Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of ...cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.
Debris-covered ice is widespread in mountain regions with debris an important control on surface ice melt and glacier retreat. Quantifying debris cover extent and its evolution through time over ...large regions remains a challenge. This study develops two Normalized Difference Supraglacial Debris Indices for mapping debris-covered ice based on thermal and near Infrared Landsat 8 bands. They were calibrated with field data. Validation suggests that they have a high level of accuracy. They are then applied to Landsat data for 2016 to produce the first detailed glacier inventory of the Afghanistan Hindu Kush Himalaya that includes debris cover. 3408 glaciers were identified which, for those ⩾0.01 km2 in area, gives an ice cover of 2,222 ± 11 km2 and a debris cover of 619 ± 40 km2. Principal components analysis was used to identify the most influential drivers of debris-covered ice extent. Lower proportions of debris cover were associated with glaciers with a higher elevation range, that were larger, longer and wider. These relations were statistically clearer when the dataset was broken down into climate and geological zones. A glaciers continue to shrink, the proportion of debris cover will become higher, making it more important to map debris cover reliably.
To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis.
We conducted a ...systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle–Ottawa Scale (NOS) for risk of bias assessment.
Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion).
Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.
Glaciers in Afghanistan are crucial elements for water resource and summer river flows. They are also threatened by rapid climate warming. This study presents an up-to-date assessment of ice cover ...loss for the entire country over two periods, 2000–2008 and 2008–2020, using newly developed remote sensing indices that include a more reliable determination of changing debris cover. The results suggest an estimated ice-covered area of 2,690.7 ± 108.2 km2 in 2020, that was 75 ± 0.7% clean ice and 25 ± 3.0 percent debris-covered ice. Total ice-covered area retreated by −0.16 ± 0.01 percent yr−1 between 2000 and 2008 and −0.46 ± 0.05 percent yr−1 between 2008 and 2020. Notably, 60 percent of ice cover loss (2000–2020) related to ice cover extents with a size ≤ 2.5 km2, comprising 60 percent of the total ice-covered area in 2000. Higher altitude accumulation zones also exhibited mass loss. However, there was also substantial spatial variation in these rates of loss based on geographical region, glacier size, and climate zones. In the north-eastern regions that are geographically close to or part of the north-west Karakoram ice cover was declining at a substantially lower rate, stable, or even increasing slightly, as compared with the northern and central regions of Afghanistan.
Previous work has shown that earthward convective flow bursts in the magnetotail have a dusk‐dawn (v⊥y ${v}_{\perp y}$) component that is controlled by the historical state of the Interplanetary ...Magnetic Field (IMF) By component. Here, we analyze 27 years of Cluster, THEMIS and Geotail plasma and magnetic field data and identify 1,639 magnetotail fast flow “detections” that demonstrate a dusk‐dawn asymmetry. We find that ∼70% has a dusk‐dawn direction consistent with that expected from the penetration of IMF By. Superposed epoch analysis suggests that the inconsistency of the remaining ∼30% is not due to a lack of the expected IMF By penetration. Instead, we find that on average, the expected sense of IMF By penetration is associated with flows irrespective of whether those flows agree or disagree with the expected dusk‐dawn asymmetry. IMF By, and the penetrated By do, however, tend to be stronger for “agree” flows. Detections which agree (disagree) tend to be accompanied by a localized perturbation to the By component of the magnetotail magnetic field in the same sign as (opposite to) the prevailing IMF By conditions, which temporarily enhances (overrides) the penetrated field. Agree (disagree) flows also appear to be observed further away from (closer to) the neutral sheet (Bx = 0) and are associated with weaker (stronger) magnetic field dipolarization. Finally, we find that the slower “background” convective flow has an average direction which is consistent with penetration of the expected IMF By, regardless of whether the fast flow itself agrees or disagrees.
Key Points
Magnetotail fast flows with a dusk‐dawn direction inconsistent with IMF By can occur irrespective of the sense of IMF By penetration
These inconsistent flows occur within a slower “background” convection that is consistent with the expected IMF By sense
Localized, transient dynamics can override or prevent IMF By control of the flow, notably when IMF By is weaker
Domain walls may play an important role in future electronic devices, given their small size as well as the fact that their location can be controlled. Here, we report the observation of ...room-temperature electronic conductivity at ferroelectric domain walls in the insulating multiferroic BiFeO(3). The origin and nature of the observed conductivity are probed using a combination of conductive atomic force microscopy, high-resolution transmission electron microscopy and first-principles density functional computations. Our analyses indicate that the conductivity correlates with structurally driven changes in both the electrostatic potential and the local electronic structure, which shows a decrease in the bandgap at the domain wall. Additionally, we demonstrate the potential for device applications of such conducting nanoscale features.
Rapid climate change is impacting water resources in Afghanistan. The consequences are poorly known. Suitable mitigation and adaptation strategies have not been developed. Thus, this paper summarizes ...current status of knowledge in relation to Afghan water resources. More than 130 scientific articles, reports and data sources are synthesized to review the potential impacts of climate change on the cryosphere, streamflow, groundwater and hydrological extremes. The available information suggests that Afghanistan is currently witnessing significant increases in temperature, less so precipitation. There is evidence of shifts in the intra-annual distribution of streamflow, with reduced summer flows in non-glaciated basins and increased winter and spring streamflow. However, in the short-term there will be an increase in summer ice melt in glaciated basins, a "glacial subsidy", which sustains summer streamflow, despite reduced snow accumulation. The future prognosis for water resources is likely to be more serious when this glacier subsidy ends.
