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A mild, organophotocatalytic N–O bond cleavage of Weinreb amides is disclosed, thereby expanding the chemistry of this venerable motif beyond acylation. This redox neutral process begins to reconcile the ubiquity of N–O bonds in contemporary synthesis with the disproportionately harsh, stoichiometric conditions that are often required for bond cleavage. The strategy is compatible with the parent alkyl derivatives (N–OMe, N–OAlkyl) thereby complementing tailored O-substituent approaches that require N–OAr groups (Ar = electron deficient). A broad range of acyclic and cyclic derivatives are dis-closed (>40 examples, up to 95%) and the synthetic utility of the method is demonstrated in a range of applications. In the case of cyclic Weinreb amide derivatives, this platform enables ambiphilic amide-aldehydes, of varying chain length, to be generated in a single transformation. Inspired by Emil Fischer´s seminal 1908 synthesis of aminoacetaldehyde using sodium amalgam, this method provides a milder route to access this important class of materials. Mechanistically-guided reaction development demonstrates the involvement of a photoinduced SET mechanism (PET), and this has been further advanced to a consecutive photoinduced electron transfer (ConPET) manifold: this has significantly expanded the scope of compatible substrates.

Marine Protected Areas (MPAs) are key tools in addressing the global decline of sharks and rays, with "marine parks" and "shark sanctuaries" of various configurations established to conserve shark populations. There is also a rapidly growing body of telemetry research used to assess MPA performance in shark protection. However, assessments of MPA efficacy in shark and ray conservation are compromised by inconsistent terminology, a lack of standardised approaches to assess how MPAs contribute to the overall conservation of sharks and rays, and ambiguity about integrating movement data into assessment processes. This paper presents a conceptual framework that standardises key terms and uses the concept of Portfolio Risk to fully describe how an MPA may contribute to shark and ray conservation. The framework also demonstrates how movement data can be integrated into the process and presents eight key questions that provide guidance for applying the framework. Understanding an MPA's contribution to shark and ray protection requires explicit consideration of the assessment scope, MPA type and purpose, the range of existing and potential threats, the species biology and ecology, and management and operational contexts. Ultimately, MPA contributions to shark and ray conservation differ according to a complex set of human and natural factors and interactions which should be carefully considered in MPA design, implementation and evaluation. Article Impact statement: Standardization of key terms and use of the portfolio risk concept describe how protected areas contribute to shark and ray conservation. This article is protected by copyright. All rights reserved.

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri., Incidence of food allergy in westernized populations is associated with low abundance of Prevotella. Here, the authors analyse the microbiome of a mother-infant prebirth cohort and find that maternal carriage, but not infant carriage, of P. copri during pregnancy predicts the absence of food allergy in the offspring.

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C–F stereocenter in high enantioselectivity, and is also amenable to stereogenic C–CF3 bonds. Extensive DFT calculations have provided insight into the reaction mechanism and the origin of catalyst selectivity. Crystal structure data shows the dominance of non-covalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and protein data bank mining has indicated benzylic fluorination using this approach has potential for improved potency in several marketed drugs.

Background: A defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions. Objective: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy. Method: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components. Results: SPINK5 variant rs9325071 (A(long rightwards arrow)G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also. Conclusions: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.

Background: High folate status in pregnancy has been implicated in the increased prevalence of allergic disease, but there are no published data relating directly measured folate status in pregnancy to challenge‐proven food allergy among offspring. The study aim was to examine the association between red blood cell (RBC) folate status in trimester three of pregnancy and allergic disease among offspring. Methods: Red blood cell folate levels were measured at 28‐32 weeks’ gestation in a prospective birth cohort (n = 1074). Food allergy outcomes were assessed in 1‐year‐old infants by skin prick testing and subsequent food challenge. Eczema was assessed by questionnaire and clinical review. High trimester three RBC folate was defined as greater than (>) 1360 nmol/L. Binomial regression was used to examine associations between trimester three RBC folate and allergic outcomes, adjusting for potential confounders. Results: Red blood cell folate levels were measured in 88% (894/1064) of pregnant women. The mean concentration was 1695.6 nmol/L (standard deviation 415.4) with 82% (731/894) >1360 nmol/L. There was no evidence of either linear or non‐linear relationships between trimester three RBC folate and allergic outcomes, nor evidence of associations between high RBC folate and food allergy (adjusted risk ratio (aRR) 2.89, 95% CI 0.90‐9.35), food sensitization (aRR 1.72, 95% CI 0.85‐3.49), or eczema (aRR 0.97, 95% CI 0.67‐1.38). Conclusion: The majority of pregnant women in this study had high RBC folate levels. There was no evidence of associations between trimester three RBC folate and food allergy, food sensitization, or eczema among the offspring, although larger studies are required.

