bluuebunny/crossref_metadata_2025 huggingface dataset:
Land and Legibility: When Do Citizens Expect Secure Property Rights in Weak States?
Authors: FERREE KAREN E. , HONIG LAUREN , LUST ELLEN , PHILLIPS MELANIE L.
Published: May 2022

Legibility and political authority are often conflated in debates over formalization processes, including land titling. This can lead to a fundamental misunderstanding of what it is that citizens anticipate would strengthen their property rights. This study examines the effects of legibility on citizens’ evaluations of property rights in Malawi, a country with limited but increasing land titling. We argue that legibility is a strategic resource for citizens, which has value in itself. To disentangle the effects of legibility and authority on tenure security, we employ a survey experiment. Our findings show that respondents perceived land with written property rights to be more secure and more desirable regardless of whether a state or customary authority granted these land rights. In contrast to scholarship that examines legibility as a technology of state control, this research suggests that legibility can help citizens advance their interests.
Negotiating social meanings in a plural society: Social perceptions of variants of /l/ in Singapore English
Authors: Sim Jasper Hong
Published: May 2022

This study illustrates how speech features that emerged from language contact and acquisition in a pluralistic society can accrue diverse social-indexical meanings over time. The social perceptions towards three variants of coda /l/ in Singapore English—namely dark-l, the variant associated with prescriptive norms, and clear-l and vocalised-l, which are variants that arose through language contact—are examined. The findings show that clear-l and vocalised-l are associated with specific ethnic groups and have equally diverse meanings, but their meanings have evolved differently; vocalised-l is an emerging local standard, whereas clear-l remains largely stigmatised. Their diverse meanings are shown to be connected by social factors within a network of interrelated signs, and their interpretations are dependent on the hearer's experiences, such that we are observing different parts of the sociolinguistic reality. Restricted experiences with the social world and regulation of social perception are also shown to potentially contribute to accent-based prejudices. (Indexicality, language contact, ethnolect, lateral consonant, new Englishes, social perception)*
A novel precise pose prediction algorithm for setting the sleeping mode of the Yutu-2 rover based on a multiview block bundle adjustment
Authors: Peng Song , Ma Youqing , Xu Xinchao , Jia Yang , Liu Shaochuang
Published: May 2022

To set the sleeping mode for the Yutu-2 rover, a visual pose prediction algorithm including terrain reconstruction and pose estimation was first studied. The terrain reconstruction precision is affected by using only the stereo navigation camera (Navcam) images and the rotation angles of the mast. However, the hazard camera (Hazcam) pose is fixed, and an image network was constructed by linking all of the Navcam and Hazcam stereoimages. Then, the Navcam pose was refined based on a multiview block bundle adjustment. The experimental results show that the mean absolute errors of the check points in the proposed algorithm were 10.4 mm over the range of
$\boldsymbol{L}$
from 2.0 to 6.1 m, and the proposed algorithm achieved good prediction results for the rover pose (the average differences of the values of the pitch angle and the roll angle were −0.19 degrees and 0.29 degrees, respectively). Under the support of the proposed algorithm, engineers have completed the remote setting of the sleeping mode for Yutu-2 successfully in the Chang’e-4 mission operations.
Time for change? Recurrent barriers to music education
Authors: Henley Jennie , Barton David
Published: May 2022

This article reports findings from a study that sought to identify barriers to music and music education in the UK. Emerging from empirical research involving n = 723 participants and clarified by an evidence base of over 10,000 research participants, the key findings presented in this paper relate to pupil and participant voice and involvement, location as a sub-theme of diversity and inclusion, collaboration and transition points. The research is contextualised by twenty years of policy initiatives seeking to address barriers to music learning. The article provides an overview of the research study before presenting the rich data that emerged within each theme reported. Research participant voice is used as much as possible to enable the reader to consider, reflect and interpret the data in a way that is meaningful for their own context. The paper concludes by asking why after 20 years of policy initiatives, research and evaluation the same barriers still exist and, as we emerge from the pandemic, suggests that this research provides a compelling case that now is the time for change.
L’expérience de retour au travail des personnes vieillissantes ayant subi une atteinte à la santé : un examen de la portée
Authors: Lecours Alexandra , Bédard-Mercier Roxanne
Published: May 2022

