bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attitude of pediatricians toward suspected cases of child sexual abuse (CSA) in Saudi Arabia
Authors: Aleissa Majed Abdualaziz , Sultana Khizra , Saleheen Hassan Nazmus , Aldihan Dalal Ahmad , Al-Omar Razan Hussain , Alharbi Rana Obaid , Allahidan Raghad Saleh , Alshagary Rema 
Published: November 2021

Objective:
To assess the attitudes of pediatricians working at the Ministry of National Guard-Health Affairs (MNGHA) to report cases of child sexual abuse (CSA) and to determine the association between the demographic, cultural characteristics, and the attitude toward reporting.

Participants and Settings:
The participants included all pediatricians, from consultants to residents, employed at the Pediatric Department of the King Abdulaziz Medical City and King Abdullah Specialist Children's Hospital, Riyadh. Additional inclusion criteria were females and males, Saudis and non-Saudis, and age 20—60 years.

Methods:
A self-administered, hard copy questionnaire was distributed to 277 pediatricians, and the response rate was 58.48%. The sensitivity/specificity emphasis mean score was calculated. Categorical variables were tested against the sensitivity/specificity emphasis mean score using an ANOVA and an independent sample t-test. The reliability of the questionnaire was measured with Cronbach's alpha.

Results:
In total, 153 completed questionnaires were analyzed. The responses were inclined toward balanced (indecisive toward reporting) and high specificity (favors the decision not to report suspected CSA). No significant difference was found in the sensitivity/specificity mean score between the different levels of professionals, experience, age, gender, and number of prior child abuse-related courses. The skepticism scale showed, for the different professional levels, that the staff physician/resident believed the 3- to 5-year-old girls and boys to be genuine. The consultants/associate consultants believed 6- to 12- year and 13- to 17-year-old girls and boys to be true most of the time. Nearly half of the participants indicated that their reporting decision was affected by the possible consequences of reporting suspected CSA for the children's families and the social perceptions of sexually abused children as adults.

Conclusion:
The results highlight the low reporting rates of CSA cases. The findings suggest a lack of training and experience of the professionals in this area of assessing, detecting, and reporting CSA cases.
ARGUMENTS AGAINST THE INEQUITABLE DISTRIBUTION OF VACCINES USING THE ACCESS AND BENEFIT SHARING TRANSACTION
Authors: Eccleston-Turner Mark , Rourke Michelle 
Published: November 2021

AbstractAccess and benefit sharing (ABS) is a transactional mechanism designed to allow countries to trade access to their sovereign genetic resources for monetary and non-monetary benefits, with the ultimate goal of channelling those benefits into sustainable development and environmental conservation. Arguments about how pathogens are not the sort of genetic resources the world ought to conserve eventually gave way to a recognition that pathogens are indeed sovereign genetic resources under the Convention on Biological Diversity and its Nagoya Protocol, and that the ABS transaction may be an effective way to deliver scarce vaccines to developing nations as benefits received in exchange for shared pathogen samples. This article argues that categorising vaccines as benefits given in exchange for access to pathogen samples creates opposing incentives for providers and users of virus samples and undermines the human right to health because it makes that right a commodity to be bought. The provision of pathogen samples to the global research commons and the fair and equitable distribution of medicines should be two parallel public goods to be pursued as goals in and of themselves. We conclude that the linking of these goals through the ABS transaction should be reassessed.
Slip Distribution and Footwall Topography of the Yanggao‐Tianzhen Fault (Northern Shanxi Graben): Implications for the Along‐Strike Variations in Fault Activity and Regional Deformation
Authors: Luo Quanxing , Li Chuanyou , Li Xinnan , Ren Guangxue , Dong Jinyuan 
Published: November 2021

