bluuebunny/crossref_metadata_2025 huggingface dataset:
48218 Preclinical modeling of BRAF(V600E)/PTEN-/- melanoma leptomeningeal disease (LMD) to assess intrathecal checkpoint blockade
Authors: Guerrieri Renato A. , Fischer Grant M. , Knighton Barbara G. , Hudgens Courtney W. , Ledesma Debora A. , Davies Michael A. , Ferguson Sherise D.
Published: March 2021

ABSTRACT IMPACT: Melanoma leptomeningeal disease (LMD) is a devastating subtype of central nervous system (CNS) metastatic disease that is associated with limited treatment options and an extremely poor prognosis, thus requiring the development of preclinical models of LMD for therapeutic development. OBJECTIVES/GOALS:

1.

Develop an immunocompetent murine model of melanoma LMD with tumors bearing genetic mutations commonly found in patients, specifically BRAF(V600E)/PTEN-/-

2.

Assess the safety of intrathecal (IT) immunotherapy, specifically anti-PD1 antibody (aPD1)

3.

Evaluate the therapeutic efficacy of IT aPD1 checkpoint blockade in murine melanoma LMD METHODS/STUDY POPULATION: To develop BRAF(V600E)/PTEN-/- LMD models, we acquired BP, D4M, and D4M-UV2 (irradiated) murine melanoma cell lines and luciferase-tagged them. 1.5x10^4 cells were suspended in 10 uL serum-free media and injected into the cisterna magna of female C57BL/6 mice. Brain and spinal cord were harvested for histologic assessment once mice were moribund. To assess safety of IT aPD1, we injected IT control IgG or IT aPD1 (13 ug, 26 ug, 39 ug) and monitored weights or harvested at days 7 or 14 for IHC staining of inflammation markers. To evaluate therapeutic efficacy of IT aPD1, BP cells were directly injected as above. After 3 days, mice underwent imaging to confirm tumor uptake and randomization to receive 13 ug IT control IgG or aPD1 once + 200 ug systemic (Sys) control IgG or aPD1 (days 0, 3, and 5), and then monitored for survival. RESULTS/ANTICIPATED RESULTS: For LMD development, all mice survived cisternal injection of BP, D4M, and D4M-UV2 cells and median survival was 17, 19, and 30 days, respectively. Presence of leptomeningeal deposits was confirmed for all tumor-bearing mice by IHC for MART1. For safety of IT aPD1, all mice survived the procedure and no mice displayed morbidity or >10% weight loss over 14 days of observation. IHC assessment of brain and spinal cord samples from mice treated with 13 ug aPD1 revealed focal ischemia related to injection site and no other signs of neurological damage or inflammation. IT aPD1 treatment of mice with BP leptomeningeal tumors demonstrated no significant survival advantage, although both IT aPD1 +/- Sys aPD1 had mice live up to days 29 and 26, respectively, compared to both IT control IgG +/- Sys aPD1, for which all mice died by day 22. DISCUSSION/SIGNIFICANCE OF FINDINGS: We demonstrate that cisternal injection of murine BRAF(V600E)/PTEN-/- melanoma cell lines yield LMD with reproducible survival and that treatment with IT aPD1 in this model is feasible and safe. Together these findings establish a new model to facilitate the development of more effective immunotherapy strategies for melanoma patients with LMD.
95355 Potential Drug Therapy for Fragile X Tremor/Ataxia Syndrome
Authors: Brown Collis , Hudson Tamaro , Sobrian Sonya K.
Published: March 2021

ABSTRACT IMPACT: The ability to restore mitochondrial health in neurons derived from FXTAS patient-induced pluripotent stem cells by novel natural compounds is critically important to the management of patients experiencing this syndrome and other Fragile X associated disorders. OBJECTIVES/GOALS: The goal of this research is to assess the biological potency of MAM, NADA and MAM analogues’ neuroprotective capacity with respect to mitochondrial damage, and antioxidant properties that can restore mitochondrial health in patients with FXTAS. METHODS/STUDY POPULATION: To establish mitochondrial dysfunction, normal human cell lines and human induced pluripotent cells will be exposed to multiple concentrations of glucose/ glucose oxidase (GluOx) at several time points to induce varying intensities of oxidative stress. The degrees of oxidative stress will be measured by apoptosis and mitochondrial reactive oxygen species (ROS) production. N-arachidonoyldopamine (NADA), macamides (MAM) and its analogue compounds, effective against oxidative damage in mitochondria, will be used to rescue glucose oxidase induced oxidative damage in both cell lines. To test the ability of these drugs to restore mitochondrial health, cell viability and cellular superoxide production will be assessed by propidium iodide and the MitoSox fluorescence assay, respectively. RESULTS/ANTICIPATED RESULTS: We anticipate that GluOx at varying concentrations and time points will proportionally increase levels of apoptosis and mitochondrial ROS, reflective of mitochondrial damage, with the most severe dysfunction occurring at the maximum dose of 40µM and the longest duration of 72-hr exposure. Moreover, administration of NADA, MAM, and MAM analogues at seven concentrations, ranging from 10-8 to 10-5 M in half-log increments, will successfully treat the oxidative defects induced in the cell lines by decreasing apoptosis, and superoxide production, and increasing cell viability. DISCUSSION/SIGNIFICANCE OF FINDINGS: This research allows for the development of an in vitro neuronal model of FXTAS, lends flexibility to testing therapeutics, and expands the discovery of mitochondrial biomedical markers for the syndrome. Data generated should inform mechanistic studies of the relationship between mitochondrial damage and FXTAS-induce neurodegeneration.
28201 A cross-sectional study of dietary patterns and nutrient intakes in the oldest old
Authors: Flores Ashley C. , Liu Yi-Hsuan , Gao Xiang , Wood G. Craig , Irving Brian A. , Still Christopher D. , Jensen Gordon L. , Mitchell Diane C.
Published: March 2021

