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The first hunting season I enjoyed with my father was 15 years ago. While most people were cozying up in their homes, preparing for winter and holidays with family, I [...]

This digest describes the implementation of a successful district-wide elementary school foreign language (FLES) program that resulted from the superintendent's vision to have all students in the district study a common foreign language throughout their schooling. This vision was based on the superintendent's belief that American secondary school graduates in the 21st century will be competing for positions in which bilingual language proficiency will offer a considerable advantage. The digest highlights five overarching themes believed to be key to the success of the program: careful and collaborative planning and evaluation; gradual program expansion; attention to progress in proficiency; high quality foreign language faculty; and reflective practitioners. (VWL)

The number of languages spoken throughout the world is estimated to be 6,000. Although a small number of languages serve as important link languages or languages of wider communication around the world, these are very often spoken as second, third, fourth, or later-acquired languages. Fewer than 25% of the world's approximately 200 countries recognize two or more official languages, with a mere handful recognizing more than two. Despite these conservative government policies, available data indicate that there are many more bilingual or multilingual individuals in the world than there are monolingual. In addition, there are many more children throughout the world who have been and continue to be educated through a second or a later-acquired language, at least for some portion of their formal education, than there are children educated exclusively via the first language. In many parts of the world, bilingualism or multilingualism and innovative approaches to education that involve the use of two or more languages constitute the normal everyday experience. Results from published, longitudinal, and critical research undertaken in varied settings throughout the world indicate that the development of multiple language proficiency is possible and is viewed as desirable by educators, policymakers, and parents in many countries. This digest discusses the use of multiple languages in education, research on the use of first and second languages in education, common threads of successful programs, cross-cutting themes, key issues warranting further attention, and questions to ask regarding multilingual education in one's community. (VWL)

Transmission spectroscopy1–3of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations’ relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species—in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5–5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec’s PRISM mode9as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10–12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2(28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2(2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST’s sensitivity to a rich diversity of exoplanet compositions and chemical processes.

The article recounts a hunting experience 15 years ago, emphasizing the reliance on the author's father for guidance in the dense wilderness, leading to the crucial lesson of preparedness and the importance of "calibrating the compass" for navigation.

Use of cannabidiol (CBD) products has become widespread due to the proposed medical benefits without the “high” of marijuana, with recent polling indicating that 1 in 7 Americans report using a CBD product. However, health care professionals have apprehension about whether these treatments are legal, safe, and effective. In this review, we provide a summary of the scientific evidence on CBD oil so that a nurse practitioner can guide patients to the safest and most beneficial products within today’s regulatory environment.

Increasing the dietary fiber of staple foods such as bread is an attractive way to promote healthy eating in a large part of the population, where dietary fiber consumption is reportedly below the recommended values. However, many consumers prefer white breads, which are typically low in dietary fiber. In this work, white bread was made from two wheat cultivars with differing fiber contents. The resulting breads showed similar quality parameters (volume, specific volume, firmness, inner structure characteristics) with any differences maintained below 7%. Bread digestibility was evaluated using a novel dynamic in vitro digestion model. Reduced digestion rates of 30% were estimated for the high-fiber white bread compared to that in the control. Overall, this work demonstrates the potential to produce healthy, high-fiber white breads that are acceptable to consumers, with a reduced rate of starch digestion, by exploiting a genetic variation in the dietary fiber content of wheat cultivars.

The ~150‐km‐wide dextral Marlborough Fault System and adjacent Kaikōura Mountains accommodate oblique convergence between the Pacific and Australian plates at the NE end of the South Island, New Zealand. Low‐temperature thermochronology from this region places new limits on the timing and style of Marlborough faulting and mountain building. We sampled rocks for apatite and zircon (U‐Th/He) and apatite fission track dating from a range of elevations spanning ~2 km within the Kaikōura Ranges, which stand high above the active Marlborough dextral faults. The data reveal Miocene cooling localized to hanging wall rocks, first along the Clarence Fault in the Inland Kaikōura Range, then along the Jordan Thrust in the Seaward Kaikōura Range, followed by widespread, rapid cooling reflected in all samples across the study area starting at ~5 Ma. Our results suggest that topographic relief in this region predates the onset of dextral faulting and that portions of the Marlborough Faults were once thrust faults that coincided with the early development of the transpressive plate boundary. We relate Pliocene to present rapid exhumation across the field site, including at low‐elevation sample sites in Marlborough Fault foot walls, to seaward translation and overthrusting of crust atop the downgoing slab by dextral Marlborough Fault motion. Our results show that spatial and temporal patterns in exhumation reflect a complex and evolving deformation field in the Marlborough Fault System over the past ~25 million years of Kaikōura orogeny. Patterns in exhumation from new low‐temperature thermochronology reflect Marlborough Fault deformation during the evolving Kaikōura orogenyMiocene exhumation limited to hanging walls indicates early thrust faulting and uplift, first in the Inland then in the Seaward Kaikōura RangeExhumation is rapid and widespread across the Marlborough Fault System after Pliocene onset of dextral faulting

Wind‐swept snow self‐organizes into bedforms. These bedforms affect local and global energy fluxes but have not been incorporated into Earth system models because the conditions governing their development are not well understood. To address this difficulty, we created statistical classifiers, drawn from 736 hr of time‐lapse footage in the Colorado Front Range, that predict bedform presence as a function of wind speed and time since snowfall. These classifiers provide the first quantitative predictions of bedform and sastrugi presence in varying weather conditions. We find that the likelihood that a snow surface is covered by bedforms increases with time since snowfall and with wind speed and that the likelihood that a surface is covered by sastrugi increases with time and with the highest wind speeds. Our observations will be useful to Earth system modelers and represent a new step toward understanding self‐organized processes that ornament 8% of the surface of the planet. Wind‐swept snow does not lie flat. It self‐organizes and forms dunes, ripples, and anvil‐shaped sastrugi. These textures cover about 8% of the surface of the Earth. They absorb more light and heat than flat snow, but they are not yet included in major climate models. We observed many fields of bedforms in the Colorado Front Range. We used these data to create and test rules that predict when snow surfaces are flat, when they form bedforms, and when they form sastrugi. These are intended to allow snow and Earth system modelers to estimate and forecast the extent of snow bedforms. We identify the wind speeds and weather variables which exert the greatest control on the shapes of snow surfaces. Snow scientists will be able to use our results to predict the behavior of wind‐blown snow more reliably from less data. Finally, our results point toward the forces that which drive the self‐organization of wind‐blown snow, which may inspire new process‐based studies of snow movement around the Earth. We collected 736 hr of time‐lapse footage documenting the evolution of snow bedforms in the Colorado Front RangeWe built and tested classifiers that predict bedform presence as a function of weatherBedform and sastrugi presence is best predicted by time since snowfall, instantaneous wind speeds, and maximum wind speeds

Burst activity is a ubiquitous feature of thalamic neurons and is well documented for visual neurons in the lateral geniculate nucleus (LGN). Although bursts are often associated with states of drowsiness, they are also known to convey visual information to cortex and are particularly effective in evoking cortical responses. The occurrence of thalamic bursts depends on (1) the inactivation gate of T-type Ca2+channels (T-channels), which become de-inactivated following periods of increased membrane hyperpolarization, and (2) the opening of the T-channel activation gate, which has voltage-threshold and rate-of-change (δv/δt) requirements. Given the time/voltage relationship for the generation of Ca2+potentials that underlie burst events, it is reasonable to predict that geniculate bursts are influenced by the luminance contrast of drifting grating stimuli, with the null phase of higher contrast stimuli evoking greater hyperpolarization followed by a larger dv/dt than the null phase of lower contrast stimuli. To determine the relationship between stimulus contrast and burst activity, we recorded the spiking activity of cat LGN neurons while presenting drifting sine-wave gratings that varied in luminance contrast. Results show that burst rate, reliability, and timing precision are significantly greater with higher contrast stimuli compared with lower contrast stimuli. Additional analysis from simultaneous recordings of synaptically connected retinal ganglion cells and LGN neurons further reveals the time/voltage dynamics underlying burst activity. Together, these results support the hypothesis that stimulus contrast and the biophysical properties underlying the state of T-type Ca2+channels interact to influence burst activity, presumably to facilitate thalamocortical communication and stimulus detection.

