7,8-Dihydro-8-oxoguanosine Lesions Inhibit the Theophylline Aptamer or Change Its Selectivity.

Aptamers are attractive constructs due to their high affinity/selectivity towards a target. Here 7,8-dihydro-8-oxoguanosine (8-oxoG) has been used, due in part to its unique H-bonding capabilities (Watson-Crick or Hoogsteen), to expand the "RNA alphabet". Its impact on the theophylline RNA aptamer was explored by modifying its binding pocket at positions G11, G25, or G26. Structural probing, with RNases A and T1 , showed that modification at G11 leads to a drastic structural change, whereas the G25-/G26-modified analogues exhibited cleavage patterns similar to that of the canonical construct. The recognition properties towards three xanthine derivatives were then explored through thermophoresis. Modifying the aptamer at position G11 led to binding inhibition. Modification at G25, however, changed the selectivity towards theobromine (Kd ≈160 µm), with a poor affinity for theophylline (Kd >1.5 mm) being observed. Overall, 8-oxoG can have an impact on the structures of aptamers in a position-dependent manner, leading to altered target selectivity.

Experimental and theoretical rationalization for the base pairing abilities of inosine, guanosine, adenosine, and their corresponding 8-oxo-7,8-dihydropurine, and 8-bromopurine analogues within A-form duplexes of RNA.

Inosine is an important RNA modification, furthermore RNA oxidation has gained interest due, in part, to its potential role in the development/progression of disease as well as on its impact on RNA structure and function. In this report we established the base pairing abilities of purine nucleobases G, I, A, as well as their corresponding, 8-oxo-7,8-dihydropurine (common products of oxidation at the C8-position of purines), and 8-bromopurine (as probes to explore conformational changes), derivatives, namely 8-oxoG, 8-oxoI, 8-oxoA, 8-BrG, and 8-BrI. Dodecamers of RNA were obtained using standard phosphoramidite chemistry via solid-phase synthesis, and used as models to establish the impact that each of these nucleobases have on the thermal stability of duplexes, when base pairing to canonical and noncanonical nucleobases. Thermal stabilities were obtained from thermal denaturation transition (Tm ) measurements, via circular dichroism (CD). The results were then rationalized using models of base pairs between two monomers, via density functional theory (DFT), that allowed us to better understand potential contributions from H-bonding patterns arising from distinct conformations. Overall, some of the important results indicate that: (a) an anti-I:syn-A base pair provides thermal stability, due to the absence of the exocyclic amine; (b) 8-oxoG base pairs like U, and does not induce destabilization within the duplex when compared to the pyrimidine ring; (c) a U:G wobble-pair is only stabilized by G; and (d) 8-oxoA displays an inherited base pairing promiscuity in this sequence context. Gaining a better understanding of how this oxidatively generated lesions potentially base pair with other nucleobases will be useful to predict various biological outcomes, as well as in the design of biomaterials and/or nucleotide derivatives with biological potential.

Evaluating consumptive and nonconsumptive predator effects on prey density using field time-series data.

Determining the degree to which predation affects prey abundance in natural communities constitutes a key goal of ecological research. Predators can affect prey through both consumptive effects (CEs) and nonconsumptive effects (NCEs), although the contributions of each mechanism to the density of prey populations remain largely hypothetical in most systems. Common statistical methods applied to time-series data cannot elucidate the mechanisms responsible for hypothesized predator effects on prey density (e.g., differentiate CEs from NCEs), nor can they provide parameters for predictive models. State-space models (SSMs) applied to time-series data offer a way to meet these goals. Here, we employ SSMs to assess effects of an invasive predatory zooplankter, Bythotrephes longimanus, on an important prey species, Daphnia mendotae, in Lake Michigan. We fit mechanistic models in an SSM framework to seasonal time series (1994-2012) using a recently developed, maximum-likelihood-based optimization method, iterated filtering, which can overcome challenges in ecological data (e.g., nonlinearities, measurement error, and irregular sampling intervals). Our results indicate that B. longimanus strongly influences D. mendotae dynamics, with mean annual peak densities of B. longimanus observed in Lake Michigan estimated to cause a 61% reduction in D. mendotae population growth rate and a 59% reduction in peak biomass density. Further, the observed B. longimanus effect is most consistent with an NCE via reduced birth rates. The SSM approach also provided estimates for key biological parameters (e.g., demographic rates) and the contribution of dynamic stochasticity and measurement error. Our study therefore provides evidence derived directly from survey data that the invasive zooplankter B. longimanus is affecting zooplankton demographics and offer parameter estimates needed to inform predictive models that explore the effect of B. longimanus under different scenarios, such as climate change.

