bluuebunny/crossref_metadata_2025_split huggingface dataset:
General Practitioners’ Roles in Disaster Health Management: Perspectives of Disaster Managers
Authors: Burns Penelope L. , FitzGerald Gerard J. , Hu Wendy C. , Aitken Peter , Douglas Kirsty A. 
Published: December 2021

AbstractIntroduction:General Practitioners (GPs) are inevitably involved when disaster strikes their communities. Evidence of health care needs in disasters increasingly suggests benefits from greater involvement of GPs, and recent research has clarified key roles. Despite this, GPs continue to be disconnected from disaster health management (DHM) in most countries.Study Objective:The aim of this study was to explore the perspectives of disaster management professionals in two countries, across a range of all-hazard disasters, regarding the roles and contributions of GPs to DHM, and to identify barriers to, and benefits of, more active engagement of GPs in disaster health care systems.Methods:A qualitative research methodology using semi-structured interviews was conducted with a purposive sample of Disaster Managers (DMs) to explore their perspectives arising from experiences and observations of GPs during disasters from 2009 through 2016 in Australia or New Zealand. These involved all-hazard disasters including natural, man-made, and pandemic disasters. Responses were analyzed using thematic analysis.Results:These findings document support from DM participants for greater integration of GPs into DHM with New Zealand DMs reporting GPs as already a valuable integrated contributor. In contrast, Australian DMs reported barriers to inclusion that needed to be addressed before sustained integration could occur. The two most strongly expressed barriers were universally expressed by Australian DMs: (1) limited understanding of the work GPs undertake, restricting DMs’ ability to facilitate GP integration; and (2) DMs’ difficulty engaging with GPs as a single group. Other considerations included GPs’ limited DHM knowledge, limited preparedness, and their heightened vulnerability.Strategies identified to facilitate greater integration of GPs into DHM where it is lacking, such as Australia, included enhanced communication, awareness, and understanding between GPs and DMs.Conclusion:Experience from New Zealand shows systematic, sustained integration of GPs into DHM systems is achievable and valuable. Findings suggest key factors are collaboration between DMs and GPs at local, state, and national levels of DHM in planning and preparedness for the next disaster. A resilient health care system that maximizes capacity of all available local health resources in disasters and sustains them into the recovery should include General Practice.
Dynamic ecophenotypy in the Silurian Monograptidae (Graptolithina)
Authors: WHITTINGHAM Misha , SPIRIDONOV Andrej , RADZEVIČIUS Sigitas 
Published: December 2021

ABSTRACTThe monograptids from the Wenlock and Ludlow (mid- to late Silurian) of the palaeotropical Baltic Basin exhibit thickened ring structures (sicular annuli) over their initial phase of growth. Appearing before the lundgreni extinction event, they persisted throughout the remainder of the Silurian, fluctuating in number over that period. To better understand the mechanisms controlling their development and variation, counts of sicular annuli were taken from three well cores in Lithuania, compared between species in each sample and compared with contemporaneous gamma ray data, accompanied by the stable isotope (δ13C), and acritarch diversity data. Mean counts of annuli fluctuated greatly over the studied interval, but showed negligible variation between species, indicating that the trait is ecophenotypic. The fluctuation in annulus presence aligned with variations in fourth- and fifth-order cycles derived from the gamma ray trends, which represent significant sea level fluctuations, δ13C ratios, and primary productivity, suggesting that annuli were more plentiful in high-stand states which are associated with the wetter climate and more productive conditions, whereas dryer, less productive conditions were not conducive to annulus development. In light of this evidence, we hypothesise that the action of upwelling as a result of intensified storm events during wetter periods would have encouraged phytoplankton blooms, increasing construction of annuli. These results show the potential utility of sicular annuli in the study of Silurian climate change and give new insights into graptolite palaeoecology.
Nationwide trends in prevalence of underweight, overweight, and obesity among people with disabilities in South Korea from 2008 to 2017
Authors: Lee Dong-Hwa , Kim So Young , Park Jong Eun , Jeon Hyun Jeong , Park Jong-Hyock , Kawachi Ichiro 
Published: December 2021

Abstract
Objectives
This study investigated the 10-year trends of weight and prevalence of underweight, overweight and obesity according to disability grade and types compared with those without disabilities.

