spp. are frequently encountered in specimens from ICUs. However, most of these detections represent colonization. Nevertheless, clinical practice shows that a considerable proportion of these ...patients will receive antifungal therapy (AT). β-(1→3)-D-glucan (BDG) and mannan are fungal biomarkers with high negative predictive values. We aimed to examine whether biomarker-guided discontinuation of AT can reduce the antifungal consumption. Therefore, we conducted a prospective, randomized intervention study between 1 April 2019 and 31 March 2020. All adult ICU patients with a newly started systemic AT but without fungal infection were eligible for inclusion. Enrolled patients were randomized into an intervention and a control group. In both groups, serum BDG and mannan were determined on days 1 and 2 of AT. If all measurements were negative, AT was discontinued in the intervention group. The primary endpoint was antifungal use. The study was terminated after 12 months. Until this time-point, 41 patients had been included. In the intervention group (
= 19), AT was stopped in only two patients because all others showed either positive BDG and/or mannan levels. One of these two patients developed candidemia and AT had to be restarted. There was no significant difference in the primary and secondary endpoints. In summary, the strategy of using two negative BDG and mannan levels to stop AT failed to reduce antifungal consumption in our cohort. Indeed, there will inevitably be patients with invasive candidiasis in whom necessary AT is discontinued. The optimal patient population, biomarker set, and termination criteria are critical to the success of biomarker-based termination strategies.
碩士
國立臺灣科技大學
應用外語系
97
This paper reports on a classroom-based case study of a North American’s learning of the Southern Min (a.k.a., Taiwanese) Language in a dyadic (one-on-one) context over the ...course of three months at a private language school in Taiwan in light of Csikszentmihalyi’s (1990) concept of flow. Data were gathered via interviews, the focal participant’s reflective journal, audio-recordings, class notes, personal communication, and stimulated recall, and analyzed qualitatively according to Strauss and Corbin’s (1990) grounded theoretical coding procedures. The study’s findings underscore the need for a more specific definition of flow for dyadic L2 learning environments that depicts it as more of a “student’s right” or a “teacher’s obligation” than a merely enhanced state of consciousness. These realizations stemmed from the discovery of a “flow window” that was found to “open” during the first five to seven minutes of class that governed whether or not the focal participant would achieve flow during that particular lesson. In the cases in which the instructor did not proffer a “flow window,” the focal participant “turned himself off” and spent the remainder of class in frustration. Results also indicated that the focal participant’s flow experiences were discerned as being both mental and physical in nature; curiously enough, he reportedly experienced “flow withdrawal-symptoms” and spiraled down into a “flow-downer stage” when flow-enhancing instruction failed to occur as the result of the instructor’s non-adherence to Grice’s Discourse Maxims (1975) or when he failed to steer the instructor into what was termed as “flow-delivery mode. Needless to say, the study’s findings underscore the need for foreign language instructors to employ time-tested teaching tools such as advance organizers (Ausubel, 1968) early on in class periods to increase the likelihood that students will reach the “flow state” in their language learning. The study’s pedagogical implications and suggested directions for future “flow-related” research are presented in the study’s discussion section and conclusion, respectively.
Global increases in population, consumption, and gross domestic product raise concerns about the sustainability of the current and future use of natural resources. The human appropriation of net ...primary production (HANPP) provides a useful measure of human intervention into the biosphere. The productive capacity of land is appropriated by harvesting or burning biomass and by converting natural ecosystems to managed lands with lower productivity. This work analyzes trends in HANPP from 1910 to 2005 and finds that although human population has grown fourfold and economic output 17-fold, global HANPP has only doubled. Despite this increase in efficiency, HANPP has still risen from 6.9 Gt of carbon per y in 1910 to 14.8 GtC/y in 2005, i.e., from 13% to 25% of the net primary production of potential vegetation. Biomass harvested per capita and year has slightly declined despite growth in consumption because of a decline in reliance on bioenergy and higher conversion efficiencies of primary biomass to products. The rise in efficiency is overwhelmingly due to increased crop yields, albeit frequently associated with substantial ecological costs, such as fossil energy inputs, soil degradation, and biodiversity loss. If humans can maintain the past trend lines in efficiency gains, we estimate that HANPP might only grow to 27–29% by 2050, but providing large amounts of bioenergy could increase global HANPP to 44%. This result calls for caution in refocusing the energy economy on land-based resources and for strategies that foster the continuation of increases in land-use efficiency without excessively increasing ecological costs of intensification.
