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Mechanical unloading during microgravity causes skeletal muscle atrophy and impairs mitochondrial energetics. The elevated production of reactive oxygen species (ROS) by mitochondria and Nox2, coupled with impairment of stress protection (e.g., SIRT1, antioxidant enzymes), contribute to atrophy. We tested the hypothesis that the SIRT1 activator, SRT2104 would rescue unloading-induced mitochondrial dysfunction. Mitochondrial function in rat gastrocnemius and soleus muscles were evaluated under three conditions (10 days): ambulatory control (CON), hindlimb unloaded (HU), and hindlimb-unloaded-treated with SRT2104 (SIRT). Oxidative phosphorylation, electron transfer capacities, H2O2 production, and oxidative and antioxidant enzymes were quantified using high-resolution respirometry and colorimetry. In the gastrocnemius, (1) integrative (per mg tissue) proton LEAK was lesser in SIRT than in HU or CON; (2) intrinsic (relative to citrate synthase) maximal noncoupled electron transfer capacity (ECI+II) was lesser, while complex I-supported oxidative phosphorylation to ECI+II was greater in HU than CON; (3) the contribution of LEAK to ECI+II was greatest, but cytochrome c oxidase activity was lowest in HU. In both muscles, H2O2 production and concentration was greatest in SIRT, as was gastrocnemius superoxide dismutase activity. In the soleus, H2O2 concentration was greater in HU compared to CON. These results indicate that SRT2104 preserves mitochondrial function in unloaded skeletal muscle, suggesting its potential to support healthy muscle cells in microgravity by promoting necessary energy production in mitochondria.

Background Disparity in cancer survival across countries has been linked to variation in cancer policy delivery but there is lack of empirical evidence for this association. We traced the evolution of cancer policies in 20 jurisdictions in Australia, Canada, Denmark, Ireland, Norway, New Zealand and the UK since 1995 and present the findings of an exploratory analysis linking cancer policy consistency to cancer survival. Methods We systematically searched and analysed national/regional cancer plans and strategies, mapping timelines of cancer policy evolution. For 10 jurisdictions, evidence was synthesised into five categories: oversight function; cancer plan; implementation plan; budget for plan implementation; and evaluation. We assigned scores evaluating whether a category was present or absent, and weighted scores for consistency. Summed scores were correlated with trends in survival from seven cancers between 1995-2014. Results All ten jurisdictions had implemented a high-level structure overseeing, steering or delivering cancer control policies (1995 - 2014); all had also published at least one major cancer plan. There was great variation in oversight mechanisms, ranging from institutionalising cancer control (New South Wales, Ontario) to cancer steering groups or taskforces (Denmark, Northern Ireland, Wales). Frequency and consistency of cancer plans also varied, from a succession of plans that build on each other (Denmark, New South Wales, Ontario) to the publication of isolated plans (New Zealand, Northern Ireland). We found a positive, albeit weak, correlation of cancer policy consistency and improvements in survival over time for six of the seven cancers. Conclusions Jurisdictions that have implemented consistent cancer control policies over time tended to be more successful in improving survival for a wide range of cancers. Our findings can help guide policymakers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes. Key messages • Sustained and consistent strategic cancer planning and investment are crucial for ensuring better patient outcomes, and this requires strong and sustained commitment at all levels. • The findings can help guide policymakers seeking approaches and frameworks to improve cancer services and, ultimately, cancer outcomes.

Delivery of therapeutic molecules to pathogenic cells is often hampered by unintended toxicity to normal cells. In principle, this problem can be circumvented if the therapeutic effector molecule is split into two inactive components, and only assembled on or within the target cell itself. Such an in situ process can be realized by exploiting target-specific molecules as templates to direct proximity-enhanced assembly. Modified nucleic acids carrying inert precursor fragments can be designed to co-hybridize on a target-specific template nucleic acid, such that the enforced proximity accelerates assembly of a functional molecule for antibody recognition. We demonstrate the in vitro feasibility of this adaptation of nucleic acid-templated synthesis (NATS) using oligonucleotides bearing modified peptides (“haplomers”), for templated assembly of a mimotope recognized by the therapeutic antibody trastuzumab. Enforced proximity promotes mimotope assembly via traceless native chemical ligation. Nevertheless, titration of participating haplomers through template excess is a potential limitation of trimolecular NATS. In order to overcome this problem, we devised a strategy where haplomer hybridization can only occur in the presence of target, without being subject to titration effects. This generalizable NATS modification may find future applications in enabling directed targeting of pathological cells.

Studies have shown a significant relationship between low oral health literacy (OHL) and poor oral health outcomes. National calls for action include better training of dental providers to meet the needs of the low OHL public. The purpose of this research was to determine the extent OHL education is being included in US dental hygiene (DH) education programs.In fall of 2020, a 23-item digital survey was sent to 321 Commission on Dental Accreditation-accredited DH schools in the US.Survey generated 90 eligible responses (28%). Respondents reported that OHL education is being included in DH curricula to some degree. Communication strategies (82.4%) were the most likely OHL concept to be taught. Subject areas included community health (89%), cultural competency (78%), and special populations (78%). Respondents ranked lack of assessment instruments, lack of concrete activities, lack of clear understanding of OHL, and difficulty in implementing OHL concepts as the top barriers to incorporating OHL education in the DH curriculum.OHL is an established determinant of oral health. As prevention and patient education experts, dental hygienists play an important role in improving patient OHL. More fully integrating OHL into DH curricula would provide future DHs with the training needed to improve oral health outcomes and would better align DH education programs with national OHL initiatives.

The invasion of Ukraine by Russia in February 2022 has resulted in destruction of healthcare infrastructure and triggered the largest wave of internally displaced populations and refugees since World War Two. Conflicts in transitioned countries such as Ukraine create new non-communicable disease (NCD) challenges, especially for cancer care for refugees and humanitarian assistance in host countries. In the early days, rapid attempts were made to model possible impacts. By evaluating open source intelligence used in the first three months of the conflict through snowball search methods, we aimed to address: (i) burden of cancer in Ukrainian population, specifically considering translating to the refugees population, and its cancer care capacity; ii) baseline capacity/strengths of cancer systems in initial host countries. Moreover, using a baseline scenario based on crude cancer incidence in Ukraine, and considering data from UNHCR, we estimated how cancer cases would be distributed across host countries. Finally, a surveillance assessment instrument was created, intersecting health system's capacity and influx of internally displaced populations and refugees. The total new cancer patients per month in pre-conflict Ukraine was estimated as 13,106, of which < 1 % are paediatric cases. The estimated cancer cases in the refugee population (combining prevalent and incident), assuming 7.5 million refugees by July 2022 and a female:male ratio of 9:1, was 33,121 individuals (Poland: 19284; Hungary: 3484; Moldova: 2651; Slovakia: 2421; Romania: 5281). According to our assessments, Poland is the only neighbouring country classified as green/yellow for cancer capacity, i.e. sufficient ablility to absorb additional burden into national health system; Slovakia we graded as yellow, Hungary and Romania as yellow/red and Moldova as red.

