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Catering for the mathematical needs of disabled learners equitably and productively requires the anti-ableist preparation and professional development of teachers. In CAPTeaM (Challenging Ableist Perspectives on the Teaching of Mathematics), we design tasks that emulate inclusion-related challenges from the mathematics classroom, and we engage teachers with these tasks in workshop settings. In this paper, we focus on evidence from one type of task in which participants engage in small groups with solving a mathematical problem while at least one of them is temporarily and artificially deprived of access to a sensory field or familiar channel of communication. In this paper, we focus on evidence of emerging resignification -- discursive and affective shifts in the participating teachers' sense-making about what makes the construction of mathematical meaning possible and valuably different -- as they work on the tasks. By linking Vygotsky's vision about the educational changes required to empower and include disabled learners with more contemporary ideas from embodied cognition and disability studies, our analyses show how engagement with the tasks affects participants' realisation and appreciation of interdependencies between learners, teacher, resources, and emotions, highlights alternative forms of mathematical agency and gives opportunities to turn initial sense of impasse and despair into joy.

Introduction: Financial toxicity has negative implications for patient well-being and health outcomes. There is a gap in understanding financial toxicity for patients undergoing palliative radiotherapy (RT). Methods: A review of patients treated with palliative RT was conducted from January 2021 to December 2022. The FACIT-COST (COST) was measured (higher scores implying better financial well-being). Financial toxicity was graded according to previously suggested cutoffs: Grade 0 (score ≥26), Grade 1 (14-25), Grade 2 (1-13), and Grade 3 (0). FACIT-TS-G was used for treatment satisfaction, and EORTC QLQ-C30 was assessed for global health status and functional scales. Results: 53 patients were identified. Median COST was 25 (range 0-44), 49% had Grade 0 financial toxicity, 32% Grade 1, 15% Grade 2, and 4% Grade 3. Overall, cancer caused financial hardship among 45%. Higher COST was weakly associated with higher global health status/Quality of Life (QoL), physical functioning, role functioning, and cognitive functioning; moderately associated with higher social functioning; and strongly associated with improved emotional functioning. Higher income or Medicare or private coverage (rather than Medicaid) was associated with less financial toxicity, whereas an underrepresented minority background or a non-English language preference was associated with greater financial toxicity. A multivariate model found that higher area income (HR .80, P = .007) and higher cognitive functioning (HR .96, P = .01) were significantly associated with financial toxicity. Conclusions: Financial toxicity was seen in approximately half of patients receiving palliative RT. The highest risk groups were those with lower income and lower cognitive functioning. This study supports the measurement of financial toxicity by clinicians.

This cross-sectional observational study sought to examine the environmental correlates of physical activity and screen-time among youth with autism spectrum disorder (ASD). Parents of youth with ASD (n = 1,165) from seven countries/regions provided responses to an online survey form measuring environmental correlates (i.e., physical activity neighborhood environment, social network, social trust and cohesion, bedroom media, social home environment) and outcomes (i.e., physical activity, screen-time). Multiple linear regression analyses were conducted to determine environmental predictors of the outcomes. Physical activity neighborhood environment (B = 0.15, p = 0.047), social network (B = 0.16, p = 0.02), and social home environment (B = 1.07, p < 0.001) were significantly associated with physical activity, whereas social trust and cohesion and bedroom media were not. Further, social trust and cohesion (B = -0.14, p = 0.001), bedroom media (B = 0.10, p = 0.001), and social home environment (B = -0.16, p < 0.001) were significantly associated with screen-time while neighborhood environment and social network were not. The identified environmental attributes of physical activity and screen-time behaviors should be targeted for health promotion among youth with ASD.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

With a runtime of 47 years, Saturday Night Live has long served as a societal mirror that captures and creates popular culture. In recent years the show has been criticized for its lack of diverse hosts, cast and staff. Out of 930 episodes only seven episodes have been hosted by an Asian host, four of whom identify as Chinese. This research examined those four episodes through quantitative analysis, finding that the qualities of each of the hosts' characters range from just below neutral to moderately positive. The use of stereotypes and satirical racial humor varied. Jackie Chan and Lucy Liu's episodes had the highest concentration of both overt and covert stereotypes, while Awkwafina had a similar number with a lower concentration. The infrequency of Chinese representation on the show is a social issue. Such a small sample size does not allow for conclusions to be drawn. Rather, this research paints a picture of how the four Chinese hosts are portrayed on SNL as influenced by their own unique identities and the year of their appearance. In addition, the insights this case study offers has implications for shows performed in colleges and K-12 schools. Directors and sponsors of school based shows can learn from this case study how to avoid perpetuating stereotypes and how to advance diversity, equity and inclusion at their institutions.