ABSTRACT IMPACT: Understanding dietary patterns and nutrient intakes of the aging population may help address concerns and dietary guidelines regarding their nutritional needs. OBJECTIVES/GOALS: The objective of this study is to test the hypothesis that a healthy dietary pattern in the oldest old (aged 80 years and older) is related to greater compliance with dietary recommendations and better nutrient intake profiles. METHODS/STUDY POPULATION: We conducted a cross-sectional study of 122 participants aged 82 to 97 years old from the Geisinger Rural Aging Study (GRAS) cohort in rural Pennsylvania (n = 56 men and 66 women). The main outcome measures of the investigation were the daily nutrient intakes and food group intakes evaluated from the average of three 24-hour dietary recalls. The dietary patterns were determined by cluster analysis from 28 food groups. Diet quality and adherence to the Dietary Guidelines for Americans was assessed by the Healthy Eating Index (HEI)-2015 and the Dietary Screening Tool (DST). Recommended intakes were determined by the Recommended Dietary Allowances (RDAs) or Adequate Intakes (AIs). RESULTS/ANTICIPATED RESULTS: Less than 50% of participants met the dietary recommended intakes for vitamins D, E, K, B6, dietary fiber, zinc, potassium, and calcium. The more-nutrient-dense cluster was characterized by higher intakes of fruits and vegetables. The less-nutrient-dense cluster was characterized by higher intakes of foods including desserts and sweets. After adjusting for age, sex, and energy intake, participants in the more-nutrient-dense dietary pattern had a higher intake of vitamins A, D, K, C, fiber, and potassium (p < 0.05 for all). After adjusting for age and sex, participants in the more-nutrient-dense pattern had better diet quality assessed by the (HEI)-2015 (p < 0.001) and DST (p = 0.006). DISCUSSION/SIGNIFICANCE OF FINDINGS: Among the oldest old, many participants were found to have nutrient intakes lower than the recommended levels for fundamental nutrients suggesting that dietary guidance in addition to a dietary pattern more aligned with dietary guidelines may be beneficial for supporting healthy aging.
20680 Characterization of Clinical and Immunological Laboratory Features in Multiple Sclerosis Patients with COVID-19
Authors: Ali Ahya S , Mao-Draayer Yang
Published: March 2021

ABSTRACT IMPACT: Better understanding of the factors impacting disease severity and immunological response of MS patients on disease modifying therapy will enable better recommendations for vaccination options and risk mitigation strategies OBJECTIVES/GOALS: The Coronavirus Disease 2019 (COVID-19) and global health crisis has raised health concerns for patients with multiple sclerosis (MS). We aim to study the clinical characteristics, immunological laboratory data, and immunoglobulin response in patients with MS and COVID-19, to identify factors impacting disease severity and immune response. METHODS/STUDY POPULATION: Database search was done using DataDirect to search for MS patients who had tested positive for COVID-19 at the University of Michigan hospital. Patients with a positive nasopharyngeal swab polymerase chain reaction (PCR) for COVID-19 between March 1 and September 2020 were included. The primary outcome was the immunological laboratory data and immunoglobulin levels and the secondary outcome was their disease severity. We collected demographics, neurological history, MS treatment, Expanded Disability Scale Score (EDSS), comorbidities, and COVID-19 characteristics. A 7-point ordinal scale previously used to assess disease severity was used. Univariate and multivariate analyses will be performed to assess relationships between the collected variables. RESULTS/ANTICIPATED RESULTS: A total of 17 patients, mean age 53 (SD 11.6) years, mean disease duration, 6.2(SD 4.1) years were analyzed. 41% of patients had relapsing remitting multiple sclerosis, 17% had primary progressive MS. (88%) patients were on Disease Modifying Therapy (DMT) at the time of COVID-19 diagnosis. 2 patients died from COVID-19 complications. There was a higher proportion of patients with higher disease severity receiving Ocrelizumab. Only one patient showed positive IgG to SARS-CoV-2 after the resolution of infection. CBC with differential was obtained and a longitudinal follow-up of labs will be done. Regression analysis will be done to check the association between the use of DMT, immunological response, and COVID disease severity in them. The impact of COVID-19 on MS relapse, EDSS, and MRI activities will also be studied. DISCUSSION/SIGNIFICANCE OF FINDINGS: Recommendations to continue current DMT have been made, however, the immune response has not been correlated with the individual’s risk profile. Certain therapies may interfere with mounting a protective immune response of COVID-19 and this knowledge is crucial when advising patients regarding the choice of vaccine and risk mitigation strategies.
Methylation multiplicity and its clinical values in cancer
Authors: Dai Xiaofeng , Ren Tiejun , Zhang Yuxin , Nan Nan
Published: March 2021

