Tandem Steps Research Articles

Direct Synthesis of an α,ω-Diester from 2,7-Octadienol as Bulk Feedstock in Three Tandem Catalytic Steps.

A new tandem catalytic process was designed and developed as a tool for the direct conversion of the widely available feedstock 2,7-octadienol into an α,ω-diester. This innovative auto-tandem catalysis is atom efficient and consists of three consecutive palladium-catalysed reactions: ether formation, ether carbonylation and alkoxycarbonylation. By using the design of experiments (DoE) approach, significant parameters were determined and the yield of the desired α,ω-diester was optimised. Model substrates allowed deeper insight into the progress of the reaction to be gained and, as a result, the reaction sequence was uncovered. Furthermore, by simply applying other ligands, a different reaction path was followed, allowing other, new tandem catalytic sequences to be explored and enabling new compounds to be obtained.

Strong base- or acid-mediated chemoselectivity shifts in the synthesis of 2H-chromene or coumarin derivatives from common Baylis-Hillman adducts

Reaction of tert-butyl 3-(2-hydroxyphenyl)-2-methylenepropanoate esters with aqueous KOH provides convenient and chemoselective one-pot access to 2H-chromene-3-carboxylic acids, the overall transformation involving tandem conjugate addition, hydrolysis and elimination steps. The methodology complements the chemoselective, acid-catalysed route to 3-substituted coumarins from the same substrates by switching the regioselectivity of cyclisation.

Effect of a combination of whole body vibration exercise and squat training on body balance, muscle power, and walking ability in the elderly

A randomized controlled trial was conducted to clarify the beneficial effect of whole body vibration (WBV) exercise plus squat training on body balance, muscle power, and walking ability in the elderly with knee osteoarthritis and/or spondylosis. Of 35 ambulatory patients (14 men and 21 women) who were recruited at our outpatient clinic, 28 (80.0%, 12 men and 16 women) participated in the trial. The subjects (mean age 72.4 years) were randomly divided into two groups (n=14 in each group), ie, a WBV exercise alone group and a WBV exercise plus squat training group. A 4-minute WBV exercise (frequency 20 Hz) was performed 2 days per week in both groups; squat training (20 times per minute) was added during the 4-minute WBV training session in the WBV exercise plus squat training group. The duration of the trial was 6 months. The exercise and training program was safe and well tolerated. WBV exercise alone improved indices of body balance and walking velocity from baseline values. However, WBV exercise plus squat training was more effective for improving tandem gait step number and chair-rising time compared with WBV exercise alone. These results suggest the benefit and safety of WBV exercise plus squat training for improving physical function in terms of body balance and muscle power in the elderly.

Diesel and Alkane Fuels From Biomass by Organocatalysis and Metal–Acid Tandem Catalysis

Combo deal: Biomass furaldehydes are upgraded into oxygenated diesel and high-quality C10-12 linear alkane fuels. The first of two steps involves solvent-free self-condensation (Umpolung) through organocatalysis using an N-heterocyclic carbene (NHC), yielding C10 -C12 furoin intermediates. In the metal-acid tandem catalysis step, in water, the furoin intermediates are converted into oxygenated biodiesel by hydrogenation, etherification or esterification; or into premium alkane jet fuels by hydrodeoxygenation.

Sleep Enhances Learning of a Functional Motor Task in Young Adults

Sleep has been demonstrated to enhance simple motor skill learning "offline" in young adults. "Offline learning" refers to either the stabilization or the enhancement of a memory through the passage of time without additional practice. It remains unclear whether a functional motor task will benefit from sleep to produce offline motor skill enhancement. Physical therapists often teach clients functional motor skills; therefore, it is important to understand how sleep affects learning of these skills. The purpose of this study was to determine whether sleep enhances the learning of a functional motor task. A prospective, cross-sectional, repeated-measures design was used. Young participants who were healthy (N=24) were randomly assigned to either a sleep group or a no-sleep group. The sleep group practiced a novel walking task in the evening and underwent retention testing the following morning, and the no-sleep group practiced the task in the morning and underwent retention testing in the evening. Outcome measures included time around the walking path and spatiotemporal gait parameters. Only participants who slept after practicing the novel walking task demonstrated a significant offline improvement in performance. Compared with the no-sleep group, participants in the sleep group demonstrated a significant decrease in the time around the walking path, an increase in tandem velocity, an increase in tandem step length, and a decline in tandem step time. Time-of-day effect and inability to ensure a certain amount of sleep quantity and quality of participants were limitations of the study. This study is the first to provide evidence that sleep facilitates learning clinically relevant functional motor tasks. Sleep is an important factor that physical therapists should consider when teaching clients motor skills.