Reductions in nonresidential water demand during the COVID-19 pandemic highlighted the importance of understanding how water age impacts drinking water quality and microbiota in piped distribution systems. Using benchtop model distribution systems, we aimed to characterize the impacts of elevated water age on microbiota in bulk water and pipe wall biofilms. Five replicate constant-flow reactors were fed with municipal chloraminated tap water for 6 months prior to building closures and 7 months after. After building closures, chloramine levels entering the reactors dropped; in the reactor bulk water and biofilms the mean cell counts and ATP concentrations increased over an order of magnitude while the detection of opportunistic pathogens remained low. Water age, and the corresponding physicochemical changes, strongly influenced microbial abundance and community composition. Differential initial microbial colonization also had a lasting influence on microbial communities in each reactor (i.e., historical contingency).

PurposeThe objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes.Methods and materialsThis was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included.ResultsMedian follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival.ConclusionsPost-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.

This study aimed to identify the prevalence of current smoking and examine the association between meeting combinations of the 24-h movement guidelines and current smoking in autistic adults. This cross-sectional study administered an electronic survey to a national sample of autistic adults in the United States. The study outcome was current smoking. Independent variables included the 24-h movement behaviors. Multivariable statistical modeling was used to assess the study aims. The study sample (n = 259) had a mean age of 31.05 years (standard deviation = 7.70), 58.7% were male, 11.2% were fully independent, and 35.5% were current smokers. Current smokers met significantly fewer 24-h movement guidelines than non-smokers (mean = 1.52 (standard deviation = 0.73) vs mean= 1.93 (standard deviation = 0.88), respectively, t = 3.77, p < 0.01). Autistic adults with high levels of sedentary behavior were almost three times more likely (odds ratio = 2.784, 95% confidence interval = 1.490, 5.237) to be a current smoker than those who did not meet these guidelines. Autistic adults not meeting sleep and sedentary behavior recommendations had a 1.581 increased odds (odds ratio = 1.581 95% confidence interval = 1.25, 2.001) of being a smoker as compared to those meeting these recommendations. Current smoking was highly prevalent in this sample. Improving sleep health and reducing sedentary time may be viable intervention targets to help promote smoking cessation in autistic adults.

Placement as a form of work-integrated learning is a valued element of undergraduate education. Prior work explores how placement provides a site for developing professional values, skills and competences as well as identifying how students build awareness of professional requirements. Greater focus on how such processes of awareness are realised, negotiated and enacted is still required. This study frames student placement experiences as enabling processes of recursive negotiation between the self and the setting. The empirical contribution is to document and track this with 40 students on accounting placements, interviewed at three points in time (pre-, during, post-placement) exploring their subjective experiences. Findings evidence various trajectories of experience emerging from which a model capturing four distinct forms of fit (personal, reflected, projected, absence of fit) with professional identity is developed. This suggests student placement experiences in all their variations lead to and constitute more than merely technical or academic outcomes. Conceptually framing placement experiences as recursive negotiations between the self and the setting in the professionalisation journey uncovers how professional identity formation processes are constructed and (re)negotiated. As well as providing students with terminology to understand and articulate the multiplicity of possible placement experiences, educators, employers and professional bodies can benefit from the more nuanced possibilities for work-integrated learning that are suggested.

Operational definitions have a significant history in applied behavior analysis. The practice's importance stems from the role operational definitions play in detecting an event, human thought, or action. While operationalizing target behaviors has enjoyed widespread practice, some concerns have recently arisen with translation validity and detection accuracy. Additionally, a review of the literature produces few articles assessing the validity of operational definitions. Pinpoints represent an alternative for describing target behaviors. A pinpoint has a formula for construction that includes using an action verb, an object, or event that receives the action, and a comprehensibly defined context where the observation of the action verb + object or event occurs. Pinpoints also have few empirical studies demonstrating their validity. The following experiment compared the detection accuracy of an operational definition for self-injurious behavior and a corresponding pinpoint across professionals who worked in a school that served clients with autism spectrum disorder. The results indicate lower accuracy scores for the operational definition when compared to the pinpoint. Additionally, the consistency of scores varied more for the operational definition than the pinpoint.