Methylation at DNA, RNA and protein levels plays critical roles in many cellular processes and is associated with diverse differentiation events, physiological activities and human diseases. To aid in the diagnostic and therapeutic design for cancer treatment utilising methylation, this review provides a boutique yet comprehensive overview on methylation at different levels including the mechanisms, cross-talking and clinical implications with a particular focus on cancers. We conclude that DNA methylation is the sole type of methylation that has been largely translated into clinics and used for, mostly, early diagnosis. Translating the onco-therapeutic and prognostic values of RNA and protein methylations into clinical use deserves intensive efforts. Simultaneous examination of methylations at multiple levels or together with other forms of molecular markers represents an interesting research direction with profound clinical translational potential.
Thermal capillary wave growth and surface roughening of nanoscale liquid films
Authors: Zhang Y. , Sprittles J.E. , Lockerby D.A.
Published: March 2021

The well-known thermal capillary wave theory, which describes the capillary spectrum of the free surface of a liquid film, does not reveal the transient dynamics of surface waves, e.g. the process through which a smooth surface becomes rough. Here, a Langevin model is proposed that can capture this dynamics, goes beyond the long-wave paradigm which can be inaccurate at the nanoscale, and is validated using molecular dynamics simulations for nanoscale films on both planar and cylindrical substrates. We show that a scaling relation exists for surface roughening of a planar film and the scaling exponents belong to a specific universality class. The capillary spectra of planar films are found to advance towards a static spectrum, with the roughness of the surface

$W$

increasing as a power law of time

$W\sim t^{1/8}$

before saturation. However, the spectra of an annular film (with outer radius

$h_0$

) are unbounded for dimensionless wavenumber

$qh_0<1$

due to the Rayleigh–Plateau instability.
Generalist versus specialist CEO and R&D commitment: evidence from an emerging market
Authors: Agnihotri Arpita , Bhattacharya Saurabh
Published: March 2021

Leveraging the human capital specificity and the Chief Executive Officer (CEO)–top management team (TMT) interface literature, this study explores the impact of generalistversusspecialist CEOs on R&D commitments by Indian firms under the boundary conditions of TMTs' functional and educational diversity. Based on a sample of 253 firms over a period of 6 years, in contrast to previous studies, our findings suggest that specialist CEOs are more likely to invest in R&D than generalist CEOs; however, when supported by functionally and educationally diverse TMT, the R&D commitment of generalist CEOs increases as well.
‘A transverse scar on the neck’ – psychosomatic approach in the differential diagnosis and surgical treatment of hyperthyroidism in post-war Finland
Authors: Hyrkäs Eve-Riina
Published: March 2021

In the Finnish medical discussion during the middle decades of the twentieth century, the challenging differential diagnostics between hyperthyroidism and various neuroses was perceived to yield a risk of unnecessary surgical interventions of psychiatric patients. In 1963, the Finnish surgeon Erkki Saarenmaa claimed that ‘the most significant mark of a neurotic was a transverse scar on the neck’, a result of an unnecessary thyroid surgery. The utterance was connected to the complex nature of thyroid diseases, which seemed to be to ‘a great extent psychosomatic’. Setting forth from this statement, the article aims to decipher the connection between hyperthyroidism, unnecessary surgical treatment and the psychosomatic approach in Finnish medicine. Utilising a wide variety of published medical research and discussion in specialist journals, the article examines the theoretical debate around troublesome diagnostics of functional complaints. It focuses on the introduction of new medical ideas, namely the concepts of ‘psychosomatics’ and ‘stress’. In the process, the article aims to unveil a definition of psychosomatic illness that places it on a continuum between psychological and somatic illness. That psychosomatic approach creates a space with interpretative potential can be applied to the historiography of psychosomatic phenomena more generally. Further inquiry into the intersections of surgery and psychosomatics would enrich both historiographies. It is also argued that the historical study of psychosomatic syndromes may become skewed, if the term ‘psychosomatic’ is from the outset taken to signify something that is all in the mind.
Large-Scale Ideal Point Estimation
Authors: Peress Michael
Published: March 2021

