bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic drug-metabolizing enzymes and drug transporters in Wilson’s disease patients with liver failure
Authors: Szeląg-Pieniek Sylwia , Oswald Stefan , Post Mariola , Łapczuk-Romańska Joanna , Droździk Marek , Kurzawski Mateusz
Published: June 2021

Background

Wilson’s disease is a genetic disorder inherited in a recessive manner, caused by mutations in the copper-transporter ATP7B. Although it is a well-known disease, currently available treatments are far from satisfactory and their efficacy varies in individual patients. Due to the lack of information about drug-metabolizing enzymes and drug transporters profile in Wilson’s disease livers, we aimed to evaluate the mRNA expression and protein abundance of selected enzymes and drug transporters in this liver disorder.

Methods

We analyzed gene expression (qPCR) and protein abundance (LC–MS/MS) of 14 drug-metabolizing enzymes and 16 drug transporters in hepatic tissue from Wilson’s disease patients with liver failure (n = 7, Child–Pugh class B and C) and metastatic control livers (n = 20).

Results

In presented work, we demonstrated a downregulation of majority of CYP450 and UGT enzymes. Gene expression of analyzed enzymes ranged between 18 and 65% compared to control group and significantly lower protein content of CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 enzymes was observed in Wilson’s disease. Moreover, a general decrease in hepatocellular uptake carriers from SLC superfamily (significant at protein level for NTCP and OATP2B1) was observed. As for ABC transporters, the protein abundance of BSEP and MRP2 was significantly lower, while levels of P-gp and MRP4 transporters were significantly higher in Wilson’s disease.

Conclusions

Altered hepatic expression of drug‐metabolizing enzymes and drug transporters in Wilson’s disease patients with liver failure may result in changes of drug pharmacokinetics in that group of patients.
The non-political classroom: The (dis)missed opportunities of an Israeli multicultural-bilingual high school civics course
Authors: Cohen Aviv , Bekerman Zvi
Published: June 2021

The body of research on civic education points to the importance of teachers creating open democratic environments, leading to what has been termed the political classroom. This yearlong study of an Israeli multicultural and bilingual high school civics course, in which students from different citizenship status participated, presents a case in which teachers were unsuccessful in achieving this goal, raising the question of what limited this class's potential to create an educational environment where democratic discourses could have taken place? The main argument points to Israel's current disputative political environment that led to the enactment of four educational mechanisms that resulted in such a futile reality. These included: conflicting objectives, avoiding discussion of controversial issues, implementing traditional teaching practices, and overlooking language issues. The neo-liberal educational environment and a culture of fear and self-censorship were both identified as a common explanation to these, leading to an educational reality in which there was a detach between the lessons and the students’ transcultural lived political experiences. From a methodological perspective, the study illuminates the importance of focusing on such unsuccessful cases, examining their elements, and understanding what influences them.
Oil Crisis in Iran
Authors: Abrahamian Ervand
Published: June 2021

Focusing on the turbulent twenty-eight months between April 1951 and August 1953, this book, based on recently declassified CIA and US State Department documents from the Mossadeq administration tell the story of the Iranian oil crisis, which would culminate in the coup of August 1953. Throwing fresh light on US involvement in Iran, Ervand Abrahamian reveals exactly how immersed the US was in internal Iranian politics long before the 1953 coup, in parliamentary politics and even in saving the monarchy in 1952. By weighing rival explanations for the coup, from internal discontent, a fear of communism and oil nationalization, Abrahamian shows how the Truman and Eisenhower administrations did not differ significantly in their policies towards Mossadeq, and how the surprising main obstacle to an earlier coup was the shah himself. In tracing the key involvement of the US and CIA in Iran, this study shows how the 1953 coup would eventually pave the way to the 1979 Iranian revolution, two of the most significant and widely studied episodes of modern Iranian history.
Twenty Ways to Assess Personnel
Authors: Furnham Adrian
Published: June 2021

Over the years, there has been more and more research to test the validity of personnel assessment methods, an area which is far from easy. This book compares traditional practices against new techniques, including social media analytics, wearables, mobile phone logs, and gamification. Researchers and businesses alike know the importance of making good, and avoiding bad, selection decisions, but are unsure of how to proceed effectively. This book maps out the viable options and advises on best practice. The author combines both practical applications and academic, psychological research to explain how each method works, the theory behind it, and the extent of the evidence that supports it.
Law and Sentiment in International Politics
Authors: Traven David
Published: June 2021

