Merit Review Research Articles

From a Reformist Professor to a “Mouthpiece” for Capital: Tsunao Miyajima in an International Context

AbstractTsunao Miyajima (1884–1965), qua economist, has gone unsung among historians of economics; however, his intellectual trajectory merits review in an international context. From the early 1910s to the middle of the1920s, he advocated the labor cause and social reform as a professor in Tokyo and Osaka. However, he converted his stance to its antithesis between the late 1920s and early 1930s, when he was acting as chief of the permanent Japanese employers' delegation to the International Labour Organization in Geneva. Observations on his volte-face, placed in the context of relations with famed economists at the time—such as Émile Waxweiler, Charles Gide, John Bates Clark, and Gustav Cassel—provide insight to a significant episode in the internationalization and international networking in economics and, more broadly, in global intellectual history. Furthermore, particular attention to his objection to the “Eurocentric” organization's attempt to impose minimum wage fixing machinery on and allegations of social dumping in Japan sheds new light on the international development of policy-oriented economics, namely, from the hitherto unheeded perspective of an emerging economy from Asia.

Adverse Events From Nitrate Administration During Right Ventricular Myocardial Infarction: A Systematic Review and Meta-Analysis

New studies (cumulatively, n=1113) have challenged the single cohort study (n=40) underlying the contraindication on nitrate use during right ventricular myocardial infarction (RVMI), suggesting that this topic merits review.

Preventing death following unsafe abortion: a case series from urban Uganda

BACKGROUNDMaternal deaths from unsafe abortion continue to occur globally, with particularly high rates in Sub-Saharan Africa where most abortions are classified as unsafe. Maternal death reviews are an effective part of cohesive strategies to prevent future deaths while abortion remains illegal.OBJECTIVEThis study aimed to conduct maternal death reviews for all deaths occurring following unsafe abortion during the study period, to assess preventability, and to synthesize key learning points that may help to prevent future maternal deaths following unsafe abortions.STUDY DESIGNFull case reviews of all maternal deaths (350 cases from Jan 2016 to Dec 2018) at the study center (a national referral hospital in urban Uganda) were conducted by specially trained multidisciplinary panels of obstetricians and midwives. We extracted the reviews of women who died following unsafe abortions (13 [2.6%]) for further analysis.RESULTSMost maternal deaths owing to unsafe abortion were found to be preventable. The key recommendations that emerged from the reviews were (1) that clinicians should maintain a high index of suspicion for delayed presentation and rapid decompensation in cases where unsafe abortion has occurred, (2) that a low threshold for early intravenous antibiotic therapy should be applied, and (3) that any admission with complications following an unsafe abortion merits review by an experienced clinician as soon as possible.CONCLUSIONPostabortion care is part of essential emergency medical care and should be provided with high standards, especially in areas where there is limited or no legal access to abortion care. Implementing the recommended learning points is likely to be feasible even in low-resource obstetrical settings and, given the high rates of preventability found in maternal deaths owing to unsafe abortion, is likely to be effective.

Abstract P199: Tenfibgen nanoencapsulated RNAi feCK2 inhibits protein kinase CK2 and induces apoptosis in feline oral squamous cell carcinomas in vivo

