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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystemic disease with a multifactorial pathogenesis involving dietary, environmental, and genetic factors. Previous mouse models suggested that circadian misalignment may additionally influence its development as it influences metabolism in diverse organs including the liver. Further, data from sleep questionnaires proved sleep-wake disruption in patients with MASLD. We objectively assessed sleep-wake rhythms in patients with biopsy-proven MASLD (n = 35) and healthy controls (HC, n = 16) using actigraphy 24/7 for 4 weeks. With the aim to re-align sleep rhythms a single standardized sleep hygiene education session was performed after 2 weeks. Actigraphy data revealed that MASLD patients had more awakenings per night (MASLD vs. HC 8.5 vs. 5.5, p = 0.0036), longer wakefulness after sleep onset (MASLD vs. HC 45.4 min vs. 21.3 min, p = 0.0004), and decreased sleep efficiency (MASLD vs. HC 86.5% vs. 92.8%, p = 0.0008) compared with HC despite comparable sleep duration. Patients with MASLD self-reported shorter sleep duration (MASLD vs. HC 6 h vs. 6 h 45 min, p = 0.01) and prolonged sleep latency contributing to poorer sleep quality. Standardized sleep hygiene education did not produce significant changes in sleep parameters. Our findings indicate fragmented nocturnal sleep in patients with MASLD, characterized by increased wakefulness and reduced sleep efficiency, perceived subjectively as shortened sleep duration and delayed onset. A single sleep hygiene education session did not improve sleep parameters., Competing Interests: Author JW was employed by NovoLytiX GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schaeffer, Bogdanovic, Hildebrandt, Flint, Geng, Pecenko, Lussier, Strumberger, Meyer, Weber, Heim, Cajochen and Bernsmeier.)

Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hypertension (HTN), a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In the present study, in a mouse model of HTN, we find that the neurovascular and cognitive dysfunction depends on interleukin (IL)-17, a cytokine elevated in individuals with HTN. However, neither circulating IL-17 nor brain angiotensin signaling can account for the dysfunction. Rather, IL-17 produced by T cells in the dura mater is the mediator released in the cerebrospinal fluid and activating IL-17 receptors on border-associated macrophages (BAMs). Accordingly, depleting BAMs, deleting IL-17 receptor A in brain macrophages or suppressing meningeal T cells rescues cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. Our data unveil a critical role of meningeal T cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction in a mouse model of HTN., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Idiosyncratic drug-induced liver injury (DILI) is a rare, unpredictable hepatic adverse event and the most common cause of acute liver failure in Europe and the US. Ribociclib is a potent Cyclin-dependent kinase 4 and 6 (CDK4/6)-inhibitor administered for advanced hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Previous reports have shown hepatotoxicity without liver necrosis related to ribociclib., Case Presentation: A 41-year-old female patient with primary metastatic HR-positive, HER2-negative breast cancer developed liver enzyme elevation under treatment with ribociclib. Ribociclib was withdrawn 8 weeks after initiation due to liver enzyme elevation. A liver biopsy, performed due to further enzyme increase (peak ALT 2836 U/l), onset of jaundice (peak bilirubin 353 µmol/l) and coagulopathy (INR 1.8) two weeks later, revealed acute hepatitis with 30% parenchymal necrosis. Roussel Uclaf Causality Assessment Method (RUCAM) score was 7 points (probable). Under treatment with prednisone (60mg), initiated 2 weeks after drug withdrawal, and subsequently N-acetylcysteine (Prescott regimen) liver enzymes normalized within 8 weeks along with prednisone tapering., Conclusion: This case illustrates the development of a severe idiosyncratic hepatocellular pattern DILI grade 3 (International DILI Expert Working Group) induced by ribociclib. Routine liver enzyme testing during therapy, immediate hepatologic work-up and treatment interruption in case of liver enzyme elevation are highly recommended. Corticosteroid treatment should be considered in cases of severe necroinflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Schaeffer, Lutz, Dobbie, Terracciano, Matter, Vosbeck, Heim and Bernsmeier.)