AbstractSpatial patterns in fault activity were examined along the Yanggao‐Tianzhen Fault (YTF) in the northern Shanxi Graben, North China. First, we reconstructed the distribution of fault slips and quantified slip rates at seven sites along the fault, based on satellite image interpretation, field investigation, topographic surveying, and optically stimulated luminescence dating. The T3terraces and their contemporaneous alluvial fans with a best‐estimate age of 31.7 ± 1.4 kyr were used as strain markers to estimate slip magnitudes. We determined vertical slip and dip‐slip rates of ∼0.10–0.31 mm/yr and ∼0.11–0.37 mm/yr, respectively, at the surface. Assuming fault dips of 40 ± 10° at seismogenic depths, we predicted extension rates of ∼0.17–0.55 mm/yr. This suggests that at least 10% and up to 28%–54% (95% confidence interval) of the total extension of the northern Shanxi Graben is inhomogeneously partitioned by different sections of the YTF. We also evaluated the along‐fault relative tectonic activity by analyzing of five widely used geomorphic indices: hypsometric integral, basin elongation ratio, asymmetric factor, valley‐floor‐width‐to‐height ratio, and mountain front sinuosity. The determined fault slip rates and geomorphic indices demonstrate that the most prominent fault activity center occurred in the middle of the fault, and that fault activity wanes toward the fault tips. Moreover, the fault activity is highly heterogeneous and fluctuates along the fault strike, which may be attributed to either fault segmentation and linkage or the possible strike‐slip component of motion along the fault. Further exploration of fault kinematics and paleoseismic history is warranted.
PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells
Authors: Sheshadri Namratha , Poria Dipak K. , Sharan Shikha , Hu Ying , Yan Chunhua , Koparde Vishal N. , Balamurugan Kuppusamy , Sterneck Esta 
Published: November 2021

AbstractCancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.
CaMKK2 facilitates Golgi-associated vesicle trafficking to sustain cancer cell proliferation
Authors: Stewart Lorna M. , Gerner Lisa , Rettel Mandy , Stein Frank , Burrows James F. , Mills Ian G. , Evergren Emma 
Published: November 2021

AbstractCalcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates cell and whole-body metabolism and supports tumorigenesis. The cellular impacts of perturbing CAMKK2 expression are, however, not yet fully characterised. By knocking down CAMKK2 levels, we have identified a number of significant subcellular changes indicative of perturbations in vesicle trafficking within the endomembrane compartment. To determine how they might contribute to effects on cell proliferation, we have used proteomics to identify Gemin4 as a direct interactor, capable of binding CAMKK2 and COPI subunits. Prompted by this, we confirmed that CAMKK2 knockdown leads to concomitant and significant reductions in δ-COP protein. Using imaging, we show that CAMKK2 knockdown leads to Golgi expansion, the induction of ER stress, abortive autophagy and impaired lysosomal acidification. All are phenotypes of COPI depletion. Based on our findings, we hypothesise that CAMKK2 sustains cell proliferation in large part through effects on organelle integrity and membrane trafficking.
Coexistence of structural and magnetic phases in van der Waals magnet CrI3
Authors: Meseguer-Sánchez Jaume , Popescu Catalin , García-Muñoz José Luis , Luetkens Hubertus , Taniashvili Grigol , Navarro-Moratalla Efrén , Guguchia Zurab , Santos Elton J. G. 
Published: November 2021

AbstractCrI3 has raised as an important system to the emergent field of two-dimensional van der Waals magnetic materials. However, it is still unclear why CrI3 which has a ferromagnetic rhombohedral structure in bulk, changed to anti-ferromagnetic monoclinic at thin layers. Here we show that this behaviour is due to the coexistence of both monoclinic and rhombohedral crystal phases followed by three magnetic transitions at TC1 = 61 K, TC2 = 50 K and TC3 = 25 K. Each transition corresponds to a certain fraction of the magnetically ordered volume as well as monoclinic and rhombohedral proportion. The different phases are continuously accessed as a function of the temperature over a broad range of magnitudes. Our findings suggest that the challenge of understanding the magnetic properties of thin layers CrI3 is in general a coexisting structural-phase problem mediated by the volume-wise competition between magnetic phases already present in bulk.
A comparative analysis of cell surface targeting aptamers
Authors: Kelly Linsley , Maier Keith E. , Yan Amy , Levy Matthew 
Published: November 2021

