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The call characteristics and distribution of blue whales in the North Pacific were examined by use of acoustic surveys. Two distinct vocalisation types have been previously attributed to blue whales from limited regions in the North Pacific (cf. Thompson and Friedl, 1982; Rivers, 1997). Hydrophone data from sixteen sites in the North Pacific were examined for these blue whale vocalisations. There were distinct geographic and seasonal differences between the occurrence of the two vocalisation types. The hydrophones that were more westerly recorded the ‘northwestern’ Pacific vocalisation, those in the eastern Pacific recorded the ‘northeastern’ Pacific vocalisation and those in the central Pacific recorded both types. Northeastern vocalisations were recorded from July-December in the northeast Pacific and February-May in the eastern tropical Pacific. Northwestern vocalisations were recorded most often from July-December, and were essentially absent from March-May in the northwestern Pacific. These results suggest that the different vocalisation types may represent at least two distinct groups of blue whales in the North Pacific.

Purpose: This study evaluated the impact of 1-day workshops on teachers’ knowledge, practices, and dispositions using known characteristics of quality professional development and Guskey’s five levels of professional development evaluation. Method: Eight workshops were evaluated over a 2-year period using pre/post surveys, end-of-workshop surveys, observations, interviews, and artifacts. Results: Participants reported high levels of satisfaction and trainer effectiveness scores at the end of workshops. Statistical analyses revealed improvements in four of six outcome variables 4 weeks after workshop completion: self-reported knowledge, utilization of implementation strategies, presence of a community of continued learning, and teacher efficacy. Qualitative data corroborated these results but offered mixed evidence of teacher implementation and improved student outcomes. Discussion/Conclusion: Findings confirm that 1-day workshops aligned with characteristics of quality professional development are highly valued by participants and can improve teachers’ knowledge and efficacy, but teacher practice and student learning may be more difficult to influence and document.

The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1–NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.

Glires (rodents, lagomorphs and their fossil kin) is the most speciose and arguably most diversified clade of living placentals. Different lineages within the Glires evolved basically opposite chewing movements: a mostly transversal power stroke in lagomorphs, and a mostly proal power stroke in rodents, but the ancestral condition for Glires is still unclear. To address this knowledge gap, we studied the mandibles of Chinese Palaeocene Glires representing the duplicidentate (lagomorph-like; Mimotona ) and simplicidentate (rodent-like; Eomylus and Heomys ) lineages. To assess the mechanical resistance of mandibles to bending and torsion, we calculated the section modulus. The dentaries differ greatly in morphology and the region where the maximum grinding force was likely applied. The early Palaeocene Mimotona lii and the middle Palaeocene Mimotona robusta and Heomys orientalis all show a pattern of increasing strength moving posteriorly along the mandible, similar to sciurids and the mountain beaver. By contrast, the late Palaeocene Eomylus sp. mandible was strongest in the m1 region, a pattern seen in lagomorphs and the stem placental Zofialestes . Our results indicate the early diversification of mandible structure of Glires, demonstrate a mixture of duplicidentate and simplicidentate characters among the basal Glires and suggest an early occurrence of a lagomorph-like morphotype. This article is part of the theme issue ‘The mammalian skull: development, structure and function’.

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.Significance:Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia.This article is highlighted in the In This Issue feature, p. 587

Supplementary movie from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

Supplementary table from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

Supplementary Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

Supplementary Figure from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Supplementary acknowledgments.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).Results: We observed no significant association between genetic variants and prostate cancer survival.Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.

Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (≥5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5′ region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 × 10−15]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer. [Cancer Res 2007;67(5):1893–7]

ObjectivesRheumatoid arthritis (RA) and ulcerative colitis (UC) are two autoimmune diseases where patients report high levels of fatigue, pain, and depression. The effect of systemic inflammation from these diseases is likely affecting the brain, however, it is unknown whether there are measurable neuroanatomical changes and whether these are a contributing factor to these central symptoms.MethodsWe included 258 RA patients with 774 age and sex matched controls and 249 UC patients with 747 age and sex matched controls in a case control study utilising the UK Biobank dataset. We used imaging derived phenotypes (IDPs) to determine whether there were differences in (1) hippocampal volume and (2) additional subcortical brain volumes between patients compared to controls and if there were common regions affected between these two diseases.ResultsPatients with UC had moderately smaller hippocampi compared to age and sex matched controls (difference: 134.15 mm3, SD ± 64.76, p = 0.035). This result was not seen in RA patients. RA patients had a significantly smaller amygdala volume than age and sex matched controls (difference: 91.27 mm3, SD ± 30.85, p = 0.0021, adjusted p value = 0.012). This result was not seen in UC patients. All other subcortical structures analysed were comparable between the patients and control groups.ConclusionThese results indicate there are subcortical brain differences between UC, RA and controls but different regions of the limbic system are preferentially affected by UC and RA. This study may provide evidence for different neurodegenerative mechanisms in distinct autoimmune diseases.Key MessagesCentral effects such as fatigue and pain place significant burden on patients with autoimmune diseasesRheumatoid arthritis patients have smaller amygdala volumes compared to matched controls.Ulcerative colitis patients have smaller hippocampal volumes compared to matched controls.