Objective: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy., Methods: In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1., Results: Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development., Interpretation: Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background & Aims: Recurrent somatic mutations of the RPS6KA3 gene encoding for the serine/threonine kinase RSK2 were identified in hepatocellular carcinomas (HCCs), suggesting its tumour-suppressive function. Our goal was to demonstrate the tumour suppressor role of RSK2 in the liver and investigate the functional consequences of its inactivation., Methods: We analysed a series of 1,151 human HCCs for RSK2 mutations and 20 other driver genetic alterations. We then modelled RSK2 inactivation in mice in various mutational contexts recapitulating or not those naturally found in human HCC, using transgenic mice and liver-specific carcinogens. These models were monitored for liver tumour appearance and subjected to phenotypic and transcriptomic analyses. Functional consequences of RSK2 rescue were also investigated in a human RSK2-deficient HCC cell line., Results: RSK2-inactivating mutations are specific to human HCC and frequently co-occur with AXIN1-inactivating or β-catenin-activating mutations. Modelling of these co-occurrences in mice showed a cooperative effect in promoting liver tumours with transcriptomic profiles recapitulating those of human HCCs. By contrast, there was no cooperation in liver tumour induction between RSK2 loss and BRAF-activating mutations chemically induced by diethylnitrosamine. In human liver cancer cells, we also showed that RSK2 inactivation confers some dependency to the activation of RAS/MAPK signalling that can be targeted by MEK inhibitors., Conclusions: Our study demonstrates the tumour suppressor role of RSK2 and its specific synergistic effect in hepatocarcinogenesis when its loss of function is specifically combined with AXIN1 inactivation or β-catenin activation. Furthermore, we identified the RAS/MAPK pathway as a potential therapeutic target for RSK2-inactivated liver tumours., Impact and Implications: This study demonstrated the tumour suppressor role of RSK2 in the liver and showed that its inactivation specifically synergises with AXIN1 inactivation or β-catenin activation to promote the development of HCC with similar transcriptomic profiles as found in humans. Furthermore, this study highlights that activation of the RAS/MAPK pathway is one of the key signalling pathways mediating the oncogenic effect of RSK2 inactivation that can be targeted with already available anti-MEK therapies., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Apolipoprotein-E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4 we report that border associated macrophages (BAM), myeloid cells closely apposed to neocortical microvessels, are both the source and the target of the ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAM is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.

Purpose: To assess the association between internal medicine (IM) residents' race/ethnicity and clinical performance assessments., Method: The authors conducted a cross-sectional analysis of clinical performance assessment scores at 6 U.S. IM residency programs from 2016 to 2017. Residents underrepresented in medicine (URiM) were identified using self-reported race/ethnicity. Standardized scores were calculated for Accreditation Council for Graduate Medical Education core competencies. Cross-classified mixed-effects regression assessed the association between race/ethnicity and competency scores, adjusting for rotation time of year and setting; resident gender, postgraduate year, and IM In-Training Examination percentile rank; and faculty gender, rank, and specialty., Results: Data included 3,600 evaluations by 605 faculty of 703 residents, including 94 (13.4%) URiM residents. Resident race/ethnicity was associated with competency scores, with lower scores for URiM residents (difference in adjusted standardized scores between URiM and non-URiM residents, mean [standard error]) in medical knowledge (-0.123 [0.05], P = .021), systems-based practice (-0.179 [0.05], P = .005), practice-based learning and improvement (-0.112 [0.05], P = .032), professionalism (-0.116 [0.06], P = .036), and interpersonal and communication skills (-0.113 [0.06], P = .044). Translating this to a 1 to 5 scale in 0.5 increments, URiM resident ratings were 0.07 to 0.12 points lower than non-URiM resident ratings in these 5 competencies. The interaction with faculty gender was notable in professionalism (difference between URiM and non-URiM for men faculty -0.199 [0.06] vs women faculty -0.014 [0.07], P = .01) with men more than women faculty rating URiM residents lower than non-URiM residents. Using the 1 to 5 scale, men faculty rated URiM residents 0.13 points lower than non-URiM residents in professionalism., Conclusions: Resident race/ethnicity was associated with assessment scores to the disadvantage of URiM residents. This may reflect bias in faculty assessment, effects of a noninclusive learning environment, or structural inequities in assessment., (Copyright © 2022 by the Association of American Medical Colleges.)

Background: Disparities in objective assessments in graduate medical education such as the In-Training Examination (ITE) that disadvantage women and those self-identifying with race/ethnicities underrepresented in medicine (URiM) are of concern., Objective: Examine ITE trends longitudinally across post-graduate year (PGY) with gender and race/ethnicity., Design: Longitudinal analysis of resident ITE metrics at 7 internal medicine residency programs, 2014-2019. ITE trends across PGY of women and URiM residents compared to non-URiM men assessed via ANOVA. Those with ITE scores associated with less than 90% probability of passing the American Board of Internal Medicine certification exam (ABIM-CE) were identified and odds of being identified as at-risk between groups were assessed with chi square., Participants: A total of 689 IM residents, including 330 women and URiM residents (48%)., Main Measures: ITE score KEY RESULTS: There was a significant difference in ITE score across PGY for women and URiM residents compared to non-URiM men (F (2, 1321) 4.46, p=0.011). Adjusting for program, calendar year, and baseline ITE, women and URiM residents had smaller ITE score gains (adjusted mean change in score between PGY1 and PGY3 (se), non-URiM men 13.1 (0.25) vs women and URiM residents 11.4 (0.28), p<0.001). Women and URiM residents had greater odds of being at potential risk for not passing the ABIM-CE (OR 1.75, 95% CI 1.10 to 2.78) with greatest odds in PGY3 (OR 3.13, 95% CI 1.54 to 6.37)., Conclusion: Differences in ITE over training were associated with resident gender and race/ethnicity. Women and URiM residents had smaller ITE score gains across PGY translating into greater odds of potentially being seen as at-risk for not passing the ABIM-CE. Differences in ITE over training may reflect differences in experiences of women and URiM residents during training and may lead to further disparities., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

