Analysis of the Valgamicin Biosynthetic Pathway Reveals a General Mechanism for Cyclopropanol Formation across Diverse Natural Product Scaffolds.

Cyclopropanol rings are highly reactive and may function as molecular "warheads" that affect natural product bioactivity. Yet, knowledge on their biosynthesis is limited. Using gene cluster analyses, isotope labeling, and in vitro enzyme assays, we shed first light on the biosynthesis of the cyclopropanol-substituted amino acid cleonine, a residue in the antimicrobial depsipeptide valgamicin C and the cytotoxic glycopeptide cleomycin A2. We decipher the biosynthetic origin of valgamicin C and show that the cleonine cyclopropanol ring is derived from dimethylsulfoniopropionate (DMSP). Furthermore, we demonstrate that part of the biosynthesis is analogous to the formation of malleicyprol polyketides in pathogenic bacteria. By genome mining and metabolic profiling, we identify the potential to produce cyclopropanol rings in other bacterial species. Our results reveal a general mechanism for cyclopropyl alcohol biosynthesis across diverse natural products that may be harnessed for bioengineering and drug discovery.

Precursor-directed biosynthesis and biological activity of tripropeptin Cpip, a new tripropeptin C analog containing pipecolic acid.

Tripropeptin C, a non-ribosomal cyclic lipopeptide containing three proline residues, exhibits excellent efficacy in the mouse-methicillin-resistant Staphylococcus aureus septicemia model. Since tripropeptins contain L-prolyl-D-proline and, as a result, are known to form a hairpin structure in proteins, it was of interest to determine whether this substructure contributes to their antibacterial activity. In this study, prolines in tripropeptin C were replaced with pipecolic acid(s) using precursor-directed biosynthesis. Only a new tripropeptin analog, tripropeptin Cpip, which has one L-pipecolic acid in place of L-proline, was isolated. The in vitro antimicrobial activity of the new analog was approximately two to four times weaker activity against Gram-positive bacteria, including drug-resistant species, compared with that of tripropeptin C. These results suggest that the L-prolyl-D-proline substructure plays an important role in the observed potency of tripropeptins.

Quality Evaluation of Gentamicin Sulfate Reference Standards in Japanese Pharmacopoeia Using Hydrophilic Interaction Chromatography Combined With Tandem Mass Spectrometry.

BACKGROUND: Through the recent development of analytical technology, antibiotics quantification in the Japanese Pharmacopoeia (JP) has changed from traditional microbiological assays to physicochemical methods with high specificity and precision. However, for several multicomponent antibiotics without typical UV absorption, potency cannot be directly determined using instrumental methods such as high-performance liquid chromatography; therefore, traditional microbiological assays are still used. Gentamicin sulfate (GmS), which consists of three major components, C1, C1a, and C2, is such a typical antibiotic, and its antimicrobial potency continues to be assayed using microbiological methods in JP monographs. Introduction of a physicochemical assay for GmS is needed to help ensure its quality and quantity. OBJECTIVE: This study aimed to develop quality control measures for GmS that could be complementary to quantitative assays and purity tests specified in the JP. METHODS: For each gentamicin C component (C1, C2, and C1a), theoretical potencies were determined based on the quantitative relationship between purity and potency, as measured by quantitative 1H NMR and microbiological assays, respectively. Two lots of the JP reference standard (RS) were used as test samples, with the contents of each component and impurity (sisomicin and garamine) being determined using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). RESULTS: The ratios of theoretical potency for C1, C2, and C1a were 1.00, 1.21, and 1.80, respectively. The potencies of the GmS JP RSs, which were estimated based on the contents and theoretical potency of each C component, corresponded well with those determined through microbiological assays. Marked differences in impurities (%) between the two RS lots were highlighted by quantifying sisomicin and garamine. CONCLUSIONS: The developed analytical procedure enabled the characterization of two different JP RSs in terms of content ratio, potencies, and impurities. HIGHLIGHTS: Novel analytical procedures useful for routine quality control of GmS were developed using HILIC-MS/MS.

Two new adenopeptins B and C inhibit sphere formation of pancreatic cancer cells.