Mobility impairment is associated with urge but not stress urinary incontinence in community‐dwelling older women: results from the Ossébo study

To assess the association between functional limitations related to mobility and urinary incontinence (UI) in elderly women. An observational cross-sectional study. Nine 'balance' workshops in France. A total of 1942 community-dwelling women aged 75-85 years, who were invited, based on voter registration lists, to a 'balance assessment'. Mobility and balance test results for incontinent women were compared with those for continent women according to the severity and type of incontinence. Data on UI were collected using a self-administered questionnaire (International Consultation on Incontinence Questionnaire-Short Form). Motor-related physical abilities were assessed using standardised balance and functional gait tests. Forty-two per cent of women had involuntary urine leakage, with daily leaks in 57% of them; 24% had stress UI, 31% had urge UI, and 37% had mixed UI. Results for each functional test were poorer for women with UI and the limitation was more pronounced when the incontinence was severe. Multivariate logistic regression analyses showed that balance and gait impairments were significantly and independently associated with urge UI (walking speed, lower versus higher quartile, odds ratio (OR) 2.2; 95% confidence interval (95% CI) 1.4-3.5; walking balance, unable versus able to do four tandem steps (OR 1.6; 95% CI 1.2-2.2) but not with stress UI. In this large population of older women living at home, there was a strong association between limitation of motor and balance skills and UI, which was proportional to the severity of incontinence and related specifically to urge incontinence. These results offer new perspectives on the prevention and treatment of urge incontinence in elderly women.

A method to investigate discrepancies between perceived and actual balance in older women

Despite the established relationship between low balance confidence and poorer balance and gait performance, discrepancies may occur between an individual's perceived and actual abilities. This study determined if trunk sway measures could assist in identifying potential discrepancies between perceived and actual balance. Older women completed the Activities-specific Balance Confidence (ABC) scale and performed a series of 16 stance, gait and tandem gait tasks. Duration (or completed steps for tandem gait tasks) and trunk pitch and roll angle and angular velocity were calculated. Low (mean ABC score≤70%, n=33) and high (mean ABC score≥90%, n=99) balance confidence groups were identified from a pool of 204 participants. The low balance confidence group had greater stance trunk pitch and roll sway, shorter one leg stance durations, reduced gait trunk roll sway, longer gait durations, less tandem gait trunk roll sway and completed fewer tandem gait steps compared to the high balance confidence group. Stepwise linear discriminant analysis identified four variables that were used to achieve a classification accuracy of 75.8% for low and 90.9% for high balance confidence groups. This study reinforces the influence of low balance confidence on stance and gait control and provides direction for the identification and treatment of individuals with discrepancies between perceived and actual balance.

Differentiating Malingering Balance Disorder Patients from Healthy Controls, Compensated Unilateral Vestibular Loss, and Whiplash Patients Using Stance and Gait Posturography

Differentiating balance disorder patients who are malingering from those with organic balance disorders is difficult and costly. We used trunk sway measured during several stance and gait tasks in 18 patients suspected of malingering in order to differentiate these from 20 patients who had suffered unilateral vestibular loss 3 months earlier, 20 patients with documented whiplash injuries, and 34 healthy controls. Classification results ranged from 72 to 96% and were equally accurate for task or criteria variables based on 90% sway values. The tasks yielding the best discrimination were: standing with eyes closed on a foam and firm surface; standing with eyes open on a firm surface; standing on 1 leg; and walking tandem steps. The criteria yielding the best discrimination were: standing with eyes open on a firm surface; the difference between standing with eyes closed on foam and firm surfaces; the difference between walking tandem steps and standing on 1 leg with eyes open; and the difference between roll and pitch velocity when walking 8 tandem steps. We conclude that discriminating suspected malingering balance disorder patients is possible using variables or criteria based on objective measures of trunk sway during several stance and gait tasks.

