes of chemical exposure are as much about the cellular response to the chemical as it is an effect of the chemical. We are growing in our understanding of the genotoxic interaction ...between chemistry and biology. For example, recent data has revealed the biological basis for mutation induction curves for a methylating chemical, which has been shown to be dependent on the repair capacity of the cells. However, this is just one end point in the toxicity pathway from chemical exposure to cell death. Much remains to be known in order for us to predict how cells will respond to a certain dose. Methylating agents, a subset of alkylating agents, are of particular interest, because of the variety of adverse genetic end points that can result, not only at increasing doses, but also over time. For instance, methylating agents are mutagenic, their potency, for this end point, is determined by the cellular repair capacity of an enzyme called methylguanine DNA-methyltransferase (MGMT) and its ability to repair the induceed methyl adducts. However, methyl adducts can become clastogenic. Erroneous biological processing will convert mutagenic adducts to clastogenic events in the form of double strand breaks (DSBs). How the cell responds to DSBs is via a cascade of protein kinases, which is called the DNA damage response (DDR), which will determine if the damage is repaired effectively, via homologous recombination, or with errors, via nonhomologous end joining, or whether the cell dies via apoptosis or enters senescence. The fate of cells may be determined by the extent of damage and the resulting strength of DDR signaling. Therefore, thresholds of damage may exist that determine cell fate. Such thresholds would be dependent on each of the repair and response mechanisms that these methyl adducts stimulate. The molecular mechanism of how methyl adducts kill cells is still to be fully resolved. If we are able to quantify each of these thresholds of damage for a given cell, then we can ascertain, of the many adducts that are induced, what proportion of them are mutagenic, what proportion are clastogenic, and how many of these clastogenic events are toxic. This review examines the possibility of dose and damage thresholds for methylating agents, from the perspective of the underlying evolutionary mechanisms that may be accountable.
Coral reefs world-wide are threatened by escalating local and global impacts, and some impacted reefs have shifted from coral dominance to a state dominated by macroalgae. Therefore, there is a ...growing need to understand the processes that affect the capacity of these ecosystems to return to coral dominance following disturbances, including those that prevent the establishment of persistent stands of macroalgae. Unlike many reefs in the Caribbean, over the last several decades, reefs around the Indo-Pacific island of Moorea, French Polynesia have consistently returned to coral dominance following major perturbations without shifting to a macroalgae-dominated state. Here, we present evidence of a rapid increase in populations of herbivorous fishes following the most recent perturbation, and show that grazing by these herbivores has prevented the establishment of macroalgae following near complete loss of coral on offshore reefs. Importantly, we found the positive response of herbivorous fishes to increased benthic primary productivity associated with coral loss was driven largely by parrotfishes that initially recruit to stable nursery habitat within the lagoons before moving to offshore reefs later in life. These results underscore the importance of connectivity between the lagoon and offshore reefs for preventing the establishment of macroalgae following disturbances, and indicate that protecting nearshore nursery habitat of herbivorous fishes is critical for maintaining reef resilience.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Corticosteroids, in particular dexamethasone, are one of the primary treatment options for critically ill COVID-19 patients. However, there are a growing number of cases that involve ...COVID-19-associated pulmonary aspergillosis (CAPA), and it is unclear whether dexamethasone represents a risk factor for CAPA. Our aim was to investigate a possible association of the recommended dexamethasone therapy with a risk of CAPA.
We performed a study based on a cohort of COVID-19 patients treated in 2020 in our 13 intensive care units at Charité Universitätsmedizin Berlin. We used ECMM/ISHM criteria for the CAPA diagnosis and performed univariate and multivariable analyses of clinical parameters to identify risk factors that could result in a diagnosis of CAPA.
Altogether, among the n = 522 intensive care patients analyzed, n = 47 (9%) patients developed CAPA. CAPA patients had a higher simplified acute physiology score (SAPS) (64 vs. 53, p < 0.001) and higher levels of IL-6 (1,005 vs. 461, p < 0.008). They more often had severe acute respiratory distress syndrome (ARDS) (60% vs. 41%, p = 0.024), renal replacement therapy (60% vs. 41%, p = 0.024), and they were more likely to die (64% vs. 48%, p = 0.049). The multivariable analysis showed dexamethasone (OR 3.110, CI95 1.112-8.697) and SAPS (OR 1.063, CI95 1.028-1.098) to be independent risk factors for CAPA.
In our study, dexamethasone therapy as recommended for COVID-19 was associated with a significant three times increase in the risk of CAPA.