Cancer remains one of the leading causes of death worldwide, particularly pancreatic cancer being lethal because of its aggressiveness and lack of early detection methods. A factor that contributes to malignancy are cancer stem cell-like characteristics promoted by the tumor-stromal interaction. Given that fibroblast conditioned medium (CM) promotes sphere formation of cancer cells, a cancer stem cell-like characteristic, its inhibitor could be a new anticancer agent. By exploring microbial cultures as a source, we found new compounds, namely, adenopeptins B (1) and C (2), from Acremonium sp. ESF00140. 1 and 2 selectively and potently inhibited the sphere formation of pancreatic cancer cells cultured in the fibroblast CM compared with the control medium. Oxygen consumption rate (OCR) assays showed that 1 and 2 inhibit OCR in pancreatic cancer cells. Studies of similar compounds suggested mitochondrial complex V inhibition. Therefore, results of measuring the activity of human mitochondrial complex V revealed that 1 and 2 inhibited its activity. Oligomycin A, an inhibitor of mitochondrial complex V, as well as 1 and 2, strongly inhibited the sphere formation of pancreatic cancer cells cultured in fibroblast CM. The addition of 1 and 2 to pancreatic cancer cells cultured in fibroblast CM increased reactive oxygen species (ROS) production compared with that in the control medium. In pancreatic cancer cells cultured in fibroblast CM, mitochondria significantly influence sphere formation, and targeting their function with 1 and 2 might provide a new therapeutic approach for pancreatic cancer.

Catenulopyrizomicins, new anti-Hepatitis B virus compounds, from the rare actinomycete Catenuloplanes sp. MM782L-181F7.

Hepatitis B virus (HBV) causes chronic hepatitis in humans, and current antiviral therapies rarely treat viral infections. To improve the treatment efficacy, novel therapeutic agents, especially those with different mechanisms of action, need to be developed for use in combination with the current antivirals. Here, we isolated new anti-HBV compounds, named catenulopyrizomicins A-C, from the fermentation broth of rare actinomycete Catenuloplanes sp. MM782L-181F7. Structural analysis revealed that these compounds contained a structure that is composed of thiazolyl pyridine moiety. The catenulopyrizomicins reduced the amount of intracellular viral DNA in HepG2.2.15 cells with EC50 values ranging from 1.94 to 2.63 µM with small but notable selectivity. Mechanistic studies indicated that catenulopyrizomicin promotes the release of immature virion particles that fail to be enveloped through alterations in membrane permeability.

The Risk Factors and Preventive Strategies of Poor Knee Functions and Osteoarthritis after Anterior Cruciate Ligament Reconstruction: A Narrative Review.

Anterior cruciate ligament reconstruction (ACLR) is the standard surgical treatment for ACL injury, which typically uses a graft to replace the torn ligament in the knee that uses small incisions with minimally invasive surgery. The optimal knee functions following ACLR depend on rehabilitation processes before and after the surgery. Knee function is the ability of the knee to perform various types of functional movements like walking, squatting, running, jumping, and pivoting where patients expect to achieve maximum knee function or at least more than 80% of its initial condition before the injury to avoid being categorized as poor knee function after ACLR. Patients use patient-reported outcome measures to collect data on their health status and quality of life after ACLR. Post-traumatic osteoarthritis (PTOA) is a type of OA that manifests in local cartilage injury caused by chondrocyte death, and matrix dispersion occurs following a joint injury like ACL injury. Gender, time from injury to surgery, and graft type were considered as risk factors for poor knee function after ACLR, while overweight, meniscus tear, and cartilage defect as risk factors for PTOA. However, age is an internal risk factor for both poor knee function and PTOA following ACLR. This review suggests several strategies to prevent both conditions, including a pre-operative program, comprehensive rehabilitation, body weight control, and return to sport (RTS) consideration based on physical capacity, proper time, and psychological readiness.

Effect of driving training on car crashes and driving skills in older people: A systematic review and meta-analysis.