Drawing on recent research in moral psychology and neuroscience, this book argues that universal moral beliefs and emotions shaped the evolution of the laws of war, and in particular laws that protect civilians. It argues that civilian protection norms are not just a figment of the modern West, but that these norms were embryonic in earlier societies and civilizations, including Ancient China, early Islam, and medieval Europe. However, despite their ubiquity, this book argues that civilian protection rules are inherently fragile, and that their fragility lies not just in failures of compliance, but also in how moral emotions shaped the design of the law. The same beliefs and emotions that lead people to judge that it is wrong to intentionally target civilians can paradoxically constitute the basis for excusing states for incidental civilian casualties, or collateral damage. To make the laws of war work better for civilians, this book argues that we need to change how we think about the ethics of killing in war.
The Rise of Discourse Markers
Authors: Heine Bernd , Kaltenböck Gunther , Kuteva Tania , Long Haiping
Published: June 2021

Discourse markers constitute an important part of linguistic communication, and research on this phenomenon has been a thriving field of study over the past three decades. However, a problem that has plagued this research is that these markers exhibit a number of structural characteristics that are hard to interpret based on existing methodologies, such as grammaticalization. This study argues that it is possible to explain such characteristics in a meaningful way. It presents a cross-linguistic survey of the development of discourse markers, their important role in communication, and their relation to the wider context of sociocultural behaviour, with the goal of explaining their similarities and differences across a typologically wide range of languages. By giving a clear definition of discourse markers, it aims to provide a guide for future research, making it essential reading for students and researchers in linguistics, and anyone interested in exploring this fascinating linguistic phenomenon.
Remaking Mutirikwi
Authors: Fontein Joost
Published: June 2021

The Mutirikwi river was dammed in the early 1960s to make Zimbabwe's second largest lake. This was a key moment in the Europeanisation of Mutirikwi's landscapes, which had begun with colonial land appropriations in the 1890s. But African landscapes were not obliterated by the dam. They remained active and affective. At independence in 1980, local clans reasserted ancestral land claims in a wave ofsquatting around Lake Mutirikwi. They were soon evicted as the new government asserted control over the remaking of Mutirikwi's landscapes. Amid fast-track land reform in the 2000s, the same people returned again to reclaim the land. Many returned to the graves and ruins of past lives forged in the very substance of the soil, and even incoming war veterans and new farmers appealed to autochthonous knowledge to make safe their resettlements. This book explores those reoccupations and the complex contests over landscape, water and belonging they provoked. The 2000s may have heralded a long-delayed re-Africanisation of Lake Mutirikwi, but just as African presence had survived the dam, so white presence remains active and affective through Rhodesian-era discourses, place-names and the materialities of ruined farms, contour ridging and old irrigation schemes. Through lenses focused on the political materialities of water and land, this book reveals how the remaking of Mutirikwi's landscapes has always been deeply entangled with changing strategies of colonial and postcolonial statecraft. It highlights how the traces of different pasts intertwine in contemporary politics through the active, enduring yet emergent, forms and substances of landscape. Joost Fontein is Director of the British Institute in Eastern Africa and Lecturer in Social Anthropology at the University of Edinburgh. Published in association with the British Institute in Eastern Africa.
Women, Migration & the Cashew Economy in Southern Mozambique
Authors: Penvenne Jeanne Marie
Published: June 2021

Between the late 1940s and independence in 1975, rural Mozambican women migrated to the capital, Lourenço Marques, to find employment in the cashew shelling industry. This book tells of the labour and social history of what became of Mozambique's most important late colonial era industry through the oral history and songs of three generations of the workforce. In the 1950s, Jiva Jamal Tharani recruited a largely female labour force and inaugurated industrial cashew shelling in the Chamanculo neighbourhood. Seasonal cashew brews had long been an essential component of the region's household, gift and informal economies, but by the 1970s cashew exports comprised the largest share of the colony's foreign exchange earnings.

This book demonstrates that Mozambique's cashew economy depended fundamentally on women's work and should be understood as 'whole cloth'. Drawing on over one hundred interviews, the rich narratives convey layered histories: the rural crises that triggered the flight of women, their lives as factory workers, widespread payment and wage fraud, the formation of innovative urban families, and the health costs that all African families paid for municipal neglect of their neighbourhoods.

Jeanne Marie Penvenne is Associate Professor of History and International Relations Core Faculty at Tufts University. She is the author of the Herskovits shortlisted 'African Workers and Colonial Racism' (James Currey/Heinemann, 1995)
RETRACTED–Assessing Hospital Adaptive Resource Allocation Strategies in Responding to Mass Casualty Incidents
Authors: Faccincani Roberto , Trucco Paolo , Nocetti Claudio , Carlucci Michele , Weinstein Eric S.
Published: June 2021

Background:

Hospitals are expected to operate at a high performance level even under exceptional conditions of peak demand and resource disruptions. This understanding is not mature yet and there are wide areas of possible improvement. In particular, the fast mobilization and reconfiguration of resources frequently result into the severe disruption of elective activities, worsening the quality of care. This becomes particularly evident during the on-going coronavirus disease 2019 (COVID-19) pandemic. More resilient resource allocation strategies, that is, which adapt to the dynamics of the prevailing circumstance, are needed to maximize the effectiveness of health-care delivery. In this study, a simulation approach was adopted to assess and compare different hospital’s adaptive resource allocation strategies in responding to a sudden onset disaster mass casualty incident (MCI).