The active layer of permafrost in Ny Ålesund, Svalbard (79°N) around the Bayelva River in the Leirhaugen glacier moraine is measured as a small net carbon sink at the brink of becoming a carbon source. In many permafrost-dominating ecosystems, microbes in the active layers have been shown to drive organic matter degradation and greenhouse gas production, creating positive feedback on climate change. However, the microbial metabolisms linking the environmental geochemical processes and the populations that perform them have not been fully characterized. In this paper, we present geochemical, enzymatic, and isotopic data paired with 10 Pseudomonas sp. cultures and metagenomic libraries of two active layer soil cores (BPF1 and BPF2) from Ny Ålesund, Svalbard, (79°N). Relative to BPF1, BPF2 had statistically higher C/N ratios (15 ± 1 for BPF1 vs. 29 ± 10 for BPF2; n = 30, p < 10 -5 ), statistically lower organic carbon (2% ± 0.6% for BPF1 vs. 1.6% ± 0.4% for BPF2, p < 0.02), statistically lower nitrogen (0.1% ± 0.03% for BPF1 vs. 0.07% ± 0.02% for BPF2, p < 10 -6 ). The d 13 C values for inorganic carbon did not correlate with those of organic carbon in BPF2, suggesting lower heterotrophic respiration. An increase in the δ 13 C of inorganic carbon with depth either reflects an autotrophic signal or mixing between a heterotrophic source at the surface and a lithotrophic source at depth. Potential enzyme activity of xylosidase and N-acetyl-β-D-glucosaminidase increases twofold at 15°C, relative to 25°C, indicating cold adaptation in the cultures and bulk soil. Potential enzyme activity of leucine aminopeptidase across soils and cultures was two orders of magnitude higher than other tested enzymes, implying that organisms use leucine as a nitrogen and carbon source in this nutrient-limited environment. Besides demonstrating large variability in carbon compositions of permafrost active layer soils only ∼84 m apart, results suggest that the Svalbard active layer microbes are often limited by organic carbon or nitrogen availability and have adaptations to the current environment, and metabolic flexibility to adapt to the warming climate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sipes, Paul, Fine, Li, Liang, Boike, Onstott, Vishnivetskaya, Schaeffer and Lloyd.)

Background: Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1 -OPG murine models, we previously demonstrated that murine Nf1 -OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo . While these interactions are critical for established Nf1 -OPG tumor growth, their importance in tumor formation has not been explored., Methods: A combination of bulk and single-cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments., Results: We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8 + T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor ( Ccr4 ) expression in CD8 + , but not CD4 + , T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment., Conclusions: Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The brain is supplied by an elaborate vascular network that originates extracranially and reaches deep into the brain. The concept of the neurovascular unit provides a useful framework to investigate how neuronal signals regulate nearby microvessels to support the metabolic needs of the brain, but it does not consider the role of larger cerebral arteries and systemic vasoactive signals. Furthermore, the recently emerged molecular heterogeneity of cerebrovascular cells indicates that there is no prototypical neurovascular unit replicated at all levels of the vascular network. Here, we examine the cellular and molecular diversity of the cerebrovascular tree and the relative contribution of systemic and brain-intrinsic factors to neurovascular function. Evidence supports the concept of a 'neurovascular complex' composed of segmentally diverse functional modules that implement coordinated vascular responses to central and peripheral signals to maintain homeostasis of the brain. This concept has major implications for neurovascular regulation in health and disease and for brain imaging., (© 2021. Springer Nature America, Inc.)

Public health concerns related to the COVID-19 pandemic are leading many residency and fellowship programs to transition from in-person to videoconference interviews (VCIs). The magnitude and speed of the shift to VCIs, the lack of existing research around bias and VCIs, and the underlying stress on all involved related to the pandemic put programs at risk of implementing virtual interviews without fully exploring their implications for diversity and equity. VCIs can promote diversity efforts by reducing the need for travel, making interviews more convenient and cost effective for applicants. However, VCIs may also introduce new biases and amplify existing biases in recruitment. VCIs introduce a dependence on technology to conduct the interview process, which may amplify systemic inequities in access to broadband internet and high-quality hardware. Communication delays due to technology challenges may negatively affect interview scores. Additionally, users experience increased cognitive load when participating in videoconferences, which can activate implicit biases. Exposure to cues in the interviewee's personal living situation previously unavailable to interviewers may lead to unconscious assumptions by interviewers, which may also influence scoring. Graduate medical education programs committed to maintaining equitable recruitment processes must be able to recognize potential biases in VCIs and implement strategies to mitigate them. This article identifies some of the biases VCIs can introduce to the recruitment process and offers strategies for programs to mitigate them. These include making interviewers aware of potential technology-based inequities, encouraging interviewers to minimize multitasking, and offering guidance on use of standardized backgrounds. The authors also recognize the limitations of offering behavioral strategies to mitigate systemic inequities and suggest that structural changes are needed to ensure equitable access to technology., (Copyright © 2021 by the Association of American Medical Colleges.)