Previously institutionalized children on average show persistent deficits in physiological and behavioral regulation, as well as a lack of normative reticence towards strangers, or disinhibited social engagement (DSE). Post-adoption parenting, specifically a combination of supportive presence and structure/limit-setting, may protect against DSE over time via better adrenocortical functioning. This study examined the impact of adrenocortical activity and post-adoption parenting on DSE across the first two years post-adoption (age at adoption: 16-36 months) and observed kindergarten social outcomes in previously institutionalized children (n = 94) compared to non-adopted children (n = 52). Path analyses indicated a developmental cascade from institutional care (operationalized as a dichotomous group variable, age at adoption, and months of institutionalization) to blunted adrenocortical activity, increased DSE, and lower kindergarten social competence. Consistent with a permissive parenting style, higher parental support was associated with increased DSE, but only when not accompanied by effective structure/limit-setting. Further, parental structure reduced the association between blunted adrenocortical activity and DSE behaviors.

During space missions that travel beyond the cocoon of the Earth’s magnetosphere, astronauts are subjected to the microgravity and radiation stressors of outer space [...]

CONTEXT: Few studies have examined the clinical characteristics that predict durable, long-term diabetes remission after bariatric surgery. OBJECTIVE: To compare diabetes prevalence and remission rates during 7-year follow-up after Roux-en-Y gastric bypass (RYGB) and laparoscopic gastric banding (LAGB). DESIGN: An observational cohort of adults with severe obesity recruited between 2006 and 2009 who completed annual research assessments for up to 7 years after RYGB or LAGB. SETTING: Ten US hospitals. PARTICIPANTS: A total sample of 2256 participants, 827 with known diabetes status at both baseline and at least 1 follow-up visit. INTERVENTIONS: Roux-en-Y gastric bypass or LAGB. MAIN OUTCOME MEASURES: Diabetes rates and associations of patient characteristics with remission status. RESULTS: Diabetes remission occurred in 57% (46% complete, 11% partial) after RYGB and 22.5% (16.9% complete, 5.6% partial) after LAGB. Following both procedures, remission was greater in younger participants and those with shorter diabetes duration, higher C-peptide levels, higher homeostatic model assessment of β-cell function (HOMA %B), and lower insulin usage at baseline, and with greater postsurgical weight loss. After LAGB, reduced HOMA insulin resistance (IR) was associated with a greater likelihood of diabetes remission, whereas increased HOMA-%B predicted remission after RYGB. Controlling for weight lost, diabetes remission remained nearly 4-fold higher compared with LAGB. CONCLUSIONS: Durable, long-term diabetes remission following bariatric surgery is more likely when performed soon after diagnosis when diabetes medication burden is low and beta-cell function is preserved. A greater weight-independent likelihood of diabetes remission after RYGB than LAGB suggests mechanisms beyond weight loss contribute to improved beta-cell function after RYGB. Trial Registration clinicaltrials.gov Identifier: NCT00465829.

BackgroundThe present study examined the efficacy of the Michigan Model of Infant Mental Health-Home Visiting (IMH-HV) infant mental health treatment to promote the socioemotional wellbeing of infants and young children. Science illuminates the role of parental “co-regulation” of infant emotion as a pathway to young children’s capacity for self-regulation. The synchrony of parent–infant interaction begins to shape the infant’s own nascent regulatory capacities. Parents with a history of childhood adversity, such as maltreatment or witnessing family violence, and who struggle with symptoms of post-traumatic stress may have greater challenges in co-regulating their infant, thus increasing the risk of their children exhibiting social and emotional problems such as anxiety, aggression, and depression. Early intervention that targets the infant–parent relationship may help buffer the effect of parental risk on child outcomes.MethodsParticipants were 58 mother–infant/toddler dyads enrolled in a longitudinal randomized control trial testing the efficacy of the relationship-based IMH-HV treatment model. Families were eligible based on child age (ResultsMaternal ACEs predicted more toddler emotional problems through their effect on maternal PTSD symptoms. Parents who received IMH-HV treatment reported more positive toddler socioemotional wellbeing at follow-up relative to the control condition. The most positive socioemotional outcomes were for toddlers of mothers with low to moderate PTSD symptoms who received IMH-HV treatment.ConclusionResults indicate the efficacy of IMH-HV services in promoting more optimal child socioemotional wellbeing even when mothers reported mild to moderate PTSD symptoms. Results also highlight the need to assess parental trauma when infants and young children present with socioemotional difficulties.

Background There is growing policy interest in reducing the length of stay (LOS) after discretionary orthopedic surgery but few data to guide improvement efforts. We characterized the primary reasons and predisposing factors associated with extended LOS after elective total shoulder arthroplasty. Methods We retrospectively identified 415 patients undergoing elective primary total shoulder arthroplasty between 2016 and 2017. Extended LOS was defined as a stay greater than the 75th percentile. Medical records were manually reviewed to ascertain the primary reason for extended LOS. Multivariable logistic regression modeling was used to determine preoperative characteristics associated with prolonged hospitalization. Results The most common reason for extended LOS was pain (41%), followed by medical problems (39%), limited social support (18%), and blood transfusions (2%). Only 41% of patients with delayed discharges had documented adverse events (any medical or surgical problem), all of which were minor. The top 4 medical issues were transient hypoxemia (42%), nausea and/or vomiting (13%), electrolyte abnormalities (12%), and altered mental status (10%). In decreasing order of magnitude, the predictors of prolonged LOS were greater number of self-reported allergies, female sex, unmarried patient, diabetes, lower American Shoulder and Elbow Surgeons score, depression, reverse shoulder arthroplasty, and American Society of Anesthesiologists score of 3 or greater. Operative time did not correlate with LOS. Conclusions Prolonged hospitalizations after shoulder arthroplasty are commonly related to pain and limited social support. Sociodemographic and psychological factors seem to have more influence than patient infirmity and technical issues. These findings support a comprehensive approach to care with attention to the physical, mental, and social determinants of health.