Aging workers represent an emerging, growing, and essential population for the contemporary labour market. Considering their unique characteristics, these individuals are at risk of experiencing periods of disability at work due to different reasons (e.g., chronic diseases, occupational injuries) and a different return-to-work experience compared to younger workers. The scoping review presented in this article aimed to identify facilitators and barriers to returning to work in aging people who suffered a health impairment. Information from 34 manuscripts was extracted and analyzed, enabling the identification of factors hindering and facilitating the return to work of aging individuals, with regard to four systems: the individual, work, health, and compensation. The results suggest levers accessible to the various stakeholders involved in the process of returning to work for aging individuals to promote their healthy, safe, and satisfactory participation in work after a period of disability.
Associations between unpasteurised camel and other milk consumption, livestock ownership, and self-reported febrile and gastrointestinal symptoms among semi-pastoralists and pastoralists in the Somali Region of Ethiopia
Authors: Roess A. A. , Hosh F. M. , Morton L. C. , Bestul N. , Davis J. , Carruth L.
Published: May 2022

Contact with livestock and consumption of unpasteurised dairy products are associated with an increased risk of zoonotic and foodborne infection, particularly among populations with close animal contact, including pastoralists and semi-pastoralists. However, there are limited data on disease risk factors among pastoralists and other populations where livestock herding, particularly of dromedary camels, is common. This cross-sectional study used a previously validated survey instrument to identify risk factors for self-reported symptoms. Adults (n = 304) were randomly selected from households (n = 171) in the Somali Region of Ethiopia, a region characterised by chronic food insecurity, population displacement, recurrent droughts and large semi-pastoralist and pastoralist populations. Multivariable logistic regression assessed associations between self-reported symptoms and type of milk consumed, controlling for demographics and human-animal interaction. Consumption of days-old unrefrigerated raw camel milk was significantly associated with symptoms in the 30 days prior to the survey (AOR = 5.07; 95% CI 2.41–10.66), after controlling for age, refugee status, sanitation, camel ownership and source of drinking water and accounting for clustering. Consumption of days-old unrefrigerated raw ruminant milk was significantly associated with symptoms (AOR = 4.00, 95% CI 1.27–12.58). Source of drinking water and camel ownership, a proxy for camel contact, were significantly associated with the outcome in each model. There were no significant associations between self-reported symptoms and fresh or soured animal milk consumption. Research is needed to identify pathogens and major routes of transmission. Tailored communication campaigns to encourage safe food preparation should also be considered.
Implantation of a cardioverter-defibrillator in an 8-kg infant: a case report and literature review
Authors: Dalili Mohammad , Sadeghpour Tabaei Ali , Rezanejad Elham
Published: May 2022

The use of an implantable cardioverter-defibrillator to prevent sudden cardiac death is an approved method. Experience is limited regarding implantation techniques in infants and low-weight children. We herein describe the implantation of an epicardial implantable cardioverter-defibrillator in a 15-month-old infant weighing 8 kg. We also briefly discuss implantable cardioverter-defibrillator implantation in paediatrics, particularly infants, hoping that our experience will be drawn upon in further such attempts.
Transcatheter closure of ventricular septal defects: preliminary results in children weighing 10 kg or less
Authors: Mirza M Kamran , Abqari Shaad , Haseen Azam , Yadav Mayank
Published: May 2022

Introduction:

Ventricular septal defect is one of the commonest heart defect in children and closure of this defect with devices has seen a rapid progression over a period of time. The availability of new and safer devices has made the transcatheter closure of ventricular septal defect a suitable option even in young children.

Aim:

The study was done to evaluate the feasibility and complications of device closure of ventricular septal defect in children weighing 10 kg or less with different types of devices.

Methods:

The present study was undertaken in a newly established dedicated Paediatric Cardiac Unit at a Tertiary Care Hospital. Relevant data were obtained retrospectively from the case files and the catheterisation records and data were analysed for first 50 patients with ventricular septal defect weighing 10 kg or less between March 2018 and March 2021.

Results:

Among these 50 patients selected, device closure was successfully done in 45 (90%) cases while 5 (10%) attempts were unsuccessful for various reasons. The mean weight in this study was 7.46 ± 1.89 kg (2.3–10 kg), 21 (42%) cases were females while 29 (58%) were males; mean age was 19.4 ± 11.88 months (4–48 months). Right heart catheterisation study showed 21 (42%) patients with normal pulmonary artery pressures (no pulmonary artery hypertension). Among 29 patients with pulmonary arterial hypertension, 13 patients (22%) were having mild pulmonary arterial hypertension, 4 (8%) were with moderate pulmonary arterial hypertension, and 12 (24%) were with severe pulmonary arterial hypertension. Mean Qp/Qs was 2.73 ± 0.72 (2.5–4.5) and mean pulmonary vascular resistance was 1.5 ± 1.04 (0.6–4.6 WU). Amplatzer Duct Occluder (ADOI) was used in 15 (30%) cases, 27 (52%) cases were closed with Amplatzer Duct Occluder (ADOII), and the 3 (6%) cases closure was done with Amplatzer muscular ventricular septal defect occluder.