Methods:

A specific set of performance metrics was developed to take into consideration multiple objectives and priorities and holistically assess the effectiveness of health-care delivery when coping with an MCI event. Discrete event simulation (DES) and system dynamics (SD) were used to model the key hospital processes and the MCI plan.

Results:

In the daytime scenario, during the recovery phase of the disaster, a gradual disengagement of resources from the emergency department (ED) to restart ordinary activities in operating rooms and wards returned the best performance. In the night scenario, the absorption capacity of the ED was evaluated by identifying the current bottleneck and assessment of the benefit of different resource mobilization strategies.

Conclusions:

The present study offers a robust approach, effective strategies and new insights to design more resilient plans to cope with MCIs. It becomes particularly relevant when considering the risk of indirect damage of emergencies, where all the available resources are shifted from the care of the ordinary to the “disaster” patients, like during the on-going COVID-19 pandemic. Future research is needed to widen the scope of the analysis and take into consideration additional resilience capacities such as operational coordination mechanisms among multiple hospitals in the same geographic area.
Diffusive time evolution of the Grad–Shafranov equation for a toroidal plasma
Authors: Montani Giovanni , Del Prete Matteo , Carlevaro Nakia , Cianfrani Francesco
Published: June 2021

We describe the evolution of a plasma equilibrium having a toroidal topology in the presence of constant electric resistivity. After outlining the main analytical properties of the solution, we illustrate its physical implications by reproducing the essential features of a scenario for the upcoming Italian experiment Divertor Tokamak Test Facility, with a good degree of accuracy. Although we find the resistive diffusion time scale to be of the order of

$10^4$

s, we observe a macroscopic change in the plasma volume on a time scale of

$10^2$

s, comparable to the foreseen duration of the plasma discharge by design. In the final part of the work, we compare our self-consistent solution to the more common Solov'ev one, and to a family of nonlinear configurations.
Isolated CHDs and neurodevelopmental follow-up using the Bayley Scales of Infant and Toddler Development and the Ages and Stages Questionnaire at 18 and 36 months
Authors: Baunsgaard Mette Marie , Henriksen Tine B. , Gilberg Charlotte K. , Wibroe Dorthe B. , Haugsted Trine , Østergaard John R. , Hjortdal Vibeke E. , Lauridsen Mette H.
Published: June 2021

Objectives:

To compare early neurocognitive development in children born with and without isolated CHD using the Bayley Scales of Infant and Toddler Development (3rd edition) and the Ages and Stages Questionnaire (3rd edition).

Methods:

Recruitment took place before birth. Women expecting fetuses with and without CHD causing disturbances in the flow of oxygenated blood to the fetal brain were included in a prospective cohort study comprising fetal MRI (previously published) and neurodevelopmental follow-up. We now present the 18- and 36-month neurodevelopmental follow-up using the Bayley Scales according to age and the 6-month-above-age Ages and Stages Questionnaire in 15 children with and 27 children without CHD.

Results:

Children with CHD had, compared with the children without CHD, an increased risk of scoring ≤ 100 in the Bayley Scales cognition category at 18 and 36 -months; relative risk 1.7 (95% confidence interval (CI): 1.0–2.8) and 3.1 (CI: 1.2–7.5), respectively. They also achieved lower scores in the 6-month-above-age Ages and Stages Questionnaires (24 and 42 months) communication; mean z-score difference −0.72 (CI: −1.4; −0.1) and −1.06 (CI: −1.8; −0.3) and gross motor; mean z-score difference: −0.87 (CI: −1.7; −0.1) and −1.22 (CI: −2.4; −0.02) categories.

Conclusions:

The children with CHD achieved lower scores in the Bayley Scales cognition category and the Ages and Stages Questionnaire communication and gross motor categories possibly indicative of early neurodevelopmental deficiencies. We recommend early screening and monitoring for neurodevelopmental delays in children with CHD in order to improve further neurodevelopment and educational achievements.
George MacDonald's Doors: Suspended Telos and the Child Believer
Authors: Plourde Aubrey
Published: June 2021

