Search

Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity (high-resolution respirometry/fluorometry), citrate synthase (enzyme activity), mtDNA content (qPCR), gene expression (qPCR), and protein expression (western blot) were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND. The molar ratio of H 2 O 2 and O 2 (H 2 O 2 :O 2 ) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity supported by pyruvate + malate, proline, and glycerol 3-phosphate. Concurrently, BAM15 enhanced the mitochondrial H 2 O 2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H 2 O 2 :O 2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense. BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aim: To identify patient factors, including gastrointestinal functions, that are predictive or associated with weight loss in response to once-daily 3 mg liraglutide administered subcutaneously (SQ) or placebo in obesity., Methods: One hundred and thirty-six obese adults (87% female) were randomized in a placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg administered SQ daily. Gastrointestinal functions were measured at baseline and 16 weeks: gastric emptying of solids (GET 1/2 ); fasting and postprandial gastric volumes; kcal ingested during ad libitum buffet meal and the nutrient drink test. GET 1/2 was also measured at 5 weeks. A multiple variable regression model examined variables associated with weight loss of more than 4 kg at 16 weeks. A parsimonious model using backward selection identified the final model., Results: Weight loss of more than 4 kg at 16 weeks occurred in 71% of liraglutide- and 16% of placebo-treated patients. In all participants combined, parameters univariately associated with a weight loss of more than 4 kg were GET 1/2 at 5 and 16 weeks, weight loss at 5 weeks and kcal intake during the buffet meal at 16 weeks. The final parsimonious model (area under the receiver operator characteristics [AUROC] curve = 0.832) identified that factors associated with more than 4-kg weight loss were GET 1/2 at 5 weeks (OR = 2.505; 95% CI: 1.57-3.997) per 50 minutes and kcal intake during ad libitum meal at 16 weeks (OR = 0.721; 95% CI: 0.602-0.864) per 100 kcal. Among only the 60 liraglutide-treated subjects, kcal intake at 16 weeks was associated with 4-kg weight loss (AUROC = 0.757)., Conclusions: Slower GET 1/2 and weight loss at 5 weeks predicted a weight loss of more than 4 kg at 16 weeks in all participants. Among liraglutide-treated adults, weight loss of more than 4 kg was associated with ad libitum meal kcal intake at 16 weeks., (© 2022 John Wiley & Sons Ltd.)

Aims: The perceived success of the Framework Convention on Tobacco Control (FCTC) in influencing national and global public health policies has led to growing interest in promulgating new international legal instruments to address global health issues-including calls for a Framework Convention on Alcohol Control (FCAC)., Methods: Despite broad support in the public health community, the authors caution that an analysis of the value of lawmaking for alcohol control cannot rest solely on the character of the underlying public health challenge and the similarities between alcohol control and tobacco control. Other factors must be considered, including the relative political feasibility for global health lawmaking. The potential contribution of non-binding international legal instruments to advancing global alcohol control, in particular, deserves strong consideration., Results: The authors propose a gradual international legal strategy for alcohol control, starting with a non-binding code of practice focusing on areas of critical concern with wide political consensus, leading over time to a comprehensive binding treaty. Although often dismissed as ineffective relative to treaties, non-binding international legal instruments have particular strengths and can create both norms and processes that impact the behavior of states and other actors, overcoming a number of limitations of more rigid legally binding strategies., Conclusions: Ultimately, the authors contend that the negotiation and adoption of a non-binding international legal instrument as a first step in a long-run legal strategy offers a more politically realistic, and potentially superior, alternative to immediate efforts to achieve a Framework Convention on Alcohol Control., (© 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.)

Regeneration of mineralized tissues affected by chronic diseases comprises a major scientific and clinical challenge. Periodontitis, one such prevalent disease, involves destruction of the tooth-supporting tissues, alveolar bone, periodontal-ligament and cementum, often leading to tooth loss. In 1997, it became clear that, in addition to their function in enamel formation, the hydrophobic ectodermal enamel matrix proteins (EMPs) play a role in the regeneration of these periodontal tissues. The epithelial EMPs are a heterogeneous mixture of polypeptides encoded by several genes. It was not clear, however, which of these many EMPs induces the regeneration and what mechanisms are involved. Here we show that a single recombinant human amelogenin protein (rHAM(+)), induced in vivo regeneration of all tooth-supporting tissues after creation of experimental periodontitis in a dog model. To further understand the regeneration process, amelogenin expression was detected in normal and regenerating cells of the alveolar bone (osteocytes, osteoblasts and osteoclasts), periodontal ligament, cementum and in bone marrow stromal cells. Amelogenin expression was highest in areas of high bone turnover and activity. Further studies showed that during the first 2 weeks after application, rHAM(+) induced, directly or indirectly, significant recruitment of mesenchymal progenitor cells, which later differentiated to form the regenerated periodontal tissues. The ability of a single protein to bring about regeneration of all periodontal tissues, in the correct spatio-temporal order, through recruitment of mesenchymal progenitor cells, could pave the way for development of new therapeutic devices for treatment of periodontal, bone and ligament diseases based on rHAM(+).

