Deprotective Functionalization: A Direct Conversion of Nms-Amides to Carboxamides Using Carboxylic Acids.

The nature of protecting group chemistry necessitates a deprotection step to restore the initially blocked functionality prior to further transformation. As this aspect of protecting group manipulation inevitably adds to the step count of any synthetic sequence, the development of methods enabling simultaneous deprotection and functionalization ("deprotective functionalization"-distinct from "deprotection followed by functionalization") is appealing, as it has the potential to improve efficiency and streamline synthetic routes. Herein, we report a deprotective functionalization of the newly introduced Nms-amides guided by density functional theory (DFT) analysis, which exploits the inherent Nms reactivity. Mechanistic studies further substantiate and help rationalize the exquisite reactivity of Nms-amides, as other commonly used protecting groups are shown not to exhibit the same reactivity patterns. The practicality of this approach was ultimately demonstrated in selected case studies.

Nms-Amides: An Amine Protecting Group with Unique Stability and Selectivity.

p-Toluenesulfonyl (Tosyl) and nitrobenzenesulfonyl (Nosyl) are two of the most common sulfonyl protecting groups for amines in contemporary organic synthesis. While p-toluenesulfonamides are known for their high stability/robustness, their use in multistep synthesis is plagued by difficult removal. Nitrobenzenesulfonamides, on the other hand, are easily cleaved but display limited stability to various reaction conditions. In an effort to resolve this predicament, we herein present a new sulfonamide protecting group, which we term Nms. Initially developed through in silico studies, Nms-amides overcome these previous limitations and leave no room for compromise. We have investigated the incorporation, robustness and cleavability of this group and found it to be superior to traditional sulfonamide protecting groups in a broad range of case studies.

Fecal Short-Chain Fatty Acid Ratios as Related to Gastrointestinal and Depressive Symptoms in Young Adults.

OBJECTIVE: Short-chain fatty acids (SCFAs) are produced by the gut microbiota and may reflect health. Gut symptoms are common in individuals with depressive disorders, and recent data indicate relationships between gut microbiota and psychiatric health. We aimed to investigate potential associations between SCFAs and self-reported depressive and gut symptoms in young adults. METHODS: Fecal samples from 164 individuals (125 were patients with psychiatric disorders: mean [standard deviation] age = 21.9 [2.6] years, 14% men; 39 nonpsychiatric controls: age = 28.5 [9.5] years, 38% men) were analyzed for the SCFA acetate, butyrate, and propionate by nuclear magnetic resonance spectroscopy. We then compared SCFA ratios with dimensional measures of self-reported depressive and gut symptoms. RESULTS: Depressive symptoms showed a positive association with acetate levels (ρ = 0.235, p = .003) and negative associations with both butyrate (ρ = -0.195, p = .014) and propionate levels (ρ = -0.201, p = .009) in relation to total SCFA levels. Furthermore, symptoms of diarrhea showed positive associations with acetate (ρ = 0.217, p = .010) and negative associations with propionate in relation to total SCFA levels (ρ = 0.229, p = 0-007). Cluster analysis revealed a heterogeneous pattern where shifts in SCFA ratios were observed in individuals with elevated levels of depressive symptoms, elevated levels of gut symptoms, or both. CONCLUSIONS: Shifts in SCFAs are associated with both depressive symptoms and gut symptoms in young adults and may have of relevance for treatment.

Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury: a prospective, observational study.

BACKGROUND: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. METHODS: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (QA), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. RESULTS: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with QA, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR2 = 9.2%) were independent outcome predictors also following step-down modelling. CONCLUSIONS: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.

A cross-sectional study of gastrointestinal symptoms, depressive symptoms and trait anxiety in young adults.

BACKGROUND: >Patients with functional gastrointestinal disorders have a high psychiatric co-morbidity. This study aimed to investigate and characterise gastrointestinal symptoms in relation to depressive symptoms and trait anxiety in a well-defined population of young adult psychiatric outpatients and healthy controls. METHODS: Gastrointestinal symptoms were assessed with the Gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS). Depressive symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale- Self assessment (MADRS-S). Trait anxiety was estimated with three of the Swedish universities of Personality (SSP) scales: Somatic trait anxiety, Psychic trait anxiety and Stress susceptibility. Self-ratings were collected from 491 young adult psychiatric outpatients and 85 healthy controls. Gastrointestinal symptom severity was compared between patients with and without current psychotropic medication and controls. Associations between gastrointestinal symptoms, depressive symptoms and trait anxiety were assessed using Spearman's coefficients and generalized linear models adjusting for possible confounders (sex, body mass index, bulimia nervosa). RESULTS: Patients, with and without current psychotropic medication, reported significantly more gastrointestinal symptoms than controls. In the generalized linear models, total MADRS-S score (p < 0.001), Somatic trait anxiety (p < 0.001), Psychic trait anxiety (p = 0.002) and Stress susceptibility (p = 0.002) were independent predictors of the total GSRS-IBS score. Further exploratory analysis using unsupervised learning revealed a diverse spectrum of symptoms that clustered into six groups. CONCLUSION: Gastrointestinal symptoms are both highly prevalent and diverse in young adult psychiatric outpatients, regardless of current psychotropic medication. Depressive symptom severity and degree of trait anxiety are independently related to the total gastrointestinal symptom burden.

