Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.

Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.

Elemental biomapping of human tissues suggests toxic metals such as mercury play a role in the pathogenesis of cancer.

Toxic metals such as mercury, lead, and cadmium have multiple carcinogenic capacities, including the ability to damage DNA and incite inflammation. Environmental toxic metals have long been suspected to play a role in the pathogenesis of cancer, but convincing evidence from epidemiological studies that toxic metals are risk factors for common neoplasms has been difficult to gain. Another approach is to map the location of potentially toxic elements in normal human cells where common cancers originate, as well as in the cancers themselves. In this Perspective, studies are summarized that have used elemental biomapping to detect toxic metals such as mercury in human cells. Two elemental biomapping techniques, autometallography and laser ablation-inductively coupled-mass spectrometry imaging, have shown that multiple toxic metals exist in normal human cells that are particularly prone to developing cancer, and are also seen in neoplastic cells of breast and pancreatic tumors. Biomapping studies of animals exposed to toxic metals show that these animals take up toxic metals in the same cells as humans. The finding of toxic metals such as mercury in human cells prone to cancer could explain the increasing global incidence of many cancers since toxic metals continue to accumulate in the environment. The role of toxic metals in cancer remains to be confirmed experimentally, but to decrease cancer risk a precautionary approach would be to reduce emissions of mercury and other toxic metals into the environment from industrial and mining activities and from the burning of fossil fuels.

Zeptonewton and attotesla per centimeter metrology with coupled oscillators.

We present the coupled oscillator: A new mechanism for signal amplification with widespread application in metrology. We introduce the mechanical theory of this framework and support it by way of simulations. We present a particular implementation of coupled oscillators: A microelectromechanical system (MEMS) that uses one large (∼100mm) N52 magnet coupled magnetically to a small (∼0.25mm), oscillating N52 magnet, providing a force resolution of 200zN measured over 1s in a noiseless environment. We show that the same system is able to resolve magnetic gradients of 130aT/cm at a single point (within 500µm). This technology, therefore, has the potential to revolutionize force and magnetic gradient sensing, including high-impact areas such cardiac and brain imaging.

Implementing global positioning system trackers for people with dementia who are at risk of wandering.

OBJECTIVE: The main aim of this study was to evaluate the feasibility and acceptability of using a GPS tracker to mitigate the risks associated with wandering for people with dementia and those caring for them and further evaluate the impact of trackers in delaying 24-hour care and the potential for reducing the involvement of support services, such as the police, in locating patients. METHODS: We recruited forty-five wearers-carers dyads, and a GPS tracker was issued to each participant. Dyads completed pre-and post-outcome questionnaires after six months, and a use-log of experiences was maintained through monthly monitoring calls. At six months, focus groups were conducted with 14 dyads where they shared ideas and learning. Data analyses were performed on outcome questionnaires, use-log analysis, and focus groups discussion. RESULTS: A 24% (N = 14) attrition rate was recorded, with 76% (N = 34) of the participants completing pre- and post-outcome questionnaires, of which 41% (N = 14) attended four focus group meetings. Participants reported enhanced independence for wearers as fewer restrictions were placed on their movements, peace of mind and reduced burden for the carers with less need to involve police or social services, and delays in 24-hour care. CONCLUSION: The results supported the feasibility of routine implementation of GPS trackers in dementia care with clear guidance, monitoring and support to family carers on safe use. This could delay admission into 24-hour care as wearers and carers have a greater sense of safety and are better connected should help be required. Studies with larger sample sizes, diverse participants and health economic analysis are needed to develop the evidence base further ahead of the routine implementation of GPS trackers in health and social care services.

Delineating the contribution of ageing and physical activity to changes in mitochondrial characteristics across the lifespan.

Ageing is associated with widespread physiological changes prominent within all tissues, including skeletal muscle and the brain, which lead to a decline in physical function. To tackle the growing health and economic burdens associated with an ageing population, the concept of healthy ageing has become a major research priority. Changes in skeletal muscle mitochondrial characteristics have been suggested to make an important contribution to the reductions in skeletal muscle function with age, and age-related changes in mitochondrial content, respiratory function, morphology, and mitochondrial DNA have previously been reported. However, not all studies report changes in mitochondrial characteristics with ageing, and there is increasing evidence to suggest that physical activity (or inactivity) throughout life is a confounding factor when interpreting age-associated changes. Given that physical activity is a potent stimulus for inducing beneficial adaptations to mitochondrial characteristics, delineating the influence of physical activity on the changes in skeletal muscle that occur with age is complicated. This review aims to summarise our current understanding and knowledge gaps regarding age-related changes to mitochondrial characteristics within skeletal muscle, as well as to provide some novel insights into brain mitochondria, and to propose avenues of future research and targeted interventions. Furthermore, where possible, we incorporate discussions of the modifying effects of physical activity, exercise, and training status, to purported age-related changes in mitochondrial characteristics.

Structural maturation of myofilaments in engineered 3D cardiac microtissues characterized using small angle x-ray scattering.

Understanding the structural and functional development of human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) is essential to engineering cardiac tissue that enables pharmaceutical testing, modeling diseases, and designing therapies. Here we use a method not commonly applied to biological materials, small angle x-ray scattering, to characterize the structural development of hiPSC-CMs within three-dimensional engineered tissues during their preliminary stages of maturation. An x-ray scattering experimental method enables the reliable characterization of the cardiomyocyte myofilament spacing with maturation time. The myofilament lattice spacing monotonically decreases as the tissue matures from its initial post-seeding state over the span of 10 days. Visualization of the spacing at a grid of positions in the tissue provides an approach to characterizing the maturation and organization of cardiomyocyte myofilaments and has the potential to help elucidate mechanisms of pathophysiology, and disease progression, thereby stimulating new biological hypotheses in stem cell engineering.

Method of Anesthesia and Perioperative Risk Factors, Maternal Anesthesia Complications, and Neonatal Mortality Following Cesarean Delivery in Africa: A Substudy of a 7-Day Prospective Observational Cohort Study.

BACKGROUND: The African Surgical Outcomes Study (ASOS) found that maternal mortality following cesarean delivery in Africa is 50 times higher than in high-income countries, and associated with obstetric hemorrhage and anesthesia complications. Mothers who died were more likely to receive general anesthesia (GA). The associations between GA versus spinal anesthesia (SA) and preoperative risk factors, maternal anesthesia complications, and neonatal outcomes following cesarean delivery in Africa are unknown. METHODS: This is a secondary explanatory analysis of 3792 patients undergoing cesarean delivery in ASOS, a prospective observational cohort study, across 22 African countries. The primary aim was to estimate the association between preoperative risk factors and the outcome of the method of anesthesia delivered. Secondary aims were to estimate the association between the method of anesthesia and the outcomes (1) maternal intraoperative hypotension, (2) severe maternal anesthesia complications, and (3) neonatal mortality. Generalized linear mixed models adjusting for obstetric gravidity and gestation, American Society of Anesthesiologists (ASA) category, urgency of surgery, maternal comorbidities, fetal distress, and level of anesthesia provider were used. RESULTS: Of 3709 patients, SA was performed in 2968 (80%) and GA in 741 (20%). Preoperative factors independently associated with GA for cesarean delivery were gestational age (adjusted odds ratio [aOR], 1.093; 95% confidence interval [CI], 1.052-1.135), ASA categories III (aOR, 11.84; 95% CI, 2.93-46.31) and IV (aOR, 11.48; 95% CI, 2.93-44.93), eclampsia (aOR, 3.92; 95% CI, 2.18-7.06), placental abruption (aOR, 6.23; 95% CI, 3.36-11.54), and ruptured uterus (aOR, 3.61; 95% CI, 1.36-9.63). SA was administered to 48 of 94 (51.1%) patients with eclampsia, 12 of 28 (42.9%) with cardiac disease, 14 of 19 (73.7%) with preoperative sepsis, 48 of 76 (63.2%) with antepartum hemorrhage, 30 of 55 (54.5%) with placenta previa, 33 of 78 (42.3%) with placental abruption, and 12 of 29 (41.4%) with a ruptured uterus. The composite maternal outcome "all anesthesia complications" was more frequent in GA than SA (9/741 [1.2%] vs 3/2968 [0.1%], P < .001). The unadjusted neonatal mortality was higher with GA than SA (65/662 [9.8%] vs 73/2669 [2.7%], P < .001). The adjusted analyses demonstrated no association between method of anesthesia and (1) intraoperative maternal hypotension and (2) neonatal mortality. CONCLUSIONS: Analysis of patients undergoing anesthesia for cesarean delivery in Africa indicated patients more likely to receive GA. Anesthesia complications and neonatal mortality were more frequent following GA. SA was often administered to high-risk patients, including those with eclampsia or obstetric hemorrhage. Training in the principles of selection of method of anesthesia, and the skills of safe GA and neonatal resuscitation, is recommended.

A Five-Week Periodized Carbohydrate Diet Does Not Improve Maximal Lactate Steady-State Exercise Capacity and Substrate Oxidation in Well-Trained Cyclists compared to a High-Carbohydrate Diet.

There is a growing interest in studies involving carbohydrate (CHO) manipulation and subsequent adaptations to endurance training. This study aimed to analyze whether a periodized carbohydrate feeding strategy based on a daily training session has any advantages compared to a high-carbohydrate diet in well-trained cyclists. Seventeen trained cyclists (VO2peak = 70.8 ± 6.5 mL·kg-1·min-1) were divided into two groups, a periodized (PCHO) group and a high-carbohydrate (HCHO) group. Both groups performed the same training sessions for five weeks. In the PCHO group, 13 training sessions were performed with low carbohydrate availability. In the HCHO group, all sessions were completed following previous carbohydrate intake to ensure high pre-exercise glycogen levels. In both groups, there was an increase in the maximal lactate steady state (MLSS) (PCHO: 244.1 ± 29.9 W to 253.2 ± 28.4 W; p = 0.008; HCHO: 235.8 ± 21.4 W to 246.9 ± 16.7 W; p = 0.012) but not in the time to exhaustion at MLSS intensity. Both groups increased the percentage of muscle mass (PCHO: p = 0.021; HCHO: p = 0.042) and decreased the percent body fat (PCHO: p = 0.021; HCHO: p = 0.012). We found no differences in carbohydrate or lipid oxidation, heart rate, and post-exercise lactate concentration. Periodizing the CHO intake in well-trained cyclists during a 5-week intervention did not elicit superior results to an energy intake-matched high-carbohydrate diet in any of the measured outcomes.

Small peptides: could they have a big role in metabolism and the response to exercise?

Exercise is a powerful non-pharmacological intervention for the treatment and prevention of numerous chronic diseases. Contracting skeletal muscles provoke widespread perturbations in numerous cells, tissues and organs, which stimulate multiple integrated adaptations that ultimately contribute to the many health benefits associated with regular exercise. Despite much research, the molecular mechanisms driving such changes are not completely resolved. Technological advancements beginning in the early 1960s have opened new avenues to explore the mechanisms responsible for the many beneficial adaptations to exercise. This has led to increased research into the role of small peptides (<100 amino acids) and mitochondrially derived peptides in metabolism and disease, including those coded within small open reading frames (sORFs; coding sequences that encode small peptides). Recently, it has been hypothesized that sORF-encoded mitochondrially derived peptides and other small peptides play significant roles as exercise-sensitive peptides in exercise-induced physiological adaptation. In this review, we highlight the discovery of mitochondrially derived peptides and newly discovered small peptides involved in metabolism, with a specific emphasis on their functions in exercise-induced adaptations and the prevention of metabolic diseases. In light of the few studies available, we also present data on how both single exercise sessions and exercise training affect expression of sORF-encoded mitochondrially derived peptides. Finally, we outline numerous research questions that await investigation regarding the roles of mitochondrially derived peptides in metabolism and prevention of various diseases, in addition to their roles in exercise-induced physiological adaptations, for future studies.