Orthogonality Catastrophe in Dissipative Quantum Many-Body Systems.

We present an analog of the phenomenon of orthogonality catastrophe in quantum many-body systems subject to a local dissipative impurity. We show that the fidelity F(t), giving a measure for distance of the time-evolved state from the initial one, displays a universal scaling form F(t)∝t^{θ}e^{-γt}, when the system supports long-range correlations, in a fashion reminiscent of traditional instances of orthogonality catastrophe in condensed matter. An exponential falloff at rate γ signals the onset of environmental decoherence, which is critically slowed down by the additional algebraic contribution to the fidelity. This picture is derived within a second-order cumulant expansion suited for Liouvillian dynamics, and substantiated for the one-dimensional transverse field quantum Ising model subject to a local dephasing jump operator, as well as for XY and XX quantum spin chains, and for the two-dimensional Bose gas deep in the superfluid phase with local particle heating. Our results hint that local sources of dissipation can be used to inspect real-time correlations and to induce a delay of decoherence in open quantum many-body systems.

Photocycloaddition of S,S-Dioxo-benzothiophene-2-methanol, Reactivity in the Solid State and in Solution: Mechanistic Studies and Diastereoselective Formation of Cyclobutyl Rings.

The formation of cyclobutane rings is a promising strategy in the development of potential drugs and/or synthetic intermediates, typically challenging to obtain due to their constrained nature. In this work, the [2 + 2] photocycloaddition reaction of S,S-dioxobenzothiophene-2-methanol was explored in microcrystalline powders and its outcome was compared to that observed in solution. It was found that the molecular constraints inherited within the crystal lattice provide an optimal environment that leads to photodimer 4 as the major product in ca. 9.6:0.4 diastereomeric ratios with conversions >95%. The photoreaction was analyzed via X-ray, displaying a crystalline-to-amorphous transformation and showing that units of monomer 2 align to generate the corresponding dimer with a syn-head-to-tail regio- and diastereoselectivity. This result contrasted with that obtained in solution, where the diastereomeric ratio varied as a function of the excited state that is generated, to yield mixtures of dimers 4 and 5 (anti-head-to-tail), or exclusively 5 in the triplet-sensitized photoreaction, in the presence of benzophenone. Density functional theory was used to elucidate a plausible detailed mechanism for the phototransformation, which aided in justifying the results that led to the corresponding dimers. X-ray crystallography allowed us to establish the stereochemical assignment of the obtained cyclobutyl rings. Thus, the use of solid-state or solution photochemistry can be used to gain control of diastereo- and regioselectivities in the formation of this important moiety.

Managing menopausal symptoms after cancer.

The joint burden of cancer and menopause impacts millions of women globally. This review provides an approach to management of menopausal symptoms after cancer in all settings. This includes an overview of current evidence for both hormonal and non-hormonal treatments for vasomotor symptoms and vaginal dryness after cancer. Systemic menopausal hormone therapy provides symptom control and may be used after most cancers but should be avoided after estrogen receptor-positive breast cancer and after some other estrogen-dependent cancers. Non-hormonal therapies have been minimally studied in women after a cancer diagnosis and, where they have been studied, it is usually in women with breast cancer. Non-hormonal methods to manage vasomotor symptoms include cognitive behavioral therapy, hypnosis, selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, clonidine, and gabapentin. Vaginal estrogen may be useful to address vaginal dryness. However, safety data in breast cancer patients are still lacking and there is currently no consensus. Lubricants may also help with pain with sexual activity. Management of menopausal symptoms after cancer may be challenging and should include information about induced menopause and possible symptoms as well as available treatments. Management then requires a holistic and multidisciplinary approach with individualized care.

Biophysical properties, thermal stability and functional impact of 8-oxo-7,8-dihydroguanine on oligonucleotides of RNA-a study of duplex, hairpins and the aptamer for preQ1 as models.

