Synthesis of the Indolizidine Core of Virosinine A via a Microwave-Promoted Cascade Cyclization Involving Iminyl Radicals.

The indolizidine core of virosinine A was synthesized by means of a microwave-promoted cascade reaction featuring 5-exo-trig iminyl radical cyclization, thiyl radical elimination, and intramolecular imine alkylation. The resulting bicyclic iminium ion underwent stereoselective reduction by Red-Al to deliver the target compound. DFT calculations suggested that both the radical cyclization and thiyl radical elimination steps are reversible at high reaction temperatures.

Longitudinal analysis of physical function in older adults: The effects of physical inactivity and exercise training.

Lack of exercise contributes to systemic inflammation and is a major cause of chronic disease. The long-term impact of initiating and sustaining exercise in late life, as opposed to sustaining a sedentary lifestyle, on whole-body health measures such as physical performance is not well known. This is an exploratory study to compare changes in physical performance among older adults initiating exercise late in life versus inactive older adults. Data from two observational cohorts were included in this analysis, representing two activity groups. The Active group cohort comprises older adults (n = 318; age 72.5 ± 7.2 years) enrolled in a supervised exercise program, "Gerofit." The inactive group comprises older adults (n = 146; age 74.5 ± 5.5 years) from the Italian study "Act on Ageing" (AOA) who self-reported being inactive. Participants in both groups completed physical performance battery at baseline and 1-year including: 6-min walk test, 30-s chair stand, and timed up-and-go. Two-sample t-tests measured differences between Gerofit and AOA at baseline and 1-year across all measures. Significant between-group effects were seen for all performance measures (ps = 0.001). The AOA group declined across all measures from baseline to 1 year (range -18% to -24% change). The Gerofit group experienced significant gains in function for all measures (range +10% to +31% change). Older adults who initiated routine, sustained exercise were protected from age-related declines in physical performance, while those who remained sedentary suffered cumulative deficits across strength, aerobic endurance, and mobility. Interventions to reduce sedentary behaviors and increase physical activity are both important to promote multi-system, whole-body health.

Formal γ-C(sp3)-H Activation of Ketones via Microwave-Promoted and Iminyl-Radical-Mediated 1,5-Hydrogen Atom Transfer.

Microwave irradiation of O-phenyloximes triggers N-O homolysis and 1,5-hydrogen atom transfer (HAT), resulting in formal γ-C-H functionalization of ketones after trapping of the radical intermediate and in situ imine hydrolysis. The Lewis acid InCl3·H2O facilitated HAT, enabling functionalization of benzylic and nonbenzylic secondary carbon atoms. Functionalization of primary carbons was feasible but afforded low yields, requiring ClCH2CO2H instead of InCl3·H2O as an additive. C-O and C-C bond formation could both be accomplished by this method.

Physical Function Effects of Live Video Group Exercise Interventions for Older Adults: A Systematic Review and Veteran's Gerofit Group Case Study.

Background: Literature on telehealth interventions for older adults has been primarily on asynchronous interventions. During the COVID-19 pandemic, older adult exercise programs transitioned to an online format. This systematic review and case study examines the effectiveness of older adult live video exercise group interventions on physical health with insights from a Los Angeles VA program, Gerofit. Methods: PubMed was searched for live video older adult exercise groups from database inception to November 2021. All eligible studies included assessments of physical health and were limited to participants with an average age of 65 years or greater. Ten Veterans, who had participated in both in-person and virtual Gerofit sessions, were surveyed in the case study. Results: Nine studies met the inclusion criteria. Four studies included an equivalent in-person group as a comparator to the live video group and reported no significant between-group differences in outcomes, including energy expenditure and 6-minute walking distance test (6MWD). The other five studies reported statistically significant in-group improvement in outcomes including isokinetic knee strength. Case study participants reported similar attendance rates and perceived benefits, such as improved balance, when comparing virtual and in-person sessions. Discussion: Live video exercise groups in older adults demonstrated an improvement in physical function that was not statistically different from the comparison in-person sessions with the added benefit of averaging a higher attendance rate, providing initial support for the use of live video in older adult exercise programs. Insights from the case study supplement this by demonstrating older adults' positive attitude on these groups.

Microwave- and Thermally Promoted Iminyl Radical Cyclizations: A Versatile Method for the Synthesis of Functionalized Pyrrolines.