We explore two ways in which the mechanical properties of rock potentially influence fluvial incision and sediment transport within a watershed: rock erodibility is inversely proportional to rock cohesion, and fracture spacing influences the initial grain sizes produced upon erosion. Fault‐weakened zones show these effects well because of the sharp strength gradients associated with localized shear abrasion. A natural example of fault erosion is used to motivate our calibration of a generalized landscape evolution model. Numerical experiments are used to study the sensitivity of river erosion and transport processes to variable degrees of rock weakening. In the experiments, rapid erosion and transport of fault gouge steers surface runoff, causing high‐order channels to become confined within the structure of weak zones when the relative degree of rock weakening exceeds 1 order of magnitude. Erosion of adjacent, intact bedrock produces relatively coarser grained gravels that accumulate in the low relief of the eroded weak zone. The thickness and residence time of sediments stored there depends on the relief of the valley, which in these models depends on the degree of rock weakening. The frequency with which the weak zone is armored by bed load increases with greater weakening, causing the bed load to control local channel slope. Conversely, small tributaries feeding into the weak zone are predominantly detachment limited. Our results indicate that mechanical heterogeneity can exert strong controls on rates and patterns of erosion and should be considered in future landscape evolution studies to better understand the role of heterogeneity in structuring landscapes. Heavily fractured rocks erode more easily than strong bedrock, and the sediments produced upon erosion are also easier to transport because they tend to be a finer grain size. Larger gravels that come from the erosion of strong bedrock will often be deposited over the weaker rock, causing an armoring effect. The pattern of river drainage tends to reflect the underlying pattern of rock strength. Rock damage associated with shear abrasion locally enhances erodibility and transport of substrateRapid erosion of weak zones causes accumulation of coarse sediments from adjacent sourcesSediment residence time scales with erodibility of weak zone

Instabilities and turbulence extending to the smallest dynamical scales play important roles in the deposition of energy and momentum by gravity waves throughout the atmosphere. However, these dynamics and their effects have been impossible to quantify to date due to lack of observational guidance. Serendipitous optical images of polar mesospheric clouds at ∼82 km obtained by star cameras aboard a cosmology experiment deployed on a stratospheric balloon provide a new observational tool, revealing instability and turbulence structures extending to spatial scales < 20 m. At 82 km, this resolution provides sensitivity extending to the smallest turbulence scale not strongly influenced by viscosity: the “inner scale” of turbulence, l0∼10(ν3/ϵ)1/4. Such images represent a new window into small‐scale dynamics that occur throughout the atmosphere but are impossible to observe in such detail at any other altitude. We present a sample of images revealing a range of dynamics features and employ numerical simulations that resolve these dynamics to guide our interpretation of several observed events. Instabilities and turbulence play key roles in gravity wave momentum depositionNew PMC imaging reveals dynamics extending to the smallest scales of turbulenceNew modeling helps quantify PMC imaging of instability and turbulence dynamics

In this presentation, I propose to describe briefly the rapidly changing demography of the U.S. school population and the implications of these changes for pedagogical practice(s). I will then summarize current research priorities for the language education profession that have recently been articulated by several professional associations and task forces. I will conclude by discussing some of the implications of these suggested research priorities and directions for the work of those concerned with improving the effectiveness of language learning and teaching through the use of innovative technologies.

Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC50 of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras 1, as well as selectivity (ratio of IC50 on parental RAT2 cells/ IC50 on Ras1 cells > 2000). Moreover this compound also showed encouraging “in vivo” activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.

Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro data to predict the in vivo consequences of enzyme inhibition, less attention has been given to the quantitative impact of enzyme induction as a mechanism of drug-drug interaction (DDI) and as a component of compound selection and early drug development. We discuss current approaches in the context of a mechanistic framework for the prediction of the extent and time-course of enzyme induction in vivo based on in vitro experimentation. Factors influencing the extent of DDI due to CYP induction are summarised, and areas deficient in information that would allow more accurate prediction within target populations are highlighted.