George MacDonald'sThe Princess and the Goblin(1872) is frequently read as a reflection of the scandalous theological doctrine conventionally attached to the author's name, the principle of universalism. But if the fairy tale seems to serve up an optimistic teleology of faith—belief triumphant, no matter the long odds—it also undermines its own project. The very overwrought Christian symbols that most seem to depict MacDonald's universalism in fact suggest its opposite, imagining spiritual progress and individual growth as contingent, indeterminate, and perpetually in process. Recognizing that representations of progress in MacDonald'sPrincessbooks are compromised at best and deliberately diverted, more likely, reveals a surprisingly inconsistent treatment of childhood, which he imagines not—or not just—as the telos of spiritual growth but also as a state of suspended development. In this way,The Princess and the Goblinendorses the concept of terminal spirituality while theorizing religious subjectivity as an intermittent temporal process.
A qualitative inquiry of food insecurity in Belize
Authors: Stevenson Laurel D , Reznar Melissa M , Onye Elizabeth , Bendali Amor Lynna , Lopez Andre J , DeFour Rita
Published: June 2021

Objective:

To explore and provide contextual meaning around issues surrounding food insecurity, namely factors influencing food access, as one domain of food security.

Design:

A community-based, qualitative inquiry using semi-structured face-to-face interviews was conducted as part of a larger sequential mixed-methods study.

Setting:

Cayo District, Belize, May 2019–August 2019.

Participants:

Thirty English-speaking individuals (eight males, twenty-two females) between the ages of 18–70, with varying family composition residing within the Cayo District.

Results:

Participants describe a complex interconnectedness between family- and individual-level barriers to food access. Specifically, family composition, income, education and employment influence individuals’ ability to afford and access food for themselves or their families. Participants also cite challenges with transportation and distance to food sources and educational opportunities as barriers to accessing food.

Conclusion:

These findings provide insight around food security and food access barriers in a middle-income country and provide avenues for further study and potential interventions. Increased and sustained investment in primary and secondary education, including programmes to support enrollment, should be a priority to decreasing food insecurity. Attention to building public infrastructure may also ease burdens around accessing foods.
Meaning, Purpose, and Job Satisfaction
Authors: Klussman Kristine , Lee Nichols Austin , Langer Julia
Published: June 2021

Abstract. Finding meaning and purpose in one's life facilitates several important work outcomes. A global pandemic that changes both the lives of employees and the way they work likely affects the relationships between workers' meaning in life and work. Making meaning salient to employees, despite the circumstances, may strengthen and preserve these relationships. To examine this, 71 employed adults completed a photo-taking task that either focused on objects of meaning ( n = 36) or objects that were blue (i.e., the control; n = 35). The results suggested that meaning salience increased job satisfaction. In addition, it moderated the relationship between purpose (but not meaning) and job satisfaction. In all, this highlights the challenges of new working circumstances and the importance of continuously making meaning salient to employees.
Older and Younger Job Seekers' Impression Management on LinkedIn
Authors: Krings Franciska , Gioaba Irina , Kaufmann Michèle , Sczesny Sabine , Zebrowitz Leslie
Published: June 2021

Abstract. The use of social networking sites such as LinkedIn in recruitment is ubiquitous. This practice may hold risks for older job seekers. Not having grown up using the internet and having learned how to use social media only in middle adulthood may render them less versed in online self-presentation than younger job seekers. Results of this research show some differences and many similarities between younger and older job seekers' impression management on their LinkedIn profiles. Nevertheless, independent of their impression management efforts, older job seekers received fewer job offers than younger job seekers. Only using a profile photo with a younger appearance reduced this bias. Implications for the role of job seeker age in online impression management and recruitment are discussed.
Reducing Systematic Biases Over the Indian Region in CFS V2 by Dynamical Downscaling
Authors: Hari Prasad K. B. R. R. , Ramu Dandi A. , Rao Suryachandra A. , Hameed Saji N. , Samanta Dhrubajyoti , Srivastava Ankur
Published: June 2021

The usefulness of dynamical downscaling of seasonal reforecasts of Indian Monsoon is explored to address the seasonal mean biases in the reforecasts. Almost all the current generation global coupled models, including the Climate Forecast System version 2 (CFSv2, T126 ∼110 km), exhibit systematic mean dry bias over the central Indian region during the summer monsoon season. Cold sea surface temperature (SST) biases in the Indian Ocean and a weak monsoon circulation due to a colder tropospheric temperature contribute to this dry bias. Such systematic biases restrict the use of skillful forecasts from these models in climate applications (such as agriculture or hydrology). Dynamical downscaling of seasonal forecasts (∼110 km resolution) using the Weather Research and Forecasting (WRF) model coupled to a simple ocean mixed layer model (OML; WRFOML) at 38 km resolution significantly reduces the majority of the systematic biases reported earlier. The seasonal mean dry bias reduces to 16% in WRFOML as compared to 44% (33%) in the CFSv2‐T126 (WRFCTL) over the Indian land region. Warmer SSTs in the Indian Ocean and a more robust monsoon circulation emanating from a realistic simulation of the tropospheric temperature reduced the systematic biases in WRFOML compared to CFSv2‐T126 and WRFCTL. Additionally, category‐wise rainfall distributions are also improved drastically in the downscaled simulations (WRFOML). Downscaled reforecasts with reduced systematic biases have better suitability for climate applications.
Timing Calibration and Windowing Technique Comparison for Lightning Mapping Arrays
Authors: Hare Brian M. , Edens Harald , Krehbiel Paul , Rison William , Scholten O. , Buitink S. , Corstanje A. , Falcke H. , Hörandel J. R. , Huege Tim , Krampah G. K. , Mitra P. , Mulrey K. , Nelles Anna , Pandya Hershal , Rachen J. P. , Thoudam S. , Trinh T. N. , ter Veen S. , Winchen Tobias
Published: June 2021

