This paper presents an axiomatic model of decision making under uncertainty which incorporates objective but imprecise information. Information is assumed to take the form of a ...probability–possibility set, that is, a set
P of probability measures on the state space. The decision maker is told that the true probability law lies in
P and is assumed to rank pairs of the form
(
P
,
f
)
where
f is an act mapping states into outcomes. The key representation result delivers maxmin expected utility (MEU) where the min operator ranges over a set of probability priors—just as in the MEU representation result of Gilboa and Schmeidler Maxmin expected utility with a non-unique prior, J. Math. Econ. 18 (1989) 141–153. However, unlike the MEU representation, the representation here also delivers a mapping,
ϕ
, which links the probability–possibility set, describing the available information, to the set of revealed priors. The mapping
ϕ
is shown to represent the decision maker's attitude to imprecise information: under our axioms, the set of representation priors is constituted as a selection from the probability–possibility set. This allows both expected utility when the selected set is a singleton and extreme pessimism when the selected set is the same as the probability–possibility set, i.e.,
ϕ
is the identity mapping. We define a notion of comparative imprecision aversion and show it is characterized by inclusion of the sets of revealed probability distributions, irrespective of the utility functions that capture risk attitude. We also identify an explicit attitude toward imprecision that underlies usual hedging axioms. Finally, we characterize, under extra axioms, a more specific functional form, in which the set of selected probability distributions is obtained by (i) solving for the “mean value” of the probability–possibility set, and (ii) shrinking the probability–possibility set toward the mean value to a degree determined by preferences.
Since tetrazines are important tools to the field of bioorthogonal chemistry, there is a need for new approaches to synthesize unsymmetrical and 3‐monosubstituted tetrazines. Described here is a ...general, one‐pot method for converting (3‐methyloxetan‐3‐yl)methyl carboxylic esters into 3‐thiomethyltetrazines. These versatile intermediates were applied to the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and in the first catalytic thioether reduction to access monosubstituted tetrazines. This method enables the development of new tetrazine compounds possessing a favorable combination of kinetics, small size, and hydrophilicity. It was applied to a broad range of aliphatic and aromatic ester precursors and to the synthesis of heterocycles including BODIPY fluorophores and biotin. In addition, a series of tetrazine probes for monoacylglycerol lipase (MAGL) were synthesized and the most reactive one was applied to the labeling of endogenous MAGL in live cells.
Divergent tetrazine synthesis: Described is a new strategy for the one‐pot synthesis of 3‐thiomethyltetrazines from carboxylic ester precursors, which provides a platform for the synthesis of unsymmetrical tetrazines through Pd‐catalyzed cross‐coupling and the first catalytic thioether reduction to access monosubstituted tetrazines.
Electrophilic small molecules that can reversibly modify proteins are of growing interest in drug discovery. However, the ability to study reversible covalent probes in live cells can be limited by ...their reversible reactivity after cell lysis and in proteomic workflows, leading to scrambling and signal loss. We describe how thiomethyltetrazines function as reversible covalent warheads for cysteine modification, and this dynamic labeling behavior can be “switched off” via bioorthogonal chemistry inside live cells. Simultaneously, the tetrazine serves as a bioorthogonal reporter enabling the introduction of tags for fluorescent imaging or affinity purification. Thiomethyltetrazines can label isolated proteins, proteins in cellular lysates, and proteins in live cells with second-order rate constants spanning 2 orders of magnitude (k 2, 1–100 M–1 s–1). Reversible modification by thiomethyltetrazines can be switched off upon the addition of trans-cyclooctene in live cells, converting the dynamic thiomethyltetrazine tag into a Diels–Alder adduct which is stable to lysis and proteomic workflows. Time-course quenching experiments were used to demonstrate temporal control over electrophilic modification. Moreover, it is shown that “locking in” the tag through Diels–Alder chemistry enables the identification of protein targets that are otherwise lost during sample processing. Three probes were further evaluated to identify unique pathways in a live-cell proteomic study. We anticipate that discovery efforts will be enabled by the trifold function of thiomethyltetrazines as electrophilic warheads, bioorthogonal reporters, and switches for “locking in” stability.