Introduction The error‐related negativity (ERN) is a neural response that reflects error monitoring. Contradictorily, an enlarged (more negative) ERN has been cited as both a risk factor and a protective factor, which hinders its utility as a predictive indicator. The aim of the current study was to examine the associations between ERN measured in early childhood with the development of cognitive control (CC), emotion regulation, and internalizing/externalizing symptoms over 1–2 years. Methods When children were ages 5–7, EEG was collected during a Go/No‐Go task. A subset of the original participants (n = 30) were selected based on their baseline ERN in an extreme‐case design: half with high‐amplitude ERN, matched by age and sex with another group with low‐amplitude ERN. Results At follow‐up, children in the High‐Amplitude group showed better executive function, less self‐reported anxiety and depression, less affect dysregulation, more parent‐rated CC, less lability/negativity, and fewer parent‐reported externalizing problems. Many results held even when accounting for baseline levels. Further, emotion dysregulation mediated the relationship between the ERN and both anxiety and externalizing problems, while CC mediated the ERN's relationship with externalizing problems only. Conclusions These results can inform identification and intervention efforts for children at risk for psychopathology., High‐amplitude error‐related negativity (ERN), measured in early childhood, predicts better self‐control, including executive function and cognitive control and less affect dysregulation in middle childhood, and predicts fewer anxiety, depression, and externalizing symptoms over time. Emotion dysregulation mediated the relationship between the ERN and both anxiety and externalizing problems, while cognitive control mediated the ERN's relationship with externalizing problems only.

There have been 77 TNOs discovered to be librating in the distant trans-Neptunian resonances (beyond the 2:1 resonance, at semimajor axes greater than 47.7 au) in four well-characterized surveys: the Outer Solar System Origins Survey (OSSOS) and three similar prior surveys. Here, we use the OSSOS Survey Simulator to measure their intrinsic orbital distributions using an empirical parameterized model. Because many of the resonances had only one or very few detections, j:k resonant objects were grouped by k in order to have a better basis for comparison between models and reality. We also use the Survey Simulator to constrain their absolute populations, finding that they are much larger than predicted by any published Neptune migration model to date; we also find population ratios that are inconsistent with published models, presenting a challenge for future Kuiper Belt emplacement models. The estimated population ratios between these resonances are largely consistent with scattering–sticking predictions, though further discoveries of resonant TNOs with high-precision orbits will be needed to determine whether scattering–sticking can explain the entire distant resonant population or not.

Context Postbariatric hypoglycemia (PBH), characterized by enteroinsular axis overstimulation and hyperinsulinemic hypoglycemia, is a complication of bariatric surgery for which there is no approved therapy. Objective To evaluate efficacy and safety of avexitide [exendin (9-39)], a glucagon-like peptide-1 antagonist, for treatment of PBH. Methods A multicenter, Phase 2, randomized, placebo-controlled crossover study (PREVENT). Eighteen female patients with PBH were given placebo for 14 days followed by avexitide 30 mg twice daily and 60 mg once daily, each for 14 days in random order. The main outcome measures were glucose nadir and insulin peak during mixed-meal tolerance testing (MMTT) and hypoglycemic events captured by self-monitoring of blood glucose (SMBG), electronic diary, and blinded continuous glucose monitoring (CGM). Results Compared with placebo, avexitide 30 mg twice daily and 60 mg once daily raised the glucose nadir by 21% (P = .001) and 26% (P = .0002) and lowered the insulin peak by 23% (P = .029) and 21% (P = .042), corresponding to 50% and 75% fewer participants requiring rescue during MMTT, respectively. Significant reductions in rates of Levels 1 to 3 hypoglycemia were observed, defined, respectively, as SMBG Conclusion Avexitide administered for 28 days was well tolerated and resulted in robust and consistent improvements across multiple clinical and metabolic parameters, reinforcing the targeted therapeutic approach and demonstrating durability of effect. Avexitide may represent a first promising treatment for patients with severe PBH.

Megaconstellations of thousands to tens of thousands of artificial satellites (satcons) are rapidly being developed and launched. These satcons will have negative consequences for observational astronomy research, and are poised to drastically interfere with naked-eye stargazing worldwide should mitigation efforts be unsuccessful. Here we provide predictions for the optical brightnesses and on-sky distributions of several satcons, including Starlink, OneWeb, Kuiper, and StarNet/GW, for a total of 65,000 satellites on their filed or predicted orbits. We develop a simple model of satellite reflectivity, which is calibrated using published Starlink observations. We use this model to estimate the visible magnitudes and on-sky distributions for these satellites as seen from different places on Earth, in different seasons, and different times of night. For latitudes near 50 degrees North and South, satcon satellites make up a few percent of all visible point sources all night long near the summer solstice, as well as near sunrise and sunset on the equinoxes. Altering the satellites' altitudes only changes the specific impacts of the problem. Without drastic reduction of the reflectivities, or significantly fewer total satellites in orbit, satcons will significantly change the night sky worldwide., Comment: accepted to AJ

Reduced mechanical loading results in atrophy of skeletal muscle fibers. Increased reactive oxygen species (ROS) are causal in sarcolemmal dislocation of nNOS and FoxO3a activation. The Nox2 isoform of NADPH oxidase and mitochondria release ROS during disuse in skeletal muscle. Activation of the angiotensin II type 1 receptor (AT1R) can elicit Nox2 complex formation. The AT1R blocker losartan was used to test the hypothesis that AT1R activation drives Nox2 assembly, nNOS dislocation, FoxO3a activation, and thus alterations in morphology in the unloaded rat soleus. Male Fischer 344 rats were divided into four groups: ambulatory control (CON), ambulatory + losartan (40 mg kg−1 day−1) (CONL), 7 days of tail‐traction hindlimb unloading (HU), and HU + losartan (HUL). Losartan attenuated unloading‐induced loss of muscle fiber cross‐sectional area (CSA) and fiber‐type shift. Losartan mitigated unloading‐induced elevation of ROS levels and upregulation of Nox2. Furthermore, AT1R blockade abrogated nNOS dislocation away from the sarcolemma and elevation of nuclear FoxO3a. We conclude that AT1R blockade attenuates disuse remodeling by inhibiting Nox2, thereby lessening nNOS dislocation and activation of FoxO3a., Angiotensin receptor blockade (ARB) reduced unloading‐induced atrophy of skeletal muscle. Losartan mitigated assembly of the Nox2 complex, and thus oxidative stress ARB attenuated loss of sarcolemmal nNOSµ and nuclear levels of FoxO3a.

Introduction: Previously referred to as late dumping syndrome, post-bariatric hypoglycemia (PBH) is thought to represent at least 1% of all hospitalizations for hypoglycemia and 10% of all clinically recognized hypoglycemia cases. However, through the advent of CGM and more strict criteria over the last decade these numbers are likely an underestimate. As obesity continues to remain prevalent and with rising bariatric centers to help deal with this epidemic, endocrinologists will play an increasing role in managing PBH patients. Clinical Case: A 39-year female with a PMH of hypothyroidism and bariatric surgery (BS) in 2009 presented to our ER for a seizure. She has been having seizures nearly every 2 weeks for one year. Neurology started her on Keppra; however, no etiology was identified. EMS had documented a blood glucose of 40 mg/dL; the patient was given an amp of D50 with resolution of neuroglycopenic symptoms. TSH and cortisol levels were within normal range. A sulfonylurea panel in the ED was negative. The patient states the symptoms can occur while fasting but also mainly post-prandial. A 72-hr fast was conducted with the patient nadir POC glucose of 77. Subsequently, the patient had a mixed meal tolerance performed and after 2 hours had a seizure and was found to have a BG of 50 mg/dL with an insulin level of 49 uIU/mL and a c-peptide of 18.8 ng/mL. The patient was diagnosed with PBH, and was discharged with a CGM, started on acarbose and was seen by nutrition to discuss dietary modifications. She is now seen in our clinic with control of her symptoms with the addition of diazoxide. Conclusion: Altered anatomy after bariatric surgery, particularly after gastric bypass and sleeve gastrectomy is thought to play a major role in developing PBH. By bypassing normal anatomy, gastric emptying is increased 2–3 x, which leads to a higher and more rapid appearance of glucose in the distal foregut. This subsequently leads to an amplified incretin response leading to a hyperinsulinemic response in patients who have had bariatric surgery; however, for unclear reasons some patients develop an even more amplified hyperinsulinemic response that leads to subsequent hypoglycemia. History of neuroglycopenic symptoms 1–3 hours after eating in a patient who had a gastric bypass > 6–12 months and with relief of symptoms with carbohydrates should raise an endocrinologist’s suspicion of PBH. Fasting hypoglycemia is an atypical feature that should raise one’s suspicion of a broader differential. Altered nutrition habits is the cornerstone of therapy with which the primary aim is to reduce post-prandial glucose spikes in these patients after they eat carbohydrates. These spikes in turn lead to hyperinsulinism leading to subsequent hypoglycemia. Primary diet modifications include controlled carbohydrate consumption of less than 30g per meal, avoiding high glycemic carbs, and always taking in ample fat and proteins with every meal.

Using the high-cadence lightcurves collected from the FOSSIL survey, rotation periods of 17 small (diameter 1 km < D < 3 km) Hilda asteroids (hereinafter Hildas) were obtained. Combined with the previously measured rotation periods of Hildas, a spin-rate limit appears at around 3 hr. Assuming rubble-pile structures for the Hildas, a bulk density of ∼1.5 g cm−3 is required to withstand this spin-rate limit. This value is similar to that of the C-type asteroids (1.33 g cm−3) and higher than the ∼1 g cm−3 bulk density of the Jupiter Trojans. This suggests that the Hildas population may contain more C-type asteroids than expected, and the limit at 3 hr simply reflects the spin-rate limit for C-type asteroids. In addition, a Hilda superfast rotator was found, which has a rotation period of 1.633 hr and an estimated diameter of 0.7 km. This object is unlikely to be explained by a rubble-pile or monolithic structure.

Proton transfer in the nanoscopic water channels of polyelectrolyte fuel cell membranes was studied using a photoacid, 8-hydroxypyrene-1,3,6-trisulfonic acid sodium salt (HPTS), in the channels. The local environment of the probe was determined using 8-methoxypyrene-1,3,6-trisulfonic acid sodium salt (MPTS), which is not a photoacid. Three fully hydrated membranes, Nafion (DuPont) and two 3M membranes, were studied to determine the impact of different pendant chains and equivalent weights on proton transfer. Fluorescence anisotropy and excited state population decay data that characterize the local environment of the fluorescent probes and proton transfer dynamics were measured. The MPTS lifetime and anisotropy results show that most of the fluorescent probes have a bulk-like water environment with a relatively small fraction interacting with the channel wall. Measurements of the HPTS protonated and deprotonated fluorescent bands' population decays provided information on the proton transport dynamics. The decay of the protonated band from ∼0.5 ns to tens of nanoseconds is in part determined by dissociation and recombination with the HPTS, providing information on the ability of protons to move in the channels. The dissociation and recombination is manifested as a power law component in the protonated band fluorescence decay. The results show that equivalent weight differences between two 3M membranes resulted in a small difference in proton transfer. However, differences in pendant chain structure did significantly influence the proton transfer ability, with the 3M membranes displaying more facile transfer than Nafion.

Children reared in orphanages typically experience the lack of stable, reliable caregivers and are at increased risk for deficits in regulatory abilities including difficulties in inhibitory control, attention, and emotion regulation. Although adoption results in a radical shift in caregiving quality, there remains variation in postadoption parenting, yet little research has examined postadoption parenting that may promote recovery in children experiencing early life adversity in the form of institutional care. Participants included 93 postinstitutionalized children adopted between 15 and 36 months of age and 52 nonadopted same-aged peers. Parenting was assessed four times during the first 2 years postadoption (at 2, 8, 16, and 24 months postadoption) and children's regulation was assessed at age 5 (Mage = 61.68 months) and during kindergarten (Mage = 71.55 months). Multiple parenting dimensions including sensitivity/responsiveness, structure/limit setting, and consistency in routines were examined. Both parental sensitivity and structure moderated the effect of preadoption adversity on children's emotion regulation while greater consistency was associated with better inhibitory control and fewer attention problems. Results support the notion that postadoption parenting during toddlerhood and the early preschool years promotes better regulation skills following early adversity.

Avexitide (formerly exendin 9-39) is a first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist in development as a liquid formulation for subcutaneous (SC) injection for treatment of post-bariatric hypoglycemia (PBH). PBH, a rare disease with high unmet medical need and no approved pharmacologic therapy, develops as a late complication of bariatric surgery. Patients with PBH exhibit exaggerated GLP-1 levels with dysregulated secretion of insulin and symptomatic hypoglycemia 1-3 hours after meals, putting them at risk for severe neuroglycopenic outcomes such as loss of consciousness, seizures, falls and motor vehicle accidents. Previous studies involving in-clinic SC injection of avexitide in patients with PBH have demonstrated attenuation of the insulinotropic effect of GLP-1 and prevention of hypoglycemia. PREVENT (NCT03373435), a Phase 2, multi-center, placebo-controlled study is the first to investigate the safety and durability of effect of 28-day outpatient dosing of SC avexitide in patients with severe, refractory PBH. Eighteen patients enrolled across five U.S. academic centers received placebo SC injections for 14 days in a single-blinded manner followed by avexitide SC 30 mg twice daily (BID) injections for 14 days and 60 mg once daily (QD) injections for 14 days, for a total of 28 days active dosing, in a double-blinded to dose, cross-over design. The primary efficacy endpoint of improved postprandial glucose nadir during mixed meal tolerance testing (MMTT) was achieved with avexitide 30 mg BID (57.1 vs 47.1 mg/dL; p = 0.001) and 60 mg QD (59.2 vs 47.1 mg/dL; p=0.0002), with fewer patients requiring glycemic rescue during each of the active dosing regimens than during placebo dosing. The secondary endpoint of reduced postprandial insulin peak during MMTT was achieved with avexitide 30 mg BID (349.5 vs 454.5 μIU/mL; p < 0.03) and 60 mg QD (357.2 vs 454.5 μIU/mL; p = 0.04). Metabolic and clinical improvements were monitored in the outpatient setting with electronic diaries and continuous glucose monitoring (CGM). Patients experienced fewer episodes of hypoglycemia (hypoglycemia symptoms confirmed by self-monitored blood glucose (SMBG) concentrations of

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading, however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

Age-related loss of skeletal muscle mass and function, referred to as sarcopenia, is mitigated by lifelong calorie restriction as well as exercise. In aged skeletal muscle fibers there is compromised integrity of the cell membrane that may contribute to sarcopenia. The purpose of this study was to determine if lifelong mild (8%) caloric restriction (CR) and lifelong CR + voluntary wheel running (WR) could ameliorate disruption of membrane scaffolding and signaling proteins during the aging process, thus maintaining a favorable, healthy membrane environment in plantaris muscle fibers. Fischer-344 rats were divided into four groups: 24-month old adults fed ad libitum (OAL); 24-month old on 8% caloric restriction (OCR); 24 month old 8% caloric restriction + wheel running (OCRWR); 6-month old sedentary adults fed ad libitum (YAL) were used to determine age-related changes. Aging resulted in discontinuous membrane expression of dystrophin glycoprotein complex (DGC) proteins: dystrophin and α-syntrophin. Older muscle also displayed decreased content of neuronal nitric oxide synthase (nNOS), a key DGC signaling protein. In contrast, OCR and OCRWR provided significant protection against age-related DGC disruption. In conjunction with the age-related decline in membrane DGC patency, key membrane repair proteins (MG53, dysferlin, annexin A6, and annexin A2) were significantly increased in the OAL plantaris. However, lifelong CR and CRWR interventions were effective at maintaining membrane repair proteins near YAL levels of. OAL fibers also displayed reduced protein content of NADPH oxidase isoform 2 (Nox2) subunits (p67phox and p47phox), consistent with a perturbed sarcolemmal environment. Loss of Nox2 subunits was prevented by lifelong CR and CRWR. Our results are therefore consistent with the hypothesis that lifelong CR and WR are effective countermeasures against age-related alterations in the myofiber membrane environment.

A substantial number of obese individuals are relatively insulin sensitive and the etiology for this variation remains unknown.The primary objective was to detect factors in adipose tissue differentiating obese insulin-sensitive (OBIS) from obese insulin-resistant (OBIR) individuals and investigate whether adipose tissue hypoxia is a contributing factor in the pathogenesis of insulin resistance.This was a cross-sectional study in the general community.Subjects consisted of nondiabetic OBIS and OBIR subjects with similar body mass index, age, and total body fat but different insulin sensitivity index as well as lean insulin-sensitive subjects.There were no interventions.We examined adipocytokines and the expression of candidate genes regulating hypoxia, inflammation, and lipogenesis in adipose tissue and adipose tissue oxygenation.OBIS subjects had increased plasma adiponectin but similar plasma TNFα and leptin levels as compared with OBIR subjects. Genes regulating inflammation (CD68, MCP1, scavenger receptor A, and oxidized LDL receptor 1) were increased by 40%–60% (P.05) in OBIR vs OBIS cohorts. In addition, genes involved in extracellular matrix formation such as collagen VI and MMP7 were up-regulated by 43% and 78% (P.05), respectively, in OBIR vs OBIS. The expression of HIF1α and VEGF gene expression was increased by 37% and 52%, respectively, in OBIR vs OBIS (P.01). Despite the differential expression in hypoxia-related genes, adipose tissue oxygenation measured by a Licox oxygen probe was not different between OBIS and OBIR subjects, but it was higher in lean subjects as compared with obese subjects.We confirmed that adipose tissue inflammation and fibrosis play an important role in the pathogenesis of insulin resistance independent of obesity in humans. Whether hypoxia is simply a consequence of adipose tissue expansion or is related to the pathogenesis of obesity-induced insulin resistance is yet to be understood.

Seals experience repeated bouts of ischemia–reperfusion while diving, potentially exposing their tissues to increased oxidant generation and thus oxidative damage and accelerated aging. We contrasted markers of oxidative damage with antioxidant profiles across age and sex for propulsive (longissismus dorsi) and maneuvering (pectoralis) muscles of Weddell seals to determine whether previously observed morphological senescence is associated with oxidative stress. In longissismus dorsi, old (age 17–26 years) seals exhibited a nearly 2-fold increase in apoptosis over young (age 9–16 years) seals. There was no evidence of age-associated changes in lipid peroxidation or enzymatic antioxidant profiles. In pectoralis, 4-hydroxynonenal-Lys (4-HNE-Lys) levels increased 1.5-fold in old versus young seals, but lipid hydroperoxide levels and apoptotic index did not vary with age. Glutathione peroxidase activity was 1.5-fold higher in pectoralis of old versus young animals, but no other antioxidants changed with age in this muscle. With respect to sex, no differences in lipid hydroperoxides or apoptosis were observed in either muscle. Males had higher HSP70 expression (1.4-fold) and glutathione peroxidase activity (1.3-fold) than females in longissismus dorsi, although glutathione reductase activity was 1.4-fold higher in females. No antioxidants varied with sex in pectoralis. These results show that apoptosis is not associated with oxidative stress in aged Weddell seal muscles. Additionally, the data suggest that adult seals utilize sex-specific antioxidant strategies in longissismus dorsi but not pectoralis to protect skeletal muscles from oxidative damage.

Sarcopenia is the aging-associated progressive loss of skeletal muscle; however, the pathogenic mechanism of sarcopenia is not clear. The orexigenic hormone ghrelin stimulates growth hormone secretion, increases food intake, and promotes adiposity. Here we showed that fasting-induced muscle loss was exacerbated in old ghrelin-null (Ghrl–/–) mice, exhibiting decreased expression of myogenic regulator MyoD and increased expression of protein degradation marker MuRF1, as well as altered mitochondrial function. Moreover, acylated ghrelin and unacylated ghrelin treatments significantly increased mitochondrial respiration capacity in muscle C2C12 cells. Consistently, acylated ghrelin and unacylated ghrelin treatments effectively increased myogenic genes and decreased degradation genes in the muscle in fasted old Ghrl–/– mice, possibly by stimulating insulin and adenosine monophosphate-activated protein kinase pathways. Furthermore, Ghrl–/– mice showed a profile of pro-inflammatory gut microbiota, exhibiting reduced butyrate-producing bacteria Roseburia and ClostridiumXIVb. Collectively, our results showed that ghrelin has a major role in the maintenance of aging muscle via both muscle-intrinsic and -extrinsic mechanisms. Acylated ghrelin and unacylated ghrelin enhanced muscle anabolism and exerted protective effects for muscle atrophy. Because unacylated ghrelin is devoid of the obesogenic side effect seen with acylated ghrelin, it represents an attractive therapeutic option for sarcopenia.

Background The complexity of total joint arthroplasty warrants significant patient counseling, and some surgeons are utilizing multimedia to aid in preoperative education. Our aim was to assess the effect of an educational video on patient understanding and satisfaction when supplementing a traditional office consultation for total shoulder arthroplasty. Methods This study was a surgeon-blinded, randomized control trial involving 60 consecutive patients undergoing primary total shoulder arthroplasty. Following a preoperative consultation by a single surgeon, patients were randomized in a 1:1 ratio to either a control or treatment group. All participants received a 9-question true-or-false test pertaining to basic shoulder arthroplasty knowledge. The treatment group subsequently viewed a 13-minute educational video explaining glenohumeral osteoarthritis, surgery, and postoperative expectations. At a second preoperative appointment, participants of both groups were asked to repeat the same test. Results Fifty-two patients were available for the second preoperative appointment. There was no difference in test scores between the video (7.84/9) and no video (7.89/9) groups ( P = .75). All patients in the video group reported improved satisfaction and understanding. Conclusion Patients who watched an educational video supplementing a preoperative consultation for shoulder arthroplasty reported improved satisfaction but did not demonstrate increased understanding compared to those receiving a standard preoperative consultation.

Transcriptomic profiling of colorectal cancer (CRC) has led to identification of four consensus molecular subtypes (CMS1-4), which have prognostic value in stage II/III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors. However, the clinical value of these classifications in predicting response to standard-of-care adjuvant chemotherapy remains unknown.Using samples from 4 European sites, we assembled a novel stage II/III CRC patient cohort and performed transcriptomic profiling on 156 samples, targeted sequencing and generated a tissue microarray to enable integrated "multi-omics" analyses. We also accessed data from 2 published stage II/III CRC patient cohorts: GSE39582 and GSE14333 (479 and 185 samples respectively).The epithelial-rich CMS2 subtype of CRC benefitted significantly from adjuvant chemotherapy treatment in both stage II and III disease (p=0.02 and p0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage IIPatient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying poor prognostic stage II/III patients who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.

The free radical theory of aging purports that the accumulation of cellular oxidative damage leads to aging. While this process is not expected to manifest in wild populations, which can suffer fro...

There is a significant need to develop objective measures for identifying children under the age of 8 who have anxiety and depression. If left untreated, early internalizing symptoms can lead to adolescent and adult internalizing disorders as well as comorbidity which can yield significant health problems later in life including increased risk for suicide. To this end, we propose the use of an instrumented fear induction task for identifying children with internalizing disorders, and demonstrate its efficacy in a sample of 63 children between the ages of 3 and 7. In so doing, we extract objective measures that capture the full six degree-of-freedom movement of a child using data from a belt-worn inertial measurement unit (IMU) and relate them to behavioral fear codes, parent-reported child symptoms and clinician-rated child internalizing diagnoses. We find that IMU motion data, but not behavioral codes, are associated with parent-reported child symptoms and clinician-reported child internalizing diagnosis in this sample. These results demonstrate that IMU motion data are sensitive to behaviors indicative of child psychopathology. Moreover, the proposed IMU-based approach has increased feasibility of collection and processing compared to behavioral codes, and therefore should be explored further in future studies.

Proton-transfer kinetics in both ionic and neutral reverse micelles were studied by time-correlated single-photon counting investigations of the fluorescent photoacid 8-hydroxypyrene-1,3,6-trisulfonate (HPTS). Orientational dynamics of dissolved probe molecules in the water pools of the reverse micelles were also investigated by time-dependent fluorescence anisotropy measurements of MPTS, the methoxy derivative of HPTS. These experiments were compared to the same experiments in bulk water. It was found that in ionic reverse micelles (surfactant Aerosol OT, AOT), orientational motion (fluorescence anisotropy decay) of MPTS was relatively unhindered, consistent with MPTS being located in the water core of the reverse micelle away from the water-surfactant interface. In nonionic reverse micelles (surfactant Igepal CO-520, Igepal), however, orientational anisotropy displayed a slow multiexponential decay consistent with wobbling-in-a-cone behavior, indicating MPTS is located at the water-surfactant interface. HPTS proton transfer in ionic reverse micelles followed kinetics qualitatively like those in bulk water, albeit slower, with the long-time power law time dependence associated with recombination of the proton with the dissociated photoacid, suggesting a modified diffusion-controlled process. However, the power law exponents in the ionic reverse micelles are smaller (∼ -0.55) than that in bulk water (-1.1). In neutral reverse micelles, proton-transfer kinetics did not show discernible power law behavior and were best represented by a two-component model with one relatively waterlike population and a population with a faster fluorescence lifetime and negligible proton transfer. We explain the Igepal results on the basis of close association between the probe and the neutral water-surfactant interface, with the probe experiencing a distribution of more and less waterlike environments. In addition, the observation in bulk water of a power law t(-1.1) for diffusion-controlled recombination is in contrast to the theoretical prediction of t(-1.5) and previously reported observations. The difference from prior experimental results is discussed.