Since their introduction 22 years ago, lightning mapping arrays (LMA) have played a central role in the investigation of lightning physics. Even in recent years with the proliferation of digital interferometers and the introduction of the LOw Frequency ARray (LOFAR) radio telescope, LMAs still play an important role in lightning science. LMA networks use a simple windowing technique that records the highest pulse in either 80 μs or 10 μs fixed windows in order to apply a time‐of‐arrival location technique. In this work, we develop an LMA‐emulator that uses lightning data recorded by LOFAR to simulate an LMA, and we use it to test three new styles of pulse windowing. We show that they produce very similar results as the more traditional LMA windowing, implying that LMA lightning mapping results are relatively independent of windowing technique. In addition, each LMA station has its GPS‐conditioned clock. While the timing accuracy of GPS receivers has improved significantly over the years, they still significantly limit the timing measurements of the LMA. Recently, new time‐of‐arrival techniques have been introduced that can be used to self‐calibrate systematic offsets between different receiving stations. Applying this calibration technique to a set of data with 32 ns uncertainty, observed by the Colorado LMA, improves the timing uncertainty to 19 ns. This technique is not limited to LMAs and could be used to help calibrate future multi‐station lightning interferometers.
Evaluation of Temperature and Precipitation Simulations in CMIP6 Models Over the Tibetan Plateau
Authors: Cui Tong , Li Chao , Tian Fuqiang
Published: June 2021

This study presents a comprehensive evaluation of the mean and extreme surface air temperature and precipitation in the Coupled Model Intercomparison Project Phase 6 (CMIP6) multimodel ensemble simulations over the Tibetan Plateau. Simulations from 29 climate models are compared against gridded observations for the period 1961–2012. Results show that models reasonably reproduce the overall spatial patterns of the 1961–2012 averages of seasonal mean temperature and precipitation. Nevertheless, models tend to underestimate mean temperature and overestimate precipitation accumulations. To be specific, the multimodel mean estimates of seasonal average temperatures over the plateau are 0.5°C–2.6°C colder than observed, while the corresponding estimates of seasonal precipitation accumulations are 218% (spring: March–May), 76% (summer: June–August), 129% (autumn: September–November), and 533% (winter: December–February) of those observed. As in observations, models also well capture increasing trend of mean temperature and precipitation in all seasons but underestimate the rates of increasing trends for both variables in all seasons. Models’ ability to simulate temperature and precipitation extremes is also evaluated in terms of a set of chosen extreme indices defined by the Expert Team on Climate Change Detection and Indices. On average, models tend to underestimate the averages of annual maximum daily maximum temperature, annual minimum daily minimum temperature, frost days, warm nights, and consecutive dry days but overestimate the corresponding averages of annual maximum 5‐day precipitation accumulations and simply daily intensity. Generally, models are able to simulate the signs of the trends in extreme indices but underestimate their magnitudes and misrepresent spatial patterns.
Delayed Growth of Ferropericlase and Bridgmanite Controls Slab Residence at the 660‐km Discontinuity
Authors: Chapman Timothy , Clarke Geoffrey L.
Published: June 2021

Cold subducted oceanic lithosphere may stall in the uppermost portions of the lower mantle (660–700 km depth) as a consequence of its slow thermal equilibration and the negative dP/dT of reactions forming ferropericlase and bridgmanite. Evaluations of slab buoyancy in the lower parts of the transition zone have mostly neglected the effects of dynamic P–T paths and the temperature‐dependent expansion or contraction of stalled slabs. Forward predictions from mineral equilibria and thermal modeling posit slab residence at the base of the mantle transition zone for c. 150–160 Myr, dependent on geotherm and the depth of stagnation (between 660–700 km). Slab components can attain density thresholds following heating and phase transformations over distinct periods: Basaltic crust will become positively buoyant after c. 4 Myr whereas ultramafic components will become negatively buoyant after c. 150–160 Myr. Slab components may thus separate and independently transit or escape the transition zone under circumstances of equilibrated mineral assemblages. The 660 km seismic discontinuity presents a filter for the partial recycling of the upper oceanic lithosphere into the upper mantle.
Effects of Organized Convection Parameterization on the MJO and Precipitation in E3SMv1. Part I: Mesoscale Heating
Authors: Chen C.‐C. , Richter J. H. , Liu C. , Moncrieff M. W. , Tang Q. , Lin W. , Xie S. , Rasch P. J.
Published: June 2021