Conclusions:

Transcatheter closure of ventricular septal defect in children 10 kg or less is feasible and safe alternative to surgical ventricular septal defect closure. The immediate and short-term outcomes have proven this method to be safe and valid.
Learning a Weather Dictionary of Atmospheric Patterns Using Latent Dirichlet Allocation
Authors: Fery Lucas , Dubrulle Berengere , Podvin Berengere , Pons Flavio , Faranda Davide
Published: May 2022

Mid‐latitude circulation dynamics is often described in terms of weather regimes. Each pattern is given by a given combination of several synoptic objects (cyclones and anticyclones). Such intrication makes it arduous to quantify recurrence and intensity of climate extremes. Here we apply Latent Dirichlet Allocation (LDA), used for topic modeling in linguistics, to build a weather dictionary: we define daily maps of a gridded target observable as documents, and the grid‐points composing the map as words. LDA provides a representation of documents in terms of a combination of spatial patterns named motifs, which are latent patterns inferred from the set of snapshots. For atmospheric data, we find that motifs correspond to pure synoptic objects (cyclones and anticyclones), that can be seen as building blocks of weather regimes. We show that LDA weights provide a natural way to characterize the impact of climate change on the recurrence of patterns associated with extreme events.
Polarimetric Size Sorting Signatures in the Convective Regions of Mesoscale Convective Systems in PECAN: Implications on Kinematics, Thermodynamics, and Precipitation Pathways
Authors: Tam Frederick Iat‐Hin , Yang Ming‐Jen , Lee Wen‐Chau
Published: May 2022

An object‐based technique was utilized to identify hydrometeor size‐sorting signatures at lower levels in the convective regions of 10 mesoscale convective systems (MCSs) during the 2015 Plains Elevated Convection at Night (PECAN) field campaign. Composite statistical analysis indicates that the magnitudes of size‐sorting signatures (the separation distances between rain diameter maxima and concentration maxima) are nonlinearly correlated to the echo‐top height, rain mass beneath the melting level, and precipitation rates at higher percentiles. To explore this correlation, the weather forecasting and research model was used to simulate the 20 June 2015 MCS during PECAN. Statistical analysis of the model outputs indicates more active riming growth and quicker graupel fallout at warmer temperatures near areas with larger separation distances. While updraft intensity above the melting level was also positively correlated to separation distances, this correlation was only statistically significant within certain temperature ranges. Additional analyses reveal that the higher intense precipitation potential near signatures with large separation distances could be attributed to precipitation production from the melted graupel. Finally, spatial correspondence between graupel distribution at the melting level and rain distribution at the lowest model level illustrates the critical role of graupel sedimentation and sorting in creating size‐sorting signatures in MCSs during the PECAN field experiment.
Interpretable Framework of Physics‐Guided Neural Network With Attention Mechanism: Simulating Paddy Field Water Temperature Variations
Authors: Xie W. , Kimura M. , Takaki K. , Asada Y. , Iida T. , Jia X.
Published: May 2022

With the development of large‐scale rice cultivation management initiatives in East Asia, there is concern that a reduction in the number of human cultivators per unit area may lead to poor water management, which could result in decreased land productivity, owing to abnormally high‐ and low‐temperature damage to crops. Accurate simulation of paddy field water temperature is important for studying its impact on crops and providing timely information to aid in decision‐making for more efficient management under limited resources. We propose a neural‐network framework that considers the heat transfer by the vegetation canopy and applies physical‐theory constraints in its training. A novel tuning method is proposed to cope with the trade‐off between water temperature accuracy and physical consistency during training to ensure that the calculated water temperature variations in a paddy field enjoy high accuracy and physical consistency. In the experiments, the proposed framework outperforms physical process models and pure neural network models while maintaining high accuracy in the case of sparse data sets. Furthermore, an attention‐mechanism input layer is integrated into the model to rank feature importance, providing global interpretation to the proposed framework. We also perform sensitivity analysis on the physical process and propose models to compare their different strategies of feature ranking. The results show that the two methods have different sensitivities to different feature patterns, but they complement each other. In summary, the proposed model is credible and stable for practical applications and has the potential to guide more efficient paddy management.
Predicting Slowdowns in Decadal Climate Warming Trends With Explainable Neural Networks
Authors: Labe Zachary M. , Barnes Elizabeth A.
Published: May 2022