8-10: A better understanding of the effects that oxidative lesions have on RNA is of importance to understand their role in the development/progression of disease. 8-oxo-7,8-dihydroguanine was incorporated into RNA to understand its structural and functional impact on RNA:RNA and RNA:DNA duplexes, hairpins and pseudoknots. One to three modifications were incorporated into dodecamers of RNA [AAGA GGG AUGAC] resulting in thermal destabilization (Δ T m - 10°C per lesion). Hairpins with tetraloops c-UUCG*-g* ( ), a-ACCG-g* ( ), c-UUG*G*-g* ( ) and c-ACG*G*-g* ( ) were modified and used to determine thermal stabilities, concluding that: (i) modifying the stem leads to destabilization unless adenosine is the opposing basepair of 8-oxoGua; (ii) modification at the loop is position- and sequence-dependent and varies from slight stabilization to large destabilization, in some cases leading to formation of other secondary structures (hairpin→duplex). Functional effects were established using the aptamer for preQ 1 as model. Modification at G5 disrupted the stem P1 and inhibited recognition of the target molecule 7-methylamino-7-deazaguanine (preQ 1 ). Modifying G11 results in increased thermal stability, albeit with a K d 4-fold larger than its canonical analog. These studies show the capability of 8-oxoG to affect structure and function of RNA, resulting in distinct outcomes as a function of number and position of the lesion.

Reactivity and Specificity of RNase T1, RNase A, and RNase H toward Oligonucleotides of RNA Containing 8-Oxo-7,8-dihydroguanosine.

Understanding how oxidatively damaged RNA interacts with ribonucleases is important because of its proposed role in the development and progression of disease. Thus, understanding structural aspects of RNA containing lesions generated under oxidative stress, as well as its interactions with other biopolymers, is fundamental. We explored the reactivity of RNase A, RNase T1, and RNase H toward oligonucleotides of RNA containing 8-oxo-7,8-dihydroguanosine (8oxoG). This is the first example that addresses this relationship and will be useful for understanding (1) how these RNases can be used to characterize the structural impact that this lesion has on RNA and (2) how oxidatively modified RNA may be handled intracellularly. 8-OxoG was incorporated into 10-16-mers of RNA, and its reactivity with each ribonuclease was assessed via electrophoretic analyses, circular dichroism, and the use of other C8-purine-modified analogues (8-bromoguanosine, 8-methoxyguanosine, and 8-oxoadenosine). RNase T1 does not recognize sites containing 8-oxoG, while RNase A recognizes and cleaves RNA at positions containing this lesion while differentiating if it is involved in H-bonding. The selectivity of RNase A followed the order C > 8-oxoG ≈ U. In addition, isothermal titration calorimetry showed that an 8-oxoG-C3'-methylphosphate derivative can inhibit RNase A activity. Cleavage patterns obtained from RNase H displayed changes in reactivity in a sequence- and concentration-dependent manner and displayed recognition at sites containing the modification in some cases. These data will aid in understanding how this modification affects reactivity with ribonucleases and will enable the characterization of global and local structural changes in oxidatively damaged RNA.

Smokers Display Reduced Glucocorticoid Sensitivity Prior to Symptomatic Chronic Disease Development.

Background: Chronic stress plays a critical role in many of today's diseases and causes of death. Tobacco use reliably increases the likelihood of chronic disease development and premature death. In addition, habitual tobacco use elevates risk of chronic inflammatory diseases, and glucocorticoid therapy is often less effective in smokers compared with nonsmokers. Taken together, smokers may develop glucocorticoid insensitivity, thereby removing the body's greatest anti-inflammatory mechanism. Purpose: The purpose of this study was to examine glucocorticoid sensitivity among 24 smokers and 24 age-, sex-, and body mass index-matched never smokers who were clinically healthy individuals (i.e., no diagnosis or medication use for chronic diseases and normotensive). Method: Participants visited the lab after a 12 hr fast, provided a blood sample, and completed a series of psychosocial questionnaires. Smokers continued smoking ad libitum before the lab visit. Group differences in glucocorticoid sensitivity were examined using ANCOVA and repeated with linear mixed model to account for possible dependence among immune outcomes that matching participants on age, sex, and body mass index may have introduced. Results: Prior to clinical disease onset, smokers' peripheral blood mononuclear cells (PBMCs) exhibited reduced glucocorticoid sensitivity as well as a diminished inflammatory response to lipopolysaccharide compared with never smokers' PBMCs; results were identical regardless of statistical modeling used. Conclusions: Cigarette smoking, a self-initiated pharmacological chronic stressor, may provide a unique opportunity to examine early wear and tear on physiological functioning that may lead to chronic disease development. Additional research into PBMCs' intracellular changes must be examined as well as repeating this study in a larger, more heterogeneous population.

8-Oxo-7,8-dihydroadenine and 8-Oxo-7,8-dihydroadenosine-Chemistry, Structure, and Function in RNA and Their Presence in Natural Products and Potential Drug Derivatives.