Natural killer (NK) cells play a role in the clearance of viral infections. Combinations of alleles at the polymorphic HLA-B locus and the NK cell surface killer immunoglobulin-like receptor locus ...KIR3DL1/S1 have been shown to influence time to AIDS in HIV-infected individuals and risk of seroconversion in HIV exposed seronegative (HESN) subjects. Here, we assessed time to seroconversion or duration of seronegative status in a group of 168 HIV exposed individuals, including 74 seroconverters and 94 HESN based on carriage or not of KIR3DL1/S1/HLA-B genotypes previously shown to be associated with protection from infection and/or slow time to AIDS. KIR3DL1/S1 genotyping was performed by sequence-specific primer polymerase chain reaction using two pairs of specific primers for each locus. The MHC class IB locus was typed to four-position resolution to resolve Bw4 and Bw6 alleles and the amino acid present at position 80. KIR3DL1/S1 heterozygotes became HIV infected significantly faster than KIR3DS1 homozygotes. Individuals who carried both KIR3DS1 and Bw4*80I did not remain HIV seronegative longer than those from a control group who were homozygous for HLA-Bw6 and carried no HLA-A locus Bw4 alleles Subjects who were *h/*y+B*57 showed a trend towards slower time to serconversion than those with other KIR3DL1 homozygous and KIR3DL1/S1 heterozygous genotypes. Thus, KIR3DS1 homozygosity is associated with protection from HIV infection while co-carriage of KIR3DS1 and Bw4*80I is not. The requirements for protection from HIV infection can differ from those that influence time to AIDS in HIV infected individuals.
The purpose of this study was to examine the effect of an acute bout of prolonged sitting with and without exercise breaks on cerebrovascular function in 7‐ to 13‐year‐old children. Forty‐two ...children and adolescents were recruited to a crossover trial, with 15 girls (mean age 10.1 ± 2.5 years) and 16 boys (mean age 10.5 ± 1.3 years) completing the two trial conditions: SIT, uninterrupted sitting for 3 h and CYCLE, 3 h of sitting interrupted hourly with a 10‐min moderate intensity exercise break. Cerebrovascular function was measured Pre and Post SIT and CYCLE from blood flow (Q̇${\dot{Q}}$), diameter, and shear rate of the internal carotid artery (ICA) at rest and in response to CO2. Blood velocity in the middle (MCA) and posterior (PCA) cerebral arteries was assessed at rest, during a neurovascular coupling task (NVC) and in response to CO2. We demonstrate that SIT but not CYCLE reduced ICA cerebrovascular reactivity to CO2 (%Δ ICA Q̇${\dot{Q}}$/Δ end‐tidal CO2: SIT: Pre 5.0 ± 2.4%/mmHg to Post 3.3 ± 2.8%/mmHg vs. CYCLE: Pre 4.4 ± 2.3%/mmHg to Post 5.3 ± 3.4%/mmHg, P = 0.05) and slowed the MCA blood velocity onset response time to hypercapnia (SIT: Pre 57.2 ± 32.6 s to Post 76.6 ± 55.2 s, vs. CYCLE: Pre 64.1 ± 40.4 s to Post 52.3 ± 28.8 s, P = 0.05). There were no changes in NVC. Importantly, breaking up prolonged sitting with hourly exercise breaks prevented the reductions in cerebrovascular reactivity to CO2 and the slowed intracranial blood velocity onset response time to hypercapnia apparent with uninterrupted sitting in children.
New Findings
What is the central question of this study?
What are the effects of interrupting prolonged sitting on cerebrovascular function in children?
What is the main finding and its importance?
Prolonged sitting results in declines in cerebrovascular reactivity, a valuable index of cerebrovascular health. Breaking up prolonged sitting with hourly 10 min exercise breaks prevented these changes. These initial findings suggest excessive sedentary behaviour does impact cerebrovascular function in childhood, but taking exercise breaks prevents declines.
The DSHEA is 30 years old and its place in providing legitimate protections for public health through relevant agency oversight has created a patchwork of legal and scientific requirements. In ...contrast, the European Union has rules on supplements and permitted ingredients. Given the context of a global supply chain for food ingredients any conflict between the legality of ingredients between the U.S/EU can inhibit the economic viability of international trade. The purpose of this review is to contrast these different systems of legislative oversight. The analysis of both markets demonstrates a fragmentation in what are considered legal food ingredients between country wide harmonization and state rules and related interpretation. There are many commonalities in this regard between the U.S/EU, from borderline medicinal classifications to their resultant preclusion from food use. However, the codified legal system existing within the EU and excessive guidance can be viewed as time consuming and inflexible, especially for placing new ingredients on the market. The US in contrast is in a holding pattern for legislative interpretation regarding NDIs, GRAS and possible drug preclusion laws. As we hit the anniversary of the DSHEA recent commentary from U.S./EU central authorities point to increased international co-operation in ingredient safety assessments but whether this results in friction-free access between markets is to be determined.
Beta-alanine in blood-plasma when administered as A) histidine dipeptides (equivalent to 40 mg . kg(-1) bwt of beta-alanine) in chicken broth, or B) 10, C) 20 and D) 40 mg . kg(-1) bwt beta-alanine ...(CarnoSyn, NAI, USA), peaked at 428 +/- SE 66, 47 +/- 13, 374 +/- 68 and 833 +/- 43 microM. Concentrations regained baseline at 2 h. Carnosine was not detected in plasma with A) although traces of this and anserine were found in urine. Loss of beta-alanine in urine with B) to D) was <5%. Plasma taurine was increased by beta-alanine ingestion but this did not result in any increased loss via urine. Pharmacodynamics were further investigated with 3 x B) per day given for 15 d. Dietary supplementation with I) 3.2 and II) 6.4 g . d(-1) beta-alanine (as multiple doses of 400 or 800 mg) or III) L-carnosine (isomolar to II) for 4 w resulted in significant increases in muscle carnosine estimated at 42.1, 64.2 and 65.8%.