Importance: Biased patient behavior negatively impacts resident well-being. Data on the prevalence and frequency of these encounters are lacking and are needed to guide the creation of institutional trainings and policies to support trainees., Objective: To evaluate the frequency of resident experiences with and responses to a range of biased patient behaviors., Design, Setting, and Participants: A retrospective survey was sent via email to 331 second- and third-year internal medicine residents from 3 academic medical centers in California and North Carolina. First-year residents were excluded owing to their limited interactions with patients at the time of participant recruitment. Data were collected from August 21 to November 25, 2019., Main Outcomes and Measures: Descriptive statistics were used to report the frequency of experience of various types of biased patient behavior, residents' responses, the factors impeding residents' responses, and residents' experiences and beliefs regarding training and policies., Results: Overall, 232 of 331 residents (70%) participated; 116 (50%) were women; 116 of 247 (47%) were White (participants had the option of selecting >1 race/ethnicity); and 23 (10%) identified as lesbian, gay, bisexual, transgender, or queer. The frequency of resident-reported experience of types of biased patient behaviors varied. The most common behaviors-belittling comments and assumption of nonphysician status-were reported to be experienced 1 or more times per week by 14% of residents (32 of 231) and 17% of residents (38 of 230), respectively. Women, Black or Latinx, and Asian residents reported experiencing biased behavior more frequently. Forty-five percent of Black or Latinx residents (17 of 38) encountered instances of explicit epithets or rejection of care. All 70 Asian residents reported experiencing inquiries into their ethnic origins. Most women residents (110 of 115 [96%]) experienced role questioning behaviors, and 87% (100 of 115) experienced sexual harassment. The need to prioritize clinical care and a sense of futility in responding were the most common factors (cited by 34% of residents [76 of 227] and 25% of residents [56 of 227], respectively) significantly impeding responses to biased behaviors. Eighty-five percent of residents (191 of 226) never reported incidents to their institution. Eighty-nine percent of residents (206 of 232) identified training and policies as necessary or very necessary., Conclusions and Relevance: This survey study suggests that biased patient behavior is experienced frequently by internal medicine residents. Non-White and women residents reported experiencing a disproportionate burden of these incidents. Residents' responses rarely included institutional involvement. Residency programs and health care systems should prioritize training and policies to address biased patient behavior and support affected residents.

Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery of blood flow to the brain. Hypertension also alters the blood-brain barrier (BBB), a critical component of brain health. Although endothelial cells are ultimately responsible for the BBB, the development and maintenance of the barrier properties depend on the interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative interaction with other cells. Perivascular macrophages (PVM), innate immune cells closely associated with cerebral microvessels, have emerged as major contributors to neurovascular dysfunction. Using 2-photon microscopy in vivo and electron microscopy in a mouse model of Ang II (angiotensin II) hypertension, we found that the vascular segments most susceptible to increased BBB permeability are arterioles and venules >10 µm and not capillaries. Brain macrophage depletion with clodronate attenuates, but does not abolish, the increased BBB permeability in these arterioles where PVM are located. Deletion of AT1R (Ang II type-1 receptors) in PVM using bone marrow chimeras partially attenuated the BBB dysfunction through the free radical-producing enzyme Nox2. In contrast, downregulation of AT1R in cerebral endothelial cells using a viral gene transfer-based approach prevented the BBB disruption completely. The results indicate that while endothelial AT1R, mainly in arterioles and venules, initiate the BBB disruption in hypertension, PVM are required for the full expression of the dysfunction. The findings unveil a previously unappreciated contribution of resident brain macrophages to increased BBB permeability of hypertension and identify PVM as a putative therapeutic target in diseases associated with BBB dysfunction.