Activated leukocyte cell adhesion molecule (ALCAM) plays an important role in cancer via its homotypical and heterotypical interactions with ALCAM or other proteins and can also mediate cell-cell ...interactions. The present study investigated the expression of ALCAM in relation to epithelial-to-mesenchymal transition (EMT) markers and its downstream signal proteins including Ezrin-Moesin-Radixin (ERM), in clinical colon cancer and in the progression of the disease.
Expression of ALCAM was determined in a clinical colon cancer cohort and assessed against the clinical pathological factors and outcome, together with the expression patterns of the ERM family and EMT markers. ALCAM protein was detected using immunohistochemistry. Cell line models, with ALCAM knock-down and over-expression, were established and used to test cells' responses to drugs.
Tumours from patients who had distant metastasis and died of colon cancer had low levels of ALCAM. Dukes B and C tumours also had lower ALCAM expression than Dukes A tumours. Patients with high levels of ALCAM had a significantly longer overall and disease-free survival than those with lower ALCAM levels (p=0.040 and p=0.044). ALCAM is not only significantly correlated with SNAI1 and TWIST, also positively correlated with SNAI2. ALCAM enhanced the adhesiveness of colorectal cancer, an effect inhibited by both sALCAM and SRC inhibitors. Finally, high ALCAM expression rendered cells resistant, especially to 5-fluorouracil.
Reduced expression of ALCAM in colon cancer is an indicator of disease progression and a poor prognostic indicator for patient's survival. However, ALCAM can enhance the adhesion ability of cancer cells and render them resistant to chemotherapy drugs.
Background
Previous research has suggested that patients with peripheral artery disease (PAD) are not offered adequate risk factor modification, despite their high cardiovascular risk. The aim of ...this study was to assess the cardiovascular profiles of patients with PAD and quantify the survival benefits of target‐based risk factor modification.
Methods
The Vascular and Endovascular Research Network (VERN) prospectively collected cardiovascular profiles of patients with PAD from ten UK vascular centres (April to June 2018) to assess practice against UK and European goal‐directed best medical therapy guidelines. Risk and benefits of risk factor control were estimated using the SMART‐REACH model, a validated cardiovascular prediction tool for patients with PAD.
Results
Some 440 patients (mean(s.d.) age 70(11) years, 24·8 per cent women) were included in the study. Mean(s.d.) cholesterol (4·3(1·2) mmol/l) and LDL‐cholesterol (2·7(1·1) mmol/l) levels were above recommended targets; 319 patients (72·5 per cent) were hypertensive and 343 (78·0 per cent) were active smokers. Only 11·1 per cent of patients were prescribed high‐dose statin therapy and 39·1 per cent an antithrombotic agent. The median calculated risk of a major cardiovascular event over 10 years was 53 (i.q.r. 44–62) per cent. Controlling all modifiable cardiovascular risk factors based on UK and European guidance targets (LDL‐cholesterol less than 2 mmol/l, systolic BP under 140 mmHg, smoking cessation, antiplatelet therapy) would lead to an absolute risk reduction of the median 10‐year cardiovascular risk by 29 (20–38) per cent with 6·3 (4·0–9·3) cardiovascular disease‐free years gained.
Conclusion
The medical management of patients with PAD in this secondary care cohort was suboptimal. Controlling modifiable risk factors to guideline‐based targets would confer significant patient benefit.
Previous research has suggested that the medical management of patients with peripheral artery disease may be suboptimal. This national project assessed the medical therapy and lipid control of individuals with established peripheral artery disease and compared it against established guidelines/treatment targets. These individuals are currently not receiving appropriate care to address their cardiovascular risk factors, which has an impact on their predicted risk of future major cardiovascular morbidity. New pathways of treatment are required to address this important issue and improve outcomes. CVD, cardiovascular disease; ARR, absolute risk reduction.
Room for improvement
Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality.
To perform a systematic review of currently available data on ...distribution, characteristics and outcome associated with carbapenem-resistant bloodstream infections in adult neutropenic patients.
Included studies were identified through Medline, Embase and Cochrane databases between January 1995 and April 2016. Random effect meta-analysis was used to quantify the association between carbapenem resistance and mortality and between carbapenem exposure and resistance.
A total of 30 studies from 21 countries were included. Overall carbapenem resistance varied from 2% to 53% (median 9%) among studies. Infections due to carbapenem-resistant Pseudomonas spp . were reported in 18 (60%) studies showing high median resistance rates (44% of all carbapenem-resistant Gram-negatives and 19% of Pseudomonas isolates). Resistance of Enterobacteriaceae was less commonly reported and bloodstream infections due to carbapenem-resistant Klebsiella spp. were mainly documented from endemic areas (Greece, Italy, Israel). Carbapenem resistance in Acinetobacter spp. was reported in 9 (30%) studies (median resistance 58% of Acinetobacter isolates). Mortality rates ranged from 33% to 71% (median 50%) in patients with carbapenem-resistant infections. Carbapenem resistance appeared to correlate with mortality (OR 4.89, 95% CI 3.30-7.26) and previous exposure to carbapenems (OR 4.63, 95% CI 3.08-6.96).
Carbapenem resistance represents a threat to neutropenic patients. In this group, resistance is likely promoted by previous carbapenem use and leads to high mortality rates. The knowledge of resistance patterns is crucial and can direct clinicians in the use of alternatives to carbapenem-based regimens.
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