Upon binding of transcription factors to cis-regulatory DNA sequences, transcriptional coregulators are required for the activation or suppression of chromatin-dependent transcriptional signaling. ...These coregulators are frequently implicated in oncogenesis via causal roles in dysregulated, malignant transcriptional control and represent one of the fastest-growing target classes in small-molecule drug discovery. However, challenges in targeting coregulators include identifying evidence of cancer-specific genetic dependency, matching the pharmacologically addressable protein fold to a functional role in disease pathology, and achieving the necessary selectivity to exploit a given genetic dependency. We discuss here how recent trends in cancer pharmacology have confronted these challenges, positioning coregulators as tractable targets in the development of new cancer therapies.
Transcriptional coactivators and corepressors (together, coregulators) are chromatin-associated proteins that mediate signaling from DNA-bound transcription factors to the activation or suppression of gene transcription.An increasing number of coregulators are annotated as cancer-specific oncogene and non-oncogene dependencies in human malignancies.Recent disclosures of drug-like small molecules have revealed that many of these proteins, and the cancer-promoting activity encoded within them, are tractable targets for pharmacological modulation.The application of these small-molecule tools is opening new views into the function of coregulators in transcriptional control and is identifying underlying mechanisms by which these genes affect cancer-specific cell survival.
ENL is a transcriptional coactivator that recruits elongation machinery to active cis-regulatory elements upon binding of its YEATS domaina chromatin reader moduleto acylated lysine side chains. ...Discovery chemistry for the ENL YEATS domain is highly motivated by its significance in acute leukemia pathophysiology, but cell-based assays able to support large-scale screening or hit validation efforts do not presently exist. Here, we report on the discovery of a target engagement assay that allows for high-throughput ligand discovery in living cells. This assay is based on the cellular thermal shift assay (CETSA) but does not require exposing cells to elevated temperatures, as small-molecule ligands are able to stabilize the ENL YEATS domain at 37 °C. By eliminating temperature shifts, we developed a simplified target engagement assay that requires just two steps: drug treatment and luminescence detection. To demonstrate its value for higher throughput applications, we miniaturized the assay to a 1536-well format and screened 37 120 small molecules, ultimately identifying an acyl-lysine-competitive ENL/AF9 YEATS domain inhibitor.
Abstract
Far-ultraviolet (FUV; ∼1200–2000 Å) spectra are fundamental to our understanding of star-forming galaxies, providing a unique window on massive stellar populations, chemical evolution, ...feedback processes, and reionization. The launch of the James Webb Space Telescope will soon usher in a new era, pushing the UV spectroscopic frontier to higher redshifts than ever before; however, its success hinges on a comprehensive understanding of the massive star populations and gas conditions that power the observed UV spectral features. This requires a level of detail that is only possible with a combination of ample wavelength coverage, signal-to-noise, spectral-resolution, and sample diversity that has not yet been achieved by any FUV spectral database. We present the Cosmic Origins Spectrograph Legacy Spectroscopic Survey (CLASSY) treasury and its first high-level science product, the CLASSY atlas. CLASSY builds on the Hubble Space Telescope (HST) archive to construct the first high-quality (S/N
1500 Å
≳ 5/resel), high-resolution (
R
∼ 15,000) FUV spectral database of 45 nearby (0.002 <
z
< 0.182) star-forming galaxies. The CLASSY atlas, available to the public via the CLASSY website, is the result of optimally extracting and coadding 170 archival+new spectra from 312 orbits of HST observations. The CLASSY sample covers a broad range of properties including stellar mass (6.2 < log
M
⋆
(
M
⊙
) < 10.1), star formation rate (−2.0 < log SFR (
M
⊙
yr
−1
) < +1.6), direct gas-phase metallicity (7.0 < 12+log(O/H) < 8.8), ionization (0.5 < O
32
< 38.0), reddening (0.02 <
E
(
B
−
V
) < 0.67), and nebular density (10 <
n
e
(cm
−3
) < 1120). CLASSY is biased to UV-bright star-forming galaxies, resulting in a sample that is consistent with the
z
∼ 0 mass–metallicity relationship, but is offset to higher star formation rates by roughly 2 dex, similar to
z
≳ 2 galaxies. This unique set of properties makes the CLASSY atlas the benchmark training set for star-forming galaxies across cosmic time.