Heterogeneity of infection and extreme shedding patterns are common features of animal infectious diseases. Individual hosts that are super-shedders are key targets for control strategies. Nevertheless, the mechanisms associated with the emergence of super-shedders remain largely unknown. During chicken salmonellosis, a high heterogeneity of infection is observed when animal-to-animal cross-contaminations and reinfections are reduced. We hypothesized that unlike super-shedders, low-shedders would be able to block the first Salmonella colonization thanks to a different gut microbiota. The present study demonstrates that (i) axenic and antibiotic-treated chicks are more prone to become super-shedders; (ii) super or low-shedder phenotypes can be acquired through microbiota transfer; (iii) specific gut microbiota taxonomic features determine whether the chicks develop a low- and super-shedder phenotype after Salmonella infection in isolator; (iv) partial protection can be conferred by inoculation of four commensal bacteria prior to Salmonella infection. This study demonstrates the key role plays by gut microbiota composition in the heterogeneity of infection and pave the way for developing predictive biomarkers and protective probiotics., (© 2020 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Importance: Gender bias may affect assessment in competency-based medical education., Objective: To evaluate the association of gender with assessment of internal medicine residents., Design, Setting, and Participants: This multisite, retrospective, cross-sectional study included 6 internal medicine residency programs in the United States. Data were collected from July 1, 2016, to June 30, 2017, and analyzed from June 7 to November 6, 2019., Exposures: Faculty assessments of resident performance during general medicine inpatient rotations., Main Outcomes and Measures: Standardized scores were calculated based on rating distributions for the Accreditation Council for Graduate Medical Education's core competencies and internal medicine Milestones at each site. Standardized scores are expressed as SDs from the mean. The interaction of gender and postgraduate year (PGY) with standardized scores was assessed, adjusting for site, time of year, resident In-Training Examination percentile rank, and faculty rank and specialty., Results: Data included 3600 evaluations for 703 residents (387 male [55.0%]) by 605 faculty (318 male [52.6%]). Interaction between resident gender and PGY was significant in 6 core competencies. In PGY2, female residents scored significantly higher than male residents in 4 of 6 competencies, including patient care (mean standardized score [SE], 0.10 [0.04] vs 0.22 [0.05]; P = .04), systems-based practice (mean standardized score [SE], -0.06 [0.05] vs 0.13 [0.05]; P = .003), professionalism (mean standardized score [SE], -0.04 [0.06] vs 0.21 [0.06]; P = .001), and interpersonal and communication skills (mean standardized score [SE], 0.06 [0.05] vs 0.32 [0.06]; P < .001). In PGY3, male residents scored significantly higher than female patients in 5 of 6 competencies, including patient care (mean standardized score [SE], 0.47 [0.05] vs 0.32 [0.05]; P = .03), medical knowledge (mean standardized score [SE], 0.47 [0.05] vs 0.24 [0.06]; P = .003), systems-based practice (mean standardized score [SE], 0.30 [0.05] vs 0.12 [0.06]; P = .02), practice-based learning (mean standardized score [SE], 0.39 [0.05] vs 0.16 [0.06]; P = .004), and professionalism (mean standardized score [SE], 0.35 [0.05] vs 0.18 [0.06]; P = .03). There was a significant increase in male residents' competency scores between PGY2 and PGY3 (range of difference in mean adjusted standardized scores between PGY2 and PGY3, 0.208-0.391; P ≤ .002) that was not seen in female residents' scores (range of difference in mean adjusted standardized scores between PGY2 and PGY3, -0.117 to 0.101; P ≥ .14). There was a significant increase in male residents' scores between PGY2 and PGY3 cohorts in 6 competencies with female faculty and in 4 competencies with male faculty. There was no significant change in female residents' competency scores between PGY2 to PGY3 cohorts with male or female faculty. Interaction between faculty-resident gender dyad and PGY was significant in the patient care competency (β estimate [SE] for female vs male dyad in PGY1 vs PGY3, 0.184 [0.158]; β estimate [SE] for female vs male dyad in PGY2 vs PGY3, 0.457 [0.181]; P = .04)., Conclusions and Relevance: In this study, resident gender was associated with differences in faculty assessments of resident performance, and differences were linked to PGY. In contrast to male residents' scores, female residents' scores displayed a peak-and-plateau pattern whereby assessment scores peaked in PGY2. Notably, the peak-and-plateau pattern was seen in assessments by male and female faculty. Further study of factors that influence gender-based differences in assessment is needed.

Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 ( GYG1 ) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164&#95;165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies., (© 2020 Published by Elsevier Inc.)

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Dietary habits and vascular risk factors promote both Alzheimer's disease and cognitive impairment caused by vascular factors 1-3 . Furthermore, accumulation of hyperphosphorylated tau, a microtubule-associated protein and a hallmark of Alzheimer's pathology 4 , is also linked to vascular cognitive impairment 5,6 . In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion 7 . Here we report that dietary salt induces hyperphosphorylation of tau followed by cognitive dysfunction in mice, and that these effects are prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduces neuronal calpain nitrosylation and results in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin-dependent kinase 5. Salt-induced cognitive impairment is not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. These findings identify a causal link between dietary salt, endothelial dysfunction and tau pathology, independent of haemodynamic insufficiency. Avoidance of excessive salt intake and maintenance of vascular health may help to stave off the vascular and neurodegenerative pathologies that underlie dementia in the elderly.