The global mean surface temperature (GMST) record exhibits both interannual to multidecadal variability and a long‐term warming trend due to external climate forcing. To explore the predictability of temporary slowdowns in decadal warming, we apply an artificial neural network (ANN) to climate model data from the Community Earth System Model Version 2 Large Ensemble. Here, an ANN is tasked with whether or not there will be a slowdown in the rate of the GMST trend by using maps of ocean heat content (OHC) at the onset. Through a machine learning explainability method, we find the ANN is learning off‐equatorial patterns of anomalous OHC that resemble transitions in the phase of the Interdecadal Pacific Oscillation in order to make slowdown predictions. Finally, we test our ANN on observed historical data, which further reveals how explainable neural networks are useful tools for understanding decadal variability in both climate models and observations.
Relativistic Electron Precipitation Driven by Nonlinear Resonance With Whistler‐Mode Waves
Authors: Tsai Ethan , Artemyev Anton , Zhang Xiao‐Jia , Angelopoulos Vassilis
Published: May 2022

Electron losses from the outer radiation belt are typically attributed to resonant electron scattering by whistler‐mode waves. Although the quasi‐linear diffusive regime of such scattering is well understood, the observed waves are often quite intense and in the nonlinear regime of resonant wave‐particle interaction. Such nonlinear resonant interactions are still being actively studied due to their potential for driving fast precipitation. However, direct observations of nonlinear resonance of whistler‐mode waves with electron distributions are scarce. Here, we present evidence for such resonance with high‐resolution electron energy and pitch angle spectra acquired at low‐altitudes by the dual Electron Losses and Fields INvestgation (ELFIN) CubeSats combined with conjugate measurements of equatorial plasma parameters, wave properties, and electron energy spectra by the Time History of Events and Macroscale Interactions during Substorms and Magnetospheric MultiScale missions. ELFIN has obtained numerous conjunction events exhibiting whistler wave driven precipitation; in this study, we present two such events which epitomize signatures of nonlinear resonant scattering. A test particle simulation of electron interactions with intense whistler‐mode waves prescribed at the equator is employed to directly compare modeled precipitation spectra with ELFIN observations. We show that the observed precipitating spectra match expectations to within observational uncertainties of wave amplitude for reasonable assumptions of wave power distribution along the magnetic field line. These results indicate the importance of nonlinear resonant effects when describing intense precipitation patterns of energetic electrons and open the possibility of remotely investigating equatorial wave properties using just properties of precipitation energy and pitch angle spectra.
Investigating aluminum cookpots as a source of lead exposure in Afghan refugee children resettled in the United States
Authors: Fellows Katie M. , Samy Shar , Rodriguez Yoni , Whittaker Stephen G.
Published: May 2022

Background

Afghan refugee children resettled in Washington State have the highest prevalence of elevated blood lead levels (BLLs) of any other refugee or immigrant population. Resettled families brought several lead-containing items with them from Afghanistan, including aluminum cookpots.

Objectives

To evaluate the potential contribution of lead-containing cookpots to elevated BLLs in Afghan children and determine whether safer alternative cookware is available.

Methods

We screened 40 aluminum cookpots for lead content using an X-ray fluorescence (XRF) analyzer and used a leachate method to estimate the amount of lead that migrates into food. We also tested five stainless steel cookpots to determine whether they would be safer alternatives.

Results

Many aluminum cookpots contained lead in excess of 100 parts per million (ppm), with a highest detected concentration of 66,374 ppm. Many also leached sufficient lead under simulated cooking and storage conditions to exceed recommended dietary limits. One pressure cooker leached sufficient lead to exceed the childhood limit by 650-fold. In contrast, stainless steel cookpots leached much lower levels of lead.

Significance

Aluminum cookpots used by refugee families are likely associated with elevated BLLs in local Afghan children. However, this investigation revealed that other U.S. residents, including adults and children, are also at risk of poisoning by lead and other toxic metals from some imported aluminum cookpots.

Impact Statement

Some aluminum cookware brought from Afghanistan by resettled families as well as cookpots available for purchase in the United States represent a previously unrecognized source of lead exposure.
Mutations in trpγ, the homologue of TRPC6 autism candidate gene, causes autism-like behavioral deficits in Drosophila
Authors: Palacios-Muñoz Angelina , de Paula Moreira Danielle , Silva Valeria , García Isaac E. , Aboitiz Francisco , Zarrei Mehdi , Campos Gabriele , Rennie Olivia , Howe Jennifer L. , Anagnostou Evdokia , Ambrozewic Patricia , Scherer Stephen W. , Passos-Bueno Maria Rita , Ewer John
Published: May 2022

Autism Spectrum Disorder (ASD) is characterized by impaired social communication, restricted interests, and repetitive and stereotyped behaviors. The TRPC6 (transient receptor potential channel 6) represents an ASD candidate gene under an oligogenic/multifactorial model based on the initial description and cellular characterization of an individual with ASD bearing a de novo heterozygous mutation disrupting TRPC6, together with the enrichment of disruptive TRPC6 variants in ASD cases as compared to controls. Here, we perform a clinical re-evaluation of the initial non-verbal patient, and also present eight newly reported individuals ascertained for ASD and bearing predicted loss-of-function mutations in TRPC6. In order to understand the consequences of mutations in TRPC6 on nervous system function, we used the fruit fly, Drosophila melanogaster, to show that null mutations in transient receptor gamma (trpγ; the fly gene most similar to TRPC6), cause a number of behavioral defects that mirror features seen in ASD patients, including deficits in social interactions (based on courtship behavior), impaired sleep homeostasis (without affecting the circadian control of sleep), hyperactivity in both young and old flies, and defects in learning and memory. Some defects, most notably in sleep, differed in severity between males and females and became normal with age. Interestingly, hyperforin, a TRPC6 agonist and the primary active component of the St. John’s wort antidepressant, attenuated many of the deficits expressed by trpγ mutant flies. In summary, our results provide further evidence that the TRPC6 gene is a risk factor for ASD. In addition, they show that the behavioral defects caused by mutations in TRPC6 can be modeled in Drosophila, thereby establishing a paradigm to examine the impact of mutations in other candidate genes.
A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response
Authors: Kim Ji Young , Cho Tae-Min , Park Jung Min , Park Soeun , Park Minsu , Nam Kee Dal , Ko Dongmi , Seo Juyeon , Kim Seongjae , Jung Eunsun , Farrand Lee , Nguyen Cong-Truong , Hoang Van-Hai , Thanh La Minh , Ann Jihyae , Nam Gibeom , Park Hyun-Ju , Lee Jeewoo , Kim Yoon-Jae , Seo Jae Hong
Published: May 2022

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.
Role of p38 MAP kinase in cancer stem cells and metastasis
Authors: Kudaravalli Sriya , den Hollander Petra , Mani Sendurai A.
Published: May 2022

Therapeutic resistance and metastatic progression are responsible for the majority of cancer mortalities. In particular, the development of resistance is a significant barrier to the efficacy of cancer treatments such as chemotherapy, radiotherapy, targeted therapies, and immunotherapies. Cancer stem cells (CSCs) underlie treatment resistance and metastasis. p38 mitogen-activated protein kinase (p38 MAPK) is downstream of several CSC-specific signaling pathways, and it plays an important role in CSC development and maintenance and contributes to metastasis and chemoresistance. Therefore, the development of therapeutic approaches targeting p38 can sensitize tumors to chemotherapy and prevent metastatic progression.
BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
Authors: Cremona Mattia , Vandenberg Cassandra J. , Farrelly Angela M. , Madden Stephen F. , Morgan Clare , Kalachand Roshni , McAlpine Jessica N. , Toomey Sinead , Huntsman David G. , Grogan Liam , Breathnach Oscar , Morris Patrick , Carey Mark S. , Scott Clare L. , Hennessy Bryan T.
Published: May 2022

Background

We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered inBRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.

Methods

The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.

Results

Expression of X-linked inhibitor of apoptosis (XIAP) is increased inBRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP.BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both aBRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restoredBRCA1remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.

Conclusion

A clinical trial may be justified to further investigate the utility of IAP inhibitors.
Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis
Authors: Lei Yujie , Huang Yunchao , Lin Jianbin , Sun Shihui , Che Keda , Shen Junting , Liao Jun , Chen Yangming , Chen Kai , Lin Zhaoxian , Lin Xing
Published: May 2022

The purpose of the current study was to define the role of MAX interactor 1 (Mxi1) in the pathogenesis of lung cancer and its underlying molecular mechanism. Bioinformatics analysis was performed to identify important regulatory pathway related to lung cancer. Dual luciferase reporter and ChIP assays were adopted to validate the interaction among Mxi1, miR-300 and KLF9. Loss- and gain-of-function studies were conducted to determine the roles of Mxi1, miR-300, and KLF9 in cell proliferation, migration, and invasion in vitro and their effects on myeloid-derived suppressor cell (MDSC) recruitment in vivo. Mxi1 was poorly expressed in lung cancer tissues and cells and its poor expression was associated with poor prognosis. Mxi1 inhibited miR-300 by suppressing its transcription. miR-300 suppressed the expression of KLF9, and KLF9 negatively regulated GADD34 expression in lung cancer cells. Mxi1 or KLF9 elevation or miR-300 repression inhibited lung cancer cell proliferation, as evidenced by reduced Ki67 and PCNA expression, and lowered invasion and migration. In vivo findings revealed that silencing KLF9 induced tumor growth by enhancing MDSC-mediated immunosuppression through upregulation of GADD34. Collectively, these findings suggest that Mxi1 can inhibit lung cancer progression by regulating the miR-300/KLF9 axis and GADD34-mediated immunosuppression.
UHMK1 aids colorectal cancer cell proliferation and chemoresistance through augmenting IL-6/STAT3 signaling
Authors: Gao Xuedi , Bao Wenfang , Bai Jin , Fan Kailing , Li Li , Li Yandong
Published: May 2022