The primary aim of this systematic review was to examine the efficacy of driving interventions with regard to a reduction in motor vehicle crashes and improvements in driving skills among older people. The secondary aim was to identify the optimal type (on-road or off-road) and dosage (period, sessions, and duration) of driving interventions for improving driving skills in older people. We searched MEDLINE, EMBASE, PsycINFO, and Scopus of Systematic Reviews for papers published from their inception to December 1, 2020, as well as the reference lists of the included papers. The selected studies were randomized controlled trials examining the effects of driving interventions among community-dwelling older drivers aged 65 years and over. A meta-analysis of two studies (n = 960) showed that driving interventions significantly reduced the number of motor vehicle crashes per person-years. Ten studies (n = 575) were included in the meta-analysis showing that the interventions significantly improved the driving skill scores. Driving skill scores significantly improved after on-road training, and in interventions of at least 3 h, 3 sessions, and 3 weeks. Driving interventions significantly improve driving skills and reduce motor vehicle crashes among older drivers aged 65 years and over. On-road training is more efficacious than off-road training and driving interventions of at least 3 h taking place in 3 sessions over a period of 3 weeks may be required to improve driving skills in older drivers. Geriatr Gerontol Int 2023; 23: 771-778.

Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most concerning pathogenic bacteria. We screened antibiotics using a highly drug-sensitive P. aeruginosa strain and an oligotrophic medium, and successfully isolated novel antibiotics, namely cycloimidamicins (CIMs), from a rare actinomycete strain, Lentzea sp. MM249-143F7. X-ray and nuclear magnetic resonance analyses revealed that CIMs possess a distinctive and unprecedented molecular structure, containing tetramic acid and an imidazole ring bound directly to indolone. The CIMs exhibited potent antibacterial activity against Gram-negative bacteria, as well as translation inhibition in Escherichia coli in both intact cells and in vitro. Additionally, E. coli strains resistant to known translation inhibitors did not exhibit cross-resistance to CIMs, suggesting that CIMs inhibit bacterial growth by blocking translation through a novel mechanism.

Overlapping status of frailty and fear of falling: an elevated risk of incident disability in community-dwelling older adults.

BACKGROUND: Although overlapping frailty and fear of falling (FoF) are likely to increase with population aging, the combined effect of frailty and FoF on incident disability is not yet well understood. AIMS: The purpose of this study is to examine whether frailty combined with FoF increased the risk of incident disability in older adults. Our secondary purpose was to clarify the synergistic effect of frailty and FoF on incident disability. METHODS: This is a prospective study. Participants were 9372 older adults (mean age 73.5 years). Frailty status was assessed using the Japanese Cardiovascular Health Study index, and FoF was measured using two closed questions. Incident disability was prospectively monitored by their long-term care insurance records. RESULTS: During the follow-up period (mean duration 23.4 months), 487 (5.2%) participants developed disability. The proportion of incident disability linearly increased according to FoF level regardless of baseline frailty status. Frail participants with FoF had a higher risk of incident disability than those with frailty only or neither (adjusted hazard ratio [HR] 2.63, 95% confidence interval [CI] 1.95-3.54). Frailty in combination with excessive FoF further increased the risk of incident disability (adjusted HR 4.30, 95% CI 2.56-7.23) although no synergistic effect was observed (relative excessive risk due to interaction 1.69, 95% CI - 0.55, 3.93). CONCLUSION: The overlapping status of frailty and FoF, especially excessive FoF, increases the risk of incident disability in older adults.

Context of walking and loneliness among community-dwelling older adults: a cross-sectional study.

BACKGROUND: Older adults are more likely to experience loneliness than younger people. Moreover, greater loneliness in older adults is associated with poor mental health and increased risk of cardiovascular disease and mortality. Physical activity is an effective intervention for reducing loneliness among older adults. Among physical activities, walking is suitable for older adults, because it is easy and safe to incorporate into daily life. We hypothesized that the association between walking and loneliness depends on the presence of others and the number of people present. The aim of this study is to investigate the association between the context of walking (the number of walkers) and loneliness among community-dwelling older adults. METHODS: This cross-sectional study included 173 community-dwelling older adults aged 65 or older. Context of walking was classified as non-walking, walking alone (days of walking alone > days of walking with someone), and walking with someone (days of walking alone ≤ days of walking with someone). Loneliness was measured using the Japanese version of the University of California Los Angeles Loneliness Scale. A linear regression model was used to investigate the relationship between context of walking and loneliness, adjusted for age, sex, living situation, social participation, and physical activity excluding walking. RESULTS: Data from 171 community-dwelling older adults (mean age = 78.0 years, 59.6% women) were analyzed. After adjustment, walking with someone was associated with lower loneliness than non-walking (adjusted ß: -0.51, 95% confidence interval: -1.00, -0.01). CONCLUSIONS: The study's findings suggest that walking with a companion may effectively prevent or reduce loneliness among older adults.