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation., Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]., Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach., Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Background: Competency-based medical education relies on meaningful resident assessment. Implicit gender bias represents a potential threat to the integrity of resident assessment. We sought to examine the available evidence of the potential for and impact of gender bias in resident assessment in graduate medical education., Methods: A systematic literature review was performed to evaluate the presence and influence of gender bias on resident assessment. We searched Medline and Embase databases to capture relevant articles using a tiered strategy. Review was conducted by two independent, blinded reviewers. We included studies with primary objective of examining the impact of gender on resident assessment in graduate medical education in the USA or Canada published from 1998 to 2018., Results: Nine studies examined the existence and influence of gender bias in resident assessment and data included rating scores and qualitative comments. Heterogeneity in tools, outcome measures, and methodologic approach precluded meta-analysis. Five of the nine studies reported a difference in outcomes attributed to gender including gender-based differences in traits ascribed to residents, consistency of feedback, and performance measures., Conclusion: Our review suggests that gender bias poses a potential threat to the integrity of resident assessment in graduate medical education. Future study is warranted to understand how gender bias manifests in resident assessment, impact on learners and approaches to mitigate this bias.

To establish an infection, Salmonella has to interact with eukaryotic cells. Invasion of non-phagocytic cells (i.e., epithelial, fibroblast and endothelial cells) involves either a trigger or a zipper mechanism mediated by the T3SS-1 or the invasin Rck, respectively. Another outer membrane protein, PagN, was also implicated in the invasion. However, other unknown invasion factors have been previously suggested. Our goal was to evaluate the invasion capability of a Salmonella Typhimurium strain invalidated for the three known invasion factors. Non-phagocytic cell lines of several animal origins were tested in a gentamicin protection assay. In most cells, we observed a drastic decrease in the invasion rate between the wild-type and the triple mutant. However, in five cell lines, the triple mutant invaded cells at a similarly high level to the wild-type, suggesting the existence of unidentified invasion factors. For the wild-type and the triple mutant, scanning-electron microscopy, confocal imaging and use of biochemical inhibitors confirmed their cellular uptake and showed a zipper-like mechanism of internalization involving both clathrin- and non-clathrin-dependent pathways. Despite a functional T3SS-1, the wild-type bacteria seemed to use the same entry route as the mutant in our cell model. All together, these results demonstrate the existence of unknown Salmonella invasion factors, which require further characterization.

Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127-9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10-20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This corrects the article DOI: 10.1038/ncomms15039.

Activity in hippocampal area CA1 is essential for consolidating episodic memories, but it is unclear how CA1 activity patterns drive memory formation. We find that in the hours following single-trial contextual fear conditioning (CFC), fast-spiking interneurons (which typically express parvalbumin (PV)) show greater firing coherence with CA1 network oscillations. Post-CFC inhibition of PV+ interneurons blocks fear memory consolidation. This effect is associated with loss of two network changes associated with normal consolidation: (1) augmented sleep-associated delta (0.5-4 Hz), theta (4-12 Hz) and ripple (150-250 Hz) oscillations; and (2) stabilization of CA1 neurons' functional connectivity patterns. Rhythmic activation of PV+ interneurons increases CA1 network coherence and leads to a sustained increase in the strength and stability of functional connections between neurons. Our results suggest that immediately following learning, PV+ interneurons drive CA1 oscillations and reactivation of CA1 ensembles, which directly promotes network plasticity and long-term memory formation.

Positron emission tomography (PET) is a highly sensitive, noninvasive imaging technique for quantifying biological functions of tissues. However, at the time of this study, PET imaging applications had not been reported in the horse. The aim of this exploratory study was to determine whether a portable high-resolution PET scanner could be used to image the equine distal limb. Images of the front feet and fetlocks of three research horses, with known lesions localized to the distal front limbs, were acquired under general anesthesia after administration of 18 F-fluorodeoxyglucose ( 18 F-FDG), with doses ranging from 1.5 to 2.9 MBq/kg. The radiation exposure measured during imaging was slightly higher than 99m Technetium scintigraphy. However, the use of general anesthesia allowed the proximity and the contact time with the patient to be minimized for the staff involved. 18 F-FDG uptake was evident throughout the soft tissues, with the highest uptake in the coronary band and the lowest uptake in the tendons. Anatomic structures could be discriminated due to the high contrast between soft tissue and bone. Detected lesions included lysis of the flexor cortex of the navicular bone, lesions of flexor tendons and suspensory ligament, and abnormal uptake through the lamina of a laminitic subject. Findings indicated that tomographic molecular imaging is feasible in the equine distal limb and could be useful as a future diagnostic technique for clinical and research studies, especially those involving tendinopathy/desmopathy and laminitis., (© 2016 American College of Veterinary Radiology.)