Methods
This serial cross-sectional analysis was conducted using national disability registration data with national general health checkup data from 2008 to 2017. Age-standardized prevalence of underweight and obesity were analyzed for each year, according to the presence, type, and severity of disabilities. Odds of underweight, overweight, obesity, and severe obesity were examined by multinomial logistic regression after adjusting for socio-demographic and clinical variables using data in 2017.

Results
Over 10 million subjects in each year were included in the analysis. In 2017, 14,246,785 people with age between 19 and 110 years were included and 53.1% was men. For 10 years, age-standardized prevalence of obesity and severe obesity showed significant increases regardless of sex and presence of disability. However, age-standardized underweight prevalence in people without disability tended to decrease whereas it was an increase in 2012 and the prevalence has remained steady since in people with disability. People with disabilities had higher odds of underweight compared to those without disability (OR 1.41, 95% CI 1.38–1.44 in male and OR 1.31, 95% CI 1.28–1.34 in female), especially in those with severe disabilities (OR 2.00, 95% CI 1.94–2.06 in male and OR 1.83, 95% CI 1.77–1.89 in female). Women with disabilities are more likely to be obese than those without disabilities regardless of disability severity (OR 1.40, 95% CI 1.38–1.41). Participants with mental disorder showed the highest prevalence of obesity, followed by epilepsy and developmental disability.

Conclusions
Having a disability was associated with higher odds/probability of both obesity and underweight. The intersection of female, severe disability, and mental/developmental disabilities was associated with probability of severe obesity. Simultaneous efforts are needed to develop health policy to reduce both the prevalence of obesity and underweight.
Thermo-optically induced transparency on a photonic chip
Authors: Clementi Marco , Iadanza Simone , Schulz Sebastian A. , Urbinati Giulia , Gerace Dario , O’Faloain Liam , Galli Matteo 
Published: December 2021

AbstractControlling the optical response of a medium through suitably tuned coherent electromagnetic fields is highly relevant in a number of potential applications, from all-optical modulators to optical storage devices. In particular, electromagnetically induced transparency (EIT) is an established phenomenon in which destructive quantum interference creates a transparency window over a narrow spectral range around an absorption line, which, in turn, allows to slow and ultimately stop light due to the anomalous refractive index dispersion. Here we report on the observation of a new form of both induced transparency and amplification of a weak probe beam in a strongly driven silicon photonic crystal resonator at room temperature. The effect is based on the oscillating temperature field induced in a nonlinear optical cavity, and it reproduces many of the key features of EIT while being independent of either atomic or mechanical resonances. Such thermo-optically induced transparency will allow a versatile implementation of EIT-analogs in an integrated photonic platform, at almost arbitrary wavelength of interest, room temperature and in a practical, low cost, and scalable system.
Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma
Authors: Xia Qing , Jia Jing , Hu Chupeng , Lu Jinying , Li Jiajin , Xu Haiyan , Fang Jianchen , Feng Dongju , Wang Liwei , Chen Yun 
Published: December 2021

AbstractIn many types of cancer, tumor cells prefer to use glycolysis as a major energy acquisition method. Here, we found that the 18fluoro-deoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based markers were positively associated with the expression of programmed cell death ligand 1 (PD-L1), pyruvate kinase M2 (PKM2), both of which indicate poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. In this study, we confirmed that transforming growth factor-beta1 (TGF-β1) secreted by tumor-associated macrophages (TAMs) was a key factor contributing to the expression of PD-L1 in PDAC cells by inducing the nuclear translocation of PKM2. Using co-immunoprecipitation and chromatin immunoprecipitation assays, we demonstrated that the interaction between PKM2 and signal transducer and activator of transcription 1 (STAT1) was enhanced by TGF-β1 stimulation, which facilitated the transactivation of PD-L1 by the binding of PKM2 and STAT1 to its promoter. In vivo, PKM2 knockdown decreased PD-L1 expression in PDAC cells and inhibited tumor growth partly by promoting natural killer cell activation and function, and the combination of PD-1/PD-L1 blockade with PKM2 knockdown limited tumor growth. In conclusion, PKM2 significantly contributes to TAM-induced PD-L1 overexpression and immunosuppression, providing a novel target for immunotherapies for PDAC.
Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors
Authors: Carter Angela M. , Kumar Nilesh , Herring Brendon , Tan Chunfeng , Guenter Rachael , Telange Rahul , Howse Wayne , Viol Fabrice , McCaw Tyler R. , Bickerton Hayden H. , Gupta Priyanka , Gillardon Frank , Woltering Eugene A. , Dhall Deepti , Totenhagen John , Banerjee Ronadip R. , Kurian Elizabeth M. , Reddy Sushanth , Chen Herbert , Schrader Joerg , Bart Rose J. , Mukhtar M. Shahid , Bibb James A. 
Published: December 2021

AbstractPancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.
Generation of in situ CRISPR-mediated primary and metastatic cancer from monkey liver
Authors: Zhong Liping , Huang Yong , He Jian , Yang Nuo , Xu Banghao , Ma Yun , Liu Junjie , Tang Chao , Luo Chengpiao , Wu Pan , Lai Zongqiang , Huo Yu , Lu Tao , Huang Dongni , Gong Wenlin , Gan Lu , Luo Yiqun , Zhang Zhikun , Liu Xiyu , Zhao Yongxiang 
Published: December 2021

AbstractNon-human primates (NHPs) represent the most valuable animals for drug discovery. However, the current main challenge remains that the NHP has not yet been used to develop an efficient translational medicine platform simulating human diseases, such as cancer. This study generated an in situ gene-editing approach to induce efficient loss-of-function mutations of Pten and p53 genes for rapid modeling primary and metastatic liver tumors using the CRISPR/Cas9 in the adult cynomolgus monkey. Under ultrasound guidance, the CRISPR/Cas9 was injected into the cynomolgus monkey liver through the intrahepatic portal vein. The results showed that the ultrasound-guided CRISPR/Cas9 resulted in indels of the Pten and p53 genes in seven out of eight monkeys. The best mutation efficiencies for Pten and p53 were up to 74.71% and 74.68%, respectively. Furthermore, the morbidity of primary and extensively metastatic (lung, spleen, lymph nodes) hepatoma in CRISPR-treated monkeys was 87.5%. The ultrasound-guided CRISPR system could have great potential to successfully pursue the desired target genes, thereby reducing possible side effects associated with hitting non-specific off-target genes, and significantly increasing more efficiency as well as higher specificity of in situ gene editing in vivo, which holds promise as a powerful, yet feasible tool, to edit disease genes to build corresponding human disease models in adult NHPs and to greatly accelerate the discovery of new drugs and save economic costs.
Millimeter-scale vertical partitioning of nitrogen cycling in hypersaline mats reveals prominence of genes encoding multi-heme and prismane proteins
Authors: Maza-Márquez P , Lee M D , Detweiler A M , Bebout B M 
Published: December 2021

Abstract
Microbial mats are modern analogues of the first ecosystems on the Earth. As extant representatives of microbial communities where free oxygen may have first been available on a changing planet, they offer an ecosystem within which to study the evolution of biogeochemical cycles requiring and inhibited by oxygen. Here, we report the distribution of genes involved in nitrogen metabolism across a vertical oxygen gradient at 1 mm resolution in a microbial mat using quantitative PCR (qPCR), retro-transcribed qPCR (RT-qPCR) and metagenome sequencing. Vertical patterns in the presence and expression of nitrogen cycling genes, corresponding to oxygen requiring and non-oxygen requiring nitrogen metabolism, could be seen across gradients of dissolved oxygen and ammonium. Metagenome analysis revealed that genes annotated as hydroxylamine dehydrogenase (proper enzyme designation EC 1.7.2.6, hao) and hydroxylamine reductase (hcp) were the most abundant nitrogen metabolism genes in the mat. The recovered hao genes encode hydroxylamine dehydrogenase EC 1.7.2.6 (HAO) proteins lacking the tyrosine residue present in aerobic ammonia oxidizing bacteria (AOB). Phylogenetic analysis confirmed that those proteins were more closely related to ɛHao protein present in Campylobacterota lineages (previously known as Epsilonproteobacteria) rather than oxidative HAO of AOB. The presence of hao sequences related with ɛHao protein, as well as numerous hcp genes encoding a prismane protein, suggest the presence of a nitrogen cycling pathway previously described in Nautilia profundicola as ancestral to the most commonly studied present day nitrogen cycling pathways.
The caspase-6–p62 axis modulates p62 droplets based autophagy in a dominant-negative manner
Authors: Valionyte Evelina , Yang Yi , Griffiths Sophie A. , Bone Amelia T. , Barrow Elizabeth R. , Sharma Vikram , Lu Boxun , Luo Shouqing 
Published: December 2021