High-resolution profiling of homing endonuclease binding and catalytic specificity using yeast surface display

Experimental analysis and manipulation of protein–DNA interactions pose unique biophysical challenges arising from the structural and chemical homogeneity of DNA polymers. We report the use of yeast surface display for analytical and selection-based applications for the interaction between a LAGLIDADG homing endonuclease and its DNA target. Quantitative flow cytometry using oligonucleotide substrates facilitated a complete profiling of specificity, both for DNA-binding and catalysis, with single base pair resolution. These analyses revealed a comprehensive segregation of binding specificity and affinity to one half of the pseudo-dimeric interaction, while the entire interface contributed specificity at the level of catalysis. A single round of targeted mutagenesis with tandem affinity and catalytic selection steps provided mechanistic insights to the origins of binding and catalytic specificity. These methods represent a dynamic new approach for interrogating specificity in protein–DNA interactions.

Simple Approach to Stabilized Micelles Employing Miktoarm Terpolymers and Stereocomplexes with Application in Paclitaxel Delivery

A simple and versatile approach to miktoarm co- and terpolymers from carbonate functional oligomers is described. The key building block employed is a carboxylic acid functional cyclic carbonate, derived from 2,2-bis(methylol)propionic acid, that was readily coupled to a hydroxyl functional monomethylether poly(ethylene glycol) oligomer. Ring-opening of the cyclic carbonate using functional amines generates a carbamate linkage bearing a functional group capable of initiating either controlled radical or ring-opening polymerization, together with a primary hydroxyl group for ring-opening polymerization. Two tandem polymerization steps were possible which add the second two arms, thus generating the targeted ABC miktoarm terpolymer. The resulting amphiphilic miktoarm terpolymers containing poly(D- and L-lactide) formed polylactide stereocomplexes in the bulk. In aqueous solution, the stereocomplex mixture of Y-shaped miktoarm copolymers, poly(ethylene glycol)-poly(D-lactide)-poly(D-lactide) and poly(ethylene glycol)-poly(L-lactide)-poly(L-lactide), or the stereoblock miktoarm poly(ethylene glycol)-poly(D-lactide)-poly(L-lactide) form stabilized micelles with a significantly lower critical micelle concentration than those derived from conventional stereo regular linear or Y-shaped amphiphiles. This simple and versatile approach provides a useful synthetic route to complex macromolecular architectures that can assemble into stable micelles. These micelles provide high capacity for loading of the anticancer drug paclitaxel and possess narrow size distribution as well as unique structure, leading to sustained and near zero-ordered release of drug without significant initial burst.

Design and Synthesis of Macrocyclic Peptomers as Mimics of a Quorum Sensing Signal from Staphylococcus aureus

We report the design and synthesis of macrocyclic peptide-peptoid hybrids (peptomers) as analogs of autoinducing peptide I (AIP-I) from Staphylococcus aureus. Our solid-phase synthetic route includes efficient microwave-assisted reactions and a tandem macrocyclization-cleavage step, and we demonstrate its compatibility with parallel synthesis through the generation of a focused peptomer library. One of the peptomers was capable of stimulating biofilm formation in S. aureus, a phenotype linked to AIP-I receptor (AgrC-I) inhibition.

Vestibular rehabilitation by auditory feedback in otolith disorders

Rehabilitation strategies have been applied successfully over the last few decades to initiate central compensation of the tonus imbalance and to facilitate substitution in different types of peripheral vestibular dysfunction. However, these vestibular rehabilitation strategies are often not successful in patients with isolated otolith disorders. The aim of the present study was therefore to evaluate a specific rehabilitation strategy for patients with an isolated otolith disorder by using an auditory feedback system. Thirteen patients, which suffered from different types of otolith disorders, but no other vestibular pathology and 13 normal controls were included in this study. Vestibular rehabilitation exercises were performed daily over a 2-week period (weekends excluded). During all exercises the patients of the test group ( n = 13) obtained an acoustic feedback signal when their trunk angle velocity exceeded a preset level while the patients of the control group ( n = 13) performed the same exercises without auditory feedback. The most effective exercise in the test group was “walking eight tandem steps on a foam support surface”. Approximately 85% of the patients showed a significant decrease of trunk sway in this condition. In contrast to these results, patients of the control group showed no significant improvement of postural control after the training. The results indicate that an auditory feedback rehabilitation program with exercises related to the specific neurotological disease could significantly improve the postural control in patients with otolith disorders.