AbstractAptamers represent a potentially important class of ligands for the development of diagnostics and therapeutics. However, it is often difficult to compare the function and specificity of many of these molecules as assay formats and conditions vary greatly. Here, with an interest in developing aptamer targeted therapeutics that could effectively deliver cargoes to cells, we chemically synthesize 15 aptamers that have been reported to target cell surface receptors or cells. Using standardized assay conditions, we assess each aptamer’s binding properties on a panel of 11 different cancer cell lines, correlate aptamer binding to antibody controls and use siRNA transfection to validate each aptamer’s binding to reported target receptors. Using a subset of these molecules known to be expressed on prostate cancers, we use near-infrared in vivo imaging to assess the tumor localization following intravenous injection. Our data demonstrate some surprising differences in the reported specificity and function for many of these molecules and raise concerns regarding their cell targeting capabilities. They also identify an anti-human transferrin aptamer, Waz, as a robust candidate for targeting prostate cancers and for future development of aptamer-based therapeutics.
Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo
Authors: Ibraheim Raed , Tai Phillip W. L. , Mir Aamir , Javeed Nida , Wang Jiaming , Rodríguez Tomás C. , Namkung Suk , Nelson Samantha , Khokhar Eraj Shafiq , Mintzer Esther , Maitland Stacy , Chen Zexiang , Cao Yueying , Tsagkaraki Emmanouela , Wolfe Scot A. , Wang Dan , Pai Athma A. , Xue Wen , Gao Guangping , Sontheimer Erik J. 
Published: November 2021

AbstractAdeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. Here, we describe single-vector, ~4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs for segmental deletions, or a single sgRNA with a homology-directed repair (HDR) template. We also use anti-CRISPR proteins to enable production of vectors that self-inactivate via Nme2Cas9 cleavage. We further introduce a nanopore-based sequencing platform that is designed to profile rAAV genomes and serves as a quality control measure for vector homogeneity. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice by HDR-based correction of the disease allele. These results will enable the engineering of single-vector AAVs that can achieve diverse therapeutic genome editing outcomes.
The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors
Authors: Gebregiworgis Teklab , Kano Yoshihito , St-Germain Jonathan , Radulovich Nikolina , Udaskin Molly L. , Mentes Ahmet , Huang Richard , Poon Betty P. K. , He Wenguang , Valencia-Sama Ivette , Robinson Claire M. , Huestis Melissa , Miao Jinmin , Yeh Jen Jen , Zhang Zhong-Yin , Irwin Meredith S. , Lee Jeffrey E. , Tsao Ming-Sound , Raught Brian , Marshall Christopher B. , Ohh Michael , Ikura Mitsuhiko 
Published: November 2021

AbstractCancer cells bearing distinct KRAS mutations exhibit variable sensitivity to SHP2 inhibitors (SHP2i). Here we show that cells harboring KRAS Q61H are uniquely resistant to SHP2i, and investigate the underlying mechanisms using biophysics, molecular dynamics, and cell-based approaches. Q61H mutation impairs intrinsic and GAP-mediated GTP hydrolysis, and impedes activation by SOS1, but does not alter tyrosyl phosphorylation. Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. Phosphorylation of wild-type and Gly12-mutant KRAS, which are associated with sensitivity to SHP2i, confers resistance to regulation by GAP and GEF activities and impairs binding to RAF, whereas the near-complete GAP/GEF-resistance of KRAS Q61H remains unaltered, and high-affinity RAF interaction is retained. SHP2 can stimulate KRAS signaling by modulating GEF/GAP activities and dephosphorylating KRAS, processes that fail to regulate signaling of the Q61H mutant.
Sustained enzymatic activity and flow in crowded protein droplets
Authors: Testa Andrea , Dindo Mirco , Rebane Aleksander A. , Nasouri Babak , Style Robert W. , Golestanian Ramin , Dufresne Eric R. , Laurino Paola 
Published: November 2021

AbstractLiving cells harvest energy from their environments to drive the chemical processes that enable life. We introduce a minimal system that operates at similar protein concentrations, metabolic densities, and length scales as living cells. This approach takes advantage of the tendency of phase-separated protein droplets to strongly partition enzymes, while presenting minimal barriers to transport of small molecules across their interface. By dispersing these microreactors in a reservoir of substrate-loaded buffer, we achieve steady states at metabolic densities that match those of the hungriest microorganisms. We further demonstrate the formation of steady pH gradients, capable of driving microscopic flows. Our approach enables the investigation of the function of diverse enzymes in environments that mimic cytoplasm, and provides a flexible platform for studying the collective behavior of matter driven far from equilibrium.
Microevolutionary dynamics show tropical valleys are deeper for montane birds of the Atlantic Forest
Authors: Thom Gregory , Gehara Marcelo , Smith Brian Tilston , Miyaki Cristina Y. , do Amaral Fábio Raposo 
Published: November 2021