Study Objective: Rivaroxaban and apixaban are part of a new group of oral anticoagulants targeting factor Xa and approved by the Food and Drug Administration in 2011 and 2012. These oral anticoagulants are administered at fixed daily doses, without the need for laboratory-guided adjustments. There are limited data available on supratherapeutic doses or overdose of the oral Xa inhibitors. This study characterizes the clinical effect in patients exposed to rivaroxaban and apixaban., Methods: A retrospective study collected data from 8 regional poison centers covering 9 states. Cases were initially identified by a search of the poison centers' databases for case mentions involving a human exposure to Xarelto, rivaroxaban, Eliquis, or apixaban. Inclusion criteria included single-substance exposure. Exclusion criteria were animal exposure, polysubstance exposure, or information call. Data for the study were collected by individual chart review, including case narratives, and compiled into a single data set., Results: There were 223 patients: 124 (56%) were female patients, mean age was 60 years, and 20 were children younger than 12 years (9%). One hundred ninety-eight patients ingested rivaroxaban (89%) and 25 ingested apixaban (11%). Dose was reported in 182 rivaroxaban patients, with a mean dose of 64.5 mg (range 15 to 1,200 mg), and in 21 apixaban patients, with a mean dose of 9.6 mg (range 2.5 to 20 mg). For rivaroxaban, prothrombin time was measured in 49 patients (25%) and elevated in 7; partial thromboplastin time, measured in 49 (25%) and elevated in 5; and international normalized ratio, measured in 61 (31%) and elevated in 13. For apixaban, prothrombin time was measured in 6 patients (24%) and elevated in none; partial thromboplastin time, measure in 6 (24%) and elevated in none; and international normalized ratio, measured in 5 patients (20%) and elevated in none. Bleeding was reported in 15 patients (7%): 11 rivaroxaban and 4 apixaban. The site of bleeding was gastrointestinal (8), oral (2), nose (1), bruising (1), urine (1), and subdural (1). The subdural bleeding occurred after fall and head injury. All cases with bleeding involved long-term ingestions. Coagulation test results were normal in most patients with bleeding: prothrombin time 5 of 6 (83%), partial thromboplastin time 5 of 6 (83%), and international normalized ratio 5 of 9 (55%). Blood products were used in 7 rivaroxaban patients (1 suicide) and 3 apixaban patients. No bleeding or altered coagulation test results occurred in children, which all involved a one-time ingestion. All 12 suicide attempts involved rivaroxaban: altered coagulation test results occurred for 5 patients (42%), no bleeding occurred in any suicide attempt patient, 1 patient was treated with fresh frozen plasma (international normalized ratio 12.47), and dose by patient history did not predict risk of altered coagulation or bleeding. Two rivaroxaban patients experienced elevation of hepatic transaminase levels greater than 1,000 U/L., Conclusion: Bleeding after Xa inhibitor ingestion as a single agent is uncommon. Prothrombin time, partial thromboplastin time, or international normalized ratio may be elevated in a minority of cases but appears unreliable to measure risk of bleeding. Massive acute ingestion in suicide attempt may result in significant anticoagulation. Single exploratory ingestion by children was not associated with toxicity., (Copyright © 2015 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Long-term phosphorus (P) and nitrogen (N) applications may seriously affect soil microbial activity. A long-term field fertilizer application trial was established on reddish paddy soils in the subtropical region of southern China in 1998. We assessed the effects of swine manure and seven different rates or ratios of NPK fertilizer treatments on (1) the absolute and specific enzyme activities per unit of soil organic carbon (SOC) or microbial biomass carbon (MBC) involved in C, N, and P transformations and (2) their relationships with soil environmental factors and soil microbial community structures. The results showed that manure applications led to increases in the absolute and specific activities of soil β-1,4-glucosidase(βG), β-1,4-N-acetylglucosaminidase (NAG), and leucine aminopeptidase (LAP). The absolute and specific acid phosphatase (AP) activities decreased as mineral P fertilizer application rates and ratios increased. Redundancy analysis (RDA) showed that there were negative correlations between absolute and specific AP activities, pH, and total P contents, while there were positive correlations between soil absolute and specific βG, NAG, and LAP enzyme activities, and SOC and total N contents. RDA showed that the contents of actinomycete and Gram-positive bacterium PLFA biomarkers are more closely related to the absolute and specific enzyme activities than the other PLFA biomarkers (P<0.01). Our results suggest that both the absolute and specific enzyme activities could be used as sensitive soil quality indicators that provide useful linkages with the microbial community structures and environmental factors. To maintain microbial activity and to minimize environmental impacts, P should be applied as a combination of inorganic and organic forms, and total P fertilizer application rates to subtropical paddy soils should not exceed 44 kg P ha(-1) year(-1)., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: African Americans are disproportionately affected by hepatitis C (HCV) and are less likely to undergo HCV treatment. Underserved populations are especially at risk for experiencing health disparity. Aim. To identify reasons for HCV non-treatment among underserved African Americans in a large safetynet system., Material and Methods: Medical records of HCV-infected African Americans evaluated at San Francisco General Hospital liver specialty clinic from 2006-2011 who did not receive HCV treatment were reviewed. Treatment eligibility and reasons for non-treatment were assessed. Factors associated with treatment ineligibility were assessed using logistic regression modeling., Results: Among 118 patients, 42% were treatment ineligible, 18% treatment eligible, and 40% were undergoing work-up to determine eligibility. Reasons for treatment ineligibility were medical (54%), non-medical (14%), psychiatric (4%), or combined (28%). When controlling for age and sex, active/recent substance abuse (OR 6.65, p = 0.001) and having two or more medical comorbidities (OR 3.39, p = 0.005) predicted treatment ineligibility. Excluding those ineligible for treatment, 72% of all other patients were lost to follow-up; they were older (55 vs. 48 years, p = 0.01) and more likely to be undergoing work up to determine treatment eligibility (86 vs. 21%, p < 0.0001) than those not lost to follow-up., Conclusions: Medical comorbidities and substance abuse predicted HCV treatment ineligibility in underserved African Americans. Importantly, the majority of those undergoing work-up to determine HCV treatment eligibility were lost to follow-up. While newer anti-HCV agents may increase treatment eligibility, culturally appropriate interventions to increase compliance with evaluation and care remain critical to HCV management in underserved African Americans.