Electrospray ionization ion trap multiple‐stage mass spectrometric fragmentation pathways of leucine and isoleucine: an ab initio computational study

We recently demonstrated the possibility to distinguish between leucine and isoleucine in several tryptic peptides by means of consecutive tandem mass steps (Armirotti et al. J. Am. Soc. Mass Spectrom. 2007; 18: 57), exploiting a gas-phase rearrangement of the immonium ion of Ile. In the present paper we explore the tandem mass spectrometric behaviour of the two amino acids. We propose a plausible structure for the diagnostic m/z 69 ion of Ile, that was reported for the first time in 1996 (Hulst and Kientz J. Mass. Spectrom. 1996; 31: 1188), and we explain why its formation is favoured with respect to Leu. Our conclusions are supported by ab initio quantum chemistry calcultations and isotope-labelled standards experiments.

ERVK9, transposons and the evolution of MHC class I duplicons within the alpha-block of the human and chimpanzee

The genomic sequences within the alpha-block (∼288–310 kb) of the human and chimpanzee MHC class I region contains ten MHC class I genes and three MIC gene fragments grouped together within alternating duplicated genomic segments or duplicons. In this study, the chimpanzee and human genomic sequences were analyzed in order to determine whether the remnants of the ERVK9 and other retrotransposon sequences are useful genomic markers for reconstructing the evolutionary history of the duplicated MHC gene families within the alpha-block. A variety of genes, pseudogenes, autologous DNA transposons and retrotransposons such as Alu and ERVK9 were used to categorize the ten duplicons into four distinct structural groups. The phylogenetic relationship of the ten duplicons was examined by using the neighbour joining method to analyze transposon sequence topologies of selected Alu members, LTR16B and Charlie9. On the basis of these structural groups and the phylogeny of the duplicated transposon sequences, a duplication model was reconstructed involving four multipartite tandem duplication steps to explain the organization and evolution of the ten duplicons within the alpha-block of the chimpanzee and human. The phylogenetic analysis and inferred duplication history suggests that the Patr/HLA-F was the first MHC class I gene to have been fixed and not required as a precursor for further duplication within the alpha-block of the ancestral species.

Macrolactamization of Glycosylated Peptide Thioesters by the Thioesterase Domain of Tyrocidine Synthetase

The 35 kDa thioesterase (TE) domain excised from the megadalton tyrocidine synthetase (Tyc Syn) retains autonomous capacity to macrocyclize peptidyl thioesters to D-Phe1-L-Leu10-macrolactams. Since a number of nonribosomal peptides undergo O-glycosylation events during tailoring to gain biological activity, the Tyc Syn TE domain was evaluated for cyclization capacity with glycosylated peptidyl-S-NAC substrates. First, Tyr7 was replaced with Tyr(beta-D-Gal) and Tyr(beta-D-Glc) as well as with Ser-containing beta-linked D-Gal, D-Glc, D-GlcNAc, and D-GlcNH2, and these new analogs were shown to be cyclized with comparable kcat/Km catalytic efficiency. Similarly, Gal- or tetra-O-acetyl-Gal-Ser could also be substituted at residues 5, 6, and 8 in the linear decapeptidyl-S-NAC sequences and cyclized without substantial loss in catalytic efficiency by Tyc Syn TE. The cyclic glycopeptides retained antibiotic activity as membrane perturbants in MIC assays, opening the possibility for library construction of cyclic glycopeptides by enzymatic macrocyclization.

Rhesus macaque class I duplicon structures, organization, and evolution within the alpha block of the major histocompatibility complex.