The current study examined the role of hypothalamic-pituitary-adrenal reactivity (a physiological indicator of stress) in early infancy as a mediator of the relationship between maternal postpartum depression and toddler behavior problems. Participants were 137 at-risk mothers and their children participating in a longitudinal study of intergenerational transmission of risk. Mothers' depression was measured five times during the infants' first 18 months. Infant cortisol was collected during a social stressor (the still-face paradigm) when infants were 6 months old, and mothers reported on toddlers' internalizing and externalizing symptoms at 18 months. Among this sample of high-risk mother-infant dyads, early postpartum depression predicted atypical infant cortisol reactivity at 6 months, which mediated the effect of maternal depression on increased toddler behavior problems. Clinical implications are discussed.

BACKGROUND As Internet and mobile phone use expands in India, there is an opportunity to develop mobile health (mHealth) interventions for marginalized populations, including men who have sex with men (MSM) and hijras (transgender women), hesitant to access traditional health care systems. OBJECTIVE The purpose of this study was to determine if an mHealth intervention was acceptable to MSM and hijras living in Mumbai, and if so, what features would be useful in targeting the prevention of HIV acquisition and to increase the quality of life among persons living with HIV/AIDS. METHODS Data from 4 focus groups with MSM and interviews with 4 hijras, 10 health service providers, and 8 mHealth developers were thematically analyzed. RESULTS Once the need for an mHealth intervention was confirmed, comments about features were organized into 3 themes: content, interface, and retention. Content subthemes included providing sex education for younger community members, providing information about STIs, and providing information and social support for persons living with HIV. Interface subthemes included presenting content using pictures; using videos to present stories of role models; using push notifications for testing, appointment, and medication reminders; using geolocation to link to just-in-time services; and using telemedicine to increase access to health service providers and community services. The 5 retention subthemes included keeping it fun, using gaming mechanics, developing content in regional languages, protecting confidentiality, and linking to social networking apps. CONCLUSIONS These findings may help inform mHealth development in India.

A key mechanism of risk transmission between maternal risk and child outcomes are the mother’s representations. The current study examined the effects of an attachment-based, trauma-informed parenting intervention, the Mom Power (MP) program, in optimizing maternal representations of high-risk mothers utilizing a randomized, controlled trial design (NCT01554215). High-risk mothers were recruited from low-income community locations and randomized to either the MP Intervention (n = 42) or a control condition (n = 33) in a parallel design. Maternal representations were assessed before and after the intervention using the Working Model of the Child Interview. The proportion of women with balanced (secure) representations increased in the MP group but not in the control group. Parenting Reflectivity for mothers in the treatment group significantly increased, with no change in the control condition. Participation in the MP program was associated with improvements in a key indicator of the security of the parent–child relationship: mothers’ representations of their children.

New findings What is the central question of this study? Translocation of nNOSμ initiates catabolic signalling via FoxO3a and skeletal muscle atrophy during mechanical unloading. Recent evidence suggests that unloading-induced muscle atrophy and FoxO3a activation are redox sensitive. Will a mimetic of superoxide dismutase and catalase (i.e. Eukarion-134) also mitigate suppression of the Akt-mTOR pathway? What is the main finding and its importance? Eukarion-134 rescued Akt-mTOR signalling and sarcolemmal nNOSμ, which were linked to protection against the unloading phenotype, muscle fibre atrophy and partial fibre-type shift from slow to fast twitch. The loss of nNOSμ from the sarcolemma appears crucial to Akt phosphorylation and is redox sensitive, although the mechanisms remain unresolved. Abstract Mechanical unloading stimulates rapid changes in skeletal muscle morphology, characterized by atrophy of muscle fibre cross-sectional area and a partial fibre-type shift from slow to fast twitch. Recent studies revealed that oxidative stress contributes to activation of forkhead box O3a (FoxO3a), proteolytic signalling and unloading-induced muscle atrophy via translocation of the μ-splice variant of neuronal nitric oxide synthase (nNOSμ) and activation of FoxO3a. There is limited understanding of the role of reactive oxygen species in the Akt-mammalian target of rapamycin (mTOR) pathway signalling during unloading. We hypothesized that Eukarion-134 (EUK-134), a mimetic of the antioxidant enzymes superoxide dismutase and catalase, would protect Akt-mTOR signalling in the unloaded rat soleus. Male Fischer 344 rats were separated into the following three study groups: ambulatory control (n = 11); 7 days of hindlimb unloading + saline injections (HU, n = 11); or 7 days of HU + EUK-134; (HU + EUK-134, n = 9). EUK-134 mitigated unloading-induced dephosphorylation of Akt, as well as FoxO3a, in the soleus. Phosphorylation of mTOR in the EUK-treated HU rats was not different from that in control animals. However, EUK-134 did not significantly rescue p70S6K phosphorylation. EUK-134 attenuated translocation of nNOSμ from the membrane to the cytosol, reduced nitration of tyrosine residues and suppressed upregulation of caveolin-3 and dysferlin. EUK-134 ameliorated HU-induced remodelling, atrophy of muscle fibres and the 12% increase in type II myosin heavy chain-positive fibres. Attenuation of the unloaded muscle phenotype was associated with decreased reactive oxygen species, as assessed by ethidium-positive nuclei. We conclude that oxidative stress affects Akt-mTOR signalling in unloaded skeletal muscle. Direct linkage of abrogation of nNOSμ translocation with Akt-mTOR signalling during unloading is the subject of future investigation.

Sexual and gender minority (SGM) youth too often live in nonsupportive environments. This study reports the influence of social support from primary and secondary social ties on confidence and self-esteem among participants in Hatch Youth, a drop-in group-level intervention for SGM youth. Each 3-hour Hatch Youth meeting consists of a social, educational, and youth-led support hour. Over 14 weeks, these meetings were randomly observed and individual interviews with participating youth ( n = 12) and staff and volunteers ( n = 12) were conducted; data underwent a content analysis. Participants perceived an increase in confidence and self-esteem through enhanced bonding with family and friends, a sense of belonging, and community empowerment because of their involvement with Hatch Youth, suggesting drop-in centers can strengthen secondary social ties and improve confidence and self-esteem.