Recent advances in the study of voting behavior and the study of legislatures have relied on ideal point estimation for measuring the preferences of political actors, and increasingly, these applications have involved very large data matrices. This has proved challenging for the widely available approaches. Limitations of existing methods include excessive computation time and excessive memory requirements on large datasets, the inability to efficiently deal with sparse data matrices, inefficient computation of standard errors, and ineffective methods for generating starting values. I develop an approach for estimating multidimensional ideal points in large-scale applications, which overcomes these limitations. I demonstrate my approach by applying it to a number of challenging problems. The methods I develop are implemented in an r package (ipe).
THE NORMS OF ALGORITHMIC CREDIT SCORING
Authors: Aggarwal Nikita
Published: March 2021

This article examines the growth of algorithmic credit scoring and its implications for the regulation of consumer credit markets in the UK. It constructs a frame of analysis for the regulation of algorithmic credit scoring, bound by the core norms underpinning UK consumer credit and data protection regulation: allocative efficiency, distributional fairness and consumer privacy (as autonomy). Examining the normative trade-offs that arise within this frame, the article argues that existing data protection and consumer credit frameworks do not achieve an appropriate normative balance in the regulation of algorithmic credit scoring. In particular, the growing reliance on consumers’ personal data by lenders due to algorithmic credit scoring, coupled with the ineffectiveness of existing data protection remedies has created a data protection gap in consumer credit markets that presents a significant threat to consumer privacy and autonomy. The article makes recommendations for filling this gap through institutional and substantive regulatory reforms.
EXPLAINING ASSIGNMENTS OF ARBITRATION AGREEMENTS
Authors: Liew Ying Khai
Published: March 2021

The case law and literature to date have struggled to locate the rationale for the assignability of arbitration agreements. While different justifications have been proffered, each of them rests on questionable premises. This has given rise to a host of uncertainties over the rules which apply in practice. This paper proposes that a satisfactory rationale can be found in the “acceptance principle”. This principle indicates, first, that arbitration agreements which are not actual burdens can be assigned, and second, that the assignability of arbitration agreements is grounded in the assignee's acceptance in the form of non-disclaimer of the assignment. Bringing the acceptance principle to the fore not only provides a theoretically sound justification for the assignability of arbitration agreements; it also suggests how the practical uncertainties in this area of law can be resolved satisfactorily.
Pregnancy during the pandemic: the impact of COVID-19-related stress on risk for prenatal depression
Authors: King Lucy S. , Feddoes Daisy E. , Kirshenbaum Jaclyn S. , Humphreys Kathryn L. , Gotlib Ian H.
Published: March 2021

Background

Pregnant women may be especially susceptible to negative events (i.e. adversity) related to the coronavirus disease 2019 (COVID-19) pandemic and negative affective responses to these events (i.e. stress). We examined the latent structure of stress and adversity related to the COVID-19 pandemic among pregnant women, potential antecedents of COVID-19-related stress and adversity in this population, and associations with prenatal depressive symptoms.

Method

We surveyed 725 pregnant women residing in the San Francisco Bay Area in March−May 2020, 343 of whom provided addresses that were geocoded and matched by census tract to measures of community-level risk. We compared their self-reported depressive symptoms to women matched on demographic factors and history of mental health difficulties who were pregnant prior to the pandemic.

Results

Women who were pregnant during the pandemic were nearly twice as likely to have possible depression than were matched women who were pregnant prior to the pandemic. Individual- and community-level factors tied to socioeconomic inequality were associated with latent factors of COVID-19-related stress and adversity. Beyond objective adversity, subjective stress responses were strongly associated with depressive symptoms during the pandemic.

Conclusions

Highlighting the role of subjective responses in vulnerability to prenatal depression and factors that influence susceptibility to COVID-19-related stress, these findings inform the allocation of resources to support recovery from this pandemic and future disease outbreaks. In addition to policies that mitigate disruptions to the environment due to the pandemic, treatments that focus on cognitions about the self and the environment may help to alleviate depressive symptoms in pregnant women.
One norm to rule them all? Corpus-derived norms in learner corpus research and foreign language teaching
Authors: Gilquin Gaëtanelle
Published: March 2021

This paper considers the issue of the norm in the context of learner corpus research and its implications for foreign language teaching. It seeks to answer three main questions: Does learner corpus research require a native norm? What corpus-derived norms are available and how do we choose? What do we do with these norms in the classroom? The first two questions are more research-oriented, reviewing the types of reference corpora that can be used in the analysis of learner corpora, whereas the third one looks into the pedagogical use of corpus-derived norms. It is shown that, while studies in learner corpus research can dispense with a native norm, they usually rely on one, and that a wide range of native and non-native norms are available, from which choosing the most appropriate one(s) is of crucial importance. This large repertoire of corpus-derived norms is then reconsidered in view of the reality of the foreign language classroom.
Stereo visual odometry with velocity constraint for ground vehicle applications
Authors: Liu Fei , Balazadegan Sarvrood Yashar , Liu Yue , Gao Yang
Published: March 2021

