bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers
Authors: Serebriiskii Ilya G. , Pavlov Valery , Tricarico Rossella , Andrianov Grigorii , Nicolas Emmanuelle , Parker Mitchell I. , Newberg Justin , Frampton Garrett , Meyer Joshua E. , Golemis Erica A. 
Published: March 2022

AbstractLoss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.
Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression
Authors: Yoo Seungyeul , Sinha Abhilasha , Yang Dawei , Altorki Nasser K. , Tandon Radhika , Wang Wenhui , Chavez Deebly , Lee Eunjee , Patel Ayushi S. , Sato Takashi , Kong Ranran , Ding Bisen , Schadt Eric E. , Watanabe Hideo , Massion Pierre P. , Borczuk Alain C. , Zhu Jun , Powell Charles A. 
Published: March 2022

AbstractHere we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma.
A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens
Authors: Roberts Kade D. , Zhu Yan , Azad Mohammad A. K. , Han Mei-Ling , Wang Jiping , Wang Lynn , Yu Heidi H. , Horne Andrew S. , Pinson Jo-Anne , Rudd David , Voelcker Nicolas H. , Patil Nitin A. , Zhao Jinxin , Jiang Xukai , Lu Jing , Chen Ke , Lomovskaya Olga , Hecker Scott J. , Thompson Philip E. , Nation Roger L. , Dudley Michael N. , Griffith David C. , Velkov Tony , Li Jian 
Published: March 2022

AbstractThe emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.
Mechanistic insights into the regulation of plant phosphate homeostasis by the rice SPX2 – PHR2 complex
Authors: Guan Zeyuan , Zhang Qunxia , Zhang Zhifei , Zuo Jiaqi , Chen Juan , Liu Ruiwen , Savarin Julie , Broger Larissa , Cheng Peng , Wang Qiang , Pei Kai , Zhang Delin , Zou Tingting , Yan Junjie , Yin Ping , Hothorn Michael , Liu Zhu 
Published: March 2022

AbstractPhosphate (Pi) starvation response (PHR) transcription factors play key roles in plant Pi homeostasis maintenance. They are negatively regulated by stand-alone SPX proteins, cellular receptors for inositol pyrophosphate (PP-InsP) nutrient messengers. How PP-InsP-bound SPX interacts with PHRs is poorly understood. Here, we report crystal structures of the rice SPX2/InsP6/PHR2 complex and of the PHR2 DNA binding (MYB) domain in complex with target DNA at resolutions of 3.1 Å and 2.7 Å, respectively. In the SPX2/InsP6/PHR2 complex, the signalling-active SPX2 assembles into a domain-swapped dimer conformation and binds two copies of PHR2, targeting both its coiled-coil (CC) oligomerisation domain and MYB domain. Our results reveal that the SPX2 senses PP-InsPs to inactivate PHR2 by establishing severe steric clashes with the PHR2 MYB domain, preventing DNA binding, and by disrupting oligomerisation of the PHR2 CC domain, attenuating promoter binding. Our findings rationalize how PP-InsPs activate SPX receptor proteins to target PHR family transcription factors.
Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease
Authors: Sun Hui , Li Hui , Yan Jie , Wang Xiangdong , Xu Mengyuan , Wang