bluuebunny/crossref_metadata_2025 huggingface dataset:
The Chengda Teachers School and Modern China's Frontier Politics: Ethnicity and Religion in the Implementation of Republican Law, 1925–49
Authors: Chen Bin
Published: January 2022

The military victories of the Northern Expedition (1926–28) ended nearly two decades of political fragmentation and ushered in a new era of centralized government in China. A key concern of the Nationalist government, based in Nanjing, was bringing the haphazard array of private schools that had emerged since the republic's founding in 1911 in line with the Nationalists’ political agenda. The Nationalist leadership also hoped to use their educational reforms to bring the frontier regions, many of which were only tenuously allied with Nanjing, more formally under their control. Thus, the new regime set out to achieve the twin goals of regulating private schools and cultivating ties among the frontier region's population. These two goals became entangled in an unexpected manner at the private Muslim Chengda Teachers School. Although the Nationalists banned private teachers schools in 1933, they deliberately exempted Chengda from such regulations to further their frontier agenda. Later, when the central government's frontier political calculations changed, the Nationalists rescinded such protection and forced Chengda to abide by the original regulations.
Effect of heat treatments on foaming and physico-chemical properties of bovine and camel sodium caseinate
Authors: Lajnaf Roua , Attia Hamadi , Ayadi Mohamed Ali
Published: January 2022

The objective of this study was to examine the foaming properties of sodium caseinates (Na-cas) extracted from bovine and camel fresh milks after heating at 70, 80, 90 and 100°C for 30 min at laboratory scale. Experimental results indicated that greater foam was obtained with camel Na-cas than with bovine Na-cas at all heating temperatures due to the higher β-casein content in camel caseins (~53.4% of total proteins, RP-HPLC results). Increasing heat-treatment temperature to 100°C significantly enhanced the foaming properties by raising surface hydrophobicity and decreasing electronegative charge as well as interfacial tension values upon heating. This study concluded that camel Na-cas has important foaming properties in agricultural and food industries.
Explaining the deadlock of the European social dialogue: negotiating in the shadow of hierarchy
Authors: Sørensen Julie Malene Eichstedt , Würtzenfeld Mathias , Hansen Magnus Paulsen
Published: January 2022

The European Social Dialogue (ESD) is a mixed story of ongoing negotiations between the social partners but with rather few binding agreements. Whereas some see the sparse actions as an inevitable consequence of deep structural and political asymmetries, others have pointed out the key role played by the Commission, as a “shadow of hierarchy”, in pushing the social partners towards binding agreements. By applying novel insights from theories of veto players and asymmetric interdependence to an in-depth case study of two agreements, the article is the first attempt to take a systematic game theoretical approach to the study of the ESD. We show that the likelihood of a binding agreement depends on the degree and changeability of the shadow of hierarchy as well as the complexity of issue and reputational risks of the social partners. The findings have implications for the likely effectiveness of the recent attempt to “re-launch” the ESD.
Four Fragments on Doing Legal History, or Thinking with and against Willard Hurst
Authors: Hartog Hendrik
Published: January 2022

But here are four fragments that will possibly play a part in a longer work: I begin with a sketch of what it is to do legal history today, in the wake of the enormous growth and development of the field of legal history in legal education, over the past forty years. I continue with an extended examination of the answers Willard Hurst, the founder of the modern discipline of legal history, gave more than fifty-five years ago to the question, what does legal history do. Finally, in the two final fragments, I spin off from Hurst to begin the work of suggesting an understanding of legal history less tied to legal thought and legal advocacy. How to practice a legal history that is something apart from legal scholarship.
Mitochondrial dysfunction and epigenetics underlying the link between early-life nutrition and non-alcoholic fatty liver disease
Authors: La Colla Anabela , Cámara Carolina Anahí , Campisano Sabrina , Chisari Andrea Nancy
Published: January 2022

Early-life malnutrition plays a critical role in foetal development and predisposes to metabolic diseases later in life, according to the concept of ‘developmental programming’. Different types of early nutritional imbalance, including undernutrition, overnutrition and micronutrient deficiency, have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the past years, special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarise the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD.
Age 18–30 trajectories of binge drinking frequency and prevalence across the past 30 years for men and women: Delineating when and why historical trends reversed across age
Authors: Jager Justin , Keyes Katherine M. , Son Daye , Patrick Megan E. , Platt Jonathan , Schulenberg John E.
Published: January 2022