BACKGROUND: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. METHODS: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. RESULTS: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were

BACKGROUND: The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. METHODS: A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. RESULTS: The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. INTERPRETATION: Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

Abstract The impact of adjuvants on malaria vaccine-induced antibody repertoire is poorly understood. Here, we characterize the impact of two adjuvants, Alhydrogel® and AS01, on antibody clonotype diversity, binding and function, post malaria vaccination. We expressed 132 recombinant anti-Pfs230D1 human monoclonal antibodies (mAbs) from participants immunized with malaria transmission-blocking vaccine Pfs230D1, formulated with either Alhydrogel® or AS01. Anti-Pfs230D1 mAbs generated by Alhydrogel® formulation showed higher binding frequency to Pfs230D1 compared to AS01 formulation, although the frequency of functional mAbs was similar between adjuvant groups. Overall, the AS01 formulation induced anti-Pfs230D1 functional antibodies from a broader array of germline sequences versus the Alhydrogel® formulation. All mAbs using IGHV1-69 gene from the Alhydrogel® cohort bound to recombinant Pfs230D1, but did not block parasite transmission to mosquitoes, similar to the IGHV1-69 mAbs isolated from the AS01 cohort. These findings may help inform vaccine design and adjuvant selection for immunization with Plasmodium antigens.

Abstract Obstructive sleep apnea (OSA) and hypertension are two important modifiable risk factors for cardiovascular disease and mortality. Numerous studies have highlighted the interplay between these two conditions. We provide a critical review of the current literature on the role of the OSA as a risk factor for hypertension and its effect on blood pressure (BP). We discuss several key topics: the effect of OSA on nocturnal BP, BP response to continuous positive airway pressure (CPAP) treatment, CPAP effect on BP in refractory hypertension, the role of OSA in BP variability (BPV), and maladaptive cardiac remodeling mediated by OSA’s effect on BP. Finally, we discuss the unique aspects of ethnicity and social determinants of health on OSA with a focus on Asian populations and the disparity in BP control and cardiovascular outcomes.

Abstract Aims Currently, there is no reliable biomarker to detect pre‐heart failure in humans. An early risk signal is an elevated left atrial pressure (LAP) and preliminary results from animal studies strongly suggest the neuropeptide neuromedin U (NMU) is released in response to this increase in LAP. However, it is unknown whether NMU is elevated in patients with heart failure. Therefore, the aim of this study was to assess if NMU levels are elevated in human cases of heart failure. Methods and results Twenty‐four serum samples were obtained from patients in stage II and III heart failure from the Royal Papworth Hospital in Cambridge UK and tested using a selective NMU‐ELISA; the data were compared with serum obtained commercially from self‐declared healthy donors. NMU concentrations in serum from heart failure patients were significantly higher (P = 0.0007; unpaired Student's t‐test) than control, 8.48 ± 0.67 ng/mL (mean ± SEM) versus 5.43 ± 0.46 ng/mL. There was no significant difference between NYHA stage II and III patients (P = 0.85, unpaired Student's t‐test), which were 8.33 ± 0.89 ng/mL (n = 9) and 8.6 ± 0.95 ng/mL (n = 15), respectively. Only mean right atrial pressure was found to have a significant correlation with serum NMU (R = 0.81, P

Abstract Environmental and lifestyle factors, including air pollution, impaired diet, and low physical activity, have been associated with cardiometabolic risk factors in childhood and adolescence. However, environmental and lifestyle exposures do not exert their physiological effects in isolation. This study investigated associations between an exposome score to measure the impact of multiple exposures, including diet, physical activity, sleep duration, air pollution, and socioeconomic status, and serum metabolites measured using LC-MS and NMR, compared to the individual components of the score. A general population of 504 children aged 6–9 years at baseline was followed up for eight years. Data were analysed with linear mixed-effects models using the R software. The exposome score was associated with 31 metabolites, of which 12 metabolites were not associated with any individual exposure category. These findings highlight the value of a composite score to predict metabolic changes associated with multiple environmental and lifestyle exposures since childhood.