A description and history of the role that 8-oxo-7,8-dihydroadenine (8-oxoAde) and 8-oxo-7,8-dihydroadenosine (8-oxoA) have in various fields has been compiled. This Review focusses on 1) the formation of this oxidatively generated modification in RNA, its interactions with other biopolymers, and its potential role in the development/progression of disease; 2) the independent synthesis and incorporation of this modified nucleoside into oligonucleotides of RNA to display the progress that has been made in establishing its behavior in biologically relevant systems; 3) reported synthetic routes, which date back to 1890, along with the progress that has been made in the total synthesis of the nucleobase, nucleoside, and their corresponding derivatives; and 4) the isolation, total synthesis, and biological activity of natural products containing these moieties as the backbone. The current state of research regarding this oxidatively generated lesion as well as its importance in the context of RNA, natural products, and potential as drug derivatives is illustrated using all available examples reported to date.

Maternal factors and the risk of birth defects after IVF and ICSI: a whole of population cohort study.

OBJECTIVE: To assess the contribution of maternal factors to major birth defects after in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and natural conception. DESIGN: Retrospective cohort study in South Australia for the period January 1986 to December 2002. SETTING: A whole of population study. POPULATION: A census of all IVF and ICSI linked to registries for births, pregnancy terminations, and birth defects (diagnosed before a child's fifth birthday). METHODS: Odds ratios (ORs) for birth defects were calculated among IVF, ICSI, and natural conceptions for maternal age, parity, pre-pregnancy BMI, smoking, pre-existing diseases, and conditions in pregnancy, with adjustment for confounding factors. MAIN OUTCOME MEASURES: Birth defects classified by International Classification of Diseases (ninth revision) and British Paediatric Association (ICD9-BPA) codes. RESULTS: There were 2211 IVF, 1399 ICSI, and 301 060 naturally conceived births. The unadjusted prevalence of any birth defect was 7.1, 9.9, and 5.7% in the IVF, ICSI, and natural conception groups, respectively. As expected, the risk of birth defects increased with maternal age among the natural conceptions. In contrast, for IVF and ICSI combined, relative to natural conceptions, births to women aged ≤29 years had a higher risk (adjusted odds ratio, aOR 1.42; 95% confidence interval, 95% CI 1.04-1.94), births to women aged 35-39 years had no difference in risk (aOR 1.01; 95% CI 0.74-1.37), and births to women aged ≥40 years had a lower risk of defects (aOR 0.45; 95% CI 0.22-0.92). Defects were also elevated for nulliparity, anaemia, and urinary tract infection in births after ICSI, but not after IVF. CONCLUSIONS: The usual age-birth defect relationship is reversed in births after IVF and ICSI, and the associations for other maternal factors and defects vary between IVF and ICSI. TWEETABLE ABSTRACT: Risk of birth defects in women over 40 years is lower after infertility treatment than for natural conceptions.

B Cell Depletion With an Anti-CD20 Antibody Enhances Alloreactive Memory T Cell Responses After Transplantation.

Alloreactive memory T cells mediate accelerated allograft rejection and transplant tolerance resistance. Recent studies have shown that B cell deficient-µMT mice fail to mount donor-specific memory T cell responses after transplantation. At the same time, other studies showed that pretransplant B cell depletion using rituximab (IgG1 anti-CD20 mAb) combined with cyclosporine A promoted the survival of islet allografts in monkeys. In this study, we investigated the effect of anti-CD20 antibody-mediated B cell depletion on the memory T cell alloresponse in mice. Wild-type and anti-OVA TCR transgenic mice were treated with an IgG2a anti-CD20 monoclonal antibody, which depleted nearly all B cells in the peripheral blood and secondary lymphoid organs but spared some B cells in the bone marrow. B cell depletion did not affect the direct alloresponse but resulted in a marked increase of indirect alloresponse after skin transplantation of naïve mice. Furthermore, in allosensitized mice, anti-CD20 mAb treatment enhanced the reactivation of allospecific memory T cells and accelerated second set rejection of skin allografts. This suggests that the effect of anti-CD20 antibodies on alloimmunity and allograft rejection might vary upon the nature of the antibodies as well as the circumstances under which they are delivered.

Synthesis, Thermal Stability, Biophysical Properties, and Molecular Modeling of Oligonucleotides of RNA Containing 2'-O-2-Thiophenylmethyl Groups.

