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Caloric restriction (CR) is the leading non-pharmacological intervention to delay induced and spontaneous tumors in pre-clinical models. These effects of CR are largely attributed to canonical inhibition of pro-growth pathways. However, our recent data suggest that CR impairs primary tumor growth and cancer progression in the murine 4T1 model of triple negative breast cancer (TNBC), at least in part, through reduced frequency of the myeloid-derived suppressor cells (MDSC). In the present study, we sought to determine whether injection of excess MDSCs could block regression in 4T1 tumor growth and metastatic spread in BALB/cJ female mice undergoing daily CR. Our findings show that MDSC injection impeded CR-mediated protection against tumor growth without increasing lung metastatic burden. Overall, these results reveal that CR can slow cancer progression by affecting immune suppressive cells. Impact statement: Inoculation of MDSCs from donor mice effectively impedes the ability of calorie restriction to protect against primary tumor growth without impacting lung metastatic burden in recipient animals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00635-y.

Objective: Design and validate a wireless, low-cost, easy-to-use, mobile, dry-electrode headset for scalp electroencephalography (EEG) recordings for closed-loop brain-computer (BCI) interface and internet-of-things (IoT) applications. Approach: The EEG-based BCI headset was designed from commercial off-the-shelf (COTS) components using a multi-pronged approach that balanced interoperability, cost, portability, usability, form factor, reliability, and closed-loop operation. Main Results: The adjustable headset was designed to accommodate 90\% of the population. A patent-pending self-positioning dry electrode bracket allowed for vertical self-positioning while parting the user's hair to ensure contact of the electrode with the scalp. In the current prototype, five EEG electrodes were incorporated in the electrode bracket spanning the sensorimotor cortices bilaterally, and three skin sensors were included to measure eye movement and blinks. An accelerometer provides monitoring of head movements. The EEG amplifier operates with 24 bits resolution up to 500 Hz sampling frequency, and can communicate with other devices using 802.11 {b/g/n/WiFi}. It has high SNR and CMRR (121 dB and 110 dB, respectively), and low input noise. In closed-loop BCI mode, the system can operate at 40 Hz, including real-time adaptive noise cancellation and 512 MB of processor memory. It supports LabVIEW as backend coding language and JS, CSS, HTML as front-end coding languages, and includes training and optimization of Support Vector Machine (SVM) neural classifiers. Extensive bench testing supports the technical specifications and human subject pilot testing of a closed-loop BCI application to support upper-limb rehabilitation provides proof-of-concept validation for device use at both the clinic and at home. Significance: The low-cost, accessibility, usability, interoperability, and programmability of the proposed closed-loop BCI system provides a low-cost solution for BCI and neurorehabilitation research and IoT applications.

Respectful maternity care (RMC) is part of a global movement addressing the previous absence of human rights in global safe maternal care guidance. RMC is grounded in kindness, compassion, dignity and respectful working conditions. The decolonisation movement in healthcare seeks to dismantle structural biases set up from a historically white, male, heteronormative Eurocentric medical system. This article applies a decolonising lens to the RMC agenda and examines barriers to its implementation in UK healthcare systems. Searches of peer-reviewed journals about decolonising maternity care in the UK revealed little. Drawing from wider information bases, we examine power imbalances constructed throughout a history of various colonial biases yet lingering in maternity care. The overarching findings of our analysis revealed 3 areas of focus: professional structures and institutional biases; power imbalances between types of staff and stakeholders of care; and person-centred care through a decolonial lens. To uproot inequity and create fairer and more respectful maternity care for women, birthing people and staff, it is vital that contemporary maternity institutions understand the decolonial perspective. This novel enquiry offers a scaffolding to undertake this process. Due to significant differences in colonial history between Western colonising powers, it is important to decolonise with respect to these different territories, histories and challenges.