Studies from several countries have reported an association between latitudes further from the equator and proxy markers of food allergy prevalence. As latitudes further from the equator are associated with lower sun exposure and vitamin D status (VDS), it has been proposed that low VDS may be a risk factor for food allergy. A range of basic science evidence supports the biological plausibility of this hypothesis; and recent work has identified a cross sectional association between low VDS and challenge proven food allergy in infants. Overall, however, the evidence regarding the relationship between VDS and food allergy remains controversial and the limited longitudinal data are discouraging. In this review we consider the evidence for and against low VDS as a risk factor for food allergy and discuss the possibility that other factors (including genetic variables) may contribute to the inconsistent nature of the available observational evidence. We then discuss whether genetic and/or environmental factors may modify the potential influence of VDS on food allergy risk. Finally, we argue that given the rising burden of food allergy, the balance of available evidence regarding the potential relevance of VDS to this phenomenon, and the inherent limitations of the existing observational data, there is a compelling case for conducting randomised clinical trials of vitamin D supplementation for the prevention of food allergy during early life.

The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n = 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2- and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [peter.vuillermin@deakin.edu.au].

Background Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE‐mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge‐proven food allergy. Objective To prospectively investigate the association between VDI during infancy and challenge‐proven food allergy at 1 year. Methods In a birth cohort (n = 1074), we used a case‐cohort design to compare 25‐hydroxyvitamin D3 (25(OH)D3) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 Results Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg‐allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70–2.22) or 6 months (aRR 0.93, 95% CI 0.41–2.14) and food allergy at 1 year. Conclusions There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.

Background Food allergies pose a considerable worldwide public health burden with incidence as high as one in ten in 12-month old infants. Few food allergy genetic risk variants have yet been identified. The Th2 immune gene IL13 is a highly plausible genetic candidate as it is central to the initiation of IgE-class switching in B cells. Objective Here we sought to investigate whether genetic polymorphisms at IL13 are associated with the development of challenge-proven IgE-mediated food allergy. Method We genotyped nine IL13 ‘tag’ single nucleotide polymorphisms (tag-SNPs) in 367 challenge-proven food allergic cases, 199 food sensitised-tolerant cases and 156 non-food allergic controls from the HealthNuts study. 12-month old infants were phenotyped using open oral food challenges. SNPs were tested using Cochran-Mantel-Haenszel test adjusted for ancestry strata. A replication study was conducted in an independent, co-located sample of four paediatric cohorts consisting of 203 food allergic cases and 330 non-food allergic controls. Replication sample phenotypes were defined by clinical history of reactivity, 95% PPV or challenge and IL13 genotyping was performed. Results IL13 rs1295686 was associated with challenge-proven food allergy in the discovery sample (P=0.003; OR=1.75; CI=1.20-2.53). This association was also detected in the replication sample (P=0.03, OR=1.37, CI=1.03-1.82) and further supported by a meta-analysis (P=0.0006, OR=1.50). However, we cannot rule out an association with food sensitisation. Carriage of the rs1295686 variant A allele was also associated with elevated total plasma IgE. Conclusions We show for the first time, in two independent cohorts, that IL13 polymorphism rs1295686 (in complete linkage disequilibrium with functional variant rs20541) is associated with challenge-proven food allergy. This article is protected by copyright. All rights reserved.