Peatland restoration and rehabilitation action has become more widely acknowledged as a necessary response to mitigating climate change risks and improving global carbon storage. Peatland ecosystems require restoration time spans of the order of decades and, thus, cannot be dependent upon the shorter-term monitoring often carried out in research projects. Hydrological assessments using geospatial tools provide the basis for planning restoration works as well as analysing associated environmental influences. “Restoration” encompasses applications to pre-restoration and post-restoration scenarios for both bogs and fens, across a range of environmental impact fields. The aim of this scoping review is to identify, describe, and categorize current process-based modelling uses in peatlands in order to investigate the applicability and appropriateness of ecohydrological and/or hydrological models for northern peatland restoration. Two literature searches were conducted using the entire Web of Science database in September 2022 and August 2023. Of the final 211 papers included in the review, models and their applications were categorized according to this review's research interests in seven distinct categories aggregating the papers' research themes and model outputs. Restoration site context was added by identifying 229 unique study site locations from the full database, which were catalogued and analysed against raster data for the Köppen–Geiger climate classification scheme. A majority of northern peatland sites were in temperate oceanic zones or humid continental zones that experienced snow. Over one in five models from the full database of papers were unnamed and likely intended for single use. Key themes emerging from topics covered by papers in the database included the following: modelling restoration development from a bog growth perspective, the prioritization of modelling greenhouse gas (GHG) emissions dynamics as a part of policymaking, the importance of spatial connectivity within or alongside process-based models to represent heterogeneous systems, and the increased prevalence of remote sensing and machine learning techniques to predict restoration progress with little physical site intervention. Models are presented according to their application to peatlands or broader ecosystem and organized from most to least complex. This review provides valuable context for the application of ecohydrological models in determining strategies for peatland restoration and evaluating post-intervention development over time.

Abstract Aim To test a serious game intervention about nursing and midwifery perceptions among adolescent school children. Background Nursing and midwifery professions face challenges in recruitment, with persistent gender stereotypes and a lack of clarity regarding the roles contributing to this issue. This study addresses the need for innovative approaches to reshape perceptions and encourage career exploration in adolescent school children. Design Employing a pre/post-test design, this study involved 137 post-primary students aged sixteen or seventeen in the United Kingdom. Methods Data collection occurred between November 2022 to April 2023, involving three post-primary schools. Participants engaged with a digital serious game designed to address misconceptions and promote a more accurate understanding of nursing and midwifery. Participants completed pre- and post-intervention questionnaires, including an adapted version of the Nursing as a Career Choice Questionnaire. Statistical analyses included descriptive statistics, paired t-tests, and independent groups t-tests. Results The serious game intervention resulted in statistically significant improvements in students’ perceptions across multiple domains. Overall, participants showed higher mean post-test scores (M = 139.57, SD = 15.10) compared to their mean pre-test score (M = 131.06, SD = 14.73) on the questionnaire. The domains of self-efficacy (p

BACKGROUND: A key question in implementation science is how to balance adaptation and fidelity in translating interventions to new settings. There is growing consensus regarding the importance of planned adaptations to deliver interventions in contextually sensitive ways. However, less research has examined ad-hoc adaptations, or those that occur spontaneously in the course of intervention delivery. A key question is whether ad-hoc adaptations ultimately contribute to or detract from intervention goals. This study aimed to (a) identify ad-hoc adaptations made during delivery of a family therapy intervention and (b) assess whether they promoted or interrupted intervention goals. METHODS: Tuko Pamoja (Swahili: We are Together) is an evidence-informed family therapy intervention aiming to improve family dynamics and mental health in Kenya. Tuko Pamoja employs a task-shifting model, delivered by lay counselors who are afforded a degree of flexibility in presenting content and in practices they use in sessions. We used transcripts of therapy sessions with 14 families to examine ad-hoc adaptations used by counselors. We first identified and characterized ad-hoc adaptations through a team-based code development, coding, and code description process. Then, we evaluated to what extent ad-hoc adaptations promoted the principles and strategies of the intervention (TP-promoting), disrupted them (TP-interrupting), or neither (TP-neutral). To do this, we first established inter-coder agreement on application of these categories with verification by the intervention developer. Then, coders categorized ad-hoc adaptation text segments as TP-promoting, TP-interrupting, or TP-neutral. RESULTS: Ad-hoc adaptations were frequent and included (in decreasing order): incorporation of religious content, exemplars/role models, community dynamics and resources, self-disclosure, and metaphors/proverbs. Ad-hoc adaptations were largely TP-promoting (49%) or neutral (39%), but practices were TP-interrupting 12% of the time. TP-interrupting practices most often occurred within religious content and exemplars/role models, which were also the most common practices overall. CONCLUSION: Extra attention is needed during planned adaptation, training, and supervision to promote intervention-aligned use of common ad-hoc adaptation practices. Discussing them in trainings can provide guidance for lay providers on how best to incorporate ad-hoc adaptations during delivery. Future research should evaluate whether well-aligned ad-hoc adaptations improve therapeutic outcomes. TRIAL REGISTRATION: Pilot trial registered at clinicaltrials.gov (C0058).

Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using in vitro models which mimic the physical properties of healthy or cancerous tissues and a physiologically relevant culture medium, we demonstrate that the chemical and physical properties of the microenvironment regulate the composition and topology of the glycocalyx. Remarkably, we find that cancer and age-related changes in the physical properties of the microenvironment are sufficient to adjust immune surveillance via the topology of the glycocalyx, a previously unknown phenomenon observable only with a physiologically relevant culture medium.

Coevolved genetic interactions within populations can be disrupted by hybridization resulting in loss of fitness in hybrid individuals (i.e., hybrid breakdown). However, the extent to which variation in fitness-related traits among hybrids is inherited across generations remains unclear, and variation in these traits may be sex-specific in hybrids due to differential effects of genetic incompatibilities in females and males. Here we present two experiments investigating variation in developmental rate among reciprocal interpopulation hybrids of the intertidal copepod Tigriopus californicus. Developmental rate is a fitness-related trait in this species that is affected by interactions between mitochondrial-encoded and nuclear-encoded genes in hybrids that result in variation in mitochondrial ATP synthesis capacities. First, we show that F2 -hybrid developmental rate is equivalent in two reciprocal crosses and is unaffected by sex, suggesting that breakdown of developmental rate is likely experienced equally by females and males. Second, we demonstrate that variation in developmental rate among F3 hybrids is heritable; times to copepodid metamorphosis of F4 offspring of fast-developing F3 parents (12.25 ± 0.05 days, μ ± SEM) were significantly faster than those of F4 offspring of slow-developing parents (14.58 ± 0.05 days). Third, we find that ATP synthesis rates in these F4 hybrids are unaffected by the developmental rates of their parents, but that mitochondria from females synthesize ATP at faster rates than mitochondria from males. Taken together, these results suggest that sex-specific effects vary among fitness-related traits in these hybrids, and that effects likely associated with hybrid breakdown display substantial inheritance across hybrid generations.

All mitochondrial-encoded proteins and RNAs function through interactions with nuclear-encoded proteins, which are critical for mitochondrial performance and eukaryotic fitness. Coevolution maintains inter-genomic (i.e., mitonuclear) compatibility within a taxon, but hybridization can disrupt coevolved interactions, resulting in hybrid breakdown. Thus, mitonuclear incompatibilities may be important mechanisms underlying reproductive isolation and, potentially, speciation. Here we utilize Pool-seq to assess the effects of mitochondrial genotype on nuclear allele frequencies in fast- and slow-developing reciprocal inter-population F2 hybrids between relatively low-divergence populations of the intertidal copepod Tigriopus californicus. We show that mitonuclear interactions lead to elevated frequencies of coevolved (i.e., maternal) nuclear alleles on two chromosomes in crosses between populations with 1.5% or 9.6% fixed differences in mitochondrial DNA nucleotide sequence. However, we also find evidence of excess mismatched (i.e., non-coevolved) alleles on three or four chromosomes per cross, respectively, and of allele frequency differences consistent with effects involving only nuclear loci (i.e., unaffected by mitochondrial genotype). Thus, our results for low-divergence crosses suggest an underlying role for mitonuclear interactions in variation in hybrid developmental rate, but despite substantial effects of mitonuclear coevolution on individual chromosomes, no clear bias favouring coevolved interactions overall.

The basic helix-loop-helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members1. Here we investigate how chromatinized E-boxes are engaged by two structurally diverse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. 2,3). Both transcription factors bind to E-boxes preferentially near the nucleosomal entry-exit sites. Structural studies with engineered or native nucleosome sequences show that MYC-MAX or CLOCK-BMAL1 triggers the release of DNA from histones to gain access. Atop the H2A-H2B acidic patch4, the CLOCK-BMAL1 Per-Arnt-Sim (PAS) dimerization domains engage the histone octamer disc. Binding of tandem E-boxes5-7 at endogenous DNA sequences occurs through direct interactions between two CLOCK-BMAL1 protomers and histones and is important for circadian cycling. At internal E-boxes, the MYC-MAX leucine zipper can also interact with histones H2B and H3, and its binding is indirectly enhanced by OCT4 elsewhere on the nucleosome. The nucleosomal E-box position and the type of bHLH dimerization domain jointly determine the histone contact, the affinity and the degree of competition and cooperativity with other nucleosome-bound factors.

Environmental temperatures have pervasive effects on the performance and tolerance of ectothermic organisms, and thermal tolerance limits likely play key roles underlying biogeographic ranges and responses to environmental change. Mitochondria are central to metabolic processes in eukaryotic cells, and these metabolic functions are thermally sensitive; however, potential relationships between mitochondrial function, thermal tolerance limits and local thermal adaptation in general remain unresolved. Loss of ATP synthesis capacity at high temperatures has recently been suggested as a mechanistic link between mitochondrial function and upper thermal tolerance limits. Here we use a common-garden experiment with seven locally adapted populations of intertidal copepods (Tigriopus californicus), spanning approximately 21.5° latitude, to assess genetically based variation in the thermal performance curves of maximal ATP synthesis rates in isolated mitochondria. These thermal performance curves displayed substantial variation among populations with higher ATP synthesis rates at lower temperatures (20-25 °C) in northern populations than in southern populations. In contrast, mitochondria from southern populations maintained ATP synthesis rates at higher temperatures than the temperatures that caused loss of ATP synthesis capacity in mitochondria from northern populations. Additionally, there was a tight correlation between the thermal limits of ATP synthesis and previously determined variation in upper thermal tolerance limits among populations. This suggests that mitochondria may play an important role in latitudinal thermal adaptation in T. californicus, and supports the hypothesis that loss of mitochondrial performance at high temperatures is linked to whole-organism thermal tolerance limits in this ectotherm.

Mitochondrial functions are intimately reliant on proteins and RNAs encoded in both the nuclear and mitochondrial genomes, leading to inter-genomic coevolution within taxa. Hybridization can break apart coevolved mitonuclear genotypes, resulting in decreased mitochondrial performance and reduced fitness. This hybrid breakdown is an important component of outbreeding depression and early-stage reproductive isolation. However, the mechanisms contributing to mitonuclear interactions remain poorly resolved. Here, we scored variation in developmental rate (a proxy for fitness) among reciprocal F2 interpopulation hybrids of the intertidal copepod Tigriopus californicus and used RNA sequencing to assess differences in gene expression between fast- and slow-developing hybrids. In total, differences in expression associated with developmental rate were detected for 2925 genes, whereas only 135 genes were differentially expressed as a result of differences in mitochondrial genotype. Upregulated expression in fast developers was enriched for genes involved in chitin-based cuticle development, oxidation-reduction processes, hydrogen peroxide catabolic processes and mitochondrial respiratory chain complex I. In contrast, upregulation in slow developers was enriched for DNA replication, cell division, DNA damage and DNA repair. Eighty-four nuclear-encoded mitochondrial genes were differentially expressed between fast- and slow-developing copepods, including 12 subunits of the electron transport system (ETS) which all had higher expression in fast developers than in slow developers. Nine of these genes were subunits of ETS complex I. Our results emphasize the major roles that mitonuclear interactions within the ETS, particularly in complex I, play in hybrid breakdown, and resolve strong candidate genes for involvement in mitonuclear interactions.