Abstract In an initial safety evaluation in domestic cats suffering from oral squamous cell carcinomas (FOSCC), nine cat subjects were treated IV with 5-6 doses given twice weekly of s50 RNAi feCK2 at either 2 or 20 ug/kg (Cannon et. al., Hu Gene Ther Clin Devel 28(2):80-6, 2017). Treatment was generally well tolerated. In one case, a clear drug-related Grade 3 side effect was rapid tumor death (tumor lysis) resulting in an open wound. This issue has been addressed successfully in separate mice studies with longer, lower-dose SQ regimens. Protein kinase CK2, as a promising target in oncology, plays vital roles in cell growth, proliferation, and suppression of apoptosis (Ahmed et al., Trends Cell Biol 12: 226-30, 2002). Anti-feCK2aa’ is a tumor-targeted 20 nm crystalline capsule bearing single-stranded RNAi oligos against both CK2 catalytic kinase subunits with a ligand-coated shell derived from Tenascin-C (tenfibgen). Tenascin-C is upregulated in multiple solid tumors and is present in tumors throughout their lifecycle. The capsule’s ultrasmall size enables efficient raft-mediated delivery of oligos to the perinuclear space of the target cell, and the ability to reach metastases without reliance on EPR (Unger et. al, Mol Cancer Ther 13:2018-29, 2014). Initial mechanistic work focused on changes in clinically scored IHC of the CK2a subunit in study tumors. In an effort to develop a future working hypothesis, remaining paraffin-embedded tissues were retrospectively examined for both kinase subunits of CK2 as a mixture (CK2aa’), cleaved PARP (CP, apoptosis marker) and Ago2 (critical enzyme required for RNAi drug activity). Previous work in murine models showed variation of Ago2 levels in primary human and xenograft tumors. Further, model xenograft and syngeneic tumors responded with increased Ago2 levels and drug activity upon 10 mg/ml IV priming followed by low-dose SQ treatment (Cancer Res 2016;76(14 Suppl):3746). Using confocal fluorescence microscopy, we observed that decreased post-treatment CK2aa’ and increased CP corresponded positively with clinical tumor responses while non-responders showed an inverse relationship. Examination of arrayed human HNC samples also showed a variation in Ago2 levels but premalignant oral lesions from a human chemoprevention trial did not. These observations suggest a possible future path for feline patient therapy of advanced lesions using Ago2 stratification, potential IV priming and more convenient, longer-term SQ dosing administered by feline caregivers. A path for human therapy may lie through chemoprevention with much to be learned from feline studies. Funding: University of Minnesota Clinical and Translational Sciences Award (1UL1 RR033183-01), NIH SBIR Contract HHSN26120 1300030C, N01-CN-15000, Mod#5, V.A. Merit Review research funds (BX00173 and BX003282) and NCI Award CA150182. Citation Format: Frank G. Ondrey, Gretchen M. Unger, Claire M. Cannon, Janeen H. Trembley, BT Kren, Jaime F. Modiano, Khalil Ahmed. Tenfibgen nanoencapsulated RNAi feCK2 inhibits protein kinase CK2 and induces apoptosis in feline oral squamous cell carcinomas in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P199.

Electrochemically-Rechargeable Liquids in Highly Flexible Energy Storage Systems

Hydrogen and electricity are expected to be the two major energy carriers of the future. Unfortunately, neither can be stored as an ambient-temperature liquid, which is the ideal energy-carrier medium. H2 can be used in a wide variety of both stationary and transportation applications, as envisioned by DOE’s H2@Scale program[1]. Although DOE has not yet established targets for stationary H2 storage, the key metrics for an “ideal hydrogen carrier” are[2]: liquid at all operating temperatures, high energy density, efficient conversions at relatively benign conditions, long cycle life, compatible with existing infrastructure for fuels, low cost, and safety (toxicological and eco-toxicological). Electrochemically-rechargeable liquids (ERLs) that can be charged using either electrical and/or hydrogen energy, which can also produce H2 or electricity on demand, can enable highly flexible energy-storage systems that may potentially be used for both stationary and transportation applications. In short, an ERL can provide essential “energy-banker services” by simultaneously converting and storing these two major “energy currencies” of the future in a single aqueous liquid. These systems can also be readily scaled up or scaled down.This talk will present an overview of potentially attractive ERL options, which can include conventional liquid-organic hydrogen carriers (i.e., LOHCs, such as organics that are liquids at room temperature, like methylcyclohexane), as well as aqueous solutions (e.g., diluted alcohols) or dissolved solids (e.g., redox-flow-battery electrolytes)[3]. A variety of ERL conversion system options shall also be presented, which includes combinations of the configurations shown in Fig. 1. The current status of this technology shall be briefly reviewed, including a summary of the key technical barriers, as well as some enabling concepts to potentially address each of these challenges. A perspective on potentially attractive end uses for ERLs shall be included, along with some recommendations on key performance indicators (KPIs) for ERLs in these applications. [1] B. Pivovar, N. Rustagi, and S. Satyapal, ECS Interface, 27 (2018) 47. [2] T. Autry and M. Bowden, “HyMARC; H2 Carriers for Bulk H2 Storage & Transport,” HFTO Annual Merit Review slides, ST204 (2020). [3] M. L. Perry & Z. Yang, J. Electrochem. Soc., 166 (2019) A3045. Figure 1

How Racism Against BIPOC Women Faculty Operates in Social Work Academia

In this article, we seek to highlight the ways in which we, as two female social work faculty members whose racial/ethnic identities fall into the categories of Black, Indigenous, and other People of Color (BIPOC), have experienced racism and White supremacy within predominantly White institutions in the United States. We seek to clarify that these experiences are not unique to any particular institution or university, but rather reflect systemic racism and the upholding of White supremacy in higher education in social work throughout the United States. We highlight the differential vulnerability faced by BIPOC women in academia, which are often unaddressed in the pursuit of what is seen to be an egalitarian or colorblind merit review. Bearing in mind our reflexivity on our positionalities, we share personal narratives regarding our own marginalization within White spaces and the emotional labor that we are often asked to carry for the institutions within which we work. We will elucidate experiences of tokenization or assumed intellectual inferiority by our peers. Given the current sociopolitical moment and the heightened awareness of diversity, equity and inclusion efforts within universities, we also reflect on how institutions of higher education, and particularly schools of social work, can move beyond simply hiring more people of color or conducting diversity trainings to ensuring that BIPOC women are more fully included in their roles within universities as faculty, administrators, staff and students.

Techno-economic analysis of long-duration energy storage and flexible power generation technologies to support high-variable renewable energy grids

Techno-economic analysis of long-duration energy storage and flexible power generation technologies to support high-variable renewable energy grids

Abstract 2336: Eradicating melanoma cells using combination of nutritional stress and checkpoint inhibitors

Abstract Arginine (Arg) deprivation can inhibit tumors which do not express argininosuccinate synthetase (ASS), a key enzyme for synthesis of Arg. Arg deiminase (ADIPEG20) has shown antitumor activity in such tumors, including melanoma and mesothelioma. Resistance to this treatment occurs due to re-expression of ASS. We have shown that this is mediated via cMyc (positive regulator) and HIF1α ( negative regulator ). Arg starvation rapidly induces chromatin remodeling complex P300-HDAC2-Sin3A which epigenetically deacetylates H3K14ac and H3K27ac at the ASS promoter. Following the PHD2-derived HIF1α-degrading system, the promoter-bound HIF1α is degraded (Sci Rep 7:10814). This allows cMyc (an E-Box binder), to turn on ASS. Arg starvation rapidly triggers externalization of Gas6 to interact with its receptor tyrosine kinase (RTK) Axl. This activates the downstream Ras-PI3K/AKT/GSK3β pathway, resulting in stabilization of cMyc. However, this activation also turns on PDL1 gene expression. This is not surprising since cMyc has been shown to bind to PDL1 promoter and increase its expression. Thus, re-expression of ASS also leads to PDL1 expression. We studied these findings in two other cell lines, Mel114 and Skmel2, and obtained similar results, Interestingly, in three cell lines with high levels of antiapoptotic protein Bcl-2, Arg starvation only leads to growth inhibition, with only less than 2 fold increase in ASS and no PDL1 expression. These results suggest that increased Bcl-2 expression negates the necessity to increase PDL1 and ASS to prevent cell death from nutritional stress. In contrast, transfection of ASS in A2058, A375, Mel1220 and SkMel2 will only confer resistance to Arg starvation, and does not affect PDL1, Bcl2 expression or other alterations in PI3K/AKT pathway. Furthermore, in samples from patients who failed ADIPEG20 due to increased ASS expression, the primary cultures or re-biopsy tumor also exhibited high levels of PDL1 expression, which most likely will make them susceptible to anti PDL1 treatment. On the other hand, six primary cultures derived from patients who failed BRAF/MEK inhibitor (BMR) also showed low levels of ASS and increase in PDL1 expression (1.5-4 fold increase both in mRNA and proteins level compared to their parental cells). These results also applied to 5 pairs of BMR cell lines (A375/BMR, A2058/BMR, Skmel2/BMR, UACC62/BMR, MelRR/BMR). These cells also are very susceptible to combination of ADIPEG20 and PD-L1 treatment. Overall, our data suggest that combination of Arg deprivation and check point inhibitors is effective in patients whose tumors do not express ASS and as salvage therapy for BRAF/MEK inhibitor resistant patients. Supported by the VA Merit Review Award(1BX003328) Citation Format: Lynn G. Feun, Chunjing Wu, Ying-Ying Li, Min You, Medhi Wangpaichitr, Miguel Suarez, Niramol G. Savaraj. Eradicating melanoma cells using combination of nutritional stress and checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2336.