Food pantry selection solutions: a randomized controlled trial in client-choice food pantries to nudge clients to targeted foods.

Background: Food pantries and food banks are interested in cost-effective methods to encourage the selection of targeted foods without restricting choices. Thus, this study evaluates the effectiveness of nudges toward targeted foods. Methods: In October/November 2014, we manipulated the display of a targeted product in a New York State food pantry. We evaluated the binary choice of the targeted good when we placed it in the front or the back of the category line (placement order) and when we presented the product in its original box or unboxed (packaging). Results: The average uptake proportion for the back treatment was 0.231, 95% CI = 0.179, 0.29, n = 205, and for the front treatment, the proportion was 0.337, 95% CI = 0.272, 0.406, n = 238 with an odds ratio of 1.688, 95% CI = 1.088, 2.523. The average uptake for the unboxed treatment was 0.224, 95% CI = 0.174, 0.280, n = 255, and for the boxed intervention, the proportion was 0.356, 95% CI = 0.288, 0.429, n = 188 with an odds ratio of 1.923, 95% CI = 1.237, 2.991. Conclusions: Nudges increased uptake of the targeted food. The findings also hold when we control for a potential confounder. Low cost and unobtrusive nudges can be effective tools for food pantry organizers to encourage the selection of targeted foods. Trial Registration Number: NCT02403882.

Lunch, recess and nutrition: responding to time incentives in the cafeteria.

OBJECTIVES: In this study, we evaluate if moving recess before lunch has an effect on the amount of fruits and vegetables elementary school students eat as part of their school-provided lunch. METHODS: Participants were 1st-6th grade students from three schools that switched recess from after to before lunch and four similar schools that continued to hold recess after lunch. We collected data for an average of 14 days at each school (4 days during spring 2011, May 3 through June 1, 2011 and 9 days during fall 2011, September 19 through November 11, 2011). All of the schools were in Orem, UT. Data was collected for all students receiving a school lunch and was based on observational plate waste data. RESULTS: We find that moving recess before lunch increased consumption of fruits and vegetables by 0.16 servings per child (a 54% increase) and increased the fraction of children eating at least one serving of fruits or vegetables by 10 percentage points (a 45% increase). In contrast, the schools in our control group actually experienced a small reduction in fruit and vegetable consumption during the same time period. CONCLUSIONS: Our results show the benefits of holding recess before lunch and suggest that if more schools implement this policy, there would be significant increases in fruit and vegetable consumption among students who eat school lunch as part of the National School Lunch Program.

Trayless cafeterias lead diners to take less salad and relatively more dessert.

OBJECTIVE: Many colleges are removing trays from their dining facilities in hope of reducing waste. How does not having a tray impact food choice? DESIGN: A field study was conducted in a university cafeteria (n 417) on two evenings with identical menus, one with tray service and one without. SETTING: A dining hall of a large north-eastern university, USA. SUBJECTS: Undergraduate students. RESULTS: Trayless dining decreased the percentage of diners (average age 19.1 years) who took salad by 65.2% but did not decrease the percentage who took dessert, leading to a markedly higher ratio of dessert to salad. CONCLUSIONS: Cafeterias going trayless should consider complementary policies to encourage balanced diets.

The impact of a supermarket nutrition rating system on purchases of nutritious and less nutritious foods.

OBJECTIVE: The current study examines the impact of a nutrition rating system on consumers' food purchases in supermarkets. DESIGN: Aggregate sales data for 102 categories of food (over 60 000 brands) on a weekly basis for 2005-2007 from a supermarket chain of over 150 stores are analysed. Change in weekly sales of nutritious and less nutritious foods, after the introduction of a nutrition rating system on store shelves, is calculated, controlling for seasonality and time trends in sales. SETTING: One hundred and sixty-eight supermarket stores in the north-east USA, from January 2005 to December 2007. SUBJECTS: Consumers purchasing goods at the supermarket chain during the study period. RESULTS: After the introduction of the nutrition ratings, overall weekly food sales declined by an average of 3637 units per category (95 % CI -5961, -1313; P<0·01). Sales of less nutritious foods fell by 8·31 % (95 % CI -13·50, -2·80 %; P=0·004), while sales of nutritious foods did not change significantly (P=0·21); as a result, the percentage of food purchases rated as nutritious rose by 1·39 % (95 % CI 0·58, 2·20 %; P<0·01). The decrease in sales of less nutritious foods was greatest in the categories of canned meat and fish, soda pop, bakery and canned vegetables. CONCLUSIONS: The introduction of the nutrition ratings led shoppers to buy a more nutritious mix of products. Interestingly, it did so by reducing purchases of less nutritious foods rather than by increasing purchases of nutritious foods. In evaluating nutrition information systems, researchers should focus on the entire market basket, not just sales of nutritious foods.

Concession stand makeovers: a pilot study of offering healthy foods at high school concession stands.

BACKGROUND: Concession stands at high school events are exempt from the US Department of Agriculture regulations for school foods. Concessions are generally stocked with unhealthy foods since healthy foods are believed to have lower sales and profit margins. METHODS: Concession stand sales for two seasons of high school fall sports in Muscatine, Iowa were compared. In between seasons, two types of changes were made: (i) addition of new healthier concession options and (ii) substitution of healthier ingredients (less saturated fat, no trans fat). Satisfaction surveys of students and parents were conducted before and after the changes. Data were collected in 2008 and 2009 and analyzed in 2012-13. RESULTS: Revenue per game was similar between years, even with the introduction of healthier items and ingredient changes. In 2009, the new healthy foods comprised 9.2% of total revenue and sales of some new items increased with each game. The 'healthy makeover' had no influence on student satisfaction but it improved parent satisfaction (P < 0.001). CONCLUSIONS: This compelling test of concept shows that offering healthier items can be good for both sales and satisfaction. While this study was conducted with concession stands, the principles can be carried over into other food retail settings.

A plant to plate pilot: a cold-climate high school garden increased vegetable selection but also waste.

AIM: Can high school gardens in cold climates influence vegetable intake in the absence of nutrition education? METHODS: This study followed a before/after design where student tray-waste data were collected using the quarter-waste method. The study took place March-April 2012 in a high school in upstate New York. The subjects were 370 enrolled high school students that purchased lunch from the school cafeteria. Prior to the introduction of garden greens in the salad, salads were served as usual. On April 24, harvested greens were included in the salad, and changes in selection and plate waste were measured. RESULTS: When the salad bar contained garden produce, the percentage of students selecting salad rose from 2% to 10% (p < 0.001), and on average, students ate two-thirds of the serving they took. Although waste increased relative to the control (from 5.56% to 33.33% per serving; p = 0.007), more students were consuming at least some salad. CONCLUSION: This preliminary investigation suggests that school gardens increased selection and intake of school-raised produce. Although a third was not eaten, it is promising to see that still more produce was consumed compared to the past.

One man's tall is another man's small: how the framing of portion size influences food choice.

Labels such as 'Large' or 'Super-size' are often used to describe portion sizes. How do these normative labels influence consumer choice and how much they ultimately either consume or waste? Although one might believe that firms use normative labels to impact choice behavior through loss aversion, a field experiment shows consumer's willingness to pay is inconsistent with a loss aversion explanation. Although portions were clearly visible, individuals appeared to use the labels as objective information about their size. Importantly, a second study showed these labels also led people to eat less when food was given a larger sounding name than a smaller name (double vs. regular; regular vs. half-size). If labels are used as size information, policies governing normative names could help reduce food consumption or reduce waste.

Chefs move to schools. A pilot examination of how chef-created dishes can increase school lunch participation and fruit and vegetable intake.

To demonstrate the feasibility of introducing a main dish designed by a professional chef in the National School Lunch Program and to document the impact on child participation, a chef was recruited to design pizza to be served in an upstate New York school district. The pizza was designed to meet both the cost and ingredient requirements of the NSLP. High school students were significantly more likely to select the pizza prepared by the chef. While the chef had no significant impact on main dish consumption given selection, more students took a vegetable and vegetable consumption increased by 16.5%. This pilot study demonstrates the plausibility of using chefs to boost participation in the school lunch program, and potentially increase nutrition through side selection, among high school students.

Foldamers controlled by functional triamino acids: structural investigation of α/γ-hybrid oligopeptides.