Mesoscale organization of convection is typically not represented in global circulation models, and hence its influence on the global circulation is not accounted for. The heating component of a parameterization that represents the dynamical and physical effects of circulations associated with organized convection, referred to as the multiscale coherent structure parameterization (MCSP), is implemented in the Energy Exascale Earth System Model version 1 (E3SMv1). Numerical simulations are conducted to assess its impact on the simulated climate. Besides E3SMv1 simulations, we performed high‐resolution (2 km) simulations using the Weather Research and Forecasting (WRF) Model to determine the temperature tendencies induced by mesoscale convective systems embedded in deep convection. We tuned the free parameters of the MCSP based on the WRF simulations. MCSP heating enhances Kevin wave spectra in E3SMv1, improves the representation of the Madden‐Julian Oscillation, and reduces precipitation biases over the tropical Pacific.
Long‐Term Trends Show Improvements in Water Quality in the Chicago Metropolitan Region With Investment in Wastewater Infrastructure, Deep Tunnels, and Reservoirs
Authors: Pluth T. B. , Brose D. A. , Gallagher D. W. , Wasik J.
Published: June 2021

The ecological degradation of streams draining urban land, known as the urban stream syndrome, is characterized by elevated nutrients and contaminants, increased hydrologic flashiness, and altered biotic assemblages. This study demonstrated an improvement in chemical characteristics by evaluating water quality trends from 1975 to 2012 and from 2013 to 2018 in the Chicago, Calumet, and Des Plaines River Systems in Cook County, Illinois. Data from 41 monitoring locations were compiled and 11 water quality parameters were analyzed for long‐term monotonic trends and differences in water quality parameters between select time periods to investigate the outcomes from improvements in water reclamation plant (WRP) and tunnel and reservoir infrastructure carried out by the Metropolitan Water Reclamation District of Greater Chicago. From 1975 to 2012, significant decreasing trends in concentrations were demonstrated at most sampling locations for total organic carbon (TOC), total Kjeldahl nitrogen (TKN), ammonium nitrogen (), total suspended solids (TSS), fecal coliform (FC), and sulfate. Significant increasing trends were demonstrated for dissolved oxygen (DO) and chloride concentrations and temperature. Total phosphorus (TP) concentrations increased downstream of the Stickney, Kirie, and Calumet WRPs from 1975 to 2012, but decreased downstream of the Kirie WRP and had no trends downstream of the Stickney and Calumet WRPs from 2013 to 2018. Improvements in TKN, , TOC, TSS, FC, TP, and DO concentrations over four decades demonstrated the benefits of expanding secondary wastewater treatment and implementing the Tunnel and Reservoir Plan System, instream and side‐stream elevated pool aeration stations, and effluent disinfection.
Dependence of Penetration Electric Field Efficiency on the Interplanetary Electric Field
Authors: Ross Jack R. , Huang Chao‐Song
Published: June 2021

Southward interplanetary magnetic field (IMF) causes the generation of penetration electric fields in the ionosphere at middle and low latitudes. Penetration efficiency, which is defined to be the ratio of the change of the equatorial ionospheric zonal electric field to the change of the dawn‐dusk (Ey) component of the interplanetary electric field, is used to represent the quantitative relationship between interplanetary and ionospheric electric fields. We have searched equatorial vertical ion drift data measured by the Jicamarca Unattended Long‐term Investigations of the Ionosphere and Atmosphere (JULIA) radar over 19 years (2001–2019) for penetration electric fields when the correlation between interplanetary and ionospheric electric fields is greater than 0.8. In total, 450 penetration electric field events are identified. It is found that the penetration efficiency peaks near noon and decreases afterward. The penetration efficiency depends on the rate of change of Ey with time, the initial Ey when the IMF starts to turn southward, and the change in Ey between the beginning of the IMF southward turning and the subsequent northward turning. The initial Ey is well‐correlated with the change in Ey. A positive initial Ey or a smaller change in Ey results in a higher penetration efficiency. The quantitative dependence of penetration efficiency on the structures of Ey is derived for the first time. The results of this study are expected to improve the accuracy of prediction of penetration electric fields.
High‐Pressure Phase Stability and Thermoelastic Properties of Iron Carbonitrides and Nitrogen in the Deep Earth
Authors: Huang Shengxuan , Wu Xiang , Zhu Feng , Lai Xiaojing , Li Jie , Neill Owen K. , Qin Shan , Rapp Robert , Zhang Dongzhou , Dera Przemyslaw , Chariton Stella , Prakapenka Vitali B. , Chen Bin
Published: June 2021