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM Objectives Long pentraxin-3 (PTX3) is a soluble pattern-recognition receptor secreted by phagocytes and non-immune cells at sites of inflammation. It has been reported to have a nonredundant role in the immune response against Aspergillus fumigatus. Indeed, PTX3 knock-out mice show an increased susceptibility to invasive pulmonary aspergillosis (IPA) with a higher mortality rate. In humans, PTX3 genetic deficiency or single nucleotide polymorphism has also been associated with an increased risk of IPA. However, the way in which PTX3 interacts with A. fumigatus and its mechanism of action has yet to be elucidated. The aim of the study was to investigate potential A. fumigatus ligands for PTX3 and the impact of A. fumigatus opsonization by PTX3 on modulating the immune response. Methods Aspergillus fumigatus conidia, the infective morphotype, were incubated with PTX3 with or without human serum, stained with anti-PTX3 antibody, and studied by immunofluorescence. Identification of potential fungal ligands for PTX3 was performed by ELISA. Fixed conidia and germinated conidia were opsonized with different serum factors and co-incubated with human monocyte-derived macrophages (hMDM) for 24 h at 37°C. Culture supernatants were collected, and pro-/anti-inflammatory cytokines were measured by sandwich ELISA. Results PTX3 did not bind A. fumigatus conidia directly but in the presence of human serum, purified collectins [surfactant protein D (SP-D) or C1q], and complement products (C3b). Pre-opsonization of conidia with these complement proteins or SP-D stimulated proinflammatory cytokine secretion by hMDM upon interaction (Fig. 1a). In contrast, secondary opsonization of complement proteins or SP-D opsonized conidia with PTX3 significantly reduced pro-inflammatory cytokines and increased anti-inflammatory cytokine secretion from hMDM. PTX3 opsonized PFA-fixed germinating conidia significantly reduced pro-inflammatory cytokine and increased anti-inflammatory cytokines secretion from hMDM (Fig. 1b). Conclusion PTX3 is an acute phase protein expressed in response to pro-inflammatory stimuli during infection and that is increased in bronchoalveolar lavage of patients with aspergillosis. Our recent data with A. fumigatus suggest that PTX3 is an immunoregulatory protein that reduces pro-inflammatory response. Although an inflammatory response is necessary to fight against fungal pathogens, the tissue damage associated with enhanced inflammation can be deleterious and facilitate A. fumigatus infection.

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the humanBDNFgene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wildtype (Val/Val)) influenced the ability of voluntary running to increase cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism.HighlightsBDNF Met/Met mice performed worse than BDNF Val/Val mice in middle-ageAerobic training (AT) increased cognitive performance in BDNF Met/Met miceAT increased neurogenesis in middle-aged BDNF Val/Val mice onlyFemale BDNF Val/Val mice had better cognitive flexibility than males regardless of ATAT increased more mature new neurons in middle-aged female mice

Objectives Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In an effort to better align trials, the Definition for the Assessment of Time to event Endpoints in CANcer trials (DATECAN) project published recommendations in 2015 to be used in mRCC clinical trial design. We analyzed mRCC trial criteria to determine if DATECAN's recommendations were followed. Materials and methods We compared eligibility criteria across 29 phase 3 mRCC trials conducted between 2003 and 2019. We then evaluated endpoints used in 10 phase 3 trials activated between 2015 and 2019 to determine their compliance with DATECAN's recommendations. Results Among the 29 trials, performance status, renal function, and disease characteristics differed in terms of requirements and measures used. In terms of endpoints, the 10 trials did not entirely follow DATECAN's recommendations. In total, 7/10 trials' primary endpoint was progression-free survival (PFS) as recommended; 4/9 trials used PFS as an endpoint but did not publish their definition of PFS, and the 5 that did, included "death from any cause" instead of DATECAN's recommendation of "death from kidney cancer." Conclusions Key eligibility criteria were somewhat inconsistent across the phase 3 mRCC trials studied. Endpoints in the newer trials did not align with DATECAN's recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN's recommendations, greater promotion and adoption of recommendations are needed to better harmonize trial design.

The diversity of backbone modifications in the study of primitive informational polymers is partly limited by the plausible formation of their prebiotic starting components. In this paper, we synthesize pyrazine nucleic acid, an acyclic polymer, with the nucleoside derivable from a prebiotic one-pot synthesis containing alanine amide and D-ribose. Pyrazine nucleic acid (PzNA) which has a backbone structurally similar to glycerol nucleic acid (GNA), contain pyrazine derived nucleosides as informational elements that may exhibit base pairing properties similar to the pyrimidines present in RNA.

Marine birds are frequently found dead on beaches, either from natural or from anthropogenic causes. Complete necropsies of those carcasses can provide valuable information, particularly for pelagic species, such as Northern Fulmars (Fulmarus glacialis) and shearwaters, which come to land only to breed and for which information on diseases that may affect them is, therefore, sparse. Between 2000 and 2012, 315 carcasses of four species of Procellariiformes (173 Northern Fulmars, 89 Great Shearwaters [Ardenna gravis], 50 Sooty Shearwaters [Ardenna grisea], and three Cory's Shearwaters [Calonectris diomedea]) were collected on Sable Island, Nova Scotia, Canada, an isolated island near the edge of the continental shelf. A complete necropsy, including examination for the presence of ingested plastic, was performed on all carcasses. Most (70%) of these birds were immature. The cause of death was undetermined in 22% (n=70) of the birds: 36% (62/173) of the Northern Fulmars, 4% (4/89) of the Great Shearwaters, 6% (3/50) of the Sooty Shearwaters, and 33% (1/3) of the Cory's Shearwaters. Emaciation was considered the primary cause of death in 91% of the remaining 245 birds: 87% (97/111) of the Northern Fulmars, 92% (78/85) of the Great Shearwaters, 100% (47/47) of the Sooty Shearwaters, and 100% (2/2) of the Cory's Shearwaters. Notable primary causes of death other than emaciation included mycobacteriosis and neoplasia in Northern Fulmars and transmural parasitic proventriculitis in Great Shearwaters. For Northern Fulmars, nutritional condition (as determined semiquantitatively) was compared with other parameters. Birds in good nutritional condition had heavier body mass and flight muscle mass than those in poor nutritional condition (P

Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR’s stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR., Caloric restriction (CR) has been shown as an effective intervention to reduce tumorigenesis, but alternative less stringent dietary interventions have also been considered. Here, the authors show that in a murine model of breast cancer CR has a larger effect on preventing tumorigenesis and metastasis compared to periodic caloric cycling.

In this commentary, we argue that the limited experiential exposure of medical students to different cultures makes the instruction devoted to communication skills inadequate. The relationship of these dynamics to honesty in clinical encounters is explored. Absent significant experiential exposure to differing group cultures to counter the natural tendency to favor one’s own, discrimination prevails. Knowledge or awareness of cultural differences does not necessarily equate to communication proficiency. Critically, interactions based on lived experience offer a deeper knowledge and understanding of culturally meaningful nuances than that imparted through other formats. Medical students’ lack of experiential exposure to different cultures results in communication miscues. When the stakes are high, people detect those miscues diminishing trust in the doctor-patient relationship. Greater experiential cultural exposure will enhance the facility and use of culturally specific communication cues. At its core, the requisite transformation will require medical students to adapt to other cultures and greater representation by marginalized and stigmatized populations not only among the studentry but staff and faculty. The time is now to ensure that the physicians we produce can care for all Americans. What cannot be taught must be identified by the selection process. Competence with half the population is a failure for American medicine.

Objective Hepatopulmonary syndrome (HPS) is a life-threatening complication of chronic liver disease. This study aims to examine the clinical profiles and treatment outcomes of HPS in paediatric patients at a tertiary hospital in Singapore. Method A retrospective study of patients aged 0–18 years diagnosed with HPS from 1987 to 2019 was conducted. HPS was diagnosed based on evidence of arterial deoxygenation, intrapulmonary vascular dilatations/shunting, on background of chronic liver disease and/or portal hypertension. Results Five patients were included with median age of 11 years (range 3–17) and median follow-up duration of 2 years (range 4 month-20 years). Underlying aetiologies included biliary atresia (n=3), autoimmune hepatitis (n=1) and glycogen storage disease type 3 (n=1). Digital clubbing was consistent in all cases, but only 1 patient experienced dyspnoea. Median oxygen saturation on pulse oximetry was 94.5% (range 91–97). All 5 patients demonstrated intrapulmonary shunt (IPS) on contrast echocardiography (n=3) and/or lung perfusion study (n=3). Other complications of portal hypertension included variceal haemorrhage (n=3) and ascites (n=2). Median bilirubin, albumin and prothrombin values were 59 umol/L (range 33–629), 32 g/L (range 27–33) and 16.1 seconds (range 13.2–48.2). Three patients showed improvement in oxygenation with optimisation of liver disease and nutrition while awaiting transplant. Three patients underwent successful liver transplantation at median interval of 23 months (range 1–94) from HPS diagnosis. Conclusion Clinical onset of HPS in children can be subtle and correlates poorly with liver biochemistry and severity of portal hypertension. Early assessment for IPS and use of pulse oximetry may detect earlier and milder stages of HPS which may be reversible.

Our studies center on the physiological phenomenon of adaptive homeostasis in which very low, signaling levels of an oxidant can induce transient expansion of the baseline homeostatic range of protective mechanisms, resulting in transient stress protection. The 20S proteasome is a major element of such inducible defense enzymes against oxidative stress but the relative importance of each of its three proteolytic subunits, β1, β2, and β5, is only poorly understood. We focused the present studies on determining the role of the β5 subunit in adaptation, survival, and lifespan. Decreased expression of the 20S proteasome β5 subunit (with RNAi) blocked the adaptive increase in the catalytic activities of the 20S proteasome response to signaling levels of H(2)O(2) in female flies. Similarly, female-specific adaptive increases in survival following H(2)O(2) pretreatment and subsequent toxic challenge was blocked. In contrast, direct overexpression of the 20S proteasome β5 subunit enabled an increased 20S proteasome proteolytic response, but prevented further adaptive homeostatic increases through H(2)O(2) signaling, indicating there is a maximum ‘ceiling’ to the adaptive response. Males showed no adaptive change in proteasomal levels or activity whatsoever with H(2)O(2) pretreatment and exhibited no significant impact upon the other 2 proteolytic subunits of the proteasome. However, chronic loss of the β5 subunit led to shortened lifespan in both sexes. Our exploration of the importance of the 20S proteasome β5 subunit in adaptive homeostasis highlights the interconnection between signal transduction pathways and regulated gene expression in sexually divergent responses to oxidative stimulation.

Hallmarks of aging include loss of protein homeostasis and dysregulation of stress-adaptive pathways. Loss of adaptive homeostasis, increases accumulation of DNA, protein, and lipid damage. During acute stress, the Cnc-C (Drosophila Nrf2 orthologue) transcriptionally-regulated 20S proteasome degrades damaged proteins in an ATP-independent manner. Exposure to very low, non-toxic, signaling concentrations of the redox-signaling agent hydrogen peroxide (H2O2) cause adaptive increases in the de novo expression and proteolytic activity/capacity of the 20S proteasome in female D. melanogaster (fruit-flies). Female 20S proteasome induction was accompanied by increased tolerance to a subsequent normally toxic but sub-lethal amount of H2O2, and blocking adaptive increases in proteasome expression also prevented full adaptation. We find, however, that this adaptive response is both sex- and age-dependent. Both increased proteasome expression and activity, and increased oxidative-stress resistance, in female flies, were lost with age. In contrast, male flies exhibited no H2O2 adaptation, irrespective of age. Furthermore, aging caused a generalized increase in basal 20S proteasome expression, but proteolytic activity and adaptation were both compromised. Finally, continual knockdown of Keep1 (the cytosolic inhibitor of Cnc-C) in adults resulted in older flies with greater stress resistance than their age-matched controls, but who still exhibited an age-associated loss of adaptive homeostasis.

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis.Significance StatementPreviously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer’s disease and depression.

OBJECTIVES: Clustering differentiating 36 (CD36), a scavenger receptor highly expressed in macrophages and monocytes, is implicated in the early stages of atherosclerosis due to its ability to internalize oxidized low density lipoprotein (oxLDL). Although obesity is a major risk for diabetes, some obese subjects seem to be more resistant to the development of metabolic and pathological disturbances. This study was designed to compare the concentration of circulating oxLDL and the expression of monocyte CD36 in obese diabetic (OD) and obese non-diabetic (OND) subjects, and tested whether bariatric surgery exerts similar effects in both groups METHODS: Blood was collected prospectively from OD and OND subjects (n = 21 per group) before Roux-en-Y-gastric bypass (RYGB) and 12 months postoperatively. Plasma glucose and lipoproteins were measured enzymatically. Iinsulin and glycosylated hemoglobin A1c (GHbA1c) were analyzed by enzyme-linked immunosorbent (Elisa). Insulin resistance index (HOMA-IR) was calculated. The expression of monocytes CD36 was assayed by western blot and RT-PCR. RESULTS: Although OD and OND subjects had comparable body mass index Pre-RYGB (43 ± 9 vs 41 ± 8 kg/m(2), respectively), blood insulin, HbA1c and HOMA-IR were significantly higher in OD (29 ± 5 μU/mL, 7.8 ± 0.8% and 9.8 ± 2.5, respectively) than OND subjects (19 ± 4 μU/mL, 5.7 ± 0.5% and 5.9 ± 1.4, respectively). In addition, the level of plasma oxLDL (49.2 ± 11.9 vs 31.4 + 9.5 mU/ml) was greater in OD than OND subjects. Moreover, the expression of monocyte CD36 (protein level and mRNA abundance) was significantly higher in OD than OND subjects. The effect of RYGB was beneficial in both OD and OND subjects. At 12 months post-RYGB, there were comparable reduction of BMI in OD and OND subjects. Plasma levels of insulin, HbA1c and HOMA-IR also declined in both groups, but the effect was stronger in OD subjects, leading to comparable final values between groups. Plasma oxLDL and monocyte CD36 expression were also reduced in both groups and were comparable at 12 months post-RYGB. CONCLUSIONS: These results show that obese diabetic subjects exhibit high levels of oxLDL and monocyte CD36, both of which could increase the risk of cardiovascular diseases. RYGB-induced weight loss could be beneficial for both obese and obese diabetic subjects. FUNDING SOURCES: Hackensack University Medical Center.

Background Tens of millions of seniors are at risk of herpes zoster (HZ) and its complications. Live attenuated herpes zoster vaccine (HZV) reduces that risk, although questions regarding effectiveness and durability of protection in routine clinical practice remain. We used Medicare data to investigate HZV effectiveness (VE) and its durability. Methods This retrospective cohort study included beneficiaries ages ≥65 years during January 2007 through July 2014. Multiple adjustments to account for potential bias were made. HZV-vaccinated beneficiaries were matched to unvaccinated beneficiaries (primary analysis) and to HZV-unvaccinated beneficiaries who had received pneumococcal vaccination (secondary analysis). HZ outcomes in community and hospital settings were analyzed, including ophthalmic zoster (OZ) and postherpetic neuralgia (PHN). Results Among eligible beneficiaries (average age 77 years), the primary analysis found VE for community HZ of 33% (95% CI: 32%-35%) and 19% (95% CI: 17%-22%), for the first 3, and subsequent 4+ years postvaccination, respectively. In the secondary analysis, VE was, respectively, 37% (95% CI: 36%-39%) and 22% (95% CI: 20%-25%). In the primary analysis, VE for PHN was 57% (95% CI: 52%-61%) and 45% (95% CI: 36%-53%) in the first 3 and subsequent 4+ years, respectively; VE for hospitalized HZ was, respectively, 74% (95% CI: 67%-79%) and 55% (95% CI: 39%-67%). Differences in VE by age group were not significant. Conclusions In both the primary and secondary analyses, HZV provided protection against HZ across all ages, but effectiveness declined over time. VE was higher and better preserved over time for PHN and HZ-associated hospitalizations than for community HZ.

Author(s): Wong, Sarah; Giulivi, Cecilia | Abstract: BackgroundAutism spectrum disorders (ASD) are a growing concern with more than 1 in every 68 children affected in the United States by age 8. Limited scientific advances have been made regarding the etiology of autism, with general agreement that both genetic and environmental factors contribute to this disorder.ObjectiveTo explore the link between exposure to PBDE, mitochondrial dysfunction and autism risk.ResultsPerinatal exposures to PBDEs may contribute to the etiology or morbidity of ASD including mitochondrial dysfunction based on (i) their increased environmental abundance and human exposures, (ii) their activity towards implicated in neuronal development and synaptic plasticity including mitochondria, and (iii) their bioaccumulation in mitochondria.ConclusionIn this review, we propose that PBDE, and possibly other environmental exposures, during child development can induce or compound mitochondrial dysfunction, which in conjunction with a dysregulated antioxidant response, increase a child's susceptibility of autism.

Cancer is a leading cause of mortality, with its incidence only expected to rise with an increasingly aging population. Dietary interventions, primarily caloric restriction (CR), lower cellular energy metabolism and have long been utilized to slow the aging process and protect against age-related diseases, including cancer. However, due to the stringency of CR, dietary alternatives that offer the same beneficial outcomes in cancer prevention and longevity have become increasingly attractive. Periodic cycles (4 days twice a month) of low caloric intake followed by a standard ad libitum (AL) diet was previously shown to promote health-span in mice and humans and protect against primary tumorigenesis and enhanced the effects of chemotherapy. The aim of our study was to compare the tumorigenic potential of 4T1 cells, a murine model of stage IV breast cancer, in young and aged female BALB/c mice fed either periodic cycles of low caloric diets versus chronic 20% CR. Compared to AL controls, we found a significant delay in primary tumor growth in mice regardless of diet composition by the 4:10 cycles of very low caloric intake. However, unlike in CR, CR-alternative diets were not protective against lung metastases in the absence of chemotherapy. Our study sheds light into the underlying differences of calorie-based interventions in the absence of chemotherapy.

The aging process is sexually dimorphic, with males having higher occurrence rates of cancer and facing a greater risk of mortality. Sexual dimorphism in the response to cellular damage may account for distinct phenotypic changes with age as they relate to the accumulation of cellular damage leading to cancer. Cellular senescence triggers permanent cell cycle arrest in order to protect against malignant growth. However, organismal senescence increases with age and is associated with the release of pro-inflammatory signals (cytokines, chemokines, and proteases) known as the ‘senescence-associated-secretory-phenotype’ (SASP) that, if unchecked, accelerates tissue damage and creates a microenvironment ripe for cancer development. In this study, we hypothesized that sexual disparities in mortality and cancer prevalence stems from differences in the rate of accumulation of senescent cells in mice. Male and female C57BL/6J mice were fed ad libitum or subjected to 30% calorie restriction, a nutritional intervention known to delay the onset of various cancers and prevent senescent cell accumulation. Primary skin fibroblasts were collected longitudinally to allow measurement of cell proliferation, wound healing and the release of SASP factors. The results indicate that when compared to males, fibroblasts of CR-fed females showed significant improvements in cell growth rate, wound healing and SASP markers vs. AL controls. Work is underway to determine how sex influences cellular protective pathways. Thus, like other cell processes, cellular senescence is unequal between males and females and CR delays the emergence of the senescence phenotype.

Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150–180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother’s ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of - 30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of α-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1α, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype.

Adaptive homeostasis enables rapid cellular signaling, leading to transcriptional and translational modifications (Davies, 2016) [1]. The Proteasome is one of the main cellular proteolytic enzymes that plays an essential role in the rapid clearance of oxidatively damaged cellular proteins, and is highly responsive to oxidative stress. Upon exposure to even very low, signaling levels of oxidants, the predominant form of the Proteasome becomes the ATP-independent 20S proteasome that enables rapid clearance of damaged proteins. Subsequently there is also a concurrent upregulation of de novo 20S proteasome synthesis. These cellular adaptations not only ensure effective and efficient removal of damaged proteins, but prepare cells to better cope with future, more severe oxidative insults. Male and female Drosophila melanogaster fruit flies were pretreated with an adaptive amount of an oxidant (10 µM hydrogen peroxide or 0.5 µM paraquat) to assess the changes in proteolytic capacity and the role of the 20S proteasome. Additionally, the adaptive signaling by non-damaging amounts of hydrogen peroxide or paraquat) were used to assess changes in male and female fruit flies, following a subsequent more toxic amount of the two oxidants. Further analysis and detailed results about the adaptive role of the 20S proteasome in multiple D. melanogaster strains can be found in “Sexual Dimorphism in Oxidant-Induced Adaptive Homeostasis in Multiple Wild-Type D. melanogaster Strains” (Pomatto et al., 2018) [2].

Sexual dimorphism includes the physical and reproductive differences between the sexes, including differences that are conserved across species, ranging from the common fruit fly, Drosophila melanogaster, to humans. Sex-dependent variations in adaptive homeostasis, and adaptive stress responses may offer insight into the underlying mechanisms for male and female survival differences and into differences in chronic disease incidence and severity in humans. Earlier work showed sex-specific differences in adaptive responses to oxidative stressors in hybrid laboratory strains of D. melanogaster. The present study explored whether this phenomenon is also observed in wild-type D. melanogaster strains Oregon-R (Or-R) and Canton-S (Ca-S), as well as the common mutant reference strain w[1118], in order to better understand whether such findings are descriptive of D. melanogaster in general. Flies of each strain were pretreated with non-damaging, adaptive concentrations of hydrogen peroxide (H(2)O(2)) or of different redox cycling agents (paraquat, DMNQ, or menadione). Adaptive homeostasis, and changes in the expression of the proteasome and overall cellular proteasomal proteolytic capacity were assessed. Redox cycling agents exhibited a male-specific adaptive response, whereas H(2)O(2) exposure provoked female-specific adaptation. These findings demonstrate that different oxidants can elicit sexually dimorphic adaptive homeostatic responses in multiple fly strains. These results (and those contained in a parallel study [1]) highlight the need to address sex as a biological variable in both fundamental science, clinical research, and toxicology.