Peptide-like foldamers controlled by normal amide backbone hydrogen bonding have been extensively studied, and their folding patterns largely rely on configurational and conformational constraints induced by the steric properties of backbone substituents at appropriate positions. In contrast, opportunities to influence peptide secondary structure by functional groups forming individual hydrogen bond networks have not received much attention. Here, peptide-like foldamers consisting of alternating α,ß,γ-triamino acids 3-amino-4-(aminomethyl)-2-methylpyrrolidine-3-carboxylate (AAMP) and natural amino acids glycine and alanine are reported, which were obtained by solution phase peptide synthesis. They form ordered secondary structures, which are dominated by a three-dimensional bridged triazaspiranoid-like hydrogen bond network involving the non-backbone amino groups, the backbone amide hydrogen bonds, and the relative configuration of the α,ß,γ-triamino and α-amino acid building blocks. This additional stabilization leads to folding in both nonpolar organic as well as in aqueous environments. The three-dimensional arrangement of the individual foldamers is supported by X-ray crystallography, NMR spectroscopy, chiroptical methods, and molecular dynamics simulations.

Smarter lunchrooms can address new school lunchroom guidelines and childhood obesity.

New US Department of Agriculture regulations have altered what foods schools offer for lunch, but schools cannot require students to eat specific foods. An intervention using the behavioral science principle known as "libertarian paternalism" led junior-senior high school students to eat more fruits and vegetables by making these foods more convenient, attractive, and normative.

Default options, incentives and food choices: evidence from elementary-school children.

OBJECTIVE: To examine whether requiring children to place fruits and vegetables on their lunch trays increases consumption of these items. DESIGN: Observational study that exploited naturally occurring variation between two school districts and a pre­post observational study at schools that changed their lunch policy mid-year. SETTING: Fifteen elementary schools from two school districts, one requiring students to place a fruit or vegetable on their tray and one that does not. In addition, three schools that implemented a default option part way through the school year. SUBJECTS: Students at eighteen elementary schools (41 374 child-day observations) across the two experiments. RESULTS: Requiring that fruits and vegetables be placed on each child's tray increased the fraction of children who ate a serving of fruits or vegetables by 8 percentage points (P < 0·01) but led to an extra 0·7 servings being thrown away per lunch served (P < 0·01). The default option approach cost $US 1·72 to get one additional child to eat one serving of fruits and vegetables for 1 d. However, when default options were combined with a small rewards programme the efficacy of both interventions increased. CONCLUSIONS: A default option, as a stand-alone programme, had only a limited impact on fruit and vegetable consumption but was much less cost-effective than other approaches. Schools requiring children to take fruits and vegetables with their lunch might consider adopting additional interventions to ensure that the additional items served do not end up being thrown away.

College cafeteria snack food purchases become less healthy with each passing week of the semester.

OBJECTIVE: Snacks, stress and parties all contribute to the weight gain ­ the elusive 'Freshman 15' ­ that some college-goers unfortunately experience. The present study examines how a` la carte snack choice changes on a university campus during each progressing week of the academic calendar. DESIGN: How a` la carte snack choices change on a university campus with each progressing week of the academic calendar was examined. SETTING: The data were collected from three large cafeterias (or dining halls) on Cornell University's campus during four semesters (Fall 2006, Spring 2007, Fall 2007 and Spring 2008), for 18 weeks in each semester. SUBJECTS: After the a` la carte snack items were divided into healthy snacks and unhealthy snacks, the percentage share for each food category was calculated. RESULTS: Within each semester, the unhealthy snack food choices increased consistently by 0?4% per week (b50?00418, P,0?01). Furthermore, a sharp (8 %) increase occurred in the final two weeks of the semester. In contrast, healthy snack food choices decreased by almost 4% (b520?0408, P,0?01) in the final two weeks during the fall semester. CONCLUSIONS: These results demonstrate an increased demand for hedonic, or unhealthy, snack foods as the college semester progresses and in particular at the very end of the semester. To counter this tendency towards unhealthy snacking, cafeterias and stores should make extra effort to promote healthy alternatives during the later weeks of the semester.

General acid-mediated aminolactone formation using unactivated alkenes.

Spirocyclic butyrolactones and butenolides are widespread structural motifs in bioactive substances. Despite their prevalence, a simple method ensuring their direct preparation from exocyclic alkenes, ideally in a late-stage context, remains elusive. Herein, we report direct aminolactone formation using unactivated alkenes which addresses this gap, employing cheap and readily available reactants. The method relies on the hijacking of a cationic aminoalkylation pathway and affords (spiro)aminolactones with excellent functional group tolerance and chemoselectivity. The synthetic versatility of the products is demonstrated through a range of transformations, notably exploiting stereospecific rearrangement chemistry to produce sterically congested scaffolds.