Iron‐dominant metallic phases are likely the primary hosts for nitrogen in the reduced deep Earth, hence the storage of nitrogen in the lower mantle and the core is governed by the behavior of the Fe‐N‐C system at high temperatures and pressures. In this study, phase transitions and thermoelastic properties of iron carbonitrides were investigated at high pressure‐temperature conditions by diamond anvil cell experiments and first‐principles calculations. Experimental data revealed no phase transition in ε‐type Fe4 (N0.6C0.4) or Fe7 (N0.75C0.25)3 up to 60 GPa at room temperature. At high temperature, Fe7 (N0.75C0.25)3 transforms into the Fe3C‐type phase at ∼27 GPa, and then into the Fe7C3‐type phase at ∼45 GPa, which is also corroborated by our theoretical calculations. We found that the phase stability of iron carbonitrides mainly depends on the N/C ratio, and the elastic properties of iron carbonitrides are dominantly affected by the Fe/(N+C) ratio. Iron carbonitrides with diverse structures may be the main host for nitrogen in the deep mantle. Some iron carbonitride inclusions in lower mantle diamonds could be the residue of the primordial mantle or originate from subducted nitrogen‐bearing materials, rather than iron‐enriched phases of the outer core. In addition, our experiments confirmed the existence of Fe7C3‐type Fe7C3‐Fe7N3 solid solutions above 40 GPa. Fe7C3‐type Fe7(C, N)3 has comparable density and thermoelastic properties to its isostructural endmembers and may be a promising candidate constituent of the Earth's inner core.
CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice
Authors: Gan Lu , Liu Demin , Liu Jing , Chen Erya , Chen Chan , Liu Lian , Hu Hang , Guan Xiaohui , Ma Wen , Zhang Yanzi , He Yarong , Liu Bofu , Tang Songling , Jiang Wei , Xue Jianxin , Xin Hongbo
Published: June 2021

CD38 is the main enzyme for nicotinamide adenine dinucleotide (NAD) degradation in mammalian cells. Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases. Our study showed that CD38 deficiency significantly alleviated angiotensin II (Ang II)-induced vascular remodeling in mice, as shown by decreased blood pressures; reduced vascular media thickness, media-to-lumen ratio, and collagen deposition; and restored elastin expression. However, our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang II-induced vascular remodeling, suggesting that the effects of CD38 on Ang II-induced vascular remodeling might rely primarily on vascular smooth muscle cells (VSMCs), not lymphocytes. In addition, we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang II-induced vascular senescence by suppressing the biogenesis, secretion, and internalization of senescence-associated small extracellular vesicles (SA-sEVs), which facilitated the senescence of neighboring non-damaged VSMCs. Furthermore, we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction, particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria–lysosomal axis in VSMCs. In conclusion, our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang II-induced VSMC senescence and vascular remodeling.
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer
Authors: Ramesh Prashanthi , Lannagan Tamsin R. M. , Jackstadt Rene , Atencia Taboada Lidia , Lansu Nico , Wirapati Pratyaksha , van Hooff Sander R. , Dekker Danielle , Pritchard Jessica , Kirov Aleksandar B. , van Neerven Sanne M. , Tejpar Sabine , Kops Geert J. P. L. , Sansom Owen J. , Medema Jan Paul
Published: June 2021

Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
Kindlin-2 in Sertoli cells is essential for testis development and male fertility in mice
Authors: Chi Xiaochun , Luo Weiwei , Song Jiagui , Li Bing , Su Tiantian , Yu Miao , Wang Tianzhuo , Wang Zhenbin , Liu Cheng , Li Zhen , He Huiying , Zhan Jun , Zhang Hongquan
Published: June 2021

Kindlin-2 is known to play important roles in the development of mesoderm-derived tissues including myocardium, smooth muscle, cartilage and blood vessels. However, nothing is known for the role of Kindlin-2 in mesoderm-derived reproductive organs. Here, we report that loss of Kindlin-2 in Sertoli cells caused severe testis hypoplasia, abnormal germ cell development and complete infertility in male mice. Functionally, loss of Kindlin-2 inhibits proliferation, increases apoptosis, impairs phagocytosis in Sertoli cells and destroyed the integration of blood-testis barrier structure in testes. Mechanistically, Kindlin-2 interacts with LATS1 and YAP, the key components of Hippo pathway. Kindlin-2 impedes LATS1 interaction with YAP, and depletion of Kindlin-2 enhances LATS1 interaction with YAP, increases YAP phosphorylation and decreases its nuclear translocation. For clinical relevance, lower Kindlin-2 expression and decreased nucleus localization of YAP was found in SCOS patients. Collectively, we demonstrated that Kindlin-2 in Sertoli cells is essential for sperm development and male reproduction.
K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR
Authors: Zhang Pengshan , Zhang Zhe , Fu Yinkun , Zhang Ying , Washburn Michael P. , Florens Laurence , Wu Min , Huang Chen , Hou Zhaoyuan , Mohan Man
Published: June 2021

Dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2–DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.
PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53
Authors: Wang Wuyi , Wei Jinlai , Zhang Hairong , Zheng Xiangru , Zhou He , Luo Yajun , Yang Jianguo , Deng Qican , Huang Siqi , Fu Zhongxue
Published: June 2021

Colorectal cancer is the most common gastrointestinal cancer and causes severe damage to human health. PRDX2 is a member of the peroxiredoxin family reported to have a high level of expression in colorectal cancer. However, the mechanisms by which PRDX2 promotes the proliferation of colorectal cancer are still unclear. Here, the results indicated that PRDX2 expression was upregulated in colorectal cancer and closely correlated with poor prognosis. Functionally, PRDX2 promoted the proliferation of colorectal cancer cells. Mechanistically, PRDX2 could bind RPL4, reducing the interaction between RPL4 and MDM2. These findings demonstrate that the oncogenic property of PRDX2 may be attributed to its regulation of the RPL4-MDM2-p53 pathway, leading to p53 ubiquitinated degradation.
A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors
Authors: Moirangthem Ranjita Devi , Ma Kuiying , Lizot Sabrina , Cordesse Anne , Olivré Juliette , de Chappedelaine Corinne , Joshi Akshay , Cieslak Agata , Tchen John , Cagnard Nicolas , Asnafi Vahid , Rausell Antonio , Simons Laura , Zuber Julien , Taghon Tom , Staal Frank J. T. , Pflumio Françoise , Six Emmanuelle , Cavazzana Marina , Lagresle-Peyrou Chantal , Soheili Tayebeh , André Isabelle
Published: June 2021

Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).
Non-invasive electrophysiology in glaucoma, structure and function—a review
Authors: Al-Nosairy Khaldoon O. , Hoffmann Michael B. , Bach Michael
Published: June 2021

Glaucoma, its early diagnosis, and monitoring of interventions remain an ongoing challenge. We here review developments in functional assessment and its relation to morphology, evaluating recent insights in electrophysiology in glaucoma and highlighting how glaucoma research and diagnostics benefit from combined approaches of OCT and electrophysiological investigations. After concise overviews of OCT and non-invasive electrophysiology in glaucoma, we evaluate commonalities and complementarities of OCT and electrophysiology for our understanding of glaucoma. As a specific topic, the dynamic range (floor effects) of the various techniques is discussed.
Non-infectious uveitis affecting the posterior segment treated with fluocinolone acetonide intravitreal implant: 3-year fellow eye analysis
Authors: Pavesio Carlos , Heinz Carsten
Published: June 2021

Background

Prevention of non-infectious uveitis of the posterior segment (NIU-PS) recurrence using 0.2 μg/day fluocinolone acetonide implant (FAi) was assessed over 3 years (NCT01694186). Outcomes for FAi-treated and fellow eyes with NIU-PS were compared, to evaluate FAi versus conventional treatment strategies.

Methods

Eligible subjects had >1-year recurrent NIU-PS history and either ≥2 separate recurrences requiring treatment, or corticosteroid therapy (systemic or ocular) in the 12 months preceding study entry. Bilateral disease was present and analysed in 59/87 FAi-treated participants. Recurrence rates, best-corrected visual acuity (BCVA) changes, cataract surgery, intraocular pressure (IOP) events and adjunctive medication use were compared for FAi-treated and fellow eyes.

Results

Over 36 months, more FAi-treated than fellow eyes remained recurrence-free (28.8% vs. 5.1%, P = 0.001; mean 1.9 vs. 4.7 recurrences, respectively, P < 0.0001). FAi-treated eyes gained +9.6 letters BCVA, versus a loss of −4.4 in fellow eyes (P < 0.0001). Systemic medications were given to 42.4% of subjects. Intra/periocular adjunctive injections were lower in FAi-treated than fellow eyes (20.3% vs. 66.1%, P < 0.0001); topical corticosteroid use was also lower in FAi-treated than fellow eyes (27.1% vs 52.5%, P = 0.0041). IOP-related events occurred at similar rates in both FAi-treated and fellow eyes, excepting IOP-lowering surgery (5.1% vs. 15.3%, respectively; P = 0.1251). Cataract surgery occurred in 72.0% of FAi-treated and 37.0% of fellow eyes.

Conclusions

In subjects with bilateral NIU-PS, continuous, low-dose corticosteroid with 0.2 μg/day FAi reduced recurrence and adjunctive medication requirements, and improved vision over 36 months, providing greater protection against ocular inflammation than a reactive approach using standard of care.