An analysis of reported hepatic abundances of CYP3A4 and 3A5 indicated that values determined by immunoquantification using commercially available, unpurified recombinant enzymes as standards are significantly lower than those determined using purified enzymes or human liver microsomes characterized with lysosomal peptides (CYP3A4: mean 45 versus 121 pmol/mg protein, p < 0.01; CYP3A5: mean 28 versus 83 pmol/mg protein, p < 0.05). When immunoquantifying cytochromes P450 (P450s), it is assumed that the holoprotein (holo)/apoprotein ratio is the same in the samples and the standard. Estimates of holo/apoprotein ratios from data reported for a range of P450s purified from human liver and non-commercial recombinant systems indicated less than complete and variable heme coupling dependent on enzyme and system.

The published literature on mechanism based inhibition (MBI) of CYPs was evaluated with respect to experimental design, methodology and data analysis. Significant variation was apparent in the dilution factor, ratio of preincubation to incubation times and probe substrate concentrations used, and there were some anomalies in the estimation of associated kinetic parameters (kinact, K I, r). The impact of the application of inaccurate values of kinact and KI when extrapolating to the extent of inhibition in vivo is likely to be greatest for those compounds of intermediate inhibitory potency, but this also depends on the fraction of the net clearance of substrate subject to MBI and the pre-systemic and systemic exposure to the inhibitor. For potent inhibitors, the experimental procedure is unlikely to have a material influence on the maximum inhibition. Nevertheless, the bias in the values of the kinetic parameters may influence the time for recovery of enzyme activity following re-synthesis of the enzyme. Careful attention to the design of in vitro experiments to obtain accurate kinetic parameters is necessary for a reliable prediction of different aspects of the in vivo consequences of MBI. The review calls for experimental studies to quantify the impact of study design in studies of MBI, with a view to better harmonisation of protocols.

The potency of methylenedioxymethamphetamine (MDMA) as a mechanism-based inhibitor of CYP2D6 has been defined using microsomes prepared from yeast expressing the enzyme and from three human livers. The inhibitory effect was increased by preincubation through formation of a metabolic intermediate complex. Inactivation parameters (kinact and KI), defined with respect to the O-demethylation of dextromethorphan, were 0.29 ± 0.03 (S.E.) min-1 and 12.9 ± 3.6 (S.E.) µM for yeast-expressed CYP2D6, and 0.26 ± 0.02 min-1 and 14.4 ± 2.5 µM, 0.15 ± 0.01 min-1 and 8.8 ± 2.6 µM, and 0.12 ± 0.05 min-1 and 45.3 ± 32.1 µM for the liver microsomal preparations. The rate of inactivation of CYP2D6 by MDMA decreased when quinidine, a competitive inhibitor of CYP2D6, was added to the primary incubation mixture. However, inactivation was unaffected by the addition of glutathione. The results indicate that MDMA is a potent mechanism-based inhibitor of CYP2D6, with implications for understanding its in vivo disposition and drug interaction potential.

The synthesis and structure−activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16−F10 metastasis model and display very good pharmacokinetic parameters.

Various facets of the general topic of multilingualism, including language contact, have been dealt with in previous ARAL volumes (e.g., under separate entries in volumes 1, 2, 4, 5, 10, 12, 13, and 15) and as a major substantive focus in volumes 6, 14 and 17. Nonetheless, it does not seem at all surprising that we return to the specific topic of language contact and change in volume 23 given the worldwide incidence of the phenomenon and the attention, and often controversy, which various aspects of language contact, language change or language loss arouses. Thus, I find it interesting that, within the past 12 months, issues related to language contact and derivative implications have surfaced as important factors in public discussions in such disparate settings as the November 2002 elections in several of the states in the United States, the admission of new members to the European Union, and immigration to Australia. Clearly, the topics of language contact and language change are salient and likely to remain so for the foreseeable future.

Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active 1-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery.

Despite the recognition of secondary ‘modal’ resources such as modal adjectives and adverbs, there has been relatively little discussion of the full extent of their contribution to the expression of modal meaning in general. In this corpus-based study, I focus exclusively on the adverb possibly and describe the range of environments that are revealed by a data set of 2000 randomly selected citations. On the basis of the observed data, I argue for a single core sense of possibly that distinguishes it both from modal operators, such as may/might and from closely related adverbs such as perhaps and maybe. I also argue that, beyond the stereotypical function of possibly as a modal adjunct, there is massive evidence to suggest that it functions additionally as a modalising element in units at the lower rank of group. I therefore propose a revision to the structure of these units to incorporate the expression of modal meaning.