AbstractSQSTM1/p62, as a major autophagy receptor, forms droplets that are critical for cargo recognition, nucleation, and clearance. p62 droplets also function as liquid assembly platforms to allow the formation of autophagosomes at their surfaces. It is unknown how p62-droplet formation is regulated under physiological or pathological conditions. Here, we report that p62-droplet formation is selectively blocked by inflammatory toxicity, which induces cleavage of p62 by caspase-6 at a novel cleavage site D256, a conserved site across human, mouse, rat, and zebrafish. The N-terminal cleavage product is relatively stable, whereas the C-terminal product appears undetectable. Using a variety of cellular models, we show that the p62 N-terminal caspase-6 cleavage product (p62-N) plays a dominant-negative role to block p62-droplet formation. In vitro p62 phase separation assays confirm this observation. Dominant-negative regulation of p62-droplet formation by caspase-6 cleavage attenuates p62 droplets dependent autophagosome formation. Our study suggests a novel pathway to modulate autophagy through the caspase-6–p62 axis under certain stress stimuli.
Structural basis of reactivation of oncogenic p53 mutants by a small molecule: methylene quinuclidinone (MQ)
Authors: Degtjarik Oksana , Golovenko Dmitrij , Diskin-Posner Yael , Abrahmsén Lars , Rozenberg Haim , Shakked Zippora 
Published: December 2021

AbstractIn response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.
Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma
Authors: Zoumpoulidou Georgia , Alvarez-Mendoza Carlos , Mancusi Caterina , Ahmed Ritika-Mahmuda , Denman Milly , Steele Christopher D. , Tarabichi Maxime , Roy Errin , Davies Lauren R. , Manji Jiten , Cristalli Camilla , Scotlandi Katia , Pillay Nischalan , Strauss Sandra J. , Mittnacht Sibylle 
Published: December 2021

AbstractLoss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-defective cancer cells, including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-defective backgrounds and prolongs survival of mice carrying human RB1-defective osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a personalised strategy for RB1-mutated osteosarcoma and other cancers.
DeepRank: a deep learning framework for data mining 3D protein-protein interfaces
Authors: Renaud Nicolas , Geng Cunliang , Georgievska Sonja , Ambrosetti Francesco , Ridder Lars , Marzella Dario F. , Réau Manon F. , Bonvin Alexandre M. J. J. , Xue Li C. 
Published: December 2021

AbstractThree-dimensional (3D) structures of protein complexes provide fundamental information to decipher biological processes at the molecular scale. The vast amount of experimentally and computationally resolved protein-protein interfaces (PPIs) offers the possibility of training deep learning models to aid the predictions of their biological relevance. We present here DeepRank, a general, configurable deep learning framework for data mining PPIs using 3D convolutional neural networks (CNNs). DeepRank maps features of PPIs onto 3D grids and trains a user-specified CNN on these 3D grids. DeepRank allows for efficient training of 3D CNNs with data sets containing millions of PPIs and supports both classification and regression. We demonstrate the performance of DeepRank on two distinct challenges: The classification of biological versus crystallographic PPIs, and the ranking of docking models. For both problems DeepRank is competitive with, or outperforms, state-of-the-art methods, demonstrating the versatility of the framework for research in structural biology.
Bayesian optimization with adaptive surrogate models for automated experimental design
Authors: Lei Bowen , Kirk Tanner Quinn , Bhattacharya Anirban , Pati Debdeep , Qian Xiaoning , Arroyave Raymundo , Mallick Bani K. 
Published: December 2021

AbstractBayesian optimization (BO) is an indispensable tool to optimize objective functions that either do not have known functional forms or are expensive to evaluate. Currently, optimal experimental design is always conducted within the workflow of BO leading to more efficient exploration of the design space compared to traditional strategies. This can have a significant impact on modern scientific discovery, in particular autonomous materials discovery, which can be viewed as an optimization problem aimed at looking for the maximum (or minimum) point for the desired materials properties. The performance of BO-based experimental design depends not only on the adopted acquisition function but also on the surrogate models that help to approximate underlying objective functions. In this paper, we propose a fully autonomous experimental design framework that uses more adaptive and flexible Bayesian surrogate models in a BO procedure, namely Bayesian multivariate adaptive regression splines and Bayesian additive regression trees. They can overcome the weaknesses of widely used Gaussian process-based methods when faced with relatively high-dimensional design space or non-smooth patterns of objective functions. Both simulation studies and real-world materials science case studies demonstrate their enhanced search efficiency and robustness.