This paper proposes a novel method of error mitigation for stereo visual odometry (VO) applied in land vehicles. A non-holonomic constraint (NHC), which imposes physical constraint to the rightward velocity of a land vehicle, is implemented as an observation in an extended Kalman filter (EKF) to reduce the drift of stereo VO. The EKF state vector includes position errors in an Earth-centred, Earth-fixed (ECEF) frame, velocity errors in the camera frame, angular rate errors and attitude errors. All the related equations are described and presented in detail. In this approach, no additional sensors are used but NHC, namely velocity constraint in the right direction , is applied as an external measurement to improve the accuracy. Tests are conducted with the Karlsruhe Institute of Technology and Toyota Technological Institute (KITTI) datasets. Results show that the relative horizontal positioning error improved from 0⋅63% to 0⋅22% on average with the application of the velocity constraints. The maximum and root mean square of the horizontal error with velocity constraints are both reduced to less than half of the error with stand-alone stereo VO.
Linear capabilities for fully abstract compilation of separation-logic-verified code
Authors: VAN STRYDONCK THOMAS , PIESSENS FRANK , DEVRIESE DOMINIQUE
Published: March 2021

Separation logic is a powerful program logic for the static modular verification of imperative programs. However,dynamicchecking of separation logic contracts on the boundaries between verified and untrusted modules is hard because it requires one to enforce (among other things) that outcalls from a verified to an untrusted module do not access memory resources currently owned by the verified module. This paper proposes an approach to dynamic contract checking by relying on support for capabilities, a well-studied form of unforgeable memory pointers that enables fine-grained, efficient memory access control. More specifically, we rely on a form of capabilities calledlinearcapabilities for which the hardware enforces that they cannot be copied. We formalize our approach as a fully abstract compiler from a statically verified source language to an unverified target language with support for linear capabilities. The key insight behind our compiler is that memory resources described by spatial separation logic predicates can be represented at run time by linear capabilities. The compiler isseparation-logic-proof-directed: it uses the separation logic proof of the source program to determine how memory accesses in the source program should be compiled to linear capability accesses in the target program. The full abstraction property of the compiler essentially guarantees that compiled verified modules can interact with untrusted target language modules as if they were compiled from verified code as well. This article is an extended version of one that was presented at ICFP 2019 (Van Strydonck et al., 2019).
Selecting and Implementing Knowledge Management Technology in Law Firms
Authors: Tomlinson Richard
Published: March 2021

In recent years there has been an explosion of new ‘legal tech’ solutions on the market claiming to solve almost every problem or improve the efficiency of almost any process in a law firm. Alongside these new legal tech vendors are the traditional legal vendors offering enterprise solutions, and it can be challenging to identify, select and implement the right mix of solutions to solve your law firm's knowledge management (KM) needs. If you are thinking about or have been asked to introduce a new KM solution, it can be difficult to know where to get started, especially if you are in this position for the first time. This article, by Richard Tomlinson, explores some techniques and methodologies picked up over several years working in legal technology in big-law, to help you select and implement the best technology solutions for your firm.
Evaluation of care burden and preparedness of caregivers who provide care to palliative care patients
Authors: Karabulutlu Elanur Yılmaz , Turan Gülcan Bahçecioğlu , Yanmış Safiye
Published: March 2021

Objective

Caregivers have a great role in palliative care. Considering the difficult process of palliative care, the caregiver undertakes an extra burden with the responsibility of the patient. This study was carried out to evaluate the care burden and preparedness of caregivers who provide care for palliative care patients.

Method

This study was conducted in the palliative care unit of a state hospital in Turkey between January and May 2019. No sample was selected in the study, and the study was carried out with individuals who were hospitalized in the palliative care unit and who volunteered to participate in the study between the specified dates. The data were collected with Patient Relative Questionnaire Form, Burden Interview, and Preparedness for Caregiving Scale.

Results

The average Burden Interview score was found as 33.6, SD 13.03 in the study. Patient relatives perceived the patients they cared for as a burden at moderate levels. The Preparedness for Caregiving score average was found as 18.55, SD 6.83. It was found that patient relatives were moderately prepared to undertake the role of caregiver. It was found that care burden decreased as preparedness for caregiving increased and burden increased as preparedness for caregiving decreased (p = 0.001).