The amelogenin protein is considered as the major molecular marker of developing and mineralizing ectodermal enamel. It regulates the shape, size, and direction of growth of the enamel mineral crystallite. Recent data suggest other roles for amelogenin beyond regulation of enamel mineral crystal growth. The present study describes our recent discovery of amelogenin expression in soft tissues: in brain and in cells of the hematopoietic system, such as macrophages, megakaryocytes and in some of the hematopoietic stem cells. Reverse transcription-polymerase chain reaction (RT-PCR) followed by cDNA sequencing revealed, in mouse brain, two amelogenin mRNA isoforms: the full-length amelogenin including exon 4, and the isoform lacking exon 4. Immunohistochemistry revealed amelogenin expression in brain glial cells. Mouse macrophages were found to express the full-length amelogenin sequence lacking exon 4. Confocal microscopy revealed colocalization of amelogenin and CD41 (a megakaryocyte marker), as well as amelogenin and CD34 (a hematopoietic stem cell marker) in some of the bone marrow cells. The expression of amelogenin, a major structural protein of the mineralizing extracellular enamel matrix, also in cells of non-mineralizing soft tissues, suggests that amelogenin is multifunctional. Several different potential functions of amelogenin are discussed.

Objective: To construct reference centile charts for validated measures of disease activity, functional impairment, and metrology (the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Bath Ankylosing Spondylitis Functional Index [BASFI], and Bath Ankylosing Spondylitis Metrology Index [BASMI]) in a population of patients with AS, and to explore the potential application of these charts in patient care and clinical research., Methods: We collected BASDAI and BASFI data on 2,979 patients with AS from the Royal National Hospital for Rheumatic Diseases (RNHRD) database and BASMI data on 393 patients at RNHRD. Data on age, sex, and duration of AS were also obtained. Centile charts were constructed for the BASDAI, BASFI, and BASMI in both males and females, with duration of AS as the time-dependant variable. Where necessary, BASDAI, BASFI, and BASMI raw scores were transformed to ensure that the indices were normally distributed over the range of disease duration, and allowance was made for change in variability of the indices., Results: Linear models were fitted to the mean and standard deviations of BASDAI, BASFI, and BASMI scores in males and females as a function of disease duration. A standard deviation score plot confirmed goodness of fit of the models, and fitted centiles were derived. Charts showing the 5th, 10th, 25th, 50th, 75th, 90th, and 95th centiles were constructed. The charts confirmed that AS remains active after 40 years' duration (mean BASDAI score 2.22 and 2.99 in males and females, respectively). The charts also demonstrated that females have greater disease activity and more functional impairment than males, despite better metrology., Conclusion: The use of centile reference charts for disease activity, functional impairment, and metrology in AS will allow physicians and patients to interpret index scores relative to a reference population and will provide the opportunity to assess change over time and response to therapeutic interventions, to improve definition of disease status, and to enhance patients' involvement in their care.

Selective recycle has successfully been used to maintain an unstable plasmid-bearing bacterial strain as dominant in a continuous reactor, whereas the culture reverts to 100% segregant cells when selective recycle is not used. The plasmid-bearing strain is slower growing and flocculent; however, when the cells lose their plasmid, the resulting segregant cells are nonflocculent and grow at a faster rate due to their decreased metabolic burden. Both types of cells exit a chemostat and enter an inclined settler where the flocculent plasmid-bearing cells are separated from the nonflocculent segregant cells by differential sedimentation. The underflow from the cell separator, which is enriched with plasmid-bearing cells, is recycled back to the chemostat, while the segregant cells are withdrawn off the top of the settler and discarded. The experimental results agree well with selective recycle reactor theory. On the basis of the theory, a criterion is presented that has been shown to successfully predict whether or not a selective recycle reactor can maintain a plasmid-bearing strain.