Insular gigantism is an evolutionary phenomenon whereby small animals become bigger on islands compared to their mainland relatives. The abundance of insular giant taxa in the fossil record suggests the presence of a universal “giant niche” present on islands, with resource limitation as a potential driver for this process. However, insular habitats are ecologically diverse, suggesting that island taxa adopt different survival strategies, including adaptations for foraging behaviors. Here, we used finite element analysis to evaluate insular feeding niche adaptations in some of the most extreme examples of insular gigantism: Mediterranean giant dormice. We calculated stress, strain, and mechanical advantage during incisor and molar biting for 3 extinct insular giant species (Leithia melitensis, Hypnomys morpheus, and H. onicensis), an extant giant (Eliomys quercinus ophiusae), and their extant non-giant mainland relative, the generalist-feeder Eliomys quercinus. Our results show that dietary adaptations vary between giant taxa on different islands, and can occur relatively rapidly. Furthermore, the functional mandibular morphology in some insular taxa indicate adaptations moving away from a generalist feeding strategy toward greater trophic specialization. We show that the “insular giant niche” varies between islands and across time periods, arguing against a universal ecological driver for insular gigantism in small mammals.

This wisdom of experience commentary, from peer academic reviewers serving on accreditation teams, will discuss benefits and challenges of international and national virtual accreditation visits (VAVs) using a "What? So What? Now What?" reflective model.Onsite accreditation reviews for health professional education programs require investments in time, effort, and money to maintain program alignment with accreditation standards and continuously generate quality practitioners. When COVID-19 entered the accreditation world, reviewers had to pivot modalities to a VAV format.Adaptation and expectations of VAVs present several challenges. Barriers and advantages will be discussed as well as implications for the future. While medical and pharmacy education standardization has long been established, the authors propose national and international accrediting bodies will utilize the ingenuity of emergency COVID-19-driven onsite accreditation alternatives to develop protocols for novel accreditation methodology.Whether the continued mutation of COVID-19 prevents the return to previous accreditation visits or not, the experiences gained from the emergency-driven VAV, can inform and enrich accrediting bodies knowledge, theories, and practices of future VAVs.Higher-education institutions, accreditation bodies, and government entities will use experiences during COVID-19 to transform and improve academic requirements and future practices. Even if there is a full return to onsite reviews, such guidelines or improved versions of them can be applied to situations where immobility or restricted mobility is an issue, such as in illness, pregnancy, travel, war, etc. It is crucial for educators and accrediting bodies to evolve as we navigate these unprecedented times.

The process of feeding in mammals is achieved by moving the mandible relative to the cranium to bring the teeth into and out of occlusion. This process is especially complex in rodents which have a highly specialized configuration of jaw adductor muscles. Here, we used the computational technique of multi-body dynamics analysis (MDA) to model feeding in the red ( Sciurus vulgaris ) and grey squirrel ( Sciurus carolinensis ) and determine the relative contribution of each jaw-closing muscle in the generation of bite forces. The MDA model simulated incisor biting at different gapes. A series of ‘virtual ablation experiments' were performed at each gape, whereby the activation of each bilateral pair of muscles was set to zero. The maximum bite force was found to increase at wider gapes. As predicted, the superficial and anterior deep masseter were the largest contributors to bite force, but the temporalis had only a small contribution. Further analysis indicated that the temporalis may play a more important role in jaw stabilization than in the generation of bite force. This study demonstrated the ability of MDA to elucidate details of red and grey squirrel feeding biomechanics providing a complement to data gathered via in vivo experimentation.

Background The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. Methods In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan–Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. Results The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63–1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. Conclusions This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. Trial registration ClinicalTrials.gov identifier: NCT03013504.

Lyman Break Galaxy (LBG) candidates at z>10 are rapidly being identified in JWST/NIRCam observations. Due to the (redshifted) break produced by neutral hydrogen absorption of rest-frame UV photons, these sources are expected to drop out in the bluer filters while being well detected in redder filters. However, here we show that dust-enshrouded star-forming galaxies at lower redshifts (z10 LBGs, representing potential contaminants in LBG candidate samples. First, we analyze CEERS-DSFG-1, a NIRCam dropout undetected in the F115W and F150W filters but detected at longer wavelengths. Combining the JWST data with (sub)millimeter constraints, including deep NOEMA interferometric observations, we show that this source is a dusty star-forming galaxy (DSFG) at z~5.1. We also present a tentative 2.6sigma SCUBA-2 detection at 850um around a recently identified z~16 LBG candidate in the same field and show that, if the emission is real and associated with this candidate, the available photometry is consistent with a z~5 dusty galaxy with strong nebular emission lines despite its blue near-IR colors. Further observations on this candidate are imperative to mitigate the low confidence of this tentative submillimeter emission and its positional uncertainty. Our analysis shows that robust (sub)millimeter detections of NIRCam dropout galaxies likely imply z=4-6 redshift solutions, where the observed near-IR break would be the result of a strong rest-frame optical Balmer break combined with high dust attenuation and strong nebular line emission, rather than the rest-frame UV Lyman break. This provides evidence that DSFGs may contaminate searches for ultra high-redshift LBG candidates from JWST observations., Published in The Astrophysical Journal Letters (updated to match the published version)