This column describes an innovative collaboration in Michigan that could serve as a model for meaningful community-university-state partnerships. Recent legislation in Michigan threatened the infant mental health home visiting program, a service for Medicaid-eligible infants, toddlers, and families affected by mental illness. The University of Michigan is overseeing two major studies in collaboration with the Michigan Department of Health and Human Services, the Michigan Association for Infant Mental Health, the Michigan Infant Toddler Research Exchange faculty network, and community health service providers to determine the evidence base for the program and ensure its future success.

As the obesity epidemic worsens, more people are opting for weight-loss surgery, including gastric bypass. Of the possible complications associated with this procedure, hypoglycemia secondary to hyperinsulinemia is becoming a more common and therefore more relevant problem.

Adoption marks a radical transition in caregiving for thousands of children adopted internationally from institutional care; however, very little is known about the quality of this parenting compared with other populations or the transactional effects of parent and child characteristics in postadoption families during the transition to family care. The current study examined parental sensitivity/responsiveness and structure/limit-setting in a group of 68 children adopted internationally from institutions (41 girls, 27 boys; M age = 26.13 months, SD = 4.99) and their parents over the first year after adoption and compared them to a sample of nonadoptive families (26 girls, 26 boys; M age = 27.65 months, SD = 5.71). Results indicated no mean-level differences in parenting quality on either dimension between adoptive and nonadoptive parents. For postinstitutionalized youth, higher quality parental structure and limit-setting soon after adoption predicted reduced child regulation difficulties 8 months later; however, initial child regulation did not predict later parenting. There were no cross-lagged relations for parental sensitivity/responsiveness. Higher quality preadoptive care for children was associated with higher scores on both sensitivity/responsiveness and structure and limit-setting among adoptive parents. Less growth stunting, indicative of less preadoptive adversity, was associated with parents' use of more effective structure and limit-setting behaviors. Policies should promote better preadoptive care abroad, such as lower caregiver-child ratios, as well as early adoption. At least in families exhibiting generally high sensitivity/responsiveness, interventions should target parental structure and limit-setting to have the greatest effect on child behavioral regulation in the immediate years postadoption. (PsycINFO Database Record

Aging reduces cardiac function due to impaired Ca2+ homeostasis (1,2) and progressive structural remodeling. Age-related remodeling includes the loss of cardiac myocytes, a product of increased apoptosis and necrosis as well as reduced replacement by progenitor cells (3–5). Indeed, the loss of cardiac myocytes increases exponentially with advancing age in the heart, although the impact may be gender-dependent (5,6). For example, aging resulted in approximately 30% reduction in the number of cardiac myocytes in 70-year-old man (7). In addition, remaining cardiac myocytes experience reactive hypertrophy, and there is an accumulation of connective tissue (ie, fibrosis) (8). Increased fibrotic tissue reduces cardiac filling and enhances the risk of chronic heart failure (2). Previously, we reported that treadmill exercise training reduced age-induced apoptosis and remodeling in the rat heart (4). In a follow-up study (5), we reported that exercise training reduced collagenous fibrosis that was associated with aging. Collagen-I and upstream regulatory proteins tissue inhibition of metalloproteinase-1 and transforming growth factor-β (TGF-β) were lower in the hearts of exercise trained rats. Treadmill exercise training also upregulated the mitochondrial cell protective Mn isoform of superoxide dismutase (MnSOD) and reduced oxidative stress in the aging heart (9). However, the causal relationship between elevation of MnSOD in the aging heart and reduction in fibrosis and apoptosis in the aging heart is unknown. MnSOD is an essential antioxidant enzyme located in the mitochondrial matrix, protecting proteins, lipids, and DNA. MnSOD catalyzes the dismutation of superoxide anion (O2•−) produced in the mitochondrial inner membrane to hydrogen peroxide (H2O2) (10,11). MnSOD has been shown to confer cardioprotection in a number of models. For example, homozygous MnSOD (Sod2 −/−) knockout mice exhibit impaired mitochondrial enzyme and high susceptibility to oxidative mitochondrial injury (12,13). Furthermore, Sod2 −/− mice have enlarged hearts with dilated left ventricles (LV), leading to early postnatal mortality (12). In addition, the heterozygous MnSOD (Sod2 − /+) knockout mouse expresses a phenotype characterized by impaired mitochondrial enzyme activity and respiration (14). Moreover, the Sod2 −/+ mouse has a higher probability of permeability transition pore opening (15) and oxidative damage to mitochondria (16) than wild-types (WT). In contrast, overexpression of MnSOD in transgenic mice appears to protect against oxidative stress, mitochondrial oxidative capacity, apoptosis, and in liver, brain, and skeletal muscle (10,17–19). Exercise enhances stress response including enhancement of MnSOD (20), heat-shock proteins (19), and insulin-like growth factor-1 (1,3). Indeed, upregulation of stress proteins may abrogate apoptosis and remodeling in the heart. Elevation of MnSOD is an attractive protection-mechanism of habitual exercise against fibrosis and apoptosis in the aging heart because inducibility of MnSOD by exercise training is retained with age (9). Exercise may also attenuate redox-sensitive inflammatory cytokines (21), which stimulate cardiac remodeling. A primary source of elevated oxidative stress in the aging heart is believed to be complexes I and III of mitochondrial electron transport chain of the inner mitochondrial membrane (22). Furthermore, elevation of mitochondrial oxidative stress is associated with mitochondrial dysfunction (22,23). Indeed, age-related elevation of oxidative stress has been linked to pro-apoptotic proteins (eg, Bax, Bad, Bid) resulting in increased permeability transition pore opening and subsequent activation of caspases-9 and -3 (21). Therefore, we tested the hypothesis that overexpression of MnSOD (Sod2 Tg) would attenuate age-related remodeling. Specifically, we postulated that old MnSOD Tg would exhibit significantly lower levels of cardiac oxidative stress, fibrotic markers (collagen-I, TGF-β), and apoptosis (Bax, caspase-3 cleavage, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL]-positive staining, DNA fragmentation) compared with old WT.

Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow-twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma to the cytosol. We used EUK-134, a cell-permeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOSμ translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer-344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded + EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading-induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOSμ immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOSμ protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOSμ translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers.