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Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. Bid-/- mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bids membrane binding domain, BidM148T, associates with MI predisposition. Furthermore, Bid but not BidM148T associates with Mcl-1Matrix, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.

Lisa Roberts,1 Solomon Renati,2 Shreeletha Solomon,3 Susanne Montgomery4 1School of Nursing, Loma Linda University, Loma Linda, CA 92350, USA; 2Department of Psychology, Veer Wajekar A. S. & C. College, Navi Mumbai 400702, India; 3Veer Wajekar A. S. & C. College, Navi Mumbai 400702, India; 4School of Behavioral Health, Behavioral Health Institute, Loma Linda University, Loma Linda, CA 92350, USACorrespondence: Lisa RobertsSchool of Nursing, Loma Linda University, 11262 Campus Street, Loma Linda, CA 92350, USATel +1 (909) 558-1000Fax +1 (909) 558-0719Email lroberts@llu.eduBackground: Infertility is a global problem, with high prevalence in India. As a pronatalist society, infertility is particularly problematic in India, causing stigma, shame, and blame especially for women. Infertility consequences for women include discrimination, social exclusion, and abandonment, putting them at high risk for mental health distress. Furthermore, mental health is highly stigmatized and specialized care is largely unavailable. Despite the cultural importance of childbearing, research on infertility distress and resulting mental health sequelae is lacking, particularly among low-income women. The purpose of this study is to assess mental health, using validated scales, among Mumbai slum-dwelling women with a history of infertility.Methods: We conducted a mixed-method, cross-sectional study. A focus group discussion with community health workers (n = 7) informed the development of a comprehensive survey. The survey consisted of validated scales whenever possible, in addition to questions pertaining to women’s sociodemographic and reproductive history. After rigorous forward and back translation, the surveys were conducted as face-to-face structured interviews due to low literacy levels and the research naiveté of our respondents. Interviews were conducted by culturally, linguistically, gender-matched, trained research assistants.Results: Mumbai slum-dwelling women of reproductive age suffering from infertility (N = 74) participated. Most (85%) women and their husbands (66%) reported previous infertility testing. Participants had elevated mental health distress (anxiety and depression symptomology) largely explained by general health, length of marriage, and coping strategy employed.Conclusion: Women facing the double stigma of mental health and infertility need innovative programs to address their challenges.Keywords: infertility, mental health, stigma, low-income women, Mumbai, India

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.

BackgroundDonor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion.MethodsWe performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD).ResultsThere were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects.ConclusionsPlasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.

The effects of tree diversity on herbivore-enemy interactions have received relatively little attention and even fewer studies have compared the relative influence of tree intra- versus interspecific diversity on such dynamics. We evaluated the effects of mahogany (Swietenia macrophylla) genotypic diversity and tree species diversity on parasitoid attack and species richness associated with Phyllocnistis meliacella, a specialist herbivore on mahogany, in a forest diversity experiment consisting of 74 plots (21×21m2; 64plants/plot). We sampled 34 of such plots classified as: mahogany monocultures of one maternal family (i.e. genotype), mahogany monocultures of four families and polycultures of four species (including mahogany). We surveyed leafminer abundance and collected mined leaves to estimate parasitism and parasitoid species richness. Leafminer abundance was not influenced by either type of diversity. Similarly, there were no effects of genotypic diversity or species diversity on parasitism or parasitoid species richness. Plant diversity effects on parasitoids were probably absent because the species attacking P. meliacella are dietary generalists that likely recruited to multiple host species (in addition to P. meliacella) and their responses to diversity could have cancelled each other out. Future work should explicitly investigate how predator and parasitoid traits mediate the effects of plant diversity on tritrophic interactions.

Mechanisms by which climatic factors drive reproductive investment and phenology in masting species are not completely understood. Climatic conditions may act as a proximate cue, stimulating the onset of reproduction and indirectly increasing fitness through benefits associated with synchronous reproduction among individuals. Alternatively, climatic conditions may directly influence individual-level allocation to reproduction and reproductive success through effects occurring independently of synchronous reproduction. We previously showed that masting in a ponderosa pine (Pinus ponderosa) population was strongly influenced by spring mean temperature 2 years before seed cone maturation (Ti-2). However, recent work shows that the difference in temperature between previous growing seasons (ΔT) is more predictive of reproductive investment in long-lived tree species. Here, we compared four candidate models that predict seed cone production in P. ponderosa based upon different climatic factors (including Ti-2 and ΔT models). After determining the best climatic predictor, we tested for a potential mechanism by which climate might directly influence seed cone production independent of benefits via synchrony, namely effects of temperature on trade-offs between current and past reproduction (determined by underlying resource availability). We found that Ti-2 (rather than ΔT) was the best predictor of seed cone production. We further show that this same climatic factor exerts a direct fitness benefit to individuals by reducing the strength of trade-offs between current and past reproductive efforts. Synthesis. We demonstrate that a single climatic factor provides fitness benefits to individuals directly, by weakening reproductive trade-offs, and indirectly through the benefits associated with synchrony and masting. This suggests a mechanism for the origin and maintenance of masting: individuals initially respond to climatic cues that directly enhance reproduction (e.g. lower reproductive costs through weakened trade-offs) and this dynamic, expressed across multiple individuals, reinforces these benefits through the economies of scale associated with synchrony and masting.

Rapid activation causes remodeling of atrial myocytes resembling that which occurs in experimental and human atrial fibrillation (AF). Using this cellular model, we previously observed transcriptional upregulation of proteins implicated in protein misfolding and amyloidosis. For organ-specific amyloidoses such as Alzheimer's disease, preamyloid oligomers (PAOs) are now recognized to be the primary cytotoxic species. In the setting of oxidative stress, highly-reactive lipid-derived mediators known as γ-ketoaldehydes (γ-KAs) have been identified that rapidly adduct proteins and cause PAO formation for amyloid β1-42 implicated in Alzheimer's. We hypothesized that rapid activation of atrial cells triggers oxidative stress with lipid peroxidation and formation of γ-KAs, which then rapidly crosslink proteins to generate PAOs. To investigate this hypothesis, rapidly-paced and control, spontaneously-beating atrial HL-1 cells were probed with a conformation-specific antibody recognizing PAOs. Rapid stimulation of atrial cells caused the generation of cytosolic PAOs along with a myocyte stress response (e.g., transcriptional upregulation of Nppa and Hspa1a), both of which were absent in control, unpaced cells. Rapid activation also caused the formation of superoxide and γ-KA adducts in atriomyocytes, while direct exposure of cells to γ-KAs resulted in PAO production. Increased cytosolic atrial natriuretic peptide (ANP), and the generation of ANP oligomers with exposure to γ-KAs and rapid atrial HL-1 cell stimulation, strongly suggest a role for ANP in PAO formation. Salicylamine (SA) is a small molecule scavenger of γ-KAs that can protect proteins from modification by these reactive compounds. PAO formation and transcriptional remodeling were inhibited when cells were stimulated in the presence of SA, but not with the antioxidant curcumin, which is incapable of scavenging γ-KAs. These results demonstrate that γ-KAs promote protein misfolding and PAO formation as a component of the atrial cell stress response to rapid activation, and they provide a potential mechanistic link between oxidative stress and atrial cell injury.

Free radicals and oxidants are now implicated in physiological responses and in several diseases. Given the wide range of expertise of free radical researchers, application of the greater understanding of chemistry has not been uniformly applied to biological studies. We suggest that some widely used methodologies and terminologies hamper progress and need to be addressed. We make the case for abandonment and judicious use of several methods and terms and suggest practical and viable alternatives. These changes are suggested in four areas: use of fluorescent dyes to identify and quantify reactive species, methods for measurement of lipid peroxidation in complex biological systems, claims of antioxidants as radical scavengers, and use of the terms for reactive species.

Background: Episodic memory deficits are a characteristic of cognitive dysfunction in people with Down syndrome (DS). However, less is known about the processes (i.e. encoding, retention or using learned information flexibly) that underlie these deficits. Method: We explored these abilities by administering a relational memory and inference task to participants with DS and mental age-matched controls and testing both immediately and after a 24-h delay. Results: Adults with DS learned paired associates more slowly than controls but showed good recognition at both the immediate and delayed tests. Despite memory for learned pairs, adults with DS were less able to use relational learning flexibly to make inferential judgements than controls. Conclusions: These results deepen our understanding of the cognitive profile of adults with DS, demonstrating deficits in both encoding new information, and flexibly using such information. These results have important implications for workplace training and intervention programs for people with DS.