UHMK1, a serine/threonine kinase with a U2AF homology motif, is implicated in RNA processing and protein phosphorylation. Increasing evidence has indicated its involvement in tumorigenesis. However, it remains to be elucidated whether UHMK1 plays a role in the development of colorectal cancer (CRC). Here, we demonstrated that UHMK1 was frequently upregulated in CRC samples compared with adjacent normal tissue and high expression of UHMK1 predicted poor outcomes. Knockdown of UHMK1 by siRNAs restrained CRC cell proliferation and increased oxaliplatin sensitivity, whereas overexpression of UHMK1 promoted CRC cell growth and oxaliplatin resistance, suggesting that UHMK1 plays important oncogenic roles in CRC. Mechanistically, we showed that UHMK1 had a significant effect on IL6/STAT3 signaling by interacting with STAT3. The interaction of UHMK1 with STAT3 enhanced STAT3 activity in regulating gene transcription. Furthermore, we found that STAT3 could in turn transcriptionally activate UHMK1 expression in CRC cells. The complementary experiments for cell growth and oxaliplatin resistance indicated the interdependent relationship between UHMK1 and STAT3. Thus, these collective findings uncovered a new UHMK1/STAT3 positive feedback regulatory loop contributing to CRC development and chemoresistance.
The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury
Authors: Li Zixian , Liu Zejian , Luo Mianna , Li Xingyu , Chen Huixia , Gong Siqiao , Zhang Minjie , Zhang Yaozhi , Liu Huafeng , Li Xiaoyu
Published: May 2022

Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. The pathogenesis of AKI has not been fully elucidated, with a lack of effective treatment. Renal tubular epithelial cells (TECs) play an important role in AKI, and their damage and repair largely determine the progression and prognosis of AKI. In recent decades, it has been found that the mitochondria, endoplasmic reticulum (ER), lysosomes, and other organelles in TECs are damaged to varying degrees in AKI, and that they can influence each other through various signaling mechanisms that affect the recovery of TECs. However, the association between these multifaceted signaling platforms, particularly between mitochondria and lysosomes during AKI remains unclear. This review summarizes the specific pathophysiological mechanisms of the main TECs organelles in the context of AKI, particularly the potential interactions among them, in order to provide insights into possible novel treatment strategies.
A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies
Authors: Scott Jamie I. , Mendive-Tapia Lorena , Gordon Doireann , Barth Nicole D. , Thompson Emily J. , Cheng Zhiming , Taggart David , Kitamura Takanori , Bravo-Blas Alberto , Roberts Edward W. , Juarez-Jimenez Jordi , Michel Julien , Piet Berber , de Vries I. Jolanda , Verdoes Martijn , Dawson John , Carragher Neil O. , Connor Richard A. O’ , Akram Ahsan R. , Frame Margaret , Serrels Alan , Vendrell Marc
Published: May 2022

Immunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probeH5with an optimal fit into granzyme B. We demonstrate that probeH5enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probeH5may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
Vertically optimized phase separation with improved exciton diffusion enables efficient organic solar cells with thick active layers
Authors: Cai Yunhao , Li Qian , Lu Guanyu , Ryu Hwa Sook , Li Yun , Jin Hui , Chen Zhihao , Tang Zheng , Lu Guanghao , Hao Xiaotao , Woo Han Young , Zhang Chunfeng , Sun Yanming
Published: May 2022

The development of organic solar cells (OSCs) with thick active layers is of crucial importance for the roll-to-roll printing of large-area solar panels. Unfortunately, increasing the active layer thickness usually results in a significant reduction in efficiency. Herein, we fabricated efficient thick-film OSCs with an active layer consisting of one polymer donor and two non-fullerene acceptors. The two acceptors were found to possess enlarged exciton diffusion length in the mixed phase, which is beneficial to exciton generation and dissociation. Additionally, layer by layer approach was employed to optimize the vertical phase separation. Benefiting from the synergetic effects of enlarged exciton diffusion length and graded vertical phase separation, an efficiency of 17.31% (certified value of 16.9%) is obtained for the 300 nm-thick OSC, with a short-circuit current density of 28.36 mA cm−2, and a high fill factor of 73.0%. Moreover, the device with an active layer thickness of 500 nm also shows an efficiency of 15.21%. This work provides valuable insights into the fabrication of OSCs with thick active layers.
Mre11-Rad50 oligomerization promotes DNA double-strand break repair
Authors: Kissling Vera M. , Reginato Giordano , Bianco Eliana , Kasaciunaite Kristina , Tilma Janny , Cereghetti Gea , Schindler Natalie , Lee Sung Sik , Guérois Raphaël , Luke Brian , Seidel Ralf , Cejka Petr , Peter Matthias
Published: May 2022

The conserved Mre11-Rad50 complex is crucial for the detection, signaling, end tethering and processing of DNA double-strand breaks. While it is known that Mre11-Rad50 foci formation at DNA lesions accompanies repair, the underlying molecular assembly mechanisms and functional implications remained unclear. Combining pathway reconstitution in electron microscopy, biochemical assays and genetic studies, we show that S. cerevisiae Mre11-Rad50 with or without Xrs2 forms higher-order assemblies in solution and on DNA. Rad50 mediates such oligomerization, and mutations in a conserved Rad50 beta-sheet enhance or disrupt oligomerization. We demonstrate that Mre11-Rad50-Xrs2 oligomerization facilitates foci formation, DNA damage signaling, repair, and telomere maintenance in vivo. Mre11-Rad50 oligomerization does not affect its exonuclease activity but drives endonucleolytic cleavage at multiple sites on the 5′-DNA strand near double-strand breaks. Interestingly, mutations in the human RAD50 beta-sheet are linked to hereditary cancer predisposition and our findings might provide insights into their potential role in chemoresistance.
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Authors: Papes Fabio , Camargo Antonio P. , de Souza Janaina S. , Carvalho Vinicius M. A. , Szeto Ryan A. , LaMontagne Erin , Teixeira José R. , Avansini Simoni H. , Sánchez-Sánchez Sandra M. , Nakahara Thiago S. , Santo Carolina N. , Wu Wei , Yao Hang , Araújo Barbara M. P. , Velho Paulo E. N. F. , Haddad Gabriel G. , Muotri Alysson R.
Published: May 2022

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C
Authors: McCafferty Conor , Cai Tengyi , Borgel Delphine , Lasne Dominique , Renolleau Sylvain , Vedrenne-Cloquet Meryl , Bonnet Damien , Wu Jemma , Zaw Thiri , Bhatnagar Atul , Song Xiaomin , Van Den Helm Suelyn , Letunica Natasha , Attard Chantal , Karlaftis Vasiliki , Praporski Slavica , Ignjatovic Vera , Monagle Paul
Published: May 2022

COVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.
The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy
Authors: Graca Flavia A. , Rai Mamta , Hunt Liam C. , Stephan Anna , Wang Yong-Dong , Gordon Brittney , Wang Ruishan , Quarato Giovanni , Xu Beisi , Fan Yiping , Labelle Myriam , Demontis Fabio
Published: May 2022

Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
Genetic associations with healthy ageing among Chinese adults
Authors: Chang Xuling , Zhou Yan-Feng , Wang Ling , Liu Jianjun , Yuan Jian-Min , Khor Chiea-Chuen , Heng Chew-Kiat , Pan An , Koh Woon-Puay , Dorajoo Rajkumar
Published: May 2022

The genetic basis of overall healthy ageing, especially among the East-Asian population is understudied. We conducted a genome-wide association study among 1618 Singapore Chinese elderly participants (65 years or older) ascertained to have aged healthily and compared their genome-wide genotypes to 6221 participants who did not age healthily, after a 20-year follow-up. Two genetic variants were identified (PMeta < 2.59 × 10−8) to be associated with healthy aging, including theLRP1Blocus previously associated in long-lived individuals without cognitive decline. Our study sheds additional insights on the genetic basis of healthy ageing.
GGDEF domain as spatial on-switch for a phosphodiesterase by interaction with landmark protein HubP
Authors: Rick Tim , Kreiling Vanessa , Höing Alexander , Fiedler Svenja , Glatter Timo , Steinchen Wieland , Hochberg Georg , Bähre Heike , Seifert Roland , Bange Gert , Knauer Shirley K. , Graumann Peter L. , Thormann Kai M.
Published: May 2022

In bacteria, the monopolar localization of enzymes and protein complexes can result in a bimodal distribution of enzyme activity between the dividing cells and heterogeneity of cellular behaviors. In Shewanella putrefaciens, the multidomain hybrid diguanylate cyclase/phosphodiesterase PdeB, which degrades the secondary messenger c-di-GMP, is located at the flagellated cell pole. Here, we show that direct interaction between the inactive diguanylate cyclase (GGDEF) domain of PdeB and the FimV domain of the polar landmark protein HubP is crucial for full function of PdeB as a phosphodiesterase. Thus, the GGDEF domain serves as a spatially controlled on-switch that effectively restricts PdeBs activity to the flagellated cell pole. PdeB regulates abundance and activity of at least two crucial surface-interaction factors, the BpfA surface-adhesion protein and the MSHA type IV pilus. The heterogeneity in c-di-GMP concentrations, generated by differences in abundance and timing of polar appearance of PdeB, orchestrates the population behavior with respect to cell-surface interaction and environmental spreading.
Emergence of instability-driven domains in soft stratified materials
Authors: Li Jian , Slesarenko Viacheslav , Rudykh Stephan
Published: May 2022

Nature frequently employs the buckling phenomenon to facilitate the formation of complicated patterns across length-scales. Current knowledge, however, is limited to a small set of buckling-induced microstructure transformations in soft composites; and the pattern formation phenomenon remains largely unknown for a vast pool of material morphologies. Here, we investigate the unexplored rich domain of soft heterogeneous composites. We experimentally observe the formation of instability-driven domains in stratified composites with a non-dilute stiff phase. We illustrate that the discovered domain patterns are energetically favorable over wrinkling. Moreover, we introduce a closed-form analytical expression allowing us to predict the evolution of the patterns in the post-buckling regime. Finally, we show that various patterns can be pre-designed via altering material compositions. These findings can help advance our understanding of the mechanisms governing pattern formations in soft biological tissues, and potentially enable the platform for mechanical metamaterials.
Sabertooth carcass consumption behavior and the dynamics of Pleistocene large carnivoran guilds
Authors: Domínguez-Rodrigo Manuel , Egeland Charles P. , Cobo-Sánchez Lucía , Baquedano Enrique , Hulbert Richard C.
Published: May 2022

Apex predators play an important role in the top-down regulation of ecological communities. Their hunting and feeding behaviors influence, respectively, prey demography and the availability of resources to other consumers. Among the most iconic—and enigmatic—terrestrial predators of the late Cenozoic are the Machairodontinae, a diverse group of big cats whose hypertrophied upper canines have earned them the moniker “sabertooths.” Many aspects of these animals’ paleobiology, especially their prey preferences and carcass consumption behavior, remain unsettled. While skeletal anatomy, dental morphology and wear, and isotopic profiles provide important insights, the most direct way to resolve these issues is through the fossil remains of sabertooth prey. Here, we report on a taphonomic analysis of an early Pleistocene faunal assemblage from Haile 21A (Florida, USA) that preserves feeding damage from the lion-sized sabertoothXenosmilus hodsonae. Patterns of tooth-marking and bone damage indicate thatXenosmilusfully defleshed the carcasses of their prey and even engaged in some minor bone consumption. This has important implications for Pleistocene carnivoran guild dynamics, including the carcass foraging behavior of the first stone-tool-using hominins.
Discordant American Society of Anesthesiologists Physical Status Classification between anesthesiologists and surgeons and its correlation with adverse patient outcomes
Authors: Kwa Charlene Xian Wen , Cui Jiaqian , Lim Daniel Yan Zheng , Sim Yilin Eileen , Ke Yuhe , Abdullah Hairil Rizal
Published: May 2022

The American Society of Anesthesiologists Physical Status Classification (ASA) is used for communication of patient health status, risk scoring, benchmarking and financial claims. Prior studies using hypothetical scenarios have shown poor concordance of ASA classification among healthcare providers. There is a paucity of studies using clinical data, and of clinical factors or patient outcomes associated with discordant classification. The study aims to assess ASA classification concordance between surgeons and anesthesiologists, factors surrounding discordance and its impact on patient outcomes. This retrospective cohort study was conducted in a tertiary medical center on 46,284 consecutive patients undergoing elective surgery between January 2017 and December 2019. The ASA class showed moderate concordance (weighted Cohen’s κ 0.53) between surgeons and anesthesiologists. We found significant associations between discordant classification and patient comorbidities, age and race. Patients with discordant classification had a higher risk of 30-day mortality (odds ratio (OR) 2.00, 95% confidence interval (CI) = 1.52–2.62, p < 0.0001), 1-year mortality (OR 1.53, 95% CI = 1.38–1.69, p < 0.0001), and Intensive Care Unit admission > 24 h (OR 1.69, 95% CI = 1.47–1.94, p < 0.0001). Hence, there is a need for improved standardization of ASA scoring and cross-specialty review in ASA-discordant cases.