Abstract
Chromosomal maintenance is vital for the survival of bacteria. In Caulobacter crescentus, chromosome replication initiates at ori and segregation is delayed until the nearby centromere-like ...region parS is replicated. Our understanding of how this sequence of events is regulated remains limited. The segregation of parS has been shown to involve multiple steps including polar release from anchoring protein PopZ, slow movement and fast ParA-dependent movement to the opposite cell pole. In this study, we demonstrate that ParA’s competing attractions from PopZ and from DNA are critical for segregation of parS. Interfering with this balance of attractions—by expressing a variant ParA-R195E unable to bind DNA and thus favoring interactions exclusively between ParA-PopZ—results in cell death. Our data revealed that ParA-R195E’s sole interactions with PopZ obstruct PopZ’s ability to release the polar anchoring of parS, resulting in cells with multiple parS loci fixed at one cell pole. We show that the inability to separate and segregate multiple parS loci from the pole is specifically dependent on the interaction between ParA and PopZ. Collectively, our results reveal that the initial steps in chromosome segregation are highly regulated.
Graphical Abstract
Graphical Abstract
Ionospheric outflow supplies nearly all of the heavy ions observed within the magnetosphere, as well as a significant fraction of the proton density. While much is known about upflow and outflow ...energization processes, the full global pattern of outflow and its evolution is only known statistically or through numerical modeling. Because of the dominant role of heavy ions in several key physical processes, this unknown nature of the full outflow pattern leads to significant uncertainty in understanding geospace dynamics, especially surrounding storm intervals. That is, global models risk not accurately reproducing the main features of intense space storms because the amount of ionospheric outflow is poorly specified and thus magnetospheric composition and mass loading could be ill‐defined. This study defines a potential mission to observe ionospheric outflow from several platforms, allowing for a reasonable and sufficient reconstruction of the full outflow pattern on an orbital cadence. An observing system simulation experiment is conducted, revealing that four well‐placed satellites are sufficient for reasonably accurate outflow reconstructions. The science scope of this mission could include the following: reveal the global structure of ionospheric outflow; relate outflow patterns to geomagnetic activity level; and determine the spatial and temporal nature of outflow composition. The science objectives could be focused to be achieved with minimal instrumentation (only a low‐energy ion spectrometer to obtain outflow reconstructions) or with a larger scientific scope by including contextual instrumentation.
Plain Language Summary
Earth's upper atmosphere above 500 km altitude constantly loses charged particles to outer space in a process called ionospheric outflow. This outflow is important for the dynamics of the near‐Earth space environment (“space weather”) yet is poorly understood on a global scale. A mission is needed to observe the global patterns of ionospheric outflow and its relation to space weather driving conditions. The science objectives of such a mission could include not only the reconstruction of global outflow patterns but also the relation of these patterns to geomagnetic activity and the spatial and temporal nature of outflow composition. A study is presented to show that four well‐placed spacecraft would be sufficient for reasonable outflow reconstructions.
Key Points
A simulation study is conducted to determine the number of spacecraft needed for accurate reconstruction of 2D ionospheric outflow patterns
Determining the global pattern of ionospheric outflow is needed to understand the geospace system, especially during geomagnetic storms
A potential ionospheric outflow mission concept is defined that could address this unresolved key issue of space physics and space weather
Research on relational maintenance shows that mundane day-to-day talk is important in sustaining relationships. This study explores how absence associated with the visitation process shapes ...nonresidential parents’ communication with their children. Participants’ open-ended responses indicate that several factors facilitate and constrain interaction with their children during absence including their philosophy about communication boundaries, technology, and their relationship with the other parent. Participants who have limited interactions struggle to “know” their children, while those with frequent interaction with their children have access to the mundane stories of their children’s lives, which helps to maintain the relationships. This research suggests that the process of updating about what occurs during absence may be central to maintaining relationships.
Maintaining proper chromosome inheritance after the completion of each cell cycle is paramount for bacterial survival. Mechanistic details remain incomplete for how bacteria manage to retain complete ...chromosomes after each cell cycle. In this study, we examined the potential roles of the partitioning protein ParA on chromosomal maintenance that go beyond triggering the onset of chromosome segregation in Caulobacter crescentus. Our data revealed that increasing the levels of ParA result in cells with multiple origins of replication in a DnaA-ATP-dependent manner. This
supernumerary is retained even when expressing variants of ParA that are deficient in promoting chromosome segregation. Our data suggest that in Caulobacter ParA's impact on replication initiation is likely indirect, possibly through the effect of other cell cycle events. Overall, our data provide new insights into the highly interconnected network that drives the forward progression of the bacterial cell cycle.
The successful generation of a daughter cell containing a complete copy of the chromosome requires the exquisite coordination of major cell cycle events. Any mistake in this coordination can be lethal, making these processes ideal targets for novel antibiotics. In this study, we focused on the coordination between the onset of chromosome replication, and the partitioning protein ParA. We demonstrate that altering the cellular levels of ParA causes cells to accumulate multiple origins of replication in Caulobacter crescentus. Our work provides important insights into the complex regulation involved in the coordination of the bacterial cell cycle.
This study showed that there were mutations in
ARMC5,
a putative tumor-suppressor gene, in a substantial proportion of patients with corticotropin-independent macronodular adrenal hyperplasia, a ...finding that may be helpful in the diagnosis and management of this disease.
Corticotropin-independent macronodular adrenal hyperplasia can lead to excess cortisol secretion and Cushing's syndrome.
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Adrenocortical nodules in corticotropin-independent macronodular adrenal hyperplasia are, by definition, larger than 10 mm in diameter and frequently reach 30 to 40 mm in diameter. The condition is typically diagnosed in patients with Cushing's syndrome who are between 40 and 60 years of age and who have suppressed levels of circulating corticotropin. Tumor growth and cortisol dysregulation appear to progress slowly in cases of corticotropin-independent macronodular adrenal hyperplasia, and the diagnosis is often made only after several years or decades of disease progression.
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Milder forms are . . .
Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve ...age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A variety of immunohistochemical (IHC) stains have been proposed to mark either benign or malignant mesothelial proliferations. Loss of the p16 tumor suppressor (CDKN2A), through homozygous deletions ...of 9p21, is a good marker of mesotheliomas but lacks sensitivity. Recent reports indicate that some mesotheliomas are associated with loss of BRCA-associated protein 1 (BAP1) expression. Here we investigate BAP1 and p16 as potential markers of malignancy and compare test characteristics with previously proposed markers using a well-characterized tissue microarray. BAP1 protein expression was interrogated by IHC. The p16 locus was examined by fluorescence in situ hybridization (FISH) directed toward chromosome 9p21. Loss of BAP1 was identified in 7/26 mesotheliomas and 0/49 benign proliferations. Loss of p16 was identified in 14/27 mesotheliomas and 0/40 benign proliferations, yielding 100% specificity and positive predictive value for each marker. Together, BAP1 IHC and p16 FISH were 58% sensitive for detecting malignancy. Various combinations of p53, EMA, IMP3, and GLUT1 showed reasonably high specificity (96% to 98%) but poor to extremely poor sensitivity. Combined BAP1 IHC/p16 FISH testing is a highly specific method of diagnosing malignant mesotheliomas when the question is whether a mesothelial proliferation is benign or malignant and is particularly useful when tissue invasion by mesothelial cells cannot be demonstrated. However, combined BAP1/p16 FISH testing is not highly sensitive, and negative results do not rule out a mesothelioma. The test characteristics of previously proposed markers EMA, p53, GLUT1, IMP3 suggest that, even in combination, these markers are not useful tools in this clinical setting.
The diagnosis of malignant mesothelioma in effusion cytology specimens is controversial. BAP1 immunohistochemistry and p16 fluorescence in situ hybridization (FISH) have recently been reported as ...reliable markers of malignancy in biopsies of mesothelioma. To determine whether these markers, singly or in combination, might also be useful in effusion cytology specimens, we examined 15 biopsies of epithelial mesotheliomas and 3 benign mesothelial reactions and corresponding effusion cytology paraffin-embedded cell blocks. Four cytology specimens were too scanty for p16 FISH analysis but were interpretable for BAP1 immunohistochemistry. Overall, loss of BAP1 and/or deletion of p16 was seen in 11/11 (100%) of matched cytology and tissue biopsy specimens. BAP1 loss alone was seen in 10/15 (67%) biopsies and 10/15 (67%) cytology specimens. Homozygous deletion of p16 by FISH was found in 12/15 (80%) biopsy specimens and 8/11 (73%) evaluable cytology specimens. Seven of 15 (47%) biopsies and 5/11 (42%) cytology specimens showed loss of both markers. All mesothelioma biopsy/cytology pairs showed exactly the same pattern of BAP1 or p16 retention or loss in the biopsy and cytology specimens. The 2 peritoneal mesothelioma cases demonstrated loss of BAP1 but not p16. None of the benign mesothelial reactions or corresponding cytology specimens showed loss of either marker. We conclude that both BAP1 immunohistochemistry and p16 FISH analysis provide reliable markers of mesothelial malignancy in effusion cytology specimens, especially where the atypical mesothelial proliferation is well sampled. BAP1 is easier to interpret with scanty specimens. On the basis of small numbers of cases, use of both markers appears to increase sensitivity.
New York City (NYC) is an ultra-urban region, with over 50% impervious cover and buried stream channels. Traditional flood studies rely on the presence of stream gages to detect flood stage and ...discharge, but these methods cannot be used in ultra-urban areas. Here we create a high-resolution radar rainfall dataset for NYC and utilize citizen and expert reports of flooding throughout the city to study flash flooding in NYC. Results indicate that interactions between the urban area and land–sea boundary have an important impact on the spatial variability of both heavy rainfall and flooding, sometimes in contrast to results obtained for other cities. Top days of daily and hourly rainfall exhibit a rainfall maximum over the city center and an extended region of higher rainfall downwind of the city. The mechanism for flooding appears to vary across the city, with high groundwater tables influencing more coastal areas and high rain rates or large rain volumes influencing more inland areas. There is also a strong relationship between sewer type and flood frequency, with fewer floods observed in combined sewer areas. Flooding is driven by maximum one-hour to one-day rainfall, which is often substantially less rain than observed for the city-wide daily maximum.
Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and ...SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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