A detailed study of iminyl radical cyclizations of O-aryloximes tethered to alkenes is reported. The reactions can be triggered by either microwave irradiation or conventional heating in an oil bath. A variety of radical traps can be employed, enabling C-C, C-N, C-O, C-S, or C-X bond formation and producing a diverse array of functionalized pyrrolines. Substrates containing an allylic sulfide furnish terminal alkenes by a tandem cyclization-thiyl radical ß-elimination pathway. Cyclizations of hydroxylated substrates exhibit moderate diastereoselectivity that in some cases can partially be attributed to intramolecular hydrogen bonding. Computational studies suggested a possible role for thermodynamics in controlling the stereochemistry of cyclizations. The reaction temperature can be lowered from 120 to 100 °C by employing O-(p-tert-butylphenyl)oximes instead of O-phenyloximes as substrates, and these second-generation iminyl radical precursors can be used in a one-pot oxime ether formation-cyclization that is promoted by conventional heating. The functionalized pyrrolines obtained from these reactions can be conveniently transformed in several different ways.

Synthesis and Studies of Bulky Cycloalkyl α,ß-Dehydroamino Acids that Enhance Proteolytic Stability.

Three new bulky cycloalkyl α,ß-dehydroamino acids (ΔAAs) have been designed and synthesized. Each residue enhances the rigidity of model peptides and their stability to proteolysis, with larger ring sizes exhibiting greater effects. Peptides containing bulky cycloalkyl ΔAAs are inert to conjugate addition by a nucleophilic thiol. The results suggest that these residues will be effective tools for improving the proteolytic stability of bioactive peptides.

Synthesis and evaluation of potent yaku'amide A analogs.

Two full-length analogs of the anticancer peptide yaku'amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three E- and Z-ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a. Synthesis of 2a and 2b followed a convergent route that was streamlined by the absence of ΔIle in the targets. Screening of the compounds against various cancer cell lines revealed that 2a and 2b mimic the potent anticancer activity of 1a, thereby validating the computational studies.

Towards a streamlined synthesis of peptides containing α,ß-dehydroamino acids.

Investigation of a strategy to streamline the synthesis of peptides containing α,ß-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety via elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues. Z-dehydroaminobutyric acid (Z-ΔAbu) could be constructed most efficiently via EDC/CuCl-mediated dehydration of Thr. Formation of Z-ΔPhe by this or other dehydration methods was unsuccessful. Production of the bulky ΔVal residue could be accomplished by DAST-promoted dehydrations of ß-OHVal or by DBU-triggered eliminations of sulfonium ions derived from penicillamine derivatives. However, competitive formation of an oxazoline byproduct remains problematic.

Synthesis of Functionalized Pyrrolines via Microwave-Promoted Iminyl Radical Cyclizations.

O-Phenyloximes tethered to alkenes undergo 5-exo-trig iminyl radical cyclizations upon microwave irradiation. Trapping of the resulting cyclic radicals results in C-C, C-N, C-O, C-S, or C-X bond formation. Allylic sulfides undergo a tandem cyclization-thiyl radical ß-elimination, affording terminal alkenes. The cyclizations exhibit a broad scope, and in some cases they are highly diastereoselective. The pyrroline adducts are versatile intermediates that can be transformed into a range of different species.

PTSD Improvement Associated with Social Connectedness in Gerofit Veterans Exercise Program.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is common in Veterans. Symptoms can perpetuate into late life, negatively impacting physical and mental health. Exercise and social support are beneficial in treating anxiety disorders such as PTSD in the general population, although less is known about the impact on Veterans who have lived with PTSD for decades. This study assessed associations between social connectedness, physical function and self-reported change in PTSD symptoms among older Veterans specifically participating in Gerofit. DESIGN: Prospective clinical intervention. SETTING: Twelve sites of Veterans Affairs (VA) Gerofit exercise program across the United States. PARTICIPANTS: Three hundred and twenty one older Veteran Gerofit participants (mean age = 74) completed physical assessments and questionnaires regarding physical and emotional symptoms and their experience. MEASUREMENTS: Measures of physical function, including 30-second chair stands, 10-m and 6-min walk were assessed at baseline and 3 months; change in PTSD symptoms based on the Diagnostic Statistical Manual-5 (DSM-5) assessed by a self-report questionnaire; and social connection measured by the Relatedness Subscale of the Psychological Need Satisfaction in Exercise scale (PNSE) were evaluated after 3 months of participation in Gerofit. RESULTS: Ninety five (29.6%) Veterans reported PTSD. Significant improvement was noted in self-rated PTSD symptoms at 3 months (P < .05). Moderate correlation (r = .44) was found between social connectedness with other participants in Gerofit and PTSD symptom improvement for those Veterans who endorsed improvement (n = 59). All participants improved on measures of physical function. In Veterans who endorsed PTSD there were no significant associations between physical function improvement and PTSD symptoms. CONCLUSION: Veterans with PTSD that participated in Gerofit group exercise reported symptom improvement, and social connectedness was significantly associated with this improvement. In addition to physical health benefits, the social context of Gerofit may offer a potential resource for improving PTSD symptoms in older Veterans that warrants further study.

Convergent Total Synthesis of Yaku'amide†A.

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its ß-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.

Caring for older veterans with chronic low back pain using a geriatric syndrome approach: Rationale and methods for the aging back clinics (ABC) trial.

The purpose of the ongoing trial is to improve care of older Veterans with chronic low back pain (CLBP, i.e., low back pain for ≥6 months on ≥ half the days). Current CLBP care is limited by being either overly spine-focused or non-specifically prescribed and both approaches frequently lead to suboptimal reduction in pain and improvement in function. Through prior studies we have laid the foundation for a patient-centered approach to care for older Veterans with CLBP in which the spine is a source of vulnerability but not the sole treatment target. The approach considers CLBP a geriatric syndrome, a final common pathway for the expression of multiple contributors rather than a disease of the spine. We describe here the rationale and design of a randomized controlled trial to test the efficacy of an older Veteran-centered approach to CLBP care in "Aging Back Clinics (ABCs)" compared with Usual Care (UC). Three hundred thirty Veterans age 65-89 with CLBP will be randomized to ABCs or UC and followed for 12 months after randomization. We will assess the impact of ABCs on our primary outcome of pain-associated disability with the Oswestry Disability Index at 6 and 12 months, and secondary outcomes of pain intensity, health-related quality of life, balance confidence, mobility and healthcare utilization. If shown efficacious, the approach tested in ABCs has the potential to transform the care of older adults with CLBP by improving the quality of life for millions, reducing morbidity and saving substantial healthcare costs.

Secondary endosymbiont diversity of Bemisia tabaci and its parasitoids.

Cotton whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) is one of the most important insect pests worldwide. It is known as a species complex consisting of at least 40 cryptic species. Although there are substantial data regarding species composition, parasitoids and endosymbionts of B. tabaci, data on relationship between the pest, parasitoids and endosymbionts are very restricted. Therefore, in this study, secondary endosymbionts in populations of B. tabaci and their parasitoids collected from Turkey and the USA were determined by PCR-based DNA analysis. Whitefly populations in Turkey represented both Mediterranean (MED) and Middle East-Asia Minor1 (MEAM1) genotypes from single or mixed populations of both genotypes. Arsenophonus, Rickettsia and Wolbachia were found in MED, while Hamiltonella and Rickettsia in MEAM1. Whitefly populations collected from Arizona were all MEAM1 and dually infected with Hamiltonella and Rickettsia. The aphelinid parasitoids Encarsia lutea and Eretmocerus mundus predominated in all Turkish populations. While almost all En. lutea populations were infected with Wolbachia, no endosymbionts were detected in any Er. mundus. Parasitoid species and the pattern of secondary endosymbiont infection in Arizona populations were different with Rickettsia detected only from Encarsia sophia while both Rickettsia and Wolbachia were found in Eretmocerus species. As a result, four secondary endosymbionts, namely, Rickettsia, Hamiltonella, Arsenophonus and Wolbachia, were detected from B.tabaci and its parasitoids. Among them only Wolbachia and Rickettsia were found in both the pest and parasitoids. It is conclude that further studies should be pursued to determine effect of these endosymbionts on biology of the parasitoids and success in biological control of B. tabaci.

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides.

A comparative study of the impact of small, medium-sized, and bulky α,ß-dehydroamino acids (ΔAAs) on the structure and stability of Balaram's incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a-c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a-c that preferred a ß-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a-c and 3a-c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and more accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.