A prognostic and predictive computational pathology image signature for added benefit of adjuvant chemotherapy in early stage non-small-cell lung cancer.

We developed and validated a prognostic and predictive computational pathology risk score (CoRiS) using H&E stained tissue images from patients with early-stage non-small cell lung cancer (ES-NSCLC). 1330 patients with ES-NSCLC were acquired from 3 independent sources and divided into four cohorts D1-4. D1 comprised 100 surgery treated patients and was used to identify prognostic features via an elastic-net Cox model to predict overall and disease-free survival. CoRiS was constructed using the Cox model coefficients for the top features. The prognostic performance of CoRiS was evaluated on D2 (N=331), D3 (N=657) and D4 (N=242). Patients from D2 and D3 which comprised surgery+chemotherapy were used to validate CoRiS as predictive of added benefit to adjuvant chemotherapy (ACT) by comparing survival between different CoRiS defined risk groups. CoRiS was found to be prognostic on univariable analysis, D2 (hazard ratio (HR)=1.41, adjusted (adj.) P=.01) and D3 (HR=1.35, adj. P < .001). Multivariable analysis showed CoRiS was independently prognostic, D2 (HR=1.41, adj. P < .001) and D3 (HR=1.35, adj. P < .001), after adjusting for clinico-pathologic factors. CoRiS was also able to identify high-risk patients who derived survival benefit from ACT D2 (HR=0.42, adj. P=.006) and D3 (HR=0.46, adj. P=.08). CoRiS is a tissue non-destructive, quantitative and low-cost tool that could potentially help guide management of ES-NSCLC patients. Data collection, anlaysis, and computation resources of the research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers: 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA216579-01A1, R01 CA220581-01A1, 1U01 CA239055-01. National Center for Research Resources under award number 1 C06 RR12463-01. VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.

Abstract 988: Targeting immunological and apoptotic cell death to improve therapeutic efficacy in melanoma

Abstract Apoptotic and immunological cell death are the two major pathways that can lead to demise of cancer cells. Targeting both pathways by combining chemotherapy and checkpoint inhibitors has proven to be more effective in treating lung cancer but not in melanoma, due to the fact that melanoma cells often express high levels of antiapoptotic proteins Bcl-2 ( 60%) which contribute to their resistance to chemotherapy. We have previously shown that melanoma cell lines with high Bcl-2 expression , regardless of their BRAF mutation, do not possess high PD-L1 ( AACR abstract #4747 2019). This is also seen in melanoma tissue obtained from patients. Here, we attempt to explore whether there is any relationship between Bcl-2 and PD-L1 in melanoma cells using knock in and knock out methods. Two melanoma cells derived from patients ( mel1220 which possess high levels of Bcl-2 and Mel-F which possess high levels of PD-L1 ) and their BRAF/MEK counterparts, Mel-1220 BMR and MelF BMR, respectively, were used for the study. Interestingly, cell lines with high Bcl-2 , their BMR counterparts showed no changes in Bcl-2 levels, However, in cell lines with high PD-L1 expression, the levels of PD-L1 is even higher when they become BMR. This could explain why after failure to BRAF/MEK inhibitor , the clinical response to anti PD-1 check point inhibitors varies. Next, we transfected PD-L1 using the SP-GFP-CD274-NU Vector ( purchased from Addgene )into the BcL-2 over expressing cell lines. Three clones were selected. Two clones ( 1220.PD-L1/1 and 1220 PD-L1/3) showed only slight decreased Bcl-2 expression ( less than 1 fold) and in one clone ( 1220.PD-L1/2), there is no effect seen. Furthermore, there is no discernable change in other antiapoptotic proteins ( Bcl-xl, BAX, Mcl-2 survivin, NOXA and PUMA ) by westernblot noted. Similar results were obtained with their BMR counterparts. Total knock down of Bcl-2 using CRISPR knockout ( kit purchased from Origene) results in cell death. In contrast, transfection of Bcl2 into PD-L1 overexpression results in decreased PD-L1 expression by 2-4 fold both by PCR and by westernblot in both clones. however , there is no discernable changes on surface PD-L1 by flow cytometery. Transfection of BCl-2 also does not affect other BCL-2 family proteins. Similar results were obtained with their BMR counterparts. From these data, it appears that the presence of Bcl-2 ( RNA/protein) could affect intrinsic PD-L1 expression, however, the surface PD-L1 which is the key to bind PD-1 did not change. On the other hand, the presence of PD-L1 RNA/protein has no discernable effect on BcL-2 expression. Whether partial knock down BCl-2 or treatment with Bcl-2 inhibitor can lead to increased PD-L1 expression is not known and is under investigation. Overall, it appears that combination of Bcl-2 inhibitor and check point inhibitor may be more effective in melanoma patients with high Bcl-2 expression. (Supported by VA merit review award; 1BX003328) Citation Format: Niramol Savaraj, Min You, Ying-Ying Li, Chunjing Wu, Medhi Wangpaichitr, Saurez Miguel, Alfred Chicco, Macus T. Kuo, Lynn G. Feun. Targeting immunological and apoptotic cell death to improve therapeutic efficacy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 988.

