Population growth, increasing energy demand and the depletion of fossil fuel reserves necessitate a search for sustainable alternatives for electricity generation. Hydropower could replace a large ...part of the contribution of gas and oil to the present energy mix. However, previous high-resolution estimates of hydropower potential have been local, and have yet to be applied on a global scale. This study is the first to formally present a detailed evaluation of the hydropower potential of each location, based on slope and discharge of each river in the world. The gross theoretical hydropower potential is approximately 52 PWh/year divided over 11.8 million locations. This 52 PWh/year is equal to 33% of the annually required energy, while the present energy production by hydropower plants is just 3% of the annually required energy. The results of this study: all potentially interesting locations for hydroelectric power plants, are available online.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We present a novel framework to evaluate multi‐agent crowd simulation algorithms based on real‐world observations of crowd movements. A key aspect of our approach is to enable fair comparisons by ...automatically estimating the parameters that enable the simulation algorithms to best fit the given data. We formulate parameter estimation as an optimization problem, and propose a general framework to solve the combinatorial optimization problem for all parameterized crowd simulation algorithms. Our framework supports a variety of metrics to compare reference data and simulation outputs. The reference data may correspond to recorded trajectories, macroscopic parameters, or artist‐driven sketches. We demonstrate the benefits of our framework for example‐based simulation, modeling of cultural variations, artist‐driven crowd animation, and relative comparison of some widely‐used multi‐agent simulation algorithms.
OBJECTIVEPeople with attention deficit and hyperactivity disorder (ADHD) present attentional and emotional deficits and show paradoxical qualities such as hyperfocus. Previous studies have reported ...errors, slowness, and reaction time (RT) variability using eye movements. This study aimed to explore the underlying mechanisms of ADHD further. METHODSThirty French children and teenagers, 15 with ADHD and 15 neurotypical (NT), underwent a saccadic eye movement task. We conducted conventional analysis (movement duration, precision, velocity, RT) and Bayesian analysis. RESULTSSaccade duration and velocity failed to differentiate the two groups, whereas amplitude was higher in ADHD than in NT participants. Saccade RT and variability were higher in ADHD than in NT participants. In the Bayesian analysis, ADHD altered the main distribution of saccades and of early saccades but did not influence the express saccade triggering. CONCLUSIONSADHD disrupts two mechanisms of action: it reduces the gain of the decision signal, thus explaining slowness and variability; it quickens the decision process of early responses at the origin of short-latency but controlled movements. SIGNIFICANCEThese premises and their interconnections explain previous observations and support the striatal-frontal wiring of ADHD, thus explaining ADHD complexity in its negative and positive manifestations.
Treatment of clavicle fractures: current concepts review van der Meijden, Olivier A., MD; Gaskill, Trevor R., MD; Millett, Peter J., MD, MSc
Journal of shoulder and elbow surgery,
03/2012, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Clavicle fractures are common in adults and children. Most commonly, these fractures occur within the middle third of the clavicle and exhibit some degree of displacement. Whereas many midshaft ...clavicle fractures can be treated nonsurgically, recent evidence suggests that more severe fracture types exhibit higher rates of symptomatic nonunion or malunion. Although the indications for surgical fixation of midshaft clavicle fractures remain controversial, they appear to be broadening. Most fractures of the medial or lateral end of the clavicle can be treated nonsurgically if fracture fragments remain stable. Surgical intervention may be required in cases of neurovascular compromise or significant fracture displacement. In children and adolescents, these injuries mostly consist of physeal separations, which have a large healing potential and can therefore be managed conservatively. Current concepts of clavicle fracture management are discussed including surgical indications, techniques, and results.
A substantial fraction of T-cell lymphomas carry mutations in two genes —
TET2
and
DNMT3A
— that are involved in DNA methylation. The co-occurrence of these mutations suggests that inhibitors of DNA ...methylation could possibly have antitumor effects in such patients.
To the Editor:
Despite the poor prognosis of T-cell lymphomas, the genetic basis of these cancers is poorly defined.
1
We have found acquired
TET
2 mutations in both human myeloid cancers
2
and T-cell lymphoma.
3
TET proteins are involved in the epigenetic control of transcription, at least through the oxidation of methylated cytosines and DNA demethylation.
4
The catalytic activity of the TET proteins is inhibited by 2-hydroxyglutarate, an oncogenic metabolite produced by the mutated forms of the IDH1 and IDH2 enzymes.
IDH
mutations are observed in myeloid cancers, but involvement in T-cell lymphoma has not been reported. We investigated the status . . .
The NLRP3 inflammasome has emerged as a central immune regulator that senses virulence factors expressed by microbial pathogens for triggering inflammation. Inflammation can be harmful and therefore ...this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida's ability to compete for glucose and increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and activate NLRP3 when microbial load increases. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genomic studies in chronic myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MPN/MDS, have identified common mutations in genes encoding ...signaling, epigenetic, transcription, and splicing factors. In the present study, we interrogated the clonal architecture by mutation-specific discrimination analysis of single-cell–derived colonies in 28 patients with chronic myelomonocytic leukemias (CMML), the most frequent MPN/MDS. This analysis reveals a linear acquisition of the studied mutations with limited branching through loss of heterozygosity. Serial analysis of untreated and treated samples demonstrates a dynamic architecture on which most current therapeutic approaches have limited effects. The main disease characteristics are early clonal dominance, arising at the CD34+/CD38− stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent and common myeloid progenitors. Comparison of clonal expansions of TET2 mutations in MDS, MPN, and CMML, together with functional invalidation of TET2 in sorted progenitors, suggests a causative link between early clonal dominance and skewed granulomonocytic differentiation. Altogether, early clonal dominance may distinguish CMML from other chronic myeloid neoplasms with similar gene mutations.
•Early clonal dominance may distinguish chronic myelomonocytic leukemia from other chronic myeloid neoplasms with similar gene mutations.•Early dominance of TET2-mutated cells in the hematopoietic tissue promotes myeloid differentiation skewing toward the granulomonocytic line.
BACKGROUND:The authors previously identified key objective parameters that define the aesthetic ideal of the breast in a study of 100 models with natural breasts. In this follow-up article, the ...opinion of the general public on ideal breast proportions was surveyed.
METHODS:One thousand three hundred fifteen respondents were asked to rank the attractiveness of images of four women with varying breast sizes. Each of the women’s breasts were morphed into four different proportions. One of the key features was the upper pole–to–lower pole percentage proportion, corresponding to ratios of 35:65, 45:55, 50:50, and 55:45. Rankings were analyzed according to population demographics. Effects of age, sex, nationality, and ethnicity were evaluated. The responses of 53 plastic surgeons were included.
RESULTS:Breasts with an upper pole–to–lower pole ratio of 45:55 were universally scored highest, in particular, by 87 percent of women in their thirties (n = 190), 90 percent of men (n = 655), 94 percent of plastic surgeons (n = 53), 92 percent of North Americans (n = 89), 95 percent of South Americans (n = 23), 86 percent of Europeans (n = 982), 87 percent of Caucasians (n = 1016), and 87 percent of Asians (n = 209).
CONCLUSIONS:This study reaffirms the authors’ previous findings that the 45:55 ratio has universal appeal in defining the ideal breast. The authors propose that this proportion should be used as a basis for design in aesthetic surgery.
Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause ...accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.
•Enasidenib inhibits mIDH2, leading to leukemic cell differentiation with emergence of functional mIDH2 neutrophils in rrAML patients.•RAS pathway mutations and increased mutational burden overall are associated with a decreased response rate to mIDH2 inhibition.
Several prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations-including ASXL1-have been associated with poor prognosis in ...univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables.
We genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model.
ASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×10(9)/L, platelet count less than 100 ×10(9)/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001).
A new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.
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