Significance of results

As a result of the study, it was found that caregivers of palliative patients had the moderate levels of care burden and preparedness for caregiving. It was found that as the preparedness levels of caregivers increased, their burdens decreased. Accordingly, it is important that nurses will plan nursing interventions by considering the factors that affect the care burden and preparedness of caregivers.
Rusty guns and buttery soldiers: unemployment and the domestic origins of defense spending
Authors: Becker Jordan
Published: March 2021

Scholars and practitioners continue to debate transatlantic burden sharing, which has implications for broader questions of collective action and international organizations. Little research, however, has analyzed domestic and institutional drivers of burden-sharing behavior; even less has disaggregated defense spending to measure burden sharing more precisely. This paper enhances understanding of the relationship between national political economies and burden shifting, operationalizing burden shifting as the extent to which a country limits or decreases defense expenditures, while at the same time favoring personnel over equipment modernization and readiness in the composition of defense budgets. Why do countries choose to allocate defense resources to personnel, rather than equipment modernization? I find that governments slightly decrease top-line defense spending in response to unemployment while shifting much more substantial amounts within defense budgets from equipment expenditures into personnel. This research highlights the intimate connection between Europe’s economic fortunes, transatlantic security, and burden sharing in North Atlantic Treaty Organization and the European Union – of particular interest as a pandemic buffets the transatlantic economy. It also points policy analysts toward factors more amenable to political decisions than the structural variables generally associated with burden sharing, bridging significant gaps between defense economics, security studies, and comparative political economy.
Association of chemerin gene promoter methylation in maternal blood and breast milk during gestational diabetes
Authors: Fatima Syeda Sadia , Rehman Rehana , Muhammad Jibran Sualeh , Martins Russell , Mohammed Nuruddin , Khan Unab
Published: March 2021

The intrauterine environment and early-life nutrition are regulated by maternal biomarkers in the blood and breast milk. We aimed to explore epigenetic modifications that may contribute to differential chemerin expression in maternal plasma, colostrum, and breast milk and find its association with fetal cord blood and infant weight at 6 weeks postpartum. Thirty-three gestational diabetes mellitus (GDM) mothers and 33 normoglycemic mothers (NGT) were recruited. Two maternal blood samples (28th week of gestation and 6 weeks postpartum), cord blood, colostrum, and mature milk were collected. Methylation-specific polymerase chain reaction and enzyme-linked immunosorbent assay were conducted. The weight of the babies was measured at birth and 6 weeks postpartum. Serum chemerin levels at the 28th gestational week and 6 weeks postpartum were significantly lower for the NGT group as compared to the GDM group; (P < 0.05). Higher colostrum chemerin concentrations were observed in the GDM group and remained elevated in mature milk as compared to NGT (P < 0.05). Colostrum and breast milk chemerin levels showed an independent association with infant weight at 6 weeks postpartum (r = 0.270; P = 0.034) (r = 0.464; P < 0.001). Forty percent GDM mothers expressed unmethylated chemerin reflecting increased chemerin concentration in the maternal blood. This pattern was also observed in newborn cord blood where 52% of samples showed unmethylated chemerin in contrast to none in babies born to normoglycemic mothers. The results of this study highlight the critical importance of altered chemerin regulation in gestational diabetic mothers and its effect during early life period and suggest a possible role in contributing to childhood obesity.
Slowly Sinking Particles Underlie Dissolved Iron Transport Across the Pacific Ocean
Authors: Misumi K. , Nishioka J. , Obata H. , Tsumune D. , Tsubono T. , Long M. C. , Lindsay K. , Moore J. K.
Published: March 2021

Continental shelf sediments are an important source of iron (Fe) in the oceans. Observational data suggest that basin‐scale transport of sedimentary sourced Fe accompanies the ventilation of the intermediate layer in the North Pacific. Here we use a marine biogeochemical model to explore the Fe transport mechanism with a focus on the role of sinking particles. The lateral penetration of sedimentary sourced Fe was best simulated when we assumed a short desorption and disaggregation length scale of Fe from sinking particles. The simulation results indicated that Fe is laterally transported mainly through interactions with particles with sinking velocities of 180–460 m yr−1; these velocities are two orders of magnitude slower than typical sinking rates of marine aggregates determined from mass flux measurements. Slowly sinking particles drive the basin‐scale transport of Fe by prolonging its residence time and by injecting sedimentary sourced Fe supplied originally to less dense waters into the intermediate layer water across isopycnal surfaces. A large amount of Fe from shelf sediments of the Okhotsk and Bering Seas is exported to the North Pacific through this particle interaction. These results highlight a biogeochemical linkage between the marginal seas and ocean basins that has been overlooked in global ocean models.
Global Temperature Responses to Large Tropical Volcanic Eruptions in Paleo Data Assimilation Products and Climate Model Simulations Over the Last Millennium
Authors: Tejedor E. , Steiger N. , Smerdon J. E. , Serrano‐Notivoli R. , Vuille M.
Published: March 2021