Treating postpartum depression (PPD) with pharmacological antidepressants like fluoxetine (FLX) is complicated because these drugs can remain active in breast milk and potentially affect infant development. Alternatively, non-pharmacological treatments such as exercise are associated with beneficial effects on infant development but its potential ability to counter the effects of PPD are largely unknown. To investigate this, we treated dams with corticosterone (CORT) or vehicle (sesame oil) from postpartum days 2–25 to model PPD. Within oil and CORT treatments, dams were also assigned to one of these treatments: 1) exercise (voluntary running wheel) + FLX (10 mg/kg, i.p.), 2) exercise + saline (vehicle for FLX), 3) no exercise + FLX, 4) no exercise + saline. Both male and female offspring were analyzed, and this generated a total of 16 experimental groups for this study. Adult male and female offspring (125 d old) of these dams were tested for anxiety-like behavior in the novelty suppressed feeding test and stress reactivity in the dexamethasone suppression test. Hippocampal tissue was processed for doublecortin, a protein expressed in immature neurons. Regardless of sex, maternal exercise increased neurogenesis in the dorsal hippocampus of adult offspring, but concurrent exposure to maternal fluoxetine prevented this effect. Exposure to either maternal exercise or maternal FLX facilitated HPA negative feedback in adult males but not females. Maternal postpartum CORT also facilitated HPA feedback in adult offspring of both sexes. Collectively, these data indicate that maternal exercise increased dorsal hippocampal neurogenesis in both sexes but differentially affected offspring HPA axis based on sex. Alternatively, maternal postpartum FLX facilitated HPA axis negative feedback only in males. These findings indicate that different types of maternal interventions bear long-term effects on offspring outcome with implications for treating PPD.

Objective To examine if bias in attention to and interpretation of cancer-related stimuli differentiates women with persistent psychological distress from those with low/transient distress following breast cancer. Methods One-hundred forty women classified in a prior longitudinal study as having low (n = 73) or persistent high (n = 67) distress completed 2 modified dot-probe tasks assessing attention bias and an ambiguous cues task assessing interpretation bias toward cancer-related vs neutral information. Psychological distress was assessed using the Hospital Anxiety Depression Scale. Four-way repeated analysis of variance was adopted. Results Participants with persistent high distress from the original study who continued to report high Hospital Anxiety Depression Scale scores (≥8) on recruitment into the present study comprised the persistent distress group (ie, 31 reporting high anxiety and 30 reporting high depression scores). Persistent distress and low distress groups did not differ in attentional bias toward negative-stimuli or cancer-related information, but a significant time-course effect in attentional bias toward negative-stimuli or cancer-related information was observed, with women in the persistent distress group showing a significant bias away from negative-stimuli or cancer-related information under supraliminal conditions. There was a borderline difference in interpretation bias scores between low anxiety and chronic anxiety groups (P = .065), with correlation suggesting a significant positive association (r = 0.20, P = .019). Conclusion Women with persistent distress may adopt avoidance strategies to cope with breast cancer. Moreover, women reporting persistent anxiety may have a tendency to negatively interpret ambiguous information, leading to illness preoccupation. These findings offer critical insight for clinicians to develop tailored interventions to help women with persistent psychological distress.

Alaskan Husky encephalopathy (AHE(1) ) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.

Recessive mutations in GJC2, the gene encoding connexin 47 (Cx47), cause Pelizaeus-Merzbacher-like disease type 1 (PMLD1), a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype - Hereditary spastic paraplegia type 44 (SPG44). Here we present evidence that a novel Arg98Leu mutation causes an even milder phenotype - a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady state junctional conductance-junctional voltage (Gj-Vj) relations differed only slightly from those for wild-type Cx47. Our data suggest that that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.

Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)–induced oxidative burst were evaluated in granulocytes from age-, race-, and gender-matched children with autism with severity scores of ≥7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing ≥1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2–related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network.

CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These “PNS-only” mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function.

Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2′,4,4′-tetrabromodiphenyl ether [BDE-47] and 2,2′,4,5′-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC50 = 6 nM) and Complex IV (noncompetitive inhibition; IC50 = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1–3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain.