The effects of aerobic exercise training on inflammatory markers in adult tobacco smokers: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Aerobic exercise training may reduce systemic inflammation, but the effects of this on systemic inflammatory markers in adult tobacco smokers has not been systematically reviewed. Therefore, we evaluated the effects of aerobic exercise training on C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) in adult tobacco smokers using a systematic review and meta-analysis of randomized controlled trials. METHODS: A comprehensive literature search was carried out using PubMed/Medline, Web of Science, EMBASE, Google Scholar, and hand search of bibliographies of the retrieved English or Persian articles up to August 2023. This review only included randomized controlled trials which investigated the effect of aerobic exercise training on CRP and TNF-α in adult smokers, based on a predefined inclusion and exclusion criteria. RESULTS: A total of 1641 articles were identified. Six studies were included in the review and four evaluated CRP and two evaluated TNF-α in only males. The meta-analysis demonstrated that aerobic exercise training significantly decreased TNF-α concentrations in males (MD = -6.68, 95 % CI = -13.90 to -0.54, P = 0.05). CRP concentrations did not decrease significantly when the data from the four studies were pooled (MD = -0.17, 95 % CI = -0.37 to 0.03, P = 0.09). CONCLUSION: Aerobic exercise training may reduce the concentration of TNF-α in male smokers, but it does not have a significant effect on CRP concentrations. However, these findings are based upon a small number of studies, that enrolled either exclusively male or female participants, and further investigation is necessary to increase statistical inference.

ErbB3 is required for hyperaminoacidemia-induced pancreatic α cell hyperplasia.

Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver - α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mTORC1, another ErbB3 downstream effector STAT3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mTORC1 and STAT3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.

Follow-up of women with cervical adenocarcinoma in situ treated by conization: A single centre clinical experience.

OBJECTIVE: Hysterectomy has been the historical gold standard final step in the treatment algorithm of adenocarcinoma in situ (AIS) recommended by most North American colposcopy guidelines. AIS disproportionately affects young childbearing age women, therefore a fertility sparing treatment option is desirable. Our study examines the impact of conservative treatment of AIS with conization followed by serial surveillance. METHODS: A retrospective chart review was completed of patients treated for AIS from 2006 to 2020. Charts were identified by pathologic diagnosis of AIS on cervical and uterine specimens. Charts were excluded if AIS was not treated with conization, if AIS was not confirmed on initial conization specimen, or if invasive disease was found at initial conization. RESULTS: 121 patient charts were analyzed. Median age of patients at first conization and hysterectomy was 34.8 and 40.9, respectively. First conization was by Cold Knife Cone in 58% of patients, and by Loop Electrosurgical Excisional Procedure in 42% of patients. Median follow-up period in our study was 609 days. 5% of patients had recurrence, with only one patient who recurred as cancer. One case of recurrence had a positive initial conization margin. Median time to recurrence was 700 days. 47% of patients underwent eventual hysterectomy. Residual AIS was found in 23% of hysterectomy specimens. Adenocarcinoma was diagnosed on hysterectomy specimen in four patients. CONCLUSION: Our study demonstrates the oncologic safety of treating AIS with conization and serial surveillance. Routine hysterectomy completed as a part of the AIS treatment algorithm, as in current clinical guidelines, is unnecessary.

The consumption of animal products is associated with plasma levels of alpha-aminoadipic acid (2-AAA).

BACKGROUND AND AIMS: The cardiometabolic disease-associated metabolite, alpha-aminoadipic acid (2-AAA) is formed from the breakdown of the essential dietary amino acid lysine. However, it was not known whether elevated plasma levels of 2-AAA are related to dietary nutrient intake. We aimed to determine whether diet is a determinant of circulating 2-AAA in healthy individuals, and whether 2-AAA is altered in response to dietary modification. METHODS AND RESULTS: We investigated the association between 2-AAA and dietary nutrient intake in a cross-sectional study of healthy individuals (N = 254). We then performed a randomized cross-over dietary intervention trial to investigate the effect of lysine supplementation (1 week) on 2-AAA in healthy individuals (N = 40). We further assessed the effect of a vegetarian diet on 2-AAA in a short-term (4-day) dietary intervention trial in healthy omnivorous women (N = 35). We found that self-reported dietary intake of animal products, including meat, poultry, and seafood, was associated with higher plasma 2-AAA cross-sectionally (P < 0.0001). Supplementary dietary lysine (5g/day) caused no significant increase in plasma 2-AAA; however, plasma 2-AAA was altered by general dietary modification. Further, plasma 2-AAA was significantly reduced by a short-term vegetarian diet (P = 0.003). CONCLUSION: We identified associations between plasma 2-AAA and consumption of animal products, which were validated in a vegetarian dietary intervention trial, but not in a trial designed to specifically increase the 2-AAA amino acid precursor lysine. Further studies are warranted to investigate whether implementation of a vegetarian diet improves cardiometabolic risk in individuals with elevated 2-AAA.

Metabolism of the 4-Hydroxyphenylpyruvate Dioxygenase Inhibitor, Mesotrione, in Multiple-Herbicide-Resistant Palmer amaranth (Amaranthus palmeri).

Metabolic resistance to the maize-selective, HPPD-inhibiting herbicide, mesotrione, occurs via Phase I ring hydroxylation in resistant waterhemp and Palmer amaranth; however, mesotrione detoxification pathways post-Phase I are unknown. This research aims to (1) evaluate Palmer amaranth populations for mesotrione resistance via survivorship, foliar injury, and aboveground biomass, (2) determine mesotrione metabolism rates in Palmer amaranth populations during a time course, and (3) identify mesotrione metabolites including and beyond Phase I oxidation. The Palmer amaranth populations, SYNR1 and SYNR2, exhibited higher survival rates (100%), aboveground biomass (c.a. 50%), and lower injury (25-30%) following mesotrione treatment than other populations studied. These two populations also metabolized mesotrione 2-fold faster than sensitive populations, PPI1 and PPI2, and rapidly formed 4-OH-mesotrione. Additionally, SYNR1 and SYNR2 formed 5-OH-mesotrione, which is not produced in high abundance in waterhemp or naturally tolerant maize. Metabolite features derived from 4/5-OH-mesotrione and potential Phase II mesotrione-conjugates were detected and characterized by liquid chromatography-mass spectrometry (LCMS).

Diagnostic or prognostic? Decoding the role of embryo selection on in vitro fertilization treatment outcomes.

In this review, we take a fresh look at embryo assessment and selection methods from the perspective of diagnosis and prognosis. On the basis of a systematic search in the literature, we examined the evidence on the prognostic value of different embryo assessment methods, including morphological assessment, blastocyst culture, time-lapse imaging, artificial intelligence, and preimplantation genetic testing for aneuploidy.

Prairie dog responses to vector control and vaccination during an initial Yersinia pestis invasion.

We evaluated the invasion of plague bacteria Yersinia pestis into a population of black-tailed prairie dogs (Cynomys ludovicianus; BTPDs) in South Dakota. We aimed to ascertain if Y. pestis invaded slowly or rapidly, and to determine if vector (flea) control or vaccination of BTPDs assisted in increasing survival rates. We sampled BTPDs in 2007 (before Y. pestis documentation), 2008 (year of confirmed invasion), and 2009 (after invasion). We estimated annual BTPD re-encounter rates on three 9-ha plots treated annually with deltamethrin dust for flea control and three 9-ha plots lacking dust. In 2007 and 2008, approximately half the adult BTPDs live-trapped were injected subcutaneously with either an experimental plague vaccine (F1-V fusion protein) or placebo formulation; the remaining individuals were not inoculated. From 2007 to 2009, we sampled 1559 BTPDs on 2542 occasions. During 2007-2008, the prevalence and intensity of fleas on BTPDs were 69-97% lower on the dusted vs. no dust plots. From 2007 to 2008, the annual re-encounter rate of non-inoculated BTPDs was 150% higher on the dusted vs. no dust plots. During the same interval on the dusted plots, the re-encounter rate was 55% higher for vaccinated adult female BTPDs vs. nonvaccinated adult females, but the annual re-encounter rate was 19% lower for vaccinated adult males. By late August 2008, BTPDs were nearly extirpated from the no dust plots. During 2007-2008 and 2008-2009 on the dusted plots, which persisted, the BTPD re-encounter rate was 41% higher for vaccinated vs. non-vaccinated adult females but 35% lower for vaccinated adult males. Yersinia pestis erupted with vigor as it invaded. Flea control enhanced BTPD survival but did not offer full protection. Flea control and F1-V vaccination seemed to have additive, positive effects on adult females. Annual re-encounter rates were reduced for vaccinated adult males; additional experimentation is needed to further evaluate this trend.

Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, it is hypothesized that significant morphological changes in BAT mitochondria and cristae will be present with aging. A quantitative 3D electron microscopy approach is developed to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, the 3D morphology of mitochondrial cristae is investigated in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, an increase is found in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.

Quantifying resistance to very-long-chain fatty acid-inhibiting herbicides in Amaranthus tuberculatus using a soilless assay.

Resistance to preemergence (PRE) soil-applied herbicides, such as inhibitors of very-long-chain fatty acid (VLCFA) elongases, was documented in two waterhemp [Amaranthus tuberculatus (Moq.) J.D. Sauer] populations (SIR and CHR) from Illinois, USA. To limit the spread of resistant weed populations, rapid detection measures are necessary. Soil-based resistance assays are limited by edaphic factors, application timing, variable seeding depth and rainfall amount. Therefore, cost-effective techniques mitigating effects of edaphic factors that are appropriate for small- to large-scale assays are needed. Our research goal was to identify and quantify resistance to the VLCFA-inhibiting herbicides, S-metolachlor and pyroxasulfone, using a soilless greenhouse assay. Dose-response experiments were conducted under greenhouse conditions with pre-germinated waterhemp seeds planted on the vermiculite surface, which had been saturated with S-metolachlor (0.015-15 µM), pyroxasulfone (0.0005-1.5 µM), or S-metolachlor plus the cytochrome P450 (P450) inhibitor, malathion. Lethal dose estimates of 50% (LD50) and growth reduction of 50% (GR50) were calculated for S-metolachlor and pyroxasulfone PRE and used to determine resistance indices (RI) for resistant populations (CHR and SIR) relative to sensitive populations, SEN and ACR. RI values for S-metolachlor using LD50 values calculated relative to SEN and ACR were 17.2 and 15.2 (CHR) or 11.5 and 10.1 (SIR), while RI values for pyroxasulfone using LD50 values calculated relative to SEN and ACR were 3.8 and 3.1 (CHR) or 4.8 and 3.8 (SIR). Malathion decreased the GR50 of S-metolachlor to a greater degree in CHR compared to ACR, consistent with P450 involvement in S-metolachlor resistance in CHR. Results from these soilless assays are in accord with previous findings in soil-based systems that demonstrate CHR and SIR are resistant to S-metolachlor and pyroxasulfone. This method provides an effective, reproducible alternative to soil-based systems for studying suspected PRE herbicide-resistant populations and will potentially assist in identifying non-target-site resistance mechanisms.

The acute effects of endurance exercise on epithelial integrity of the airways in athletes and non-athletes: A systematic review and meta-analysis.

INTRODUCTION: Acute endurance exercise may induce airway epithelium injury. However, the response of epithelial integrity markers of the airways including club cell secretory protein (CC16) and surfactant protein D (SP-D) to endurance exercise have not been systematically reviewed. Therefore, the aim of this systematic review and meta-analysis was to assess the acute effects of endurance exercise on markers of epithelial integrity of the airways (CC16, SP-D and the CC16/SP-D ratio) in athletes and non-athletes. METHODS: A systematic search was performed utilizing PubMed/Medline, EMBASE, Web of Science, and hand searching bibliographies of retrieved articles through to September 2022. Based on the inclusion criteria, articles with available data about the acute effects of endurance exercise on serum or plasma concentrations of CC16, SP-D and CC16/SP-D ratio in athletes and non-athletes were included. Quality assessment of studies and statistical analysis were conducted via Review Manager 5.4 software. RESULTS: The search resulted in 908 publications. Finally, thirteen articles were included in the review. Acute endurance exercise resulted in an increase in CC16 (P = 0.0006, n = 13) and CC16/SP-D ratio (P = 0.005, n = 2) whereas SP-D (P = 0.47, n = 3) did not change significantly. Subgroup analysis revealed that the type (P = 0.003), but not the duration of exercise (P = 0.77) or the environmental temperature (P = 0.06) affected the CC16 response to endurance exercise. CONCLUSIONS: Acute endurance exercise increases CC16 and the CC16/SP-D ratio, as markers of epithelial integrity, but not SP-D in athletes and non-athletes.

A comparison of activity demands between trial matches and in-season matches across multiple teams and seasons in semi-professional, male rugby league players.

Trial matches are frequently used for team preparation in rugby league competitions, making it essential to understand the demands experienced to assess their specificity to actual competition. Consequently, this study aimed to compare the activity demands between pre-season trial matches and early in-season rugby league matches. Following a repeated-measures observational design, 39 semi-professional, male rugby league players from two clubs were monitored using microsensors during two trial matches and the first two in-season matches across two consecutive seasons. Total distance, average speed, peak speed, absolute and relative high-speed running (HSR; > 18 km · h-1) and low-speed running (LSR; < 18 km · h-1) distance, as well as absolute and relative impacts, accelerations (total and high-intensity > 3 m · s-2), and decelerations (total and high-intensity < -3 m · s-2) were measured. Linear mixed models and Cohen's d effect sizes were used to compare variables between match types. Playing duration was greater for in-season matches (p < 0.001, d = 0.64). Likewise, higher (p < 0.001, d = 0.45-0.70) activity volumes were evident during in-season matches indicated via total distance, HSR distance, LSR distance, total accelerations, high-intensity accelerations, total decelerations, and high-intensity decelerations. Regarding activity intensities, a higher average speed (p = 0.008, d = 0.31) and relative LSR distance (p = 0.005, d = 0.31) only were encountered during in-season matches. Despite players completing less volume, the average activity intensities and impact demands were mostly similar between trial and early in-season matches. These findings indicate trial matches might impose suitable activity stimuli to assist players in preparing for early in-season activity intensities.

Genetic architecture of soybean tolerance to off-target dicamba.

The adoption of dicamba-tolerant (DT) soybean in the United States resulted in extensive off-target dicamba damage to non-DT vegetation across soybean-producing states. Although soybeans are highly sensitive to dicamba, the intensity of observed symptoms and yield losses are affected by the genetic background of genotypes. Thus, the objective of this study was to detect novel marker-trait associations and expand on previously identified genomic regions related to soybean response to off-target dicamba. A total of 551 non-DT advanced breeding lines derived from 232 unique bi-parental populations were phenotyped for off-target dicamba across nine environments for three years. Breeding lines were genotyped using the Illumina Infinium BARCSoySNP6K BeadChip. Filtered SNPs were included as predictors in Random Forest (RF) and Support Vector Machine (SVM) models in a forward stepwise selection loop to identify the combination of SNPs yielding the highest classification accuracy. Both RF and SVM models yielded high classification accuracies (0.76 and 0.79, respectively) with minor extreme misclassifications (observed tolerant predicted as susceptible, and vice-versa). Eight genomic regions associated with off-target dicamba tolerance were identified on chromosomes 6 [Linkage Group (LG) C2], 8 (LG A2), 9 (LG K), 10 (LG O), and 19 (LG L). Although the genetic architecture of tolerance is complex, high classification accuracies were obtained when including the major effect SNP identified on chromosome 6 as the sole predictor. In addition, candidate genes with annotated functions associated with phases II (conjugation of hydroxylated herbicides to endogenous sugar molecules) and III (transportation of herbicide conjugates into the vacuole) of herbicide detoxification in plants were co-localized with significant markers within each genomic region. Genomic prediction models, as reported in this study, can greatly facilitate the identification of genotypes with superior tolerance to off-target dicamba.

Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study.

STUDY QUESTION: Does the transfer of single low-grade blastocysts result in acceptable reproductive and perinatal outcomes compared to the transfer of single good-grade blastocysts? SUMMARY ANSWER: The transfer of single low-grade blastocysts resulted in a reduced live birth rate of around 30% (14% for very low-grade blastocysts) compared to 44% for single good-grade blastocysts, but does not lead to more adverse perinatal outcomes. WHAT IS KNOWN ALREADY: It is known that low-grade blastocysts can result in live births. However, the current studies are limited by relatively small sample sizes and single-centre designs. Furthermore, evidence on perinatal outcomes after transferring low-grade blastocysts is limited. STUDY DESIGN, SIZE, DURATION: We conducted a multi-centre, multi-national retrospective cohort study of 10 018 women undergoing 10 964 single blastocyst transfer cycles between 2009 and 2020 from 14 clinics across Australia, China, and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blastocysts were graded individually based on assessment of the morphology and development of the inner cell mass (ICM) and trophectoderm (TE), and were grouped into three quality categories: good- (AB, AB, or BA), moderate- (BB), and low-grade (grade C for ICM or TE) blastocysts. CC blastocysts were individually grouped as very low-grade blastocysts. Logistic regression with generalized estimating equation was used to analyse the association between blastocyst quality and live birth as well as other reproductive outcomes. Binomial, multinomial logistic, or linear regression was used to investigate the association between blastocyst quality and perinatal outcomes. Odds ratio (OR), adjusted OR (aOR), adjusted regression coefficient, and their 95% CIs are presented. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: There were 4386 good-grade blastocysts, 3735 moderate-grade blastocysts, and 2843 low-grade blastocysts were included in the analysis, for which the live birth rates were 44.4%, 38.6%, and 30.2%, respectively. Compared to good-grade blastocysts, the live birth rate of low-grade blastocysts was significantly lower (aOR of 0.48 (0.41-0.55)). Very low-grade blastocysts were associated with an even lower live birth rate (aOR 0.30 (0.18-0.52)) and their absolute live birth rate was 13.7%. There were 4132 singleton live births included in the analysis of perinatal outcomes. Compared with good-grade blastocysts, low-grade blastocysts had comparable preterm birth rates (<37 weeks, aOR 1.00 (0.65-1.54)), birthweight Z-scores (adjusted regression coefficient 0.02 (0.09-0.14)), and rates of very low birth weight (<1500 g, aOR 0.84 (0.22-3.25)), low birth weight (1500-2500 g, aOR 0.96 (0.56-1.65)), high birth weight (>4500 g, aOR 0.93 (0.37-2.32)), small for gestational age (aOR 1.63 (0.91-2.93)), and large for gestational age (aOR 1.28 (0.97-1.70)). LIMITATIONS, REASONS FOR CAUTION: Due to the nature of the retrospective design, residual confounding could not be excluded. In addition, the number of events for some perinatal outcomes was small. Between-operator and between-laboratory variations in blastocyst assessment were difficult to control. WIDER IMPLICATIONS OF THE FINDINGS: Patients undergoing IVF should be informed that low-grade blastocysts result in a lower live birth rate, however they do not increase the risk of adverse perinatal outcomes. Further research should focus on the criteria for embryos that should not be transferred and on the follow-up of long-term outcomes of offspring. STUDY FUNDING/COMPETING INTEREST(S): H.Z. is supported by a Monash Research Scholarship. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). R.W. is supported by an NHMRC Emerging Leadership Investigator grant (2009767). B.W.J.M. reports consultancy, travel support, and research funding from Merck. The other authors do not have competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Production and Performance Assessment of a Severe Acute Respiratory Syndrome Coronavirus 2 Biomimetic in a Verification Program for Pandemic Readiness.

During the early stages of the 2019 coronavirus disease (COVID-19) pandemic in South Africa, one of many challenges included availability of control material for laboratory proficiency testing programs. Proficiency testing control material using live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or RNA extracted from cell culture was either biohazardous or costly, particularly in resource-limited settings. This study reports the development and application of a noninfectious SARS-CoV-2 biomimetic Mycobacterium smegmatis strain that mimics a positive result in the GeneXpert SARS-CoV-2 Xpert Xpress cartridge. Nucleotide sequences located in genes encoding the RNA-dependent RNA polymerase, the nucleocapsid, and the envelope proteins were used. The resulting biomimetic strain was prepared as a positive proficiency testing control and distributed in South Africa for verification of laboratories before their testing of clinical specimens. Between April and December 2020, a total of 151 GeneXpert instruments with 2532 modules were verified to bring COVID-19 mass testing in South Africa online. An average concordance of 98.6% was noted in the entire laboratory network, allowing identification of false-positive/false-negative results and instrument errors. This noninfectious, easily scalable proficiency testing control material became available within 2 months after the start of the pandemic in South Africa and represents a useful approach to consider for other diseases and future pandemics.

Advances in Targeted Therapy for the Treatment of Cervical Cancer.

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.

Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2.

Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver-α cell axis. We hypothesized that α cells detect and respond to circulating amino acids levels via a unique amino acid transporter repertoire. We found that Slc7a2ISLC7A2 is the most highly expressed cationic amino acid transporter in α cells with its expression being three-fold greater in α than ß cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that both's role in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated α cell proliferation and islet hormone secretion.

Mesenchymal Stromal Cell Secretome Is Affected by Tissue Source and Donor Age.

Variation in mesenchymal stromal cell (MSC) function depending on their origin is problematic, as it may confound clinical outcomes of MSC therapy. Current evidence suggests that the therapeutic benefits of MSCs are attributed to secretion of biologically active factors (secretome). However, the effect of donor characteristics on the MSC secretome remains largely unknown. Here, we examined the influence of donor age, sex, and tissue source, on the protein profile of the equine MSC secretome. We used dynamic metabolic labeling with stable isotopes combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify secreted proteins in MSC conditioned media (CM). Seventy proteins were classified as classically secreted based on the rate of label incorporation into newly synthesized proteins released into the extracellular space. Next, we analyzed CM of bone marrow- (n = 14) and adipose-derived MSCs (n = 16) with label-free LC-MS/MS. Clustering analysis of 314 proteins detected across all samples identified tissue source as the main factor driving variability in MSC CM proteomes. Linear modelling applied to the subset of 70 secreted proteins identified tissue-related difference in the abundance of 23 proteins. There was an age-related decrease in the abundance of CTHRC1 and LOX, further validated with orthogonal techniques. Due to the lack of flow cytometry characterization of MSC surface markers, the analysis could not account for the potential effect of cell population heterogeneity. This study provides evidence that tissue source and donor age contribute to differences in the protein composition of MSC secretomes which may influence the effects of MSC therapy.

The effects of age on dyspnea and respiratory mechanical and neural responses to exercise in healthy men.

The respiratory muscle pressure generation and inspiratory and expiratory neuromuscular recruitment patterns in younger and older men were compared during exercise, alongside descriptors of dyspnea. Healthy younger (n = 8, 28 ± 5 years) and older (n = 8, 68 ± 4 years) men completed a maximal incremental cycling test. Esophageal, gastric (Pga ) and transdiaphragmatic pressures, and electromyography (EMG) of the crural diaphragm were measured using a micro-transducer and EMG catheter. EMG of the parasternal intercostals, sternocleidomastoids, and rectus abdominis were measured using skin surface electrodes. After the exercise test, participants completed a questionnaire to evaluate descriptors of dyspnea. Pga at end-expiration, Pga expiratory tidal swings, and the gastric pressure-time product (PTPga ) at absolute and relative minute ventilation were higher (p < 0.05) for older compared to younger men. There were no differences in EMG responses between older and younger men. Younger men were more likely to report shallow breathing (p = 0.005) than older men. Our findings showed younger and older men had similar respiratory neuromuscular activation patterns and reported different dyspnea descriptors, and that older men had greater expiratory muscle pressure generation during exercise. Greater expiratory muscle pressures in older men may be due to compensatory mechanisms designed to offset increasing airway resistance due to aging. These results may have implications for exercise-induced expiratory muscle fatigue in older men.

Defining Mitochondrial Cristae Morphology Changes Induced by Aging in Brown Adipose Tissue.

Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, we hypothesized that significant morphological changes in BAT mitochondria and cristae would be present with aging. We developed a quantitative three-dimensional (3D) electron microscopy approach to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, we investigated the 3D morphology of mitochondrial cristae in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, we found increases in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.