Large volcanic eruptions are one of the dominant perturbations to global and regional atmospheric temperatures on timescales of years to decades. Discrepancies remain, however, in the estimated magnitude and persistence of the surface temperature cooling caused by volcanic eruptions, as characterized by paleoclimatic proxies and climate models. We investigate these discrepancies in the context of large tropical eruptions over the Last Millennium using two state‐of‐the‐art data assimilation products, the Paleo Hydrodynamics Data Assimilation product (PHYDA) and the Last Millennium Reanalysis (LMR), and simulations from the National Center for Atmospheric Research Community Earth System Model‐Last Millennium Ensemble (NCAR CESM‐LME). We find that PHYDA and LMR estimate mean global and hemispheric cooling that is similar in magnitude and persistence once effects from eruptions occurring in short succession are removed. The estimates also compare well to Northern‐Hemisphere reconstructions based solely or partially on tree‐ring density, which have been proposed as the most accurate proxy estimates of surface cooling due to volcanism. All proxy‐based estimates also agree well with the magnitude of the mean cooling simulated by the CESM‐LME. Differences remain, however, in the spatial patterns of the temperature responses in the PHYDA, LMR, and the CESM‐LME. The duration of cooling anomalies also persists for several years longer in the PHYDA and LMR relative to the CESM‐LME. Our results demonstrate progress in resolving discrepancies between proxy‐ and model‐based estimates of temperature responses to volcanism, but also indicate these estimates must be further reconciled to better characterize the risks of future volcanic eruptions.
Climate‐Modulated Nutrient Conditions Along the Labrador Shelf: Evidence From Nitrogen Isotopes in a Six‐Hundred‐Year‐Old Crustose Coralline Alga
Authors: Doherty John M. , Williams Branwen , Kline Esme , Adey Walter , Thibodeau Benoit
Published: March 2021

The impacts of climate change on north Atlantic nutrient chemistry remain poorly understood, as there exist a multitude of rapidly changing biological and physical drivers of nutrient conditions throughout the region. Here, we present nitrogen isotope measurements derived from a six‐hundred‐year‐old crustose coralline alga (δ15Nalgal) to elucidate historical and contemporary trends in nitrate utilization and circulation patterns along the Labrador Shelf. Prior to the early 1900s, we argue that intervals during which utilization approached completion were controlled by reduced nitrate advection linked to an increased proportion of nitrate‐poor polar waters and subdued Atlantic influence, as expected from concurrent negative modes of the Atlantic multidecadal oscillation. While nitrate conditions should have recovered in recent years, our record suggests that high utilization persisted since ∼1870, which we also attribute to reduced Atlantic advection, likely associated with the twentieth‐century anthropogenic weakening of the Atlantic meridional overturning circulation. These results highlight the role of ongoing climate‐induced circulation changes in modulating nutrient distributions throughout the subpolar north Atlantic, which may have implications for other environmental phenomena such as fisheries and oceanic carbon storage.
Ahnak deficiency attenuates high-fat diet-induced fatty liver in mice through FGF21 induction
Authors: Kim Yo Na , Shin Jae Hoon , Kyeong Dong Soo , Cho Soo Young , Kim Mi-Young , Lim Hee Jung , Jimenez Maria Raquel Rojas , Kim Il Yong , Lee Mi-Ock , Bae Yun Soo , Seong Je Kyung
Published: March 2021

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis.
Hippocampal regenerative medicine: neurogenic implications for addiction and mental disorders
Authors: Peyton Lee , Oliveros Alfredo , Choi Doo-Sup , Jang Mi-Hyeon
Published: March 2021

Psychiatric illness is a prevalent and highly debilitating disorder, and more than 50% of the general population in both middle- and high-income countries experience at least one psychiatric disorder at some point in their lives. As we continue to learn how pervasive psychiatric episodes are in society, we must acknowledge that psychiatric disorders are not solely relegated to a small group of predisposed individuals but rather occur in significant portions of all societal groups. Several distinct brain regions have been implicated in neuropsychiatric disease. These brain regions include corticolimbic structures, which regulate executive function and decision making (e.g., the prefrontal cortex), as well as striatal subregions known to control motivated behavior under normal and stressful conditions. Importantly, the corticolimbic neural circuitry includes the hippocampus, a critical brain structure that sends projections to both the cortex and striatum to coordinate learning, memory, and mood. In this review, we will discuss past and recent discoveries of how neurobiological processes in the hippocampus and corticolimbic structures work in concert to control executive function, memory, and mood in the context of mental disorders.
Efficient generation of complex vectorial optical fields with metasurfaces
Authors: Wang Dongyi , Liu Feifei , Liu Tong , Sun Shulin , He Qiong , Zhou Lei
Published: March 2021