There has been a dramatic rise in the prevalence of IgE-mediated food allergy over recent decades, particularly among infants and young children. The cause of this increase is unknown but one putative factor is a change in the composition, richness and balance of the microbiota that colonize the human gut during early infancy. The coevolution of the human gastrointestinal tract and commensal microbiota has resulted in a symbiotic relationship in which gut microbiota play a vital role in early life immune development and function, as well as maintenance of gut wall epithelial integrity. Since IgE mediated food allergy is associated with immune dysregulation and impaired gut epithelial integrity there is substantial interest in the potential link between gut microbiota and food allergy. Although the exact link between gut microbiota and food allergy is yet to be established in humans, recent experimental evidence suggests that specific patterns of gut microbiota colonization may influence the risk and manifestations of food allergy. An understanding of the relationship between gut microbiota and food allergy has the potential to inform both the prevention and treatment of food allergy. In this paper we review the theory and evidence linking gut microbiota and IgE-mediated food allergy in early life. We then consider the implications and challenges for future research, including the techniques of measuring and analyzing gut microbiota, and the types of studies required to advance knowledge in the field.

Methods The Barwon region, located approximately 100 km south of Melbourne, is centred around the city of Geelong and has metropolitan, rural and coastal communities. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n = 1069 infants). As part of the 12 month review infants undergo skin prick testing to five foods: cow’s milk, raw egg, peanut, cashew and sesame. Those with any detectable wheal size are offered a formal in-hospital oral food challenge using a validated protocol to determine their clinical allergy status.

Objectives: The objective of this study was to determine if an association existed between periodontal disease and various systemic medical conditions and tobacco use. Material and Methods: The study design was a case-controlled, retrospective chart review. Patient charts (n=2006) were selected from more than 13,000 active patients attending the University of Minnesota dental clinics. These charts were examined to determine patient's self-reported systemic condition and smoking history. In addition, the number of missing teeth and bone loss were recorded. Two examiners collected the data. One examiner abstracted patient's medical history from the standard clinic medical questionnaire. The second examiner assessed the radiographs and dental charts to determine bone loss and number of missing teeth. Each examiner was blind to the findings of the other. Results: After adjusting for age, sex, diabetes and smoking (yes/no) status, seven conditions were significantly (p=0.0003–0.04) related to bone loss or number of missing teeth (vascular disease, heart surgery, vascular surgery, heart attack, thyroid problems, arthritis, stomach ulcers). From these conditions, thyroid problems and arthritis had a negative association with bone loss. Conclusions: These findings support the results from previous investigators that a number of systemic conditions and smoking are closely associated with missing teeth or bone loss.

Background Food allergy has been associated with lower weight and height in cross-sectional studies in children; however, this has not been investigated in longitudinal studies to explore growth over time, and previous studies have not accounted for coexisting eczema. Objective The objective of this study was to examine the association of IgE-mediated food allergy and eczema with anthropometric measures at 1 and 4 years of age. Methods In the HealthNuts population-based cohort, infants recruited at age 1 year underwent a skin prick test to egg, peanut, and sesame; those sensitized had oral food challenges. Food challenges repeated at 4 years determined food allergy persistence or resolution. Eczema was defined as parent report of eczema diagnosis. Parent-reported weight and height and child health record data were used to calculate age- and sex-adjusted percentiles from World Health Organization charts. Multivariable linear regression models were fitted to examine the effect of food allergy and eczema on weight and height controlling for potential confounders. Results Children with both food allergy and eczema at age 1 had lower percentiles for mean weight (51.3 vs 58.3 percentile, P = .001) and height (48.4 vs 53.4, P = .028) at age 1 compared with those with neither condition. There was no difference for children with only food allergy or eczema at age 1. By age 4, children with persistent food allergy and persistent eczema, but not those with resolved food allergy, were still shorter and lighter. Conclusions Children with both food allergy and eczema were shorter and lighter throughout early childhood, with more pronounced differences in those with persistent food allergy.

In this paper, an integrated NexFET power module is presented to meet requirements on next-generation, high efficiency and high current density DC-DC converters for computer applications. The new power module uses an innovative stacked-die package technology, implements low Vth power MOSFET in the low-side position, and introduces monolithically integrated components to avoid shoot-through and minimize voltage ringing at the switch node. In synchronous buck application, this power module achieves over 90% efficiency and low switch node ringing at high output current rating (25A) and high operation frequency (1MHz) under 12V input and 1.3V output condition.