109 Chemogenetic silencing of corticotropin releasing factor neurons in the paraventricular nucleus: the effect on post-stress sleep

Abstract Introduction We have previously shown that pharmacological elevation of corticotropin releasing factor (CRF) signaling in the brain results in exacerbation of sleep disturbances evoked by the exposure of rats to an acute stressor, the dirty cage of a male rat. In the present study we (1) assessed wake-sleep behavior of mice after the exposure to the dirty cage stress paradigm, and (2) examined the effect of chemogenetic silencing of CRF neurons in the hypothalamic paraventricular nucleus (PVN) on sleep occurring following the exposure to this stressor. Methods First, a group of mice (n=12) was implanted with EEG/EMG electrodes. In two weeks, post-surgery, six mice were transferred to dirty cages of male rats and recorded for 24 hours. Control mice were transferred to clean cages. In the second study, a group of CRF-ires-cre mice (n=8) received bilateral injections of AAV-hSyn-DIO-hM4Di-mCherry targeting the PVN. The other group of CRF-ires-cre mice (n=8) was injected AAV-hSyn-DIO-mCherry (control vector). All mice were implanted with EEG/EMG electrodes. Dirty cage experiments were started following a 4-week postsurgical period to allow gene recombination and expression. Mice were subjected to intraperitoneal (IP) administration of clozapine-n-oxide (CNO; 3 mg/kg) at ZT1, placed into dirty cages, and recorded for post-stress sleep. Results: Results In mice expressing hM4Di inhibitory DREADDs (designer receptors activated by designer drugs) versus mice injected with control AAV, IP CNO (3 mg/kg) resulted in a significant decrease of post-stress sleep onset latency, decrease of time spent in wakefulness (first hour, 74±5.3 vs. 89±11.0, second hour, 37.2±10.3% vs. 81.3±9.3%; third hour, 40.1±3.3% vs. 47.1±14.3%; fourth hour, 44.4±6.0 vs. 55.5±9.9), and increase in non-rapid eye movement (NREM) sleep time (26.0±5.4% vs. 11.0±11.1%; 62.8%±9.8 vs. 18.7 ± 9.6%; 59.9±3.2% vs. 52.9±14.5%; 55.6±6.2 vs. 44.5±10.0). The hM4Di expressing mice exhibited longer episodes of NREM sleep, compared to mice injected with control AAV (first hour, 133.3±80.1sec vs. 21±1.7sec; second hour, 43256±83.4sec vs. 73.5±44.1sec; third hour, 459.2±139.8sec vs. 139±80.6sec; fourth hour, 233.1±82.6sec vs. 190±72.3sec). Conclusion Chemogenetic silencing of CRF neurons in the PVN attenuates acute stress-induced sleep disturbance in mice. Support (if any) Supported by Department of Veterans Affairs Merit Review Grant # BX00155605 and SRNSF (Georgia) grant FR-18-12533

007 NLRP3 inflammasomes contribute to dysregulated sleep and electroencephalogram delta power after mild and moderate TBI in mice