The alpha block of the human and chimpanzee major histocompatibility complex (MHC) class I genomic region contains 10 to 11 duplicated MHC class I genes, including the HLA/Patr-A, -G, and -F genes. In comparison, the alpha block of the rhesus macaque (Macaca mulatta, Mamu) has an additional 20 MHC class I genes within this orthologous region. The present study describes the identification and analysis of the duplicated segmental genomic structures (duplicons) and genomic markers within the alpha block of the rhesus macaque and their use to reconstruct the duplication history of the genes within this region. A variety of MHC class I genes, pseudogenes, transposons, and retrotransposons, such as Alu and ERV16, were used to categorize the 28 duplicons into four distinct structural categories. The phylogenetic relationship of MHC class I genes, Alu, and LTR16B sequences within the duplicons was examined by use of the Neighbor-Joining (NJ) method. Two single-duplicon tandem duplications, two polyduplicon tandem duplications with an accompanying inversion product per duplication, eight polyduplicon tandem duplications steps, 12 deletions, and at least two recombinations were reconstructed to explain the highly complex organization and evolution of the 28 duplicons (nine inversions) within the Mamu alpha block. On the basis of the phylogenetic evidence and the reconstructed tandem duplication history of the 28 duplicons, the Mamu/Patr/HLA-F ortholog was the first MHC class I gene to have been fixed without further duplication within the alpha block of primates. Assuming that the rhesus macaque and the chimpanzee/human lineages had started with the same number of MHC class I duplicons at the time of their divergence approximately 24 to 31 MYA, then the number of genes within the alpha block have been duplicated at an approximately three times greater rate in the rhesus macaque than in either the human or chimpanzee.

Structures of Non‐Canonical Tandem Base Pairs in RNA Helices: Review

AbstractFor Abstract see ChemInform Abstract in Full Text.

Improvements in Trunk Sway Observed for Stance and Gait Tasks during Recovery from an Acute Unilateral Peripheral Vestibular Deficit

Objectives: Our aim was to track improvements in postural control during recovery from an acute unilateral peripheral vestibular deficit (UVL), presumably due to vestibular neuritis, and to determine if recovery rates were different for stance and gait tasks. Postural control was quantified using simple measurements of trunk sway: amplitudes of trunk sway angle and angular velocity, in the roll and pitch directions as well as task duration, were examined for a battery of stance and gait tasks. These measures were collected at the onset of the deficit and then 3 weeks and 3 months later. Study Design: A repeated-measures design was used for UVL subjects and age-matched healthy controls. Stance tasks involved standing on 1 or 2 legs with eyes open or closed. Gait tasks consisted of tandem gait, walking normally with eyes closed, or with the head rotating or head pitching, walking up and down stairs and walking over a series of low barriers. Stance and tandem gait tasks were repeated using a foam support surface instead of a normal floor. Patients: Twenty-eight patients with acute UVL were examined. Main Outcome Measures: The range of trunk sway angular displacement and angular velocity in the pitch and roll directions was measured for each task in addition to task duration. The measures were compared with those of normal subjects. Results: The amplitudes of pitch trunk sway for 2-legged stance tasks with eyes closed underwent the greatest reduction 3 weeks after UVL onset. At 3 months, trunk sway was almost normal for all 2-legged stance tasks. One-legged stance tasks with eyes open showed a similar but slower improvement. Stance time without a fall showed a very rapid improvement for 1-legged tasks but was still shorter than that of normal subjects at 3 months. Trunk sway for the simple gait tasks was within normal range at 3 months; however, task duration was still longer than normal. More complex gait tasks, such as walking 8 tandem steps on foam or walking up and down stairs, showed no improvement in trunk roll sway at 3 months. A mix of variables from mainly gait tasks best identified a balance deficit due to UVL, with complex gait tasks becoming more important for identification purposes as compensation progressed. The accuracy of UVL identification with durations alone was 75% of the accuracy with combined trunk sway and duration measures. Conclusions: These data suggest that recovery of normal trunk control during the compensation process for unilateral vestibular hypofunction is more rapid for stance tasks than gait tasks. Even at 3 months, trunk sway for complex gait tasks was not normal. Thus, trunk sway for gait tasks provides a better insight into remaining deficits in balance control of vestibular-loss patients than the sway of stance tasks.

Total Synthesis of (+)‐Dihydrocuscohygrine and Cuscohygrine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total synthesis of (+)-dihydrocuscohygrine and cuscohygrine.

The first enantioselective synthesis of (+)-dihydrocuscohygrine 1 and cuscohygrine 2 is presented. 1 was obtained in nine steps and 30% overall yield with a ruthenium-catalyzed tandem ring rearrangement metathesis key step starting from enantiomerically pure cycloheptene-1,3,5-triol derivative 6. The unknown absolute configuration of natural dihydrocuscohygrine 1 could be determined as (S,S)-(-). Cuscohygrine 2 was obtained by Jones oxidation of 1 in quantitative yield but unfortunately with complete epimerization.