Plastids are actively involved in numerous plant processes critical to growth, development and adaptation. They play a primary role in photosynthesis, pigment and monoterpene synthesis, gravity sensing, starch and fatty acid synthesis, as well as oil, and protein storage. We applied two complementary methods to analyze the recently published apple genome (Malus × domestica) to identify putative plastid-targeted proteins, the first using TargetP and the second using a custom workflow utilizing a set of predictive programs. Apple shares roughly 40% of its 10,492 putative plastid-targeted proteins with that of the Arabidopsis (Arabidopsis thaliana) plastid-targeted proteome as identified by the Chloroplast 2010 project and ∼57% of its entire proteome with Arabidopsis. This suggests that the plastid-targeted proteomes between apple and Arabidopsis are different, and interestingly alludes to the presence of differential targeting of homologs between the two species. Co-expression analysis of 2,224 genes encoding putative plastid-targeted apple proteins suggests that they play a role in plant developmental and intermediary metabolism. Further, an inter-specific comparison of Arabidopsis, Prunus persica (Peach), Malus × domestica (Apple), Populus trichocarpa (Black cottonwood), Fragaria vesca (Woodland Strawberry), Solanum lycopersicum (Tomato) and Vitis vinifera (Grapevine) also identified a large number of novel species-specific plastid-targeted proteins. This analysis also revealed the presence of alternatively targeted homologs across species. Two separate analyses revealed that a small subset of proteins, one representing 289 protein clusters and the other 737 unique protein sequences, are conserved between seven plastid-targeted angiosperm proteomes. Majority of the novel proteins were annotated to play roles in stress response, transport, catabolic processes, and cellular component organization. Our results suggest that the current state of knowledge regarding plastid biology, preferentially based on model systems is deficient. New plant genomes are expected to enable the identification of potentially new plastid-targeted proteins that will aid in studying novel roles of plastids.

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.

The codling moth, Cydia pomonella, is one of the most important pests of pome fruits in the world, yet the molecular genetics and the physiology of this insect remain poorly understood. A combined assembly of 8 341 expressed sequence tags was generated from Roche 454 GS-FLX sequencing of eight tissue-specific cDNA libraries. Putative chemosensory proteins (12) and odorant binding proteins (OBPs) (18) were annotated, which included three putative general OBP (GOBP), one more than typically reported for other Lepidoptera. To further characterize CpomGOBPs, we cloned cDNA copies of their transcripts and determined their expression patterns in various tissues. Cloning and sequencing of the 698 nt transcript for CpomGOBP1 resulted in the prediction of a 163 amino acid coding region, and subsequent RT-PCR indicated that the transcripts were mainly expressed in antennae and mouthparts. The 1 289 nt (160 amino acid) CpomGOBP2 and the novel 702 nt (169 amino acid) CpomGOBP3 transcripts are mainly expressed in antennae, mouthparts, and female abdomen tips. These results indicate that next generation sequencing is useful for the identification of novel transcripts of interest, and that codling moth expresses a transcript encoding for a new member of the GOBP subfamily., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)