Bioenergy: how much can we expect for 2050? Haberl, Helmut; Erb, Karl-Heinz; Krausmann, Fridolin ...
Environmental research letters,
09/2013, Letnik:
8, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Estimates of global primary bioenergy potentials in the literature span almost three orders of magnitude. We narrow that range by discussing biophysical constraints on bioenergy potentials resulting ...from plant growth (NPP) and its current human use. In the last 30 years, terrestrial NPP was almost constant near 54 PgC yr−1, despite massive efforts to increase yields in agriculture and forestry. The global human appropriation of terrestrial plant production has doubled in the last century. We estimate the maximum physical potential of the world's total land area outside croplands, infrastructure, wilderness and denser forests to deliver bioenergy at approximately 190 EJ yr−1. These pasture lands, sparser woodlands, savannas and tundras are already used heavily for grazing and store abundant carbon; they would have to be entirely converted to bioenergy and intensive forage production to provide that amount of energy. Such a high level of bioenergy supply would roughly double the global human biomass harvest, with far-reaching effects on biodiversity, ecosystems and food supply. Identifying sustainable levels of bioenergy and finding ways to integrate bioenergy with food supply and ecological conservation goals remains a huge and pressing scientific challenge.
The spatial and temporal variation in food abundance has strong effects on wildlife feeding and nutrition. This variation is exemplified by the peatland forests of Central Kalimantan, which are ...characterized by unpredictable fruiting fluctuations, relatively low levels of fruit availability, and low fruit periods (<3% of trees fruiting) that can last nearly a year. Challenged by these environments, large, arboreal frugivores like orangutans must periodically rely on non-preferred, lower-quality foods to meet their nutritional needs. We examined variation in nutrient intake among age-sex classes and seasons over a 7-year period at the Tuanan Orangutan Research Station in Central Kalimantan. We conducted 2,316 full-day focal follows on 62 habituated orangutans (Pongo pygmaeus wurmbii). We found differences in total energy and macronutrient intake across age-sex classes, controlling for metabolic body mass. Intake of both total energy and macronutrients varied with fruit availability, and preference of dietary items increased with their nutritional quality. Foraging-related variables, such as day journey length, travel time, and feeding time, also varied among age-sex classes and with fruit availability. Our results add to the growing body of literature suggesting that great variation in foraging strategies exists among species, populations, and age-sex classes and in response to periods of resource scarcity.
The spatial and temporal variation in food abundance has strong effects on wildlife feeding and nutrition. Here we present the first long term study of the effects of variation in fruit availability and age/sex class on nutritional ecology of wild Bornean orangutans. We examined variation in nutrient intake of wild orangutans in living in a peat swamp habitat over a 7-year period at the Tuanan Orangutan Research Station in Central Kalimantan. We conducted 2,316 full-day focal follows on 62 habituated orangutans (Pongo pygmaeus wurmbii). We found differences in total energy and macronutrient intake across age-sex classes, controlling for metabolic body mass. Intake of both total energy and macronutrients varied with fruit availability, and preference of dietary items increased with their nutritional quality. Foraging-related variables, such as day journey length, travel time, and feeding time, also varied among age-sex classes and with fruit availability. Our results add to the growing body of literature suggesting that great variation in foraging strategies exists among species, populations, and age-sex classes and in response to periods of resource scarcity.
Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous ...2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials.
The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated.
Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011).
This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators.
The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence ...that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF-brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor beta-mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.
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