Wychimicins, a new class of spirotetronate polyketides from Actinocrispum wychmicini MI503-A4.

In the course of our screening program for new anti-methicillin-resistant Staphylococcus aureus antibiotics, four novel antibiotics, termed wychimicins A-D, were isolated from the culture broth of the rare actinomycete Actinocrispum wychmicini strain MI503-AF4. Wychimicins are spirotetronates possessing a macrocyclic 13-membered ring containing trans-decalin and ß-D-xylo-hexopyranose moieties connected to C-17 by an O-glycosidic linkage according to MS, NMR and X-ray analyses. In X-ray crystal structure analysis, the Flack constant was 0.10 (11). The stereochemistry of the spirocarbon C-25 was R. Wychimicins had a minimum inhibitory concentration of 0.125-2 µg ml-1 against methicillin-resistant Staphylococcus aureus.

Rediscovery of 4-Trehalosamine as a Biologically Stable, Mass-Producible, and Chemically Modifiable Trehalose Analog.

Nonreducing disaccharide trehalose is used as a stabilizer and humectant in various products and is a potential medicinal drug, showing curative effects on the animal models of various diseases. However, its use is limited as it is hydrolyzed by trehalase, a widely expressed enzyme in multiple organisms. Several trehalose analogs are prepared, including a microbial metabolite 4-trehalosamine, and their high biological stability is confirmed. For further analysis, 4-trehalosamine is selected as it shows high producibility. Compared with trehalose, 4-trehalosamine exhibits better or comparable protective activities and a high buffer capacity around the neutral pH. Another advantage of 4-trehalosamine is its chemical modifiability: simple reactions produce its various derivatives. Labeled probes and detergents are synthesized in one-pot reactions to exemplify the feasibility of their production, and their utility is confirmed for their respective applications. The labeled probes are used for mycobacterial staining. Although the derivative detergents can be effectively used in membrane protein research, long-chain detergents show 1000-3000-fold stronger autophagy-inducing activity in cultured cells than trehalose and are expected to become a drug lead and research reagent. These results indicate that 4-trehalosamine is a useful trehalose substitute for various purposes and a material to produce new useful derivative substances.

The Potential Application of Commercially Available Active Video Games to Cardiac Rehabilitation: Scoping Review.

BACKGROUND: Commercially available active video games (AVGs) have recently been used for rehabilitation in some specific patient populations but rarely in those with cardiovascular disease (CVD). Commercially available AVGs are designed to increase motivation for continuous play, which could be applicable to the long-term cardiac rehabilitation process. OBJECTIVE: The objective of this scoping review was to assess the effectiveness of AVG-induced physical exercise, safety management, and patient adherence by applying commercially available AVGs to cardiac rehabilitation. METHODS: Four databases (CINAHL, MEDLINE, PubMed, and SPORTDiscus) were searched for all years up to August 12, 2020. Articles were retained if they were written in English, included patients with CVD who were aged 18 years or older, and used AVGs as part of a physical exercise program. The included studies were then evaluated from the viewpoints of effectiveness as physical exercise, safety, and adherence management. RESULTS: Among 120 nonduplicate articles reviewed, 5 (4.2%) were eligible for inclusion, of which 3 (2.5%) were reported by the same research group. The AVG consoles used were Xbox Kinect and Nintendo Wii, and sports-related programs were adopted for the intervention. No adverse cardiac events occurred in the identified studies, and dropout rates tended to be low. CONCLUSIONS: AVGs appear to be safe and feasible for promoting an active lifestyle in patients with CVD. However, the effectiveness of AVGs alone as a therapeutic exercise to improve physical function may be limited.

Association between Abnormal Gait Patterns and an Elevated Degree of Pain after Daily Walking: A Preliminary Study.