Dodecamers of RNA [CUACGGAAUCAU] were functionalized with C2'-O-2-thiophenylmethyl groups to obtain oligonucleotides 10-14 and 17. The modified nucleotides were incorporated into RNA strands via solid-phase synthesis. The biophysical properties of these ONs were used to quantify the effects of this modification on RNA:RNA and RNA:DNA duplexes. A combination of UV-vis and circular dichroism were used to determine thermal stabilities of all strands, which hybridized into A-form geometries. Destabilization of the double stranded RNA was measured as a function of number of consecutive modifications, reflected in decreased thermal denaturation values (ΔTm, ca. 2.5-11.5 °C). Van't Hoff plots on a duplex containing one modification (10:15) displayed a ca. ΔΔG° of +4 kcal/mol with respect to its canonical analogue. Interestingly, hybridization of two modified strands (13:17, containing a total of eight modifications) resulted in increased stability and a distinct secondary structure, reflected in its CD spectrum. Molecular modeling based on DFT calculations shed light on the nature of this stability, with induced changes in the torsional angle δ (C5'-C4'-C3'-O3) and phosphate-phosphate distances that are in agreement with a compacted structure. The described synthetic methodology and structural information will be useful in the design of thermodynamically stable structures containing chemically reactive modifications.

Parasites, pathological conditions and resistance to Marteilia cochillia in lagoon cockle Cerastoderma glaucum from Galicia (NW Spain).

A histopathological survey revealed parasites and pathological conditions affecting lagoon cockles Cerastoderma glaucum along the Galician coast; serious pathological threats were not detected because the potentially pathogenic conditions (infections with a Marteilia-like parasite and bucephalid sporocysts, disseminated neoplasia and a condition involving large foci of heavy haemocytic reaction) were rare, while more prevalent parasites had negligible or limited pathogeny. Considering that C. edule and C. glaucum are sympatric in some Galician rias, it is remarkable that C. glaucum was not seriously affected by Marteilia cochillia while C. edule suffered an intense outbreak of this parasite associated with massive mortality. Comparison of the digestive gland between cockle species showed co-occurrence of digestive tubules in different phases, with abundant disintegrated tubules, in the case of C. glaucum, while C. edule showed synchronicity and absence of fully disintegrated tubules; these differences could influence their susceptibility to M. cochillia because the main location of this parasite in common cockles is the epithelia of the digestive gland. Moreover, the observation of histological sections through the digestive gland easily allows differentiating the 2 cockle species.

Biophysical properties and thermal stability of oligonucleotides of RNA containing 7,8-dihydro-8-hydroxyadenosine.

Circular dichroism (CD) was used to assess the stabilization/destabilization imposed by oxidative lesion 7,8-dihydro-8-hydroxyadenosine (8-oxoA) on strands of RNA with different structural motifs. RNA:RNA homoduplex destabilization was observed in a position dependent manner using 10-mers as models that displayed differences between 12.7 and 15.1°C. We found that increasing the number of modifications resulted in depressed Tm values of about 12-15°C per lesion. The same effect was observed on RNA:DNA heteroduplex samples. We also tested the effects of this lesion in short hairpins containing the tetraloop UUCX (X = A, 8-oxoA). We found that the stem was hypersensitive to substitution of A by 8-oxoA and that it destabilized the structure by >23°C. Concomitant substitution at the stem and loop prevented formation of this secondary structure or lead to other less-stable hairpins. Incorporation of this lesion at the first base of the loop had no effect on either structure. Overall, we found that the effects of 8-oxoA on RNA structure are position dependent and that its stabilization may vary from sharp decreases to small increments, in some cases, leading to the formation of other more/less stable structures. These structural changes may have larger biological implications, particularly if the oxidatively modified RNA persists, thus leading to changes in RNA reactivity and function.

Comparative analyses of holder pasteurization vs. HTST pasteurization for donor milk: a cost-minimization study applicable to human milk banks.