The 1'-hydroxylation of rac-bufuralol, which is catalyzed by polymorphic CYP2D6 in humans, was studied in brain microsomes from male and female Wistar rats and from the female Dark Agouti rat, a model of the CYP2D6 poor metabolizer phenotype. The kinetics of the 1'-hydroxylation of bufuralol (1-1500 microM) by brain microsomes were biphasic. The activity of the high-affinity site of metabolism was consistent with Michaelis-Menten kinetics (apparent K(m1) = 0. 61-1.42 microM, V(max1) = 4.3-4.8 fmol/min/mg of protein), whereas the low-affinity activity was better described by a Hill function (K(50%(2)) = 253-258 microM, V(max2) = 817-843 fmol/min/mg of protein, n = 1.2-1.3). Values for kinetic constants were similar in all rat strains. Quinine was only a weak inhibitor of both the high- (apparent K(i) = 90 microM) and low-affinity (210 microM) sites of metabolism. In contrast, the kinetics of 1'-hydroxylation of bufuralol by rat liver microsomes were best described by a two-site Michaelis-Menten function. V(max) values were 3 to 5 orders of magnitude greater compared with those for brain microsomes (male and female Wistar), and liver microsomes from female Dark Agouti rats were significantly less active than those from Wistar rats. These data, together with the known potent inhibitory effect of quinine on bufuralol 1'-hydroxylation by rat liver microsomes, indicate tissue-specific differences in the enzymology of this reaction. The role of brain CYP2D enzymes remains to be clarified.

Background and Purpose:Since the advent of subclavian artery percutaneous transluminal angioplasty/stenting, several authorities advocate it as the treatment of choice for patients with subclavian artery disease, claiming results equal to or better than those of reconstructive vascular surgery. However, most of their quoted surgical series included patients who may have other brachiocephalic disease who were treated nonuniformly by means of various bypass grafts with different grafts in the same series (eg, Dacron, polytetrafluoroethylene [PTFE], or vein). In this study, we analyze the long-term results of a large series of carotid-subclavian bypass grafts for subclavian artery disease in which PTFE was uniformly used; the study can be used as a future reference to compare the results of subclavian artery percutaneous transluminal angioplasty/stenting. Patient Population and Methods:Fifty-one patients with symptomatic subclavian artery disease (40 occlusions and 11 stenoses) who were treated with carotid-subclavian bypass grafts (PTFE [Goretex]) during a 20-year period were analyzed. Graft patency was determined clinically and confirmed with Doppler scanning pressures and duplex ultrasound scanning. The cumulative patency, overall survival, and symptom-free survival rates were calculated with the life table method. Results:Indications for surgery were arm ischemia in 34 patients (67%), vertebrobasilar insufficiency (VBI) in 27 (53%), and symptomatic subclavian steal in 7 (14%). A combination of arm ischemia and VBI occurred in 17 (33%) of these patients. The mean follow-up was 7.7 years with a median of 7.0 years (range, 1-19 years). The 30-day morbidity rate was 6%, with no perioperative stroke or mortality. Immediate relief of symptoms was achieved in 100% of patients; however, four patients (8%) had late recurrent symptoms (three with VBI). The primary patency and secondary patency rates at 1, 3, 5, and 10 years were 100%, 98%, 96%, and 92% and 100%, 98%, 98%, and 95%, respectively. The symptom-free survival rates at 1, 3, 5, and 10 years were 100%, 96%, 82%, and 47%, respectively. The overall survival rates at 1, 3, 5, and 10 years were 100%, 98%, 86%, and 57%. The mean hospital stay was 3.5 days in the late 70s and 80s and 2.1 days in the 90s (P<.001). Conclusions:Carotid-subclavian bypass grafts with PTFE grafts for subclavian artery disease are safe, effective, and durable and should remain the procedure of choice, particularly in good-risk patients. (J Vasc Surg 2000;32:411-9.)