An innovative educational clinical experience promoting geriatric exercise.

Formal educational training in physical activity promotion is relatively sparse throughout the medical education system. The authors describe an innovative clinical experience in physical activity directed at medical clinicians on a geriatrics rotation. The experience consists of a single 2 1/2 hour session, in which learners are partnered with geriatric patients engaged in a formal supervised exercise program. The learners are guided through an evidence-based exercise regimen tailored to functional status. This experience provides learners with an opportunity to interact with geriatric patients outside the hospital environment to counterbalance the typical geriatric rotation in which geriatric patients are often seen in clinics or hospitals. In this experience, learners are exposed to fit and engaged geriatric patients successfully living in the community despite chronic or disabling conditions. A survey of 105 learners highlighted positive responses to the experience, with 96% of survey respondents indicating that the experience increased their confidence in their ability to serve as advocates for physical activity for older adults, and 89.5% of responders to a follow-up survey indicating that the experience changed their perception of geriatric patients. Modifications to the experience, implemented at partnering facilities are described. The positive feedback from this experience warrants consideration for implementation in other settings.

Rapid Transition to Telehealth Group Exercise and Functional Assessments in Response to COVID-19.

Exercise is critical for health maintenance in late life. The COVID-19 shelter in place and social distancing orders resulted in wide-scale interruptions of exercise therapies, placing older adults at risk for the consequences of decreased mobilization. The purpose of this paper is to describe rapid transition of the Gerofit facility-based group exercise program to telehealth delivery. This Gerofit-to-Home (GTH) program continued with group-based synchronous exercise classes that ranged from 1 to 24 Veterans per class and 1 to 9 classes offered per week in the different locations. Three hundred and eight of 1149 (27%) Veterans active in the Gerofit facility-based programs made the transition to the telehealth delivered classes. Participants' physical performance testing continued remotely as scheduled with comparisons between most recent facility-based and remote testing suggesting that participants retained physical function. Detailed protocols for remote physical performance testing and sample exercise routines are described. Translation to remote delivery of exercise programs for older adults could mitigate negative health effects.

Mobility Improvements are Found in Older Veterans After 6-Months of Gerofit Regardless of BMI Classification.

Veterans represent a unique population of older adults as they are more likely to self-report disability and be overweight or obese compared to the general population. We sought to compare changes in mobility function across the obesity spectrum in older Veterans participating in six-months of Gerofit, a clinical exercise program. 270 Veterans completed baseline, three, and six-month functional assessment and were divided post-hoc into groups: normal weight, overweight, and obese. Physical function assessment included: ten-meter walk time, six-minute walk distance, 30-second chair stands, and eight-foot up-and-go time. No significant weight x time interactions were found for any measure. However, significant (P<0.02) improvements were found for all mobility measures from baseline to three-months and maintained at six-months. Six-months of participation in Gerofit, if enacted nationwide, appears to be one way to improve mobility and function in older Veterans at high risk for disability regardless of weight status.

Despite Active Public Health Campaigns, Death from Falls Increased 30% in the Past Decade: Is Ageism Part of the Barrier to Self-Awareness?

Public health messaging campaigns stating that falls are bad and can be prevented are not effective, as evidenced by a 30% increase in death from falls over the past decade. A first approach is to use measures of balance to show the magnitude of the problem. Second, the role of ageism as a barrier to required behavioral change should be addressed. Third, explanations should be provided regarding why mobility and balance have changed. As a counter to ageism, pros and cons for specific interventions and how these maximize momentum and mobility should be discussed.

Insights into base-free OsO4-catalyzed aminohydroxylations employing chiral ligands.

Attempts to perform the OsO4-catalyzed enantioselective base-free aminohydroxylation of ß,ß-disubstituted enoates are described. Low yields and racemic products were obtained in the presence of standard chiral ligands, suggesting the occurrence of a "Second Cycle" process due to slow hydrolysis of the amino alcohol product from the Os metal center. Support for this hypothesis was provided by the slightly improved enantioselectivity (60:40 er) obtained with an amino alcohol ligand. Based on density functional theory calculations, it is proposed that the lack of significant enantioselectivity is due to a low-energy (3 + 2) oxo/imido cycloaddition transition state without the chiral ligand in the Second Cycle that outcompetes protonolysis in the First Cycle.