Historical analyses based on US data indicate that recent cohorts engage in lower binge drinking at age 18 relative to past cohorts, but by the mid- to late-20s the reverse is true: recent cohorts engage in higher binge drinking relative to past cohorts. We pinpoint when – both developmentally and historically – this reversal manifested, examine possible reasons for this reversal, and examine sex convergence in these developmental and historical patterns. As part of the US national Monitoring the Future Study, over 75,000 youths from the high school classes of 1976–2006 were surveyed biennially between ages 18 and 30. We found that the reversal primarily manifested between ages 18 and 24 for men and 18 and 22 for women. We also found that the reversal emerged gradually across the last three decades, suggesting it is the result of a broad and durable historical shift. Our findings indicated that historical variation in social roles and minimum legal drinking age collectively accounted for only a modest amount of the reversal, although marriage was the most influential among the factors examined here. Finally, we found evidence that sex convergence in binge drinking was developmentally limited and far more pronounced at the beginning of the transition to adulthood.
More than a feeling? An expanded investigation of emotional responsiveness in young children with conduct problems and callous-unemotional traits
Authors: Northam Jaimie C. , Dar Hayim , Hawes David J. , Barnes Kirsten , McNair Nicolas A. , Fisher Carri A. , Dadds Mark R.
Published: January 2022

Children with conduct problems and high callous-unemotional (CP+CU) traits are characterized by dampened emotional responding, limiting their ability for affective empathy and impacting the development of prosocial behaviors. However, research documenting this dampening in young children is sparse and findings vary, with attachment-related stimuli hypothesized to ameliorate deficits in emotional responding. Here we test emotional responsiveness across various emotion-eliciting stimuli using multiple measures of emotional responsiveness (behavioral, physiological, self-reported) and attention, in young children aged 2–8 years (Mage = 5.37), with CP+CU traits (CP+CU;n= 36), CPs and low CU traits (CP−CU;n= 82) and a community control sample (CC;n= 27). We found no evidence that attachment-related stimulus ameliorated deficits in emotional responding. Rather, at a group level we found a consistent pattern of reduced responding across all independent measures of responsiveness for children with CP+CU compared to the CC group. Few differences were found between CP+CU and CP−CU groups. When independent measures were standardized and included in a regression model predicting to CU trait score, higher CU traits were associated with reduced emotional responding, demonstrating the importance of multimodal measurement of emotional responsiveness when investigating the impact of CU traits in young children.
The grammaticalization of evidentiality in English
Authors: MÉLAC ERIC
Published: January 2022

This article argues that the data on English evidential markers indicate that evidentiality is not a grammatical category which is only applicable to some languages, but can be considered a universal semantic function that tends to trigger the grammaticalization of lexical forms. This study investigates five criteria that can help us locate linguistic forms on the lexicon–grammar continuum: reduction, desemanticization, backgrounding, decategorialization and paradigmatization. Although it has not reached the full maturity of so-called ‘evidential languages’, English provides evidence of the grammaticalization of evidentiality. Evidentiality is thus a relevant notion for English which substantially impacts the organization of the lexicon of the language, and the evolution of its grammar.
Sintra Grows Healthy: development and implementation of a food literacy curriculum for primary schools
Authors: Nogueira Telma , Ferreira Raquel J , Sócrates Marta , Dias da Silva Vitória , Liñan Pinto Mariana , Borrego Rute , Sousa Joana
Published: January 2022

Objective:

Describe the process of development and implementation ofHealth at the Table– a food literacy curriculum for primary school aged children.

Design:

Through a community-based research process,Health at the Tabledevelopment and implementation took place in four stages: exploratory study, production, implementation and monitoring.

Setting:

Primary schools of Sintra’s municipality, Portugal.

Participants:

Children (6–10 years), teachers, school staff and children’s legal guardians of three primary schools during the pilot project and eight primary schools in the second year.

Results:

During the needs assessment phase, 99·1 % (n341) of the children’s legal guardians, 100 % (n34) of the teachers and 100 % (n19) of the school staff considered that the school plays an important or very important role in children’s food literacy (stage 1). During the pilot project, a manual with sixty session plans was developed (stage 2). In the second year,Health at the Tablewas implemented by seventy-two trained teachers during one school year (stage 3). Most of the teachers agreed that the curriculum was appropriate (69·2 %) and that children developed health, wellness/well-being and environmental skills (83·1 %). Most of the children said they had learned about healthy eating (86·3 %) and claimed to eat healthier since theHealth at the Tableimplementation (58·9 %) (stage 4).

Conclusions:

Health at the Tableis a food literacy curriculum that can be reproduced in similar contexts in a sustainable way. The need to combine educational strategies with a healthy school food environment is reinforced to increase effectiveness in tackling childhood obesity.
Food insecurity among active duty soldiers and their families during the coronavirus disease 2019 pandemic
Authors: Rabbitt Matthew P , Beymer Matthew R , Reagan Joanna J , Jarvis Brantley P , Watkins Eren Y
Published: January 2022

Objective:

We examined the determinants of food insecurity among active duty Army households that transitioned into food insecurity during the coronavirus disease 2019 (COVID-19) pandemic.

Design:

We compared Army households that recently transitioned into marginal food insecurity with those households that remained highly food secure (n 2832) to better understand how these households differ in their resilience to food insecurity during economic downturns using data from a military installation in the USA in 2020.