Abstract Introduction Most traumatic brain injuries (TBI) are mild to moderate and can cause persistent dysregulated sleep, although the mechanisms are not well understood. Interleukin-1 beta (IL-1β) is a pro-inflammatory molecule that is activated in the cortex after waking activity and pathogenic challenge and alters non-rapid eye movement (NREM) sleep and electroencephalogram (EEG) delta power. Nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasomes sense changes in their local environment to stimulate caspase-1 to activate IL-1β into its mature form. We previously found that NLRP3 inflammasomes are increased in the cortex after acute sleep loss and contribute to increased NREM sleep and EEG delta power after sleep loss and toxin challenge. We aimed to determine if NLRP3 inflammasomes contribute to the persistent dysregulated sleep caused by TBI. Methods Using 2-3-month-old mice lacking NLRP3 and C57BL/6J wild-type control mice, we assessed sleep states and sleep state episode durations and frequencies prior to TBI, and 24 h, 2-weeks, and 2 months after mild or moderate TBI using polysomnography. TBI occurred in the frontal cortex from a controlled cortical impact device. Additional mice received identical treatments serving as a TBI procedural control but received a craniectomy without the TBI. Results Similar sleep findings were observed between the craniectomy control group and baseline measures. However, when compared to baseline values, mice lacking NLRP3 had attenuations in the significant increased amounts of NREM sleep and EEG delta power occurring 24 h after TBI and the significant reductions in NREM sleep and EEG delta power seen 2 months after TBI that were observed in wild-type mice. These effects were similar in moderate and mild TBI groups. Mice lacking NLRP3 were not found to exhibit the fragmented sleep after mild or moderate TBI that was found to persist from 24 h to 2 months post-TBI in the wild-type mice. These effects were evident by significant increased frequencies of waking episodes induced by the TBIs. Conclusion Our findings suggest that NLRP3 inflammasomes contribute to dysregulated sleep occurring acutely or more persistently after TBI. Support (if any) Career Development Award IBX002823 (MZ) and Merit Review Award I01RX001144 (GK) from the United States Department of Veterans Affairs

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

A review for grant application and merit review in the field of synthetic chemistry of NSFC from 2018 to 2020

A review for grant application and merit review in the field of synthetic chemistry of NSFC from 2018 to 2020

Erasing the Vision Splendid? Unpacking the Formative Responses of the Federal Courts to the Fast Track Processing Regime and the ‘Limited Review’ of the Immigration Assessment Authority

The establishment of the Immigration Assessment Authority (‘IAA’) and the Fast Track Processing Regime for certain asylum seekers has posed new and important questions for Australian administrative law, especially in respect of the place, scope and effect of merits review. This article considers the early and formative jurisprudence of the federal courts in relation to ‘Fast Track decisions’ made by the IAA. It concludes that the Fast Track process represents a novel development in Australian public law: a partial review process which is not sufficient to correct the errors of the decision-maker at first instance but which appeared for a time capable of immunising elements of the decision from appeal or direct judicial review. It is, in its intention and current operation, more than a ‘targeted tinkering’ with the mechanics of merits review and of migration law in Australia. It deserves attention as it commences its journey through superior courts and as the regime settles into the Australian administrative law landscape.

Novel mechanism of hereditary pyropoikilocytosis phenotype due to co‐inheritance of β globin and α spectrin mutations

Novel mechanism of hereditary pyropoikilocytosis phenotype due to co‐inheritance of β globin and α spectrin mutations