This study aimed to investigate whether abnormal gait patterns are associated with experiencing an elevated degree of pain after daily walking. In this preliminary, cross-sectional study, 223 community-dwelling older adults were assessed for pain experienced after daily walking using a simple question that involved asking the subject about their past experiences of an elevated degree of pain after walking for 400 m or more. Gait patterns were assessed using the Comprehensive Gait Assessment using InerTial Sensor score (C-GAITS score), derived from the data measured by Inertial sensors attached to the lower trunk and heel when subjects walked along a 15 m walkway at a self-selected preferred speed. The score was the sum of 10 gait parameter scores. The lower scores indicated more and worse abnormal gait patterns. In total, 24 older adults (10.8%) reported that they experienced pain after daily walking. According to the multiple logistic regression analyses, older adults with a lower total C-GAITS score had a significantly greater probability of having past experiences of pain after walking (odds ratio = 1.11, 95% confidence interval = 1.03-1.20). The findings of this study suggest that more and worse abnormal gait patterns among older adults in a clinical walking test are associated with an elevated degree of pain after daily walking.

Environmental hazards as risk factors for trips and slips at home among Japanese older people: A pilot study toward the development of a self-assessment tool for the home environment.

AIM: Housing structures differ according to the local culture, climate, and lifestyle, and these unique characteristics usually act as potential hazards for falls, trips, and slips. The purpose of this study was to identify environmental hazards in a Japanese house and their association with falls, trips, and slips among older people. METHODS: A total of 97 older people aged ≥75 years were included in this cross-sectional study. The number of environmental hazards was measured using a 46-item tool designed specifically for this study, and the associations of environmental hazards with falls, trips, and slips were analyzed using univariate and multivariate logistic regressions. RESULTS: All houses had at least one environmental hazard, and 3-30 environmental hazards were identified. Although the number of environmental hazards was not associated with falls experienced during the past 6 months, a greater number of environmental hazards at home was correlated with the daily experience of trips and slips (odds ratio [OR]: 1.10; 95% confidence interval [CI]: 1.02-1.18). The association remained significant even after adjusting for demographic characteristics and other fall risk factors (OR: 1.11; 95% CI: 1.02-1.21). CONCLUSION: We found that Japanese housing structures had unique environmental hazards that might cause trips and slips in older people. Appropriate housing assessments and modifications may help to promote aging-in-place among older people. Geriatr Gerontol Int 2022; 22: 305-310.

Web Portals for Patients With Chronic Diseases: Scoping Review of the Functional Features and Theoretical Frameworks of Telerehabilitation Platforms.

BACKGROUND: The COVID-19 pandemic has required an increased need for rehabilitation activities applicable to patients with chronic diseases. Telerehabilitation has several advantages, including reducing clinic visits by patients vulnerable to infectious diseases. Digital platforms are often used to assist rehabilitation services for patients in remote settings. Although web portals for medical use have existed for years, the technology in telerehabilitation remains a novel method. OBJECTIVE: This scoping review investigated the functional features and theoretical approaches of web portals developed for telerehabilitation in patients with chronic diseases. METHODS: PubMed and Web of Science were reviewed to identify articles associated with telerehabilitation. Of the 477 nonduplicate articles reviewed, 35 involving 14 portals were retrieved for the scoping review. The functional features, targeted diseases, and theoretical approaches of these portals were studied. RESULTS: The 14 portals targeted patients with chronic obstructive pulmonary disease, cardiovascular, osteoarthritis, multiple sclerosis, cystic fibrosis diseases, and stroke and breast cancer survivors. Monitoring/data tracking and communication functions were the most common, followed by exercise instructions and diary/self-report features. Several theoretical approaches, behavior change techniques, and motivational techniques were found to be utilized. CONCLUSIONS: The web portals could unify and display multiple types of data and effectively provide various types of information. Asynchronous correspondence was more favorable than synchronous, real-time interactions. Data acquisition often required assistance from other digital tools. Various functions with patient-centered principles, behavior change strategies, and motivational techniques were observed for better support shifting to a healthier lifestyle. These findings suggested that web portals for telerehabilitation not only provided entrance into rehabilitation programs but also reinforced participant-centered treatment, adherence to rehabilitation, and lifestyle changes over time.

Isolation of new derivatives of the 20-membered macrodiolide bispolide from Kitasatospora sp. MG372-hF19.

New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we reported previously. The absolute structures of compounds 1-3 were elucidated by NMR and X-ray crystallography. Compounds 1-3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1-3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1-3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.

The Relationship between Sarcopenia and Respiratory Muscle Weakness in Community-Dwelling Older Adults.