AbstractTropical mountains hold more biodiversity than their temperate counterparts, and this disparity is often associated with the latitudinal climatic gradient. However, distinguishing the impact of latitude versus the background effects of species history and traits is challenging due to the evolutionary distance between tropical and temperate assemblages. Here, we test whether microevolutionary processes are linked to environmental variation across a sharp latitudinal transition in 21 montane birds of the southern Atlantic Forest in Brazil. We find that effective dispersal within populations in the tropical mountains is lower and genomic differentiation is better predicted by the current environmental complexity of the region than within the subtropical populations. The concordant response of multiple co-occurring populations is consistent with spatial climatic variability as a major process driving population differentiation. Our results provide evidence for how a narrow latitudinal gradient can shape microevolutionary processes and contribute to broader scale biodiversity patterns.
Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues
Authors: Paparella Ashleigh S. , Aboulache Briana L. , Harijan Rajesh K. , Potts Kathryn S. , Tyler Peter C. , Schramm Vern L. 
Published: November 2021

AbstractClostridium difficile causes life-threatening diarrhea and is the leading cause of healthcare-associated bacterial infections in the United States. TcdA and TcdB bacterial toxins are primary determinants of disease pathogenesis and are attractive therapeutic targets. TcdA and TcdB contain domains that use UDP-glucose to glucosylate and inactivate host Rho GTPases, resulting in cytoskeletal changes causing cell rounding and loss of intestinal integrity. Transition state analysis revealed glucocationic character for the TcdA and TcdB transition states. We identified transition state analogue inhibitors and characterized them by kinetic, thermodynamic and structural analysis. Iminosugars, isofagomine and noeuromycin mimic the transition state and inhibit both TcdA and TcdB by forming ternary complexes with Tcd and UDP, a product of the TcdA- and TcdB-catalyzed reactions. Both iminosugars prevent TcdA- and TcdB-induced cytotoxicity in cultured mammalian cells by preventing glucosylation of Rho GTPases. Iminosugar transition state analogues of the Tcd toxins show potential as therapeutics for C. difficile pathology.
Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface
Authors: Hunter Miranda V. , Moncada Reuben , Weiss Joshua M. , Yanai Itai , White Richard M. 
Published: November 2021

AbstractDuring tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.
Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody
Authors: Jo Gyunghee , Bae Jeomil , Hong Ho Jeong , Han Ah-reum , Kim Do-Kyun , Hong Seon Pyo , Kim Jung A , Lee Sangkyu , Koh Gou Young , Kim Ho Min 
Published: November 2021

AbstractAngiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.
Nuclear S-nitrosylation impacts tissue regeneration in zebrafish
Authors: Matrone Gianfranco , Jung Sung Yun , Choi Jong Min , Jain Antrix , Leung Hon-Chiu Eastwood , Rajapakshe Kimal , Coarfa Cristian , Rodor Julie , Denvir Martin A. , Baker Andrew H. , Cooke John P. 
Published: November 2021

AbstractDespite the importance of nitric oxide signaling in multiple biological processes, its role in tissue regeneration remains largely unexplored. Here, we provide evidence that inducible nitric oxide synthase (iNos) translocates to the nucleus during zebrafish tailfin regeneration and is associated with alterations in the nuclear S-nitrosylated proteome. iNos inhibitors or nitric oxide scavengers reduce protein S-nitrosylation and impair tailfin regeneration. Liquid chromatography/tandem mass spectrometry reveals an increase of up to 11-fold in the number of S-nitrosylated proteins during regeneration. Among these, Kdm1a, a well-known epigenetic modifier, is S-nitrosylated on Cys334. This alters Kdm1a binding to the CoRest complex, thus impairing its H3K4 demethylase activity, which is a response specific to the endothelial compartment. Rescue experiments show S-nitrosylation is essential for tailfin regeneration, and we identify downstream endothelial targets of Kdm1a S-nitrosylation. In this work, we define S-nitrosylation as an essential post-translational modification in tissue regeneration.