BACKGROUND: High-temperature short-time (HTST) pasteurization (72-75 °C, 15 s) is an alternative treatment to traditional Holder pasteurization (HoP) (62ºC, 30 min) for donor milk. HTST pasteurization guarantees the milk's microbiological safety and retains more of its biologically and nutritionally active compounds, but the cost of implementing this technology for a human milk bank is unknown. METHODS: A cost-minimization study was carried out on the facilities of a regional human milk bank in a public hospital. Total production costs (fixed plus variables) were quantified using HTST pasteurization and HoP in three hypothetical scenarios: (1) costs of the first 10 L of pasteurized milk in a newly opened milk bank; (2) costs of the first 10 L of pasteurized milk in an active milk bank; and (3) costs using the maximum production capacity of both technologies in the first two years of operation. The following costs were analyzed: health care professionals, equipment and software, external services, and consumables. RESULTS: In scenario 1, the total production costs were € 228,097.00 for the HTST method versus € 154,064.00 for the HoP method. In scenario 2, these costs were similar (€ 6,594.00 for HTST pasteurization versus € 5,912.00 for HoP). The cost of healthcare professionals was reduced by more than half when pasteurization was carried out by the HTST method versus the Holder method (€ 84.00 and € 191.00, respectively). In scenario 3, the unit cost of milk pasteurized by the HTST method decreased from the first to the second year by 43.5%, while for the HoP method, it decreased by 30%. CONCLUSIONS: HTST pasteurization requires a high initial investment in equipment; however, it provides a significant minimization of production costs in the long term, pasteurizes large quantities of donor milk per working day and achieves a more efficient management of the time of the health care professionals in charge of the bank's operation compared to HoP.

Atmosphere injection of sea salts during large explosive submarine volcanic eruptions.

The 15 January 2022 submarine eruption at Hunga volcano was the most explosive volcanic eruption in 140 years. It involved exceptional magma and seawater interaction throughout the entire submarine caldera collapse. The submarine volcanic jet breached the sea surface and formed a subaerial eruptive plume that transported volcanic ash, gas, sea salts and seawater up to ~ 57 km, reaching into the mesosphere. We document high concentrations of sea salts in tephra (volcanic ash) collected shortly after deposition. We also discuss the potential climatic consequences of large-scale injection of salts into the upper atmosphere during submarine eruptions. Sodium chloride in these volcanic plumes can reach extreme concentrations, and dehalogenation of chlorides and bromides poses the risk of long-term atmospheric and weather impact. Salt content in rapidly collected tephra samples may also be used as a proxy to estimate the water:magma ratio during eruption, with implications for quantification of fragmentation efficiency in submarine breaching events. The balance between salt loading into the atmosphere versus deposition in ash aggregates is a key factor in understanding the atmospheric and climatic consequences of submarine eruptions.

Increased metabolic rate and insulin sensitivity in male mice lacking the carcino-embryonic antigen-related cell adhesion molecule 2.

AIMS/HYPOTHESIS: The carcino-embryonic antigen-related cell adhesion molecule (CEACAM)2 is produced in many feeding control centres in the brain, but not in peripheral insulin-targeted tissues. Global Ceacam2 null mutation causes insulin resistance and obesity resulting from hyperphagia and hypometabolism in female Ceacam2 homozygous null mutant mice (Cc2 [also known as Ceacam2](-/-)) mice. Because male mice are not obese, the current study examined their metabolic phenotype. METHODS: The phenotype of male Cc2(-/-) mice was characterised by body fat composition, indirect calorimetry, hyperinsulinaemic-euglycaemic clamp analysis and direct recording of sympathetic nerve activity. RESULTS: Despite hyperphagia, total fat mass was reduced, owing to the hypermetabolic state in male Cc2(-/-) mice. In contrast to females, male mice also exhibited insulin sensitivity with elevated ß-oxidation in skeletal muscle, which is likely to offset the effects of increased food intake. Males and females had increased brown adipogenesis. However, only males had increased activation of sympathetic tone regulation of adipose tissue and increased spontaneous activity. The mechanisms underlying sexual dimorphism in energy balance with the loss of Ceacam2 remain unknown. CONCLUSIONS/INTERPRETATION: These studies identified a novel role for CEACAM2 in the regulation of metabolic rate and insulin sensitivity via effects on brown adipogenesis, sympathetic nervous outflow to brown adipose tissue, spontaneous activity and energy expenditure in skeletal muscle.

Photochemical control of RNA structure by disrupting π-stacking.

Photolabile nucleotides that disrupt nucleic acid structure are useful mechanistic probes and can be used as tools for regulating biochemical processes. Previous probes can be limited by the need to incorporate multiple modified nucleotides into oligonucleotides and in kinetic studies by the rate-limiting step in the conversion to the native nucleotide. Photolysis of aryl sulfide 1 produces high yields of 5-methyluridine, and product formation is complete in less than a microsecond. Aryl sulfide 1 prevents RNA hairpin formation and complete folding of the preQ(1) class I riboswitch. Proper folding is achieved in each instance upon photolysis at 350 nm. Aryl sulfide 1 is a novel tool for modulating RNA structure, and formation of 5-methyluridine within a radical cage suggests that it will be useful in kinetic studies.