An association between respiratory muscle weakness and sarcopenia may provide a clue to the mechanism of sarcopenia development. We aimed to clarify this relationship among community-dwelling older adults. In total, 117 community-dwelling older adults were assessed and classified into 4 groups: robust, respiratory muscle weakness, sarcopenia, and respiratory sarcopenia. The respiratory sarcopenia group (12%) had a significantly higher percentage of males and had lower BMI, skeletal muscle index, skeletal muscle mass, phase angle, and oral function than the robust group (32.5%). All physical functions were significantly lower. The respiratory muscle weakness group (54.7%) had a significantly lower BMI and slower walking speed, compared with the robust group. The sarcopenia group (0.8%) was excluded from the analysis. The percent maximum inspiratory pressure was significantly lower in both the respiratory muscle weakness and respiratory sarcopenia groups, compared with the robust group. Almost all participants with sarcopenia showed respiratory muscle weakness. In addition, approximately 50% had respiratory muscle weakness, even in the absence of systemic sarcopenia, suggesting that respiratory muscle weakness may be the precursor of sarcopenia. The values indicating physical function and skeletal muscle mass in the respiratory muscle weakness group were between those in the robust and the respiratory sarcopenia groups.

Effects of Telerehabilitation Interventions on Heart Failure Management (2015-2020): Scoping Review.

BACKGROUND: Heart failure is one of the world's most frequently diagnosed cardiovascular diseases. An important element of heart failure management is cardiac rehabilitation, the goal of which is to improve patients' recovery, functional capacity, psychosocial well-being, and health-related quality of life. Patients in cardiac rehabilitation may lack sufficient motivation or may feel that the rehabilitation process does not meet their individual needs. One solution to these challenges is the use of telerehabilitation. Although telerehabilitation has been available for several years, it has only recently begun to be utilized in heart failure studies. Especially within the past 5 years, we now have several studies focusing on the effectiveness of telerehabilitation for heart failure management, all with varying results. Based on a review of these studies, this paper offers an assessment of the effectiveness of telerehabilitation as applied to heart failure management. OBJECTIVE: The aim of this scoping review was to assess the effects of telerehabilitation in the management of heart failure by systematically reviewing the available scientific literature within the period from January 1, 2015, to December 31, 2020. METHODS: The literature search was carried out using PubMed and EMBASE. After duplicates were removed, 77 articles were screened and 12 articles were subsequently reviewed. The review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for scoping reviews) guidelines. As measures of the effectiveness of telerehabilitation, the following outcomes were used: patients' quality of life, physical capacity, depression or anxiety, and adherence to the intervention. RESULTS: A total of 12 articles were included in this review. In reviewing the effects of telerehabilitation for patients with heart failure, it was found that 4 out of 6 randomized controlled trials (RCTs), a single prospective study, and 4 out of 5 reviews reported increased quality of life for patients. For physical capacity, 4 RCTs and 3 systematic reviews revealed increased physical capacity. Depression or depressive symptoms were reported as being reduced in 1 of the 6 RCTs and in 2 of the 5 reviews. Anxiety or anxiety-related symptoms were reported as reduced in only 1 review. High adherence to the telerehabilitation program was reported in 4 RCTs and 4 reviews. It should be mentioned that some of the reviewed articles described the same studies although they employed different outcome measures. CONCLUSIONS: It was found that there is a tendency toward improvement in patients' quality of life and physical capacity when telerehabilitation was used in heart failure management. The outcome measures of depression, anxiety, and adherence to the intervention were found to be positive. Additional research is needed to determine more precise and robust effects of telerehabilitation.

Micromonosporamide A with Glutamine-Dependent Cytotoxicity from Micromonospora sp. MM609M-173N6: Isolation, Stereochemical Determination, and Synthesis.

An acyldipeptide, micromonosporamide A, was isolated from the fermentation broth of Micromonospora sp. MM609M-173N6 by bioassay-guided fractionation using a glutamine compensation assay. The planar structure was elucidated on the basis of comprehensive one- and two-dimensional nuclear magnetic resonance and high-resolution mass spectrometry. The relative and absolute configuration of the entire molecule were determined using a combined approach, involving chromatographic analysis by liquid chromatography-mass spectrometry, advanced Marfey's method, and total synthesis. Micromonosporamide A exhibited glutamine-dependent antiproliferative activity.