Vectorial optical fields (VOFs) exhibiting arbitrarily designed wavefronts and polarization distributions are highly desired in photonics. However, current methods to generate them either require complicated setups or exhibit limited functionalities, which is unfavorable for integration-optics applications. Here, we propose a generic approach to efficiently generate arbitrary VOFs based on metasurfaces exhibiting full-matrix yet inhomogeneous Jones-matrix distributions. We illustrate our strategy with analytical calculations on a model system and an experimental demonstration of a meta-device that can simultaneously deflect light and manipulate its polarization. Based on these benchmark results, we next experimentally demonstrate the generation of a far-field VOF exhibiting both a vortex wavefront and an inhomogeneous polarization distribution. Finally, we design/fabricate a meta-device and experimentally demonstrate that it can generate a complex near-field VOF—a cylindrically polarized surface plasmon wave possessing orbital angular momentum—with an efficiency of ~34%. Our results establish an efficient and ultracompact platform for generating arbitrary predesigned VOFs in both the near- and far-fields, which may find many applications in optical manipulation and communications.
Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function
Authors: Campbell Kirsteen J. , Mason Susan M. , Winder Matthew L. , Willemsen Rosalie B. E. , Cloix Catherine , Lawson Hannah , Rooney Nicholas , Dhayade Sandeep , Sims Andrew H. , Blyth Karen , Tait Stephen W. G.
Published: March 2021

High levels of the anti-apoptotic BCL-2 family member MCL-1 are frequently found in breast cancer and, appropriately, BH3-mimetic drugs that specifically target MCL-1’s function in apoptosis are in development as anti-cancer therapy. MCL-1 also has reported non-canonical roles that may be relevant in its tumour-promoting effect. Here we investigate the role of MCL-1 in clinically relevant breast cancer models and address whether the canonical role of MCL-1 in apoptosis, which can be targeted using BH3-mimetic drugs, is the major function for MCL-1 in breast cancer. We show that MCL-1 is essential in established tumours with genetic deletion inducing tumour regression and inhibition with the MCL-1-specific BH3-mimetic drug S63845 significantly impeding tumour growth. Importantly, we found that the anti-tumour functions achieved by MCL-1 deletion or inhibition were completely dependent on pro-apoptotic BAX/BAK. Interestingly, we find that MCL-1 is also critical for stem cell activity in human breast cancer cells and highMCL1expression correlates with stemness markers in tumours. This strongly supports the idea that the key function of MCL-1 in breast cancer is through its anti-apoptotic function. This has important implications for the future use of MCL-1-specific BH3-mimetic drugs in breast cancer treatment.
StRAP2.3, an ERF‐VII transcription factor, directly activates StInvInh2 to enhance cold-induced sweetening resistance in potato
Authors: Shi Weiling , Song Yuhao , Liu Tiantian , Ma Qiuqin , Yin Wang , Shen Yuchen , Liu Tengfei , Jiang Chunyan , Zhang Kai , Lv Dianqiu , Song Botao , Wang Jichun , Liu Xun
Published: March 2021

Potato invertase inhibitor (StInvInh2) positively regulates cold-induced sweetening (CIS) resistance by inhibiting the activity of vacuolar invertase. The distinct expression patterns ofStInvInh2have been thoroughly characterized in different potato genotypes, but the related CIS ability has not been characterized. The understanding of the regulatory mechanisms that controlStInvInh2transcription is unclear. In this study, we identified an ERF‐VII transcription factor,StRAP2.3, that directly regulatesStInvInh2to positively modulate CIS resistance. Acting as a nuclear-localized transcriptional activator, StRAP2.3 directly binds the ACCGAC cis-element in the promoter region ofStInvInh2, enabling promoter activity. Overexpression ofStRAP2.3in CIS-sensitive potato tubers inducedStInvInh2mRNA abundance and increased CIS resistance. In contrast, silencingStRAP2.3in CIS-resistant potato tubers repressed the expression ofStInvInh2and decreased CIS resistance. We conclude that cold-responsiveStInvInh2is due to the binding of StRAP2.3 to the ACCGAC cis-element in the promoter region ofStInvInh2. Overall, these findings indicate that StRAP2.3 directly regulatesStInvInh2to positively modulate CIS resistance, which may provide a strategy to improve the processing quality of potatoes.
Macrophages in microgravity: the impact of space on immune cells
Authors: Ludtka Christopher , Silberman Justin , Moore Erika , Allen Josephine B.
Published: March 2021

The effects of a microgravity environment on the myriad types of immune cells present within the human body have been assessed both by bench-scale simulation and suborbital methods, as well as in true spaceflight. Macrophages have garnered increased research interest in this context in recent years. Their functionality in both immune response and tissue remodeling makes them a unique cell to investigate in regards to gravisensitive effects as well as parameters of interest that could impact astronaut health. Here, we review and summarize the literature investigating the effects of microgravity on macrophages and monocytes regarding the microgravity environment simulation/generation methods, cell sources, experiment durations, and parameters of interest utilized within the field. We discuss reported findings on the impacts of microgravity on macrophage/monocyte structure, adhesion and migration, proliferation, genetic expression, cytokine secretion, and reactive oxygen species production, as well as polarization. Based on this body of data, we make recommendations to the field for careful consideration of experimental design to complement existing reports, as the multitude of disparate study methods previously published can make drawing direct comparisons difficult. However, the breadth of different testing methodologies can also lend itself to attempting to identify the most robust and consistent responses to microgravity across various testing conditions.