Setting:

A US military installation in the USA.

Participants:

Active duty US Army soldiers.

Results:

Prior to the pandemic, the prevalence of marginal food insecurity among Army households was similar to that reported for households in the general population. Marginal food insecurity among Army households increased over 1·5-fold – from 19 % to 33 % – with the onset of the pandemic. Relative to Army households with consistently high food security, the Army households that transitioned into marginal food insecurity after the onset of the pandemic were more likely to report concerns about financial insecurity and the job security of their family members.

Conclusions:

Army households, like their civilian counterparts, are vulnerable to food insecurity because of instability in their income during periods of economic uncertainty. Periods of economic uncertainty are more common for Army households because of the frequent relocations associated with military service which could lead to predictable periodic spikes in their food insecurity.
Vitamin D status and associations with diet, objectively measured physical activity patterns and background characteristics among adolescents in a representative national cross-sectional survey
Authors: Warensjö Lemming Eva , Petrelius Sipinen Jessica , Nyberg Gisela , Moraeus Lotta , Lindroos Anna Karin
Published: January 2022

Objective:

To report on vitamin D status, measured as plasma 25-hydroxyvitamin D concentration (25(OH)D), the prevalence of vitamin D insufficiency and deficiency, and to explore associations between vitamin D status and background characteristics.

Design:

Data were collected in a National Dietary Survey, Riksmaten adolescents 2016–2017. The participants completed dietary assessments and questionnaires on the web and wore accelerometers. (25(OH)D) was measured with a MS method.

Setting:

Representative survey conducted in schools throughout Sweden.

Participants:

Participants attended school years 5 (Y5, mean age 12. 5 years), 8 (Y8, mean age 14. 5 years) and 11 (Y11, mean age 18 years), and included 1100 participants.

Results:

Overall, there was no difference in plasma 25(OH)D between girls and boys. Vitamin D insufficiency differed between the three school years. The prevalence of insufficiency in Y5 was 32 (boys) and 48 (girls) percent, while in Y11 62 (boys) and 43 (girls) percent. The prevalence of deficiency in Y11 was 16 and 15 % in boys and girls, respectively. Being born outside of Sweden was associated with a 10-fold increased risk of being vitamin D deficient. Deficiency was also associated with longer time spent in sedentary intensity, a lower consumption of fortified dairy products and fats and oils.

Conclusions:

Vitamin D deficiency was most common in the oldest age group and being born outside of Sweden increased the risk of being deficient. The present study will form a baseline for future follow-up studies of the implementation of a new mandatory vitamin D fortification policy in 2018.
Individual and contextual factors associated with under- and over-nutrition among school-aged children and adolescents in two Nigerian states: a multi-level analysis
Authors: Adeomi Adeleye Abiodun , Fatusi Adesegun , Klipstein-Grobusch Kerstin
Published: January 2022

Objective:

This study aimed to identify individual and contextual factors that are associated with under- and over-nutrition among school-aged children and adolescents in two Nigerian states.

Design:

Community-based cross-sectional study.

Setting:

The study was carried out in rural and urban communities of Osun and Gombe States in Nigeria.

Participants:

A total of 1200 school-aged children and adolescents.

Results:

Multi-level analysis showed that the full models accounted for about 82 % and 39 % of the odds of thinness or overweight/obese across the communities, respectively. Household size (adjusted OR (aOR) 1·10; P = 0·001; 95 % CI (1·04, 1·16)) increased the odds, while the upper wealth index (aOR 0·43; P = 0·016; 95 % CI (0·22, 0·86)) decreased the odds of thinness. Age (aOR 0·86; P < 0·001; 95 % CI (1·26, 8·70)), exclusive breastfeeding (aOR 0·46; P = 0·010; 95 % CI (0·25, 0·83)), physical activity (aOR 0·55; P = 0·001; 95 % CI (0·39, 0·78)) and the upper wealth index (aOR 0·47; P = 0·018; 95 % CI (0·25, 0·88)) were inversely related with overweight/obesity, while residing in Osun State (aOR 3·32; P = 0·015; 95 % CI (1·26, 1·70)), female gender (aOR 1·73; P = 0·015; 95 % CI (1·11, 2·69)) and screen time > 2 h/d (aOR 2·33; P = 0·005; 95 % CI (1·29, 4·19)) were positively associated with overweight/obesity.

Conclusions:

The study shows that selected community and individual-level factors are strongly associated with thinness and overweight/obesity among school-aged children and adolescents.
Direct Observation of PFIB-Induced Clustering in Precipitation-Strengthened Al Alloys by Atom Probe Tomography
Authors: Tweddle David , Johnson Jonathan A. , Kapoor M. , Mileski Sean , Carsley John E. , Thompson Gregory B.
Published: January 2022

The effect of sample preparation on a pre-aged Al–Mg–Si–Cu alloy has been evaluated using atom probe tomography. Three methods of preparation were investigated: electropolishing (control), Ga+ focused ion beam (FIB) milling, and Xe+ plasma FIB (PFIB) milling. Ga+-based FIB preparation was shown to introduce significant amount of Ga contamination throughout the reconstructed sample (≈1.3 at%), while no Xe contamination was detected in the PFIB-prepared sample. Nevertheless, a significantly higher cluster density was observed in the Xe+ PFIB-prepared sample (≈25.0 × 1023 m−3) as compared to the traditionally produced electropolished sample (≈3.2 × 1023 m−3) and the Ga+ FIB sample (≈5.6 × 1023 m−3). Hence, the absence of the ion milling species does not necessarily mean an absence of specimen preparation defects. Specifically, the FIB and PFIB-prepared samples had more Si-rich clusters as compared to electropolished samples, which is indicative of vacancy stabilization via solute clustering.
Detection of Palmer amaranth (Amaranthus palmeri) and large crabgrass (Digitaria sanguinalis) with in situ hyperspectral remote sensing. I. Effects of weed density and soybean presence
Authors: Basinger Nicholas T. , Hestir Erin L. , Jennings Katherine M. , Monks David W. , Everman Wesley J. , Jordan David L.
Published: January 2022

The utilization of remote sensing in agriculture has great potential to change the methods of field scouting for weeds. Previous remote sensing research has been focused on the ability to detect and differentiate between species. However, these studies have not addressed weed density variability throughout a field. Furthermore, the impact of changing phenology of crops and weeds within and between growing seasons has not been investigated. To address these research gaps, field studies were conducted in 2016 and 2017 at the Horticultural Crops Research Station near Clinton, NC. Two problematic weed species, Palmer amaranth (Amaranthus palmeri S. Watson) and large crabgrass [Digitaria sanguinalis (L.) Scop.], were planted at four densities in soybean [Glycine max (L.) Merr.]. Additionally, these weed densities were grown in the presence and absence of the crop to determine the influence of crop presence on the detection and discrimination of weed species and density. Hyperspectral data were collected over various phenological time points in each year. Differentiation between plant species and weed density was not consistent across cropping systems, phenology, or season. Weed species were distinguishable across more spectra when no soybean was present. In 2016, weed species were not distinguishable, while in 2017, differentiation occurred at 4 wk after planting (WAP) and 15 WAP when weeds were present with soybean. When soybean was not present, differentiation occurred only at 5 WAP in 2016 and at 3 WAP through 15 WAP in 2017. Differentiation between weed densities did occur in both years with and without soybean present, but weed density could be differentiated across more spectra when soybean was not present. This study demonstrates that weed and crop reflectance is dynamic throughout the season and that spectral reflectance can be affected by weed species and density.
Submesoscale Coherent Vortices Observed in the Northeastern South China Sea
Authors: Zhang Xincheng , Zhang Zhiwei , McWilliams James C. , Sun Zhongbin , Zhao Wei , Tian Jiwei
Published: January 2022

Although submesoscale coherent vortices (SCVs) have been observed in different parts of the world's oceans, most of them were captured by accident by a limited number of hydrographic profiles. Here, using concurrent velocity and temperature/salinity measurements from a submesoscale‐resolving mooring array (2 km), two oppositely rotating SCVs are for the first time reported in detail in the northeastern South China Sea (NESCS). For the anticyclonic (cyclonic) SCV, its core lays at 210 m (180 m) with a mean Rossby number of −0.76 (0.65); its maximum swirl velocity, radius, vertical scale, and Burger number are estimated to be 0.43 m s−1, 31 ± 5 km, 235 m, and 1.5 (0.23 m s−1, 16 ± 3 km, 100 m, and 2.5), respectively. Corresponding to the SCVs' submesoscale nature, their momentum is governed by gradient‐wind rather than geostrophic balance. Consequently, kinetic energy of the anticyclonic (cyclonic) SCV would be on average underestimated (overestimated) by 47% (68%) if the traditional geostrophic relation was used to diagnose the velocity. Further analysis shows that thermohaline properties within the anticyclonic and cyclonic SCVs are close to the Kuroshio water and the local NESCS water, respectively. By combing water mass tracing and high‐resolution simulations, we suggested that the anticyclonic (cyclonic) SCV was generated in the southern Luzon Strait (southwest of Taiwan) through current‐topography interaction. We further proposed that the observed SCVs here should be a common phenomenon in the NESCS, which may provide a novel route for the tracer exchange between the NESCS and the western Pacific.
Solar Wind—Magnetosphere Coupling Functions: Pitfalls, Limitations, and Applications
Authors: Lockwood Mike
Published: January 2022

Solar wind‐magnetosphere coupling functions have now been in use for almost 50 years. In that time, a very large number of formulations have been proposed. As they become increasingly subsumed into systems analysis and machine‐learning studies of the magnetosphere, it is timely to establish best practice in their derivation and study their limitations. This paper reports on a number of studies carried out to establish some key points. Particular attention is paid to the best metric used to evaluate their performance and how it depends on the application for which the coupling function is intended.
MXene supported surface plasmons on telecommunications optical fibers
Authors: Pacheco-Peña Victor , Hallam Toby , Healy Noel
Published: January 2022

MXenes, an emerging class of two-dimensional materials, exhibit characteristics that promise significant potential for their use in next generation optoelectronic sensors. An interplay between interband transitions and boundary effects offer the potential to tune the plasma frequencies over a large spectral range from the near-infrared to the mid-infrared. This tuneability along with the ‘layered’ nature of the material not only offer the flexibility to produce plasmon resonances across a wide range of wavelengths, but also add a degree of freedom to the sensing mechanism by allowing the plasma frequency to be modulated. Here we show, numerically, that MXenes can support plasmons in the telecommunications frequency range and that surface plasmon resonances can be excited on a standard MXene coated side polished optical fiber. Thus, presenting the tantalising prospect of highly selective distributed optical fiber sensor networks.
Mechanical memory operations in piezotransistive GaN microcantilevers using Au nanoparticle-enhanced photoacoustic excitation
Authors: Bayram Ferhat , Gajula Durga , Khan Digangana , Koley Goutam
Published: January 2022

Nonlinear oscillations in micro- and nanoelectromechanical systems have emerged as an exciting research area in recent years due to their promise in realizing low-power, scalable, and reconfigurable mechanical memory and logic devices. Here, we report ultralow-power mechanical memory operations utilizing the nonlinear oscillation regime of GaN microcantilevers with embedded piezotransistive AlGaN/GaN heterostructure field effect transistors as highly sensitive deflection transducers. Switching between the high and low oscillatory states of the nonlinear oscillation regime was demonstrated using a novel phase-controlled opto-mechanical excitation setup, utilizing a piezo actuator and a pulsed laser as the primary and secondary excitation sources, respectively. Laser-based photoacoustic excitation was amplified through plasmonic absorption in Au nanoparticles deposited on a transistor. Thus, the minimum switching energy required for reliable memory operations was reduced to less than a picojoule (pJ), which translates to one of the lowest ever reported, when normalized for mass.
Socioeconomic status, BMI, and brain development in children
Authors: Dennis Evan , Manza Peter , Volkow Nora D.
Published: January 2022

Low socioeconomic status (SES) in childhood is associated with deficits in executive function and changes in cortical morphology. Furthermore, rates of childhood obesity are greater among low SES children and childhood obesity is also associated with cortical alterations and impaired neurocognition, specifically in the domain of executive function. To investigate the influence of BMI on the relationships between SES and both neurocognition and brain morphology, we used data from the Adolescent Brain Cognitive Development (ABCD) study to construct multiple linear regression models and conduct mediation analyses. Overall, SES as measured by household income, highest level of parental education, and area deprivation, was associated with lower BMI, greater total and prefrontal cortical volume, and better performance on assessments of executive function. Mediation analysis indicated that BMI had a significant indirect effect on associations between area deprivation and both total and prefrontal cortical volumes. BMI also played a mediating role in the associations between area deprivation and composite neurocognitive scores, which were driven by performance on tasks of working memory and cognitive flexibility, but not cognitive control. These findings suggest that BMI should be considered in future studies investigating the relationship between low SES and poor neurodevelopmental outcomes.
Loss of NEDD4 causes complete XY gonadal sex reversal in mice
Authors: Windley Simon P. , Mayère Chloé , McGovern Alice E. , Harvey Natasha L. , Nef Serge , Schwarz Quenten , Kumar Sharad , Wilhelm Dagmar
Published: January 2022

Gonadogenesis is the process wherein two morphologically distinct organs, the testis and the ovary, arise from a common precursor. In mammals, maleness is driven by the expression of Sry. SRY subsequently upregulates the related family member Sox9 which is responsible for initiating testis differentiation while repressing factors critical to ovarian development such as FOXL2 and β-catenin. Here, we report a hitherto uncharacterised role for the ubiquitin-protein ligase NEDD4 in this process. XY Nedd4-deficient mice exhibit complete male-to-female gonadal sex reversal shown by the ectopic upregulation of Foxl2 expression at the time of gonadal sex determination as well as insufficient upregulation of Sox9. This sex reversal extends to germ cells with ectopic expression of SYCP3 in XY Nedd4-/- germ cells and significantly higher Sycp3 transcripts in XY and XX Nedd4-deficient mice when compared to both XY and XX controls. Further, Nedd4-/- mice exhibit reduced gonadal precursor cell formation and gonadal size as a result of reduced proliferation within the developing gonad as well as reduced Nr5a1 expression. Together, these results establish an essential role for NEDD4 in XY gonadal sex determination and development and suggest a potential role for NEDD4 in orchestrating these cell fate decisions through the suppression of the female pathway to ensure proper testis differentiation.
Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
Authors: Carabias Pablo , Espelt María V. , Bacigalupo María L. , Rojas Paola , Sarrias Luciana , Rubin Ayelén , Saffioti Nicolás A. , Elola María T. , Rossi Juan P. , Wolfenstein-Todel Carlota , Rabinovich Gabriel A. , Troncoso María F.
Published: January 2022

Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ‘loss-of-function’ experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.
Advances in the pathogenesis of psoriasis: from keratinocyte perspective
Authors: Zhou Xue , Chen Youdong , Cui Lian , Shi Yuling , Guo Chunyuan
Published: January 2022

Psoriasis is a complex long-lasting inflammatory skin disease with high prevalence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis.
E2F transcription factor 2-activated DLEU2 contributes to prostate tumorigenesis by upregulating serum and glucocorticoid-induced protein kinase 1
Authors: Li Peizhang , Xu Huan , Yang Liu , Zhan Ming , Shi Yuanping , Zhang Caoxu , Gao Dajun , Gu Meng , Chen Yanbo , Wang Zhong
Published: January 2022

Long noncoding RNAs (lncRNAs) participate in biological processes in multiple types of tumors. However, the regulatory patterns of lncRNAs in prostate cancer remain largely unclear. Here, we evaluated the expression and roles of the lncRNA DLEU2 in prostate cancer. Our results showed that DLEU2 was upregulated in advanced prostate cancer tissues. Patients with prostate cancer displaying high expression of DLEU2 had a poor prognosis. Moreover, we demonstrated that overexpression of DLEU2 facilitated the proliferation, migration, and invasion of prostate cancer in vitro. Mechanistically, DLEU2 promoted serum and glucocorticoid-induced protein kinase 1 (SGK1) expression by acting as an miR-582-5p sponge, and the transcription of DLEU2 was activated by the dysregulation of E2F transcription factor 2 (E2F2) expression in prostate cancer. Furthermore, knockdown of DLEU2 attenuated prostate cancer tumorigenesis in vivo. Notably, these findings suggested that E2F2-activated DLEU2 may function as a competing endogenous RNA to facilitate prostate cancer progression by targeting the miR-582-5p/SGK1 axis.
TRIP13, identified as a hub gene of tumor progression, is the target of microRNA-4693-5p and a potential therapeutic target for colorectal cancer
Authors: Chen Yan , Chen Danqi , Qin Ying , Qiu Cheng , Zhou Yaoyao , Dai Mengmeng , Li Lulu , Sun Qinsheng , Jiang Yuyang
Published: January 2022

Colorectal cancer (CRC) is one of the digestive tract malignancies whose early symptoms are not obvious. This study aimed to identify novel targets for CRC therapy, especially early-stage CRC, by reanalyzing the publicly available GEO and TCGA databases. Thyroid hormone receptor interactor 13 (TRIP13) correlated with tumor progression and prognosis of patients after several rounds of analysis, including weighted gene correlation network analysis (WGCNA), and further chosen for experimental validation in cancer cell lines and patient samples. We identified that mRNA and protein levels of TRIP13 increased in CRC cells and tumor tissues with tumor progression. miR-4693-5p was significantly downregulated in CRC tumor tissues and bound to the 3′ untranslated region (3′UTR) of TRIP13, downregulating TRIP13 expression. DCZ0415, a small molecule inhibitor targeting TRIP13, induced anti-tumor activity in vitro and in vivo. DCZ0415 markedly suppressed CRC cell proliferation, migration, and tumor growth, promoted cell apoptosis, and resulted in the arrest of the cell cycle. Our research suggests that TRIP13 might play a crucial role in CRC progression and could be a potential target for CRC therapy.
The sensitivity of simulated streamflow to individual hydrologic processes across North America
Authors: Mai Juliane , Craig James R. , Tolson Bryan A. , Arsenault Richard
Published: January 2022

Streamflow sensitivity to different hydrologic processes varies in both space and time. This sensitivity is traditionally evaluated for the parameters specific to a given hydrologic model simulating streamflow. In this study, we apply a novel analysis over more than 3000 basins across North America considering a blended hydrologic model structure, which includes not only parametric, but also structural uncertainties. This enables seamless quantification of model process sensitivities and parameter sensitivities across a continuous set of models. It also leads to high-level conclusions about the importance of water cycle components on streamflow predictions, such as quickflow being the most sensitive process for streamflow simulations across the North American continent. The results of the 3000 basins are used to derive an approximation of sensitivities based on physiographic and climatologic data without the need to perform expensive sensitivity analyses. Detailed spatio-temporal inputs and results are shared through an interactive website.
Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer
Authors: Sushentsev Nikita , McLean Mary A. , Warren Anne Y. , Benjamin Arnold J. V. , Brodie Cara , Frary Amy , Gill Andrew B. , Jones Julia , Kaggie Joshua D. , Lamb Benjamin W. , Locke Matthew J. , Miller Jodi L. , Mills Ian G. , Priest Andrew N. , Robb Fraser J. L. , Shah Nimish , Schulte Rolf F. , Graves Martin J. , Gnanapragasam Vincent J. , Brindle Kevin M. , Barrett Tristan , Gallagher Ferdia A.
Published: January 2022

Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.
Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant
Authors: Li Baisheng , Deng Aiping , Li Kuibiao , Hu Yao , Li Zhencui , Shi Yaling , Xiong Qianling , Liu Zhe , Guo Qianfang , Zou Lirong , Zhang Huan , Zhang Meng , Ouyang Fangzhu , Su Juan , Su Wenzhe , Xu Jing , Lin Huifang , Sun Jing , Peng Jinju , Jiang Huiming , Zhou Pingping , Hu Ting , Luo Min , Zhang Yingtao , Zheng Huanying , Xiao Jianpeng , Liu Tao , Tan Mingkai , Che Rongfei , Zeng Hanri , Zheng Zhonghua , Huang Yushi , Yu Jianxiang , Yi Lina , Wu Jie , Chen Jingdiao , Zhong Haojie , Deng Xiaoling , Kang Min , Pybus Oliver G. , Hall Matthew , Lythgoe Katrina A. , Li Yan , Yuan Jun , He Jianfeng , Lu Jing
Published: January 2022

The SARS-CoV-2 Delta variant has spread rapidly worldwide. To provide data on its virological profile, we here report the first local transmission of Delta in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of quarantined individuals indicated that the viral loads of Delta infections, when they first become PCR-positive, were on average ~1000 times greater compared to lineage A/B infections during the first epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. The estimated transmission bottleneck size of the Delta variant was generally narrow, with 1-3 virions in 29 donor-recipient transmission pairs. However, the transmission of minor iSNVs resulted in at least 3 of the 34 substitutions that were identified in the outbreak, highlighting the contribution of intra-host variants to population-level viral diversity during rapid spread.
Structural basis of the ligand binding and signaling mechanism of melatonin receptors
Authors: Wang Qinggong , Lu Qiuyuan , Guo Qiong , Teng Maikun , Gong Qingguo , Li Xu , Du Yang , Liu Zheng , Tao Yuyong
Published: January 2022

Melatonin receptors (MT1and MT2in humans) are family A G protein–coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made to develop drugs targeting melatonin receptors for the treatment of insomnia, circadian rhythm disorder, and cancer. However, designing subtype-selective melatonergic drugs remains challenging. Here, we report the cryo-EM structures of the MT1–Gisignaling complex with 2-iodomelatonin and ramelteon and the MT2–Gisignaling complex with ramelteon. These structures, together with the reported functional data, reveal that although MT1and MT2possess highly similar orthosteric ligand-binding pockets, they also display distinctive features that could be targeted to design subtype-selective drugs. The unique structural motifs in MT1and MT2mediate structural rearrangements with a particularly wide opening on the cytoplasmic side. Giis engaged in the receptor core shared by MT1and MT2and presents a conformation deviating from those in other Gicomplexes. Together, our results provide new clues for designing melatonergic drugs and further insights into understanding the G protein coupling mechanism.
Genetic markers for non-syndromic orofacial clefts in populations of European ancestry: a meta-analysis
Authors: Slavec Lara , Karas Kuželički Nataša , Locatelli Igor , Geršak Ksenija
Published: January 2022

To date, the involvement of various genetic markers in the aetiopathogenesis of non-syndromic orofacial cleft (nsOFC) has been extensively studied. In the present study, we focused on studies performed on populations of European ancestry to systematically review the available literature to define relevant genetic risk factors for nsOFC. Eligible studies were obtained by searching Ovid Medline and Ovid Embase. We gathered the genetic markers from population-based case–control studies on nsOFC, and conducted meta-analysis on the repeatedly reported markers. Whenever possible, we performed stratified analysis based on different nsOFC phenotypes, using allelic, dominant, recessive and overdominant genetic models. Effect sizes were expressed as pooled odds ratios (ORs) with 95% confidence intervals (CIs), and p ≤ 0.05 were considered statistically significant. A total of 84 studies were eligible for this systematic review, with > 700 markers included. Of these, 43 studies were included in the meta-analysis. We analysed 47 genetic variants in 30 genes/loci, which resulted in 226 forest plots. There were statistically significant associations between at least one of the nsOFC phenotypes and 19 genetic variants in 13 genes/loci. These data suggest that IRF6, GRHL3, 8q24, VAX1, TGFA, FOXE1, ABCA4, NOG, GREM1, AXIN2, DVL2, WNT3A and WNT5A have high potential as biomarkers of nsOFC in populations of European descent. Although other meta-analyses that included European samples have been performed on a limited number of genetic variants, this study represents the first meta-analysis of all genetic markers that have been studied in connection with nsOFC in populations of European ancestry.
Shifts in the foraging tactics of crocodiles following invasion by toxic prey
Authors: Aiyer Abhilasha , Shine Richard , Somaweera Ruchira , Bell Tina , Ward-Fear Georgia
Published: January 2022