Integrative characterization of asymptomatic vs. symptomatic patients with moderate-severe primary mitral regurgitation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by NHLBI and Specialized Centers of Clinically Oriented Research grant in cardiac dysfunction, by Department of Veteran Affairs for Merit Review and NIH Grant P01. Background Optimal timing for surgery in primary mitral regurgitation (PMR) is a subject of debate. Purpose Use a combination of imaging, circulating biomarkers and histology to define the transition from asymptomatic (asx) to symptomatic (sx) stage in moderate-severe PMR. Methods 57 controls, 82 sx and 47 asx patients with moderate to severe PMR underwent cardiac MR(CMR), plasma BNP, levels of xanthine oxidase (XO) activity, and circulating markers of collagen (Col) synthesis (propeptide of procollagen type I, PICP) and degradation (Col type I fibers, ICTP). Results A progressive worsening in the severity of adverse LV remodeling was noted based on CMR indices listed in Table 1. The 3D mid-wall LV endocardial curvature to wall thickness was lower in normal and similar in asx and sx patients.Plasma BNP was progressively higher in normal vs. asx vs sx (Figure 1A). The levels of XO activity were higher in sx vs. asx (Figure 1B,1C). Levels of PICP were similar among the three; levels of ICTP were significantly higher in the sx vs the asx (Figure 1D,1E). LV biopsies revealed large areas of patchy replacement fibrosis and areas devoid of interstitial Col (Figure 1F). From the subgroup of 56 patients who underwent CMR 6 months after surgery, 27% had LVEF &amp;lt; 50%. The preoperative LVEF, LVESV, LVESD and LA emptying fraction were predictors of postoperative drop in LVEF. Conclusion Increased COl breakdown coupled with markers of oxidative stress and CMR-based LV remodeling characterize the transition from asx to sx PMR. Longitudinal studies are needed to define cutoff"s for patient selection and optimal timing for MV surgery. CMR indices in normal, asx and sx PMR. Normal (57) Moderate/Severe MR Asymptomatic (56) Pre-Surgery MR Symptomatic (81) P-value Age 48 (34, 55) 54 (46, 62) * 57 (50, 67) * &amp;lt;0.0001 Female/Male 30(53%)/27(47%) 35(63%)/21(38%) 25(31%)/56(69%) LVEF (%) 64 (61, 67) 62 (59, 66) 63 (59, 67) 0.3482 LV EDV (mL/m2) 71 (61, 76) 89 (73, 103) * 100 (83, 123) *# &amp;lt;0.0001 LV ESV (mL/m2) 24 (21, 29) 32 (26, 38) * 36 (28, 47) * &amp;lt;0.0001 LVSV (mL/m2) 43 (37, 50) 54 (43, 66) * 60 (54, 77) *# &amp;lt;0.0001 LVED Mass/Volume 0.7 (0.6, 0.8) 0.6 (0.5, 0.7) * 0.6 (0.6, 0.7) * 0.0012 LVED Mass/Vol x SI 1.29 (1.05, 1.50) 0.97 (0.77, 1.15) * 0.94 (0.77, 1.14) * &amp;lt;0.0001 Regurgitant Volume (mL) ― 38 (26, 54) 57 (38, 83) # 0.001 Regurgitant Fraction (%) ― 39 (28, 50) 46 (36, 56) # 0.042 Table 1 shows the CMR indices of LV remodeling in normal, asymptomatic and symptomatic patients with moderate-severe PMR. p-values *vs. Normal; # vs. Asymptomatic. Kruskal-Wallis test or unpaired t-test Abstract Figure 1.

Grain sprouts as green feed with hydroponic technique: Review of merits and limitations

Grain sprouts as green feed with hydroponic technique: Review of merits and limitations

A Solution to the Hard Problem of Soft Law

Administrative Agencies often rely on guidance documents to carry out their statutory mandate. Over the past few decades, the Food and Drug Administration (FDA) has been criticized for using soft law guidance documents to exercise powers beyond those authorized by Congress. Since attacks on the use of guidance documents persist and agencies need soft law to respond quickly and flexibly to rapid technological growth, it is essential to develop a solution that preserves this crucial regulatory mechanism and prevents its abuse. The most likely alternative to soft law guidance is formal regulation, which must be developed through the notice-and-comment process. The delays introduced by these formal processes, however, leave innovators uncertain about how to comply in the interim, which slows innovation. Alternatively, agencies may turn toward even less formal mechanisms, which are less expensive. However, these informal mechanisms also present problems, namely vagueness, contradictory rulings, and regulatory accumulation. This Note focuses on how courts can curb the abuse of guidance documents and avoid the pitfalls associated with these two alternatives. This Note identifies the ends of FDA regulation, the various mechanisms the FDA uses to achieve these ends, and the Agency’s and regulated entities’ attitudes toward guidance documents. Courts may either treat notice-and-comment rulemaking as necessary to finality and refuse merits review or classify such documents as final and conduct a merits review. This Note endorses the latter solution because it helps courts preserve agency discretion, principally limits discretion, and incentivizes uniformity and predictability. This solution is limited to documents that are practically binding on the agency.

Judicial Review, Merit Review and The 2010 Constitution: Reflections from Court Adjudications

Judicial Review, Merit Review and The 2010 Constitution: Reflections from Court Adjudications