The effect of sleep restriction, with or without high-intensity interval exercise, on behavioural alertness and mood state in young healthy males.

Mood state and alertness are negatively affected by sleep loss, and can be positively influenced by exercise. However, the potential mitigating effects of exercise on sleep-loss-induced changes in mood state and alertness have not been studied comprehensively. Twenty-four healthy young males were matched into one of three, 5-night sleep interventions: normal sleep (NS; total sleep time (TST) per night = 449 ± 22 min), sleep restriction (SR; TST = 230 ± 5 min), or sleep restriction and exercise (SR + EX; TST = 235 ± 5 min, plus three sessions of high-intensity interval exercise (HIIE)). Mood state was assessed using the profile of mood states (POMS) and a daily well-being questionnaire. Alertness was assessed using psychomotor vigilance testing (PVT). Following the intervention, POMS total mood disturbance scores significantly increased for both the SR and SR + EX groups, and were greater than the NS group (SR vs NS; 31.0 ± 10.7 A.U., [4.4-57.7 A.U.], p = 0.020; SR + EX vs NS; 38.6 ± 14.9 A.U., [11.1-66.1 A.U.], p = 0.004). The PVT reaction times increased in the SR (p = 0.049) and SR + EX groups (p = 0.033) and the daily well-being questionnaire revealed increased levels of fatigue in both groups (SR; p = 0.041, SR + EX; p = 0.026) during the intervention. Despite previously demonstrated physiological benefits of performing three sessions of HIIE during five nights of sleep restriction, the detriments to mood, wellness, and alertness were not mitigated by exercise in this study. Whether alternatively timed exercise sessions or other exercise protocols could promote more positive outcomes on these factors during sleep restriction requires further research.

Autophagy and Exercise: Current Insights and Future Research Directions.

Autophagy is a cellular process by which proteins and organelles are degraded inside the lysosome. Exercise is known to influence the regulation of autophagy in skeletal muscle. However, as gold standard techniques to assess autophagy flux in vivo are restricted to animal research, important gaps remain in our understanding of how exercise influences autophagy activity in humans. Using available datasets, we show how the gene expression profile of autophagy receptors and ATG8 family members differ between human and mouse skeletal muscle, providing a potential explanation for their differing exercise-induced autophagy responses. Furthermore, we provide a comprehensive view of autophagy regulation following exercise in humans by summarizing human transcriptomic and phosphoproteomic datasets that provide novel targets of potential relevance. These newly identified phosphorylation sites may provide an explanation as to why both endurance and resistance exercise lead to an exercise-induced reduction in LC3B-II, while possibly divergently regulating autophagy receptors, and, potentially, autophagy flux. We also provide recommendations to use ex vivo autophagy flux assays to better understand the influence of exercise, and other stimuli, on autophagy regulation in humans. This review provides a critical overview of the field and directs researchers towards novel research areas that will improve our understanding of autophagy regulation following exercise in humans.

Immunolabelling perturbs the endogenous and antibody-conjugated elemental concentrations during immuno-mass spectrometry imaging.

Immuno-mass spectrometry imaging uses lanthanide-conjugated antibodies to spatially quantify biomolecules via laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The multi-element capabilities allow for highly multiplexed analyses that may include both conjugated antibodies and endogenous metals to reveal relationships between disease and chemical composition. Sample handling is known to perturb the composition of the endogenous elements, but there has been little investigation into the effects of immunolabelling and coverslipping. Here, we used cryofixed muscle sections to examine the impact of immunolabelling steps on the concentrations of a Gd-conjugated anti-dystrophin primary antibody, and the endogenous metals Cu and Zn. Primary antibody incubation resulted in a decrease in Zn, and an increase in Cu. Zn was removed from the cytoplasm where it was hypothesised to be more labile, whereas concentrated locations of Zn remained in the cell membrane in all samples that underwent the immunostaining process. Cu increased in concentration and was found mostly in the cell membrane. The concentration of the Gd-conjugated antibody when compared to the standard air-dried sample was not significantly different when coverslipped using an organic mounting medium, whereas use of an aqueous mounting medium significantly reduced the concentration of Gd. These results build on the knowledge of how certain sample handling techniques change elemental concentrations and distributions in tissue sections. Immunolabelling steps impact the concentration of endogenous elements, and separate histological sections are required for the quantitative analysis of endogenous elements and biomolecules. Additionally, coverslipping tissue sections for complementary immunohistochemical/immunofluorescent imaging may compromise the integrity of the elemental label, and organic mounting media are recommended over aqueous mounting media.

Analysis of a 5-year, evidenced-based, rational blood utilisation project in a South African regional hospital.

BACKGROUND: Blood products are a lifesaving but limited resource, particularly in resource-limited settings. Evidence-based transfusion criteria tailored to local hospitals have shown great promise in reducing costs, minimising shortages, and ameliorating the morbidity and mortality associated with liberal blood product usage. We implemented the "Saving Blood, Saving Lives" project to: promote responsible blood product use and reduce blood product ordering inefficiencies and expenditure. METHODS: A comprehensive change management programme, preceded by 3 months of clinical department consultation and training, was implemented. A new evidence-based protocol for blood product utilisation was developed, together with an accountability form. This form was used in monthly audit meetings to refine policies, identify new problems, improve communication, and to drive hospital staff accountability and training. The primary measure of the programme's success was the change in the number of red cell concentrate units ordered. RESULTS: Project implementation required minimal time and no additional budget or staff. Annual red cell concentrate usage reduced from 7211 units in year one to 4077 units in year 5 (p < 0.001). Similar reductions were seen in freeze-dried plasma and platelet usage, as well as administrative costs. Total project saving, adjusted to baseline admission numbers, amounted to over R46 million ($2.5 million). CONCLUSIONS: As a change management programme centred the "Saving Blood, Saving Lives" project, was able to significantly reduce blood product-related administration and expenditure by implementing evidence-based transfusion criteria. The programme is simple, replicable and cost effective, making it ideally suited for use in resource-constrained environments.

Resistance-only and concurrent exercise induce similar myofibrillar protein synthesis rates and associated molecular responses in moderately active men before and after training.

Aerobic and resistance exercise (RE) induce distinct molecular responses. One hypothesis is that these responses are antagonistic and unfavorable for the anabolic response to RE when concurrent exercise is performed. This thesis may also depend on the participants' training status and concurrent exercise order. We measured free-living myofibrillar protein synthesis (MyoPS) rates and associated molecular responses to resistance-only and concurrent exercise (with different exercise orders), before and after training. Moderately active men completed one of three exercise interventions (matched for age, baseline strength, body composition, and aerobic capacity): resistance-only exercise (RE, n = 8), RE plus high-intensity interval exercise (RE+HIIE, n = 8), or HIIE+RE (n = 9). Participants trained 3 days/week for 10 weeks; concurrent sessions were separated by 3 h. On the first day of Weeks 1 and 10, muscle was sampled immediately before and after, and 3 h after each exercise mode and analyzed for molecular markers of MyoPS and muscle glycogen. Additional muscle, sampled pre- and post-training, was used to determine MyoPS using orally administered deuterium oxide (D2 O). In both weeks, MyoPS rates were comparable between groups. Post-exercise changes in proteins reflective of protein synthesis were also similar between groups, though MuRF1 and MAFbx mRNA exhibited some exercise order-dependent responses. In Week 10, exercise-induced changes in MyoPS and some genes (PGC-1ɑ and MuRF1) were dampened from Week 1. Concurrent exercise (in either order) did not compromise the anabolic response to resistance-only exercise, before or after training. MyoPS rates and some molecular responses to exercise are diminished after training.

Effects of the Toxic Non-Protein Amino Acid ß-Methylamino-L-Alanine (BMAA) on Intracellular Amino Acid Levels in Neuroblastoma Cells.

The cyanobacterial non-protein amino acid (AA) ß-Methylamino-L-alanine (BMAA) is considered to be a neurotoxin. BMAA caused histopathological changes in brains and spinal cords of primates consistent with some of those seen in early motor neuron disease; however, supplementation with L-serine protected against some of those changes. We examined the impact of BMAA on AA concentrations in human neuroblastoma cells in vitro. Cells were treated with 1000 µM BMAA and intracellular free AA concentrations in treated and control cells were compared at six time-points over a 48 h culture period. BMAA had a profound effect on intracellular AA levels at specific time points but in most cases, AA homeostasis was re-established in the cell. The most heavily impacted amino acid was serine which was depleted in BMAA-treated cells from 9 h onwards. Correction of serine depletion could be a factor in the observation that supplementation with L-serine protects against BMAA toxicity in vitro and in vivo. AAs that could potentially be involved in protection against BMAA-induced oxidation such as histidine, tyrosine, and phenylalanine were depleted in cells at later time points.

CAR+ and CAR- T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies.

Chimeric antigen receptor (CAR) T cell therapy is effective in treating B cell malignancies, but factors influencing the persistence of functional CAR+ T cells, such as product composition, patients' lymphodepletion, and immune reconstitution, are not well understood. To shed light on this issue, here we conduct a single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR+ and CAR- T cells from patients from a CARTELL study (ACTRN12617001579381) who received a donor-derived 4-1BB CAR product targeting CD19. Following infusion, CAR+ T cells and CAR- T cells shows similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. We validate these findings in 31 patients with large B cell lymphoma treated with CD19 CAR T therapy. For these patients, we identify using longitudinal mass-cytometry data an association between NK-like subsets and clinical outcomes at 6 months with both CAR+ and CAR- T cells. These results suggest that non-CAR-derived signals can provide information about patients' immune recovery and be used as correlate of clinically relevant parameters.

Investigation of the Optimum Baseline Blood Pressure for Spinal Anesthesia to Guide Vasopressor Management for Elective Cesarean Delivery: A Case-Control Design.

BACKGROUND: Current guidelines recommend prophylactic vasopressor administration during spinal anesthesia for cesarean delivery to maintain intraoperative blood pressure above 90% of the baseline value. We sought to determine the optimum baseline mean arterial pressure (MAP) reading to guide the management of spinal hypotension. METHODS: We performed a secondary analysis of data collected from normotensive patients presenting for elective cesarean delivery in a tertiary care institution from October 2018 to August 2020. We compared the magnitude of hypotension in patients who reported nausea versus those who did not, using a case-control design. Baseline MAPs at last office visit, morning of surgery, or operating room (pre-spinal) were determined. We calculated the duration and degree of hypotension using the area under the curve (AUC) when the MAP of the respective patient was below 90% of each baseline. RESULTS: The patients who experienced nausea (n=45) had longer and more profound periods of hypotension than those who did not develop nausea (n=240). A comparison of AUC using MAP baseline at the last office visit or on the morning of surgery showed a statistically significant between-group difference, P=0.02, and P=0.005, respectively, and no significant between-group difference when 90% of the MAP baseline in the operating room was used. CONCLUSIONS: Patients had the highest preoperative MAP in the operating room and the AUC was similar for those with and without nausea when the pre-spinal MAP baseline was used. Therefore, maintaining higher intraoperative blood pressure using individual pre-spinal MAP as baseline should reduce intraoperative maternal nausea.

Oral diseases are associated with cognitive function in adults over 60 years old.

OBJECTIVE: To investigate the bidirectional association between oral diseases and cognitive function comprehensively. SUBJECTS AND METHODS: This cross sectional study utilized data from the National Health and Nutrition Examination Survey. Oral diseases include periodontitis, dental caries, and tooth loss (end point of oral disease resulting in tooth extraction). Cognitive function included three domains: memory, processing speed, and executive function. A global cognitive score was then derived from sum of the three cognitive domains. Oral cognition associations were examined using various statistical models: (1) Regress oral disease on cognitive function; (2) Regress cognitive function on oral disease; and (3) Structural equation modelling treating cognition and oral disease as latent variables. RESULTS: There were 2508 participants aged 60+ who had both oral and cognitive information. Associations between various oral disease and global cognitive score were observed (Odds ratio ORcog->periodontitis 0.95, 95% Confidence Interval [0.92, 0.99]; ßcog->caries -0.13, [-0.23, -0.04]; ßcog->tooth loss -0.03 [-0.04, -0.01]; ßtooth loss->cog -0.04 [-0.06, -0.02]; ßcaries->cog -0.03 [-0.06, -0.01]; ßperiodontitis->cog -0.39 [-0.69, -0.10]). Significant correlation was also found between these oral disease and cognitive function using structural equation model (r -0.22, [-0.34, -0.10]). CONCLUSIONS: This study found robust bidirectional associations between oral disease and cognitive function using various modelling approaches among the aging population.

Concentration and Distribution of Toxic and Essential Elements in Traditional Rice Varieties of Sri Lanka Grown on an Anuradhapura District Farm.

Toxic heavy metals have been the focus of many investigations into chronic kidney disease of unknown aetiology (CKDu) within Sri Lanka. It has been hypothesised that exposure to nephrotoxic arsenic, cadmium and lead could play a role in the development of CKDu, and these metals have previously been found in unsafe concentrations in Sri Lankan rice. Traditional varieties of Sri Lankan rice remain popular due to their perceived health benefits, but their uptake of trace and toxic heavy metals remained unexplored. Here, we report a one-time, cross-sectional dataset on the concentrations of essential and toxic elements present in eleven samples of polished and unpolished traditional rice varieties, all regularly grown and sold in the Anuradhapura district, a CKDu hotspot. All rice was sourced from the same farm, with the exception of one store bought sample grown on another, unidentified farm. Cadmium concentrations varied significantly between varieties, and potentially unsafe concentrations of cadmium were detected in the store-bought sample (Suwadel, 113±13 µg kg-1). Elemental imaging of the grains revealed lead to be stored mainly in the rice bran, which is removed during polishing, while cadmium was distributed in the edible portion of the grain. Essential elements were generally higher in the traditional rice varieties than those reported for non-traditional varieties and are a potential source of trace elements for nutrient-deficient communities. The concentration of selenium, an element that plays a protective role in the kidneys, was too low to provide the minimum recommended intake. The methods developed in this study could be applied to a more comprehensive study of elemental uptake of rice under controlled growing conditions.

Discordant skeletal muscle gene and protein responses to exercise.

The ability of skeletal muscle to adapt to repeated contractile stimuli is one of the most intriguing aspects of physiology. The molecular bases underpinning these adaptations involve increased protein activity and/or expression, mediated by an array of pre- and post-transcriptional processes, as well as translational and post-translational control. A longstanding dogma assumes a direct relationship between exercise-induced increases in mRNA levels and subsequent changes in the abundance of the proteins they encode. Drawing on the results of recent studies, we dissect and question the common assumption of a direct relationship between changes in the skeletal muscle transcriptome and proteome induced by repeated muscle contractions (e.g., exercise).