Registration number DRKS00024578, Date of registration March 3rd, 2021.
Measures of brain morphometry derived from T1-weighted (T1W) magnetic resonance imaging (MRI) are widely used to elucidate the relation between brain structure and function. However, the computation ...of T1W morphometric measures can be confounded by subject-related factors such as head motion and level of hydration. A recent study reported subtle yet significant changes in brain volume from morning to evening in a large group of patient populations as well as in healthy elderly individuals. In addition, there is a growing recognition that factors such as circadian rhythm can impact MRI measures of brain function and structure. Here, we provide a comprehensive assessment of the impact of time-of-day (TOD) on widely used measures of brain morphometry in a group of 19 healthy young adults. Our results show that (a) even in a small group of healthy adult volunteers, a highly significant reduction in apparent brain volume, from morning to evening, could be detected; (b) the apparent volume of all three major tissue compartments – gray matter, white matter, and cerebrospinal fluid – were influenced by TOD, and the magnitude of the TOD effect varied across the tissue compartments; (c) measures of cortical thickness, cortical surface area, and gray matter density computed with widely used neuroimaging software suites (i.e., FreeSurfer, FSL-VBM) were all affected by TOD, while other measures, such as curvature indices and sulcal depth, were not; and (d) the effect of TOD appeared to have a greater impact on morphometric measures of the frontal and temporal lobe than on other major lobes of the brain. Our results suggest that the TOD effect is a physiological phenomenon and that controlling for the effect of TOD is crucial for proper interpretation of apparent structural differences measured with T1W morphometry.
•Time of day (TOD) impacts automatically derived measures of brain morphometry derived from T1W images.•The apparent volume of all major tissue compartments are influenced by TOD.•Measures of cortical thickness, cortical surface area and gray matter density are affected by TOD.•TOD has a greater impact on morphometric measures of the frontal and temporal lobe.
DNA damage–inducible miRNAs are likely to be functional in the DNA damage response. This response can elicit damage resolution and cell survival or apoptosis. The current, albeit incomplete, picture ...suggests that miRNAs can affect cell fate via modulation of key response proteins, but the question is, who’s in charge?
It is becoming clear that the DNA damage response orchestrates an appropriate response to a given level of DNA damage, whether that is cell cycle arrest and repair, senescence or apoptosis. It is ...plausible that the alternative regulation of the DNA damage response (DDR) plays a role in deciding cell fate following damage. MicroRNAs (miRNAs) are associated with the transcriptional regulation of many cellular processes. They have diverse functions, affecting, presumably, all aspects of cell biology. Many have been shown to be DNA damage inducible and it is conceivable that miRNA species play a role in deciding cell fate following DNA damage by regulating the expression and activation of key DDR proteins. From a clinical perspective, miRNAs are attractive targets to improve cancer patient outcomes to DNA-damaging chemotherapy. However, cancer tissue is known to be, or to become, well adapted to DNA damage as a means of inducing chemoresistance. This frequently results from an altered DDR, possibly owing to miRNA dysregulation. Though many studies provide an overview of miRNAs that are dysregulated within cancerous tissues, a tangible, functional association is often lacking. While miRNAs are well-documented in ‘ectopic biology’, the physiological significance of endogenous miRNAs in the context of the DDR requires clarification. This review discusses miRNAs of biological relevance and their role in DNA damage response by potentially ‘fine-tuning’ the DDR towards a particular cell fate in response to DNA damage. MiRNAs are thus potential therapeutic targets/strategies to limit chemoresistance, or improve chemotherapeutic efficacy.
•Cell fate following DNA damage is governed by the DNA damage response that facilitates an appropriate response to DNA damage.•The response to damage can either be survival, via cell cycle arrest and DNA repair, or death.•Post-translational modification of key response enzymes play a role in cell fate, both can be influenced by miRNAs.•miRNAs can be pro-survival or pro-death, depending on their effects on damage response enzymes.•It is possible that miRNAs differentially regulate the response enzymes towards a specific cell fate.
Human Structural Plasticity at Record Speed Johansen-Berg, Heidi; Baptista, Cassandra Sampaio; Thomas, Adam G.
Neuron (Cambridge, Mass.),
03/2012, Letnik:
73, Številka:
6
Journal Article
Recenzirano
Odprti dostop
How rapidly does learning shape our brains? A new study in this issue of Neuron by Sagi et al. (2012) that uses diffusion magnetic resonance imaging in both humans and rats suggests that just 2 hr of ...spatial learning is sufficient to change brain structure.
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