Biological invasions can modify the behaviour of vulnerable native species in subtle ways. For example, native predators may learn or evolve to reduce foraging in conditions (habitats, times of day) that expose them to a toxic invasive species. In tropical Australia, freshwater crocodiles (Crocodylus johnstoni) are often fatally poisoned when they ingest invasive cane toads (Rhinella marina). The risk may be greatest if toads are seized on land, where a predator cannot wash away the toxins before they are absorbed into its bloodstream. Hence, toad invasion might induce crocodiles to forage in aquatic habitats only, foregoing terrestrial hunting. To test this idea, we conducted standardised trials of bait presentation to free-ranging crocodiles in sites with and without invasive toads. As anticipated, crocodiles rapidly learned to avoid consuming toads, and shifted to almost exclusively aquatic foraging.
VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer
Authors: Chionh Fiona , Gebski Val , Al-Obaidi Sheren J. , Mooi Jennifer K. , Bruhn Maressa A. , Lee Chee K. , Chüeh Anderly C. , Williams David S. , Weickhardt Andrew J. , Wilson Kate , Scott Andrew M. , Simes John , Hardingham Jennifer E. , Price Timothy J. , Mariadason John M. , Tebbutt Niall C.
Published: January 2022

The phase III MAX clinical trial randomised patients with metastatic colorectal cancer (mCRC) to receive first-line capecitabine chemotherapy alone or in combination with the anti-VEGF-A antibody bevacizumab (± mitomycin C). We utilised this cohort to examine whether single nucleotide polymorphisms (SNPs) in VEGF-A, VEGFR1, and VEGFR2 are predictive of efficacy outcomes with bevacizumab or the development of hypertension. Genomic DNA extracted from archival FFPE tissue for 325 patients (69% of the MAX trial population) was used to genotype 16 candidate SNPs in VEGF-A, VEGFR1, and VEGFR2, which were analysed for associations with efficacy outcomes and hypertension. The VEGF-A rs25648 ‘CC’ genotype was prognostic for improved PFS (HR 0.65, 95% CI 0.49 to 0.85; P = 0.002) and OS (HR 0.70, 95% CI 0.52 to 0.94; P = 0.019). The VEGF-A rs699947 ‘AA’ genotype was prognostic for shorter PFS (HR 1.32, 95% CI 1.002 to 1.74; P = 0.048). None of the analysed SNPs were predictive of bevacizumab efficacy outcomes. VEGFR2 rs11133360 ‘TT’ was associated with a lower risk of grade ≥ 3 hypertension (P = 0.028). SNPs in VEGF-A, VEGFR1 and VEGFR2 did not predict bevacizumab benefit. However, VEGF-A rs25648 and rs699947 were identified as novel prognostic biomarkers and VEGFR2 rs11133360 was associated with less grade ≥ 3 hypertension.
Quantum optical immunoassay: upconversion nanoparticle-based neutralizing assay for COVID-19
Authors: Rajil Navid , Esmaeili Shahriar , Neuman Benjamin W. , Nessler Reed , Wu Hung-Jen , Yi Zhenhuan , Brick Robert W. , Sokolov Alexei V. , Hemmer Philip R. , Scully Marlan O.
Published: January 2022

In a viral pandemic, a few important tests are required for successful containment of the virus and reduction in severity of the infection. Among those tests, a test for the neutralizing ability of an antibody is crucial for assessment of population immunity gained through vaccination, and to test therapeutic value of antibodies made to counter the infections. Here, we report a sensitive technique to detect the relative neutralizing strength of various antibodies against the SARS-CoV-2 virus. We used bright, photostable, background-free, fluorescent upconversion nanoparticles conjugated with SARS-CoV-2 receptor binding domain as a phantom virion. A glass bottom plate coated with angiotensin-converting enzyme 2 (ACE-2) protein imitates the target cells. When no neutralizing IgG antibody was present in the sample, the particles would bind to the ACE-2 with high affinity. In contrast, a neutralizing antibody can prevent particle attachment to the ACE-2-coated substrate. A prototype system consisting of a custom-made confocal microscope was used to quantify particle attachment to the substrate. The sensitivity of this assay can reach 4.0 ng/ml and the dynamic range is from 1.0 ng/ml to 3.2 $$\upmu$$
μ
g/ml. This is to be compared to 19 ng/ml sensitivity of commercially available kits.