Context. Among optical stellar interferometers, the CHARA Array located at Mt Wilson in California offers the potential of very long baselines (up to 330 m) and the prospect of coupling multiple beam ...combiners. This paper presents the principle and the measured performance of VEGA, Visible spEctroGraph and polArimeter installed in September 2007 at the coherent focus of the array. Aims. With 0.3 ms of arc of spatial resolution and up to $30 000$ of spectral resolution, VEGA intends to measure fundamental parameters of stars, to study stellar activities and to image and analyze circumstellar environments. We describe the observing modes that have been implemented for this spectro-polarimeter and show actual performances measured on the sky during the first observing runs. Methods. The astrophysical programs are described in relation to the observing modes of the instrument, the presentation of the spectrograph and of the interface table is shown and finally the data is presented. We discuss the perspectives of further development in the framework of the CHARA Array. Results. We show that VEGA/CHARA is fully operational. The current limiting magnitude is nearly 7 but the results depend on the observing conditions (seeing, spectral resolution, etc.). We have validated the stability of the instrumental visibility at the level of 1 to 2% over half an hour and of the instrumental polarization for various declinations. Some examples of squared visibility and differential visibility are presented. Conclusions. The spectro-polarimeter VEGA has been installed and successfully tested on CHARA. It will permit stellar physics studies at unprecedented spectral and spatial resolutions.
New Findings
What is the central question of this study?
Gonadal hormones modulate cerebrovascular function while insulin‐like growth factor 1 (IGF‐1) facilitates exercise‐mediated cerebral ...angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF‐1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown.
What is the main finding and its importance?
Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise‐induced improvements in cerebrovascular function are attainable as early as the first decade of life.
Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia (CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$) are modulated by gonadal hormone activity, while insulin‐like growth factor 1 facilitates exercise‐mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ in n = 128 adolescents characterised as endurance‐exercise trained (males: n = 30, females: n = 36) or untrained (males: n = 29, females: n = 33). Participants were further categorised as pre‐ (males: n = 35, females: n = 33) or post‐ (males: n = 24, females: n = 36) peak height velocity (PHV) to determine pubertal or ‘maturity’ status. Three‐factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$. Data are reported as group means (SD). Pre‐PHV youth demonstrated elevated gCBF and slower CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response times than post‐PHV counterparts (both: P ≤ 0.001). gCBF was only elevated in post‐PHV trained males when compared to untrained counterparts (634 (43) vs. 578 (46) ml min−1; P = 0.007). However, CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response time was faster in pre‐ (72 (20) vs. 95 (29) s; P ≤ 0.001), but not post‐PHV (P = 0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post‐PHV youth (r2 = 0.19; P ≤ 0.001) and CVRCO2${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}$ mean response time in pre‐PHV youth (r2 = 0.13; P = 0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype.
We sought to examine in individuals with SARS-CoV-2 infection whether risk for thrombotic and thromboembolic events (TTE) is modified by presence of a diabetes diagnosis. Furthermore, we analysed ...whether differential risk for TTEs exists in type 1 diabetes mellitus (T1DM) versus type 2 diabetes mellitus (T2DM).
Retrospective case-control study.
The December 2020 version of the
COVID-19 database is a deidentified, nationwide database containing electronic medical record (EMR) data from 87 US-based health systems.
We analysed EMR data for 322 482 patients >17 years old with suspected or confirmed SARS-CoV-2 infection who received care between December 2019 and mid-September 2020. Of these, 2750 had T1DM; 57 811 had T2DM; and 261 921 did not have diabetes.
TTE, defined as presence of a diagnosis code for myocardial infarction, thrombotic stroke, pulmonary embolism, deep vein thrombosis or other TTE.
Odds of TTE were substantially higher in patients with T1DM (adjusted OR (AOR) 2.23 (1.93-2.59)) and T2DM (AOR 1.52 (1.46-1.58)) versus no diabetes. Among patients with diabetes, odds of TTE were lower in T2DM versus T1DM (AOR 0.84 (0.72-0.98)).
Risk of TTE during COVID-19 illness is substantially higher in patients with diabetes. Further, risk for TTEs is higher in those with T1DM versus T2DM. Confirmation of increased diabetes-associated clotting risk in future studies may warrant incorporation of diabetes status into SARS-CoV-2 infection treatment algorithms.
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