Self-aligned contacts (SAC) have been successfullyscaled down to 0.2 tm, for high speed SRAM fabrica-tion at the 64Mb density level. All factors affecting SACcontact resistance (Re) are investigated in depth to re-duce the overall resistance of SACs. For a 0.25x0.45 im2 poly/n contact a contact resistance of 65 (1 =8 has been obtained. The factors which allow SACs toenable fabrication technologies at and below the 0.25im size scale, are discussed.Key Words: Self-Aligned Contact, scaling. INTRODUCTION By aligning the material contacting substrate silicon toMOSFET gate edges, the contact area needed for aself-aligned contact (SAC) is reduced substantially,without reducing the patterned feature size. ThereforeSACs are significant enablers for increasing the pack-ing density in ULSI circuits. In the triple-poly, double-metal 0.25 jtm BiCMOS SRAM technology discussedin this paper, the and bitline connections in thebitcell are made with SACs. The fabrication processused here was more fully described previously .

Changes in the density of eye movement during rapid eye movement (REM) sleep are associated with changes in ventilation and ventilatory response in animals. Recent data in patients with chronic obstructive pulmonary disease suggest that periods of frequent eye movements may be associated with hypoxemia during REM sleep. We have therefore investigated the association between eye movements and ventilation and ventilatory pattern in 10 normal men. Expired ventilation was measured using a pneumotachograph attached to a valved face mask with a dead space of 50 ml and incorporating a peripheral CO2 leak detector. Ventilation was reduced (p less than 0.02) in all stages of sleep compared with that during wakefulness, with no difference between the level of ventilation in each sleep stage (awake, 7.18 +/- 0.43 SEM; Stage 2, 6.47 +/- 0.43; Stage 3/4, 6.45 +/- 0.52; REM sleep, 6.55 +/- 0.47 L/min). During REM sleep, eye movements (EMs) were associated with rapid shallow breathing. Dividing REM into 20-s epochs with or without EMs, EMs were associated with a raised breathing frequency (no EMs, 14.4 +/- 0.4 breaths/min; EMs, 15.8 +/- 0.5 breaths/min; p = 0.01), reduced tidal volume (0.49 +/- 0.03 L; 0.41 +/- 0.03 L; p less than 0.01), and reduced minute ventilation (6.87 +/- 0.45 L; 6.27 +/- 0.51 L; p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Gas-liquid chromatography indicates the presence of a number of volatile components in some species of Leptogium, and, while there are variations from one species to the next, the overall chromatographic picture shows a con- siderable degree of similarity in their chemica:l composition. Crystallization of lichen substances is reported for the first time in the genus Leptogium. No record of the occurrence of lichen substances in the Collemataceae has so far been reported (Culberson, 1969). In this communication we provide definite evidence for the presence of such substances in eight species of Leptogium. Material of L. brebissonii was available in some quantity and we have, therefore, concerned ourselves principally with this species. MATERIALS AND METHODS hydrogen chloride to esterify any free carboxyl groups. The solution was neutralized with silver carbonate, centrifuged, and the solution carefully concentrated. The products, in chloro- form, were examined by gas-liquid chromatography. In the case of L. brebissonii, crystallization of the extract was carried out as follows: the air-dried lichen (930 mg) was extracted with ether at room temperature, the extract was concentrated and again treated with ether. The ether-soluble portion was shaken with 5% sodium carbonate and, on acidification, a precipitate was obtained. The precipitate Was centrifuged, washed with water and dried, giving a yield of 38 mg; 3 mg of this residue were crystallized in GE. Standard methods of microchemical extraction were applied to portions of the thallus of L. brebissonii and L. saturninum. The former was extracted with ether and crystallized in GE; L. saturninum was extracted with benzene and crystallized in GAAn. Infra-red spectra were recorded in chloroform on a Perkin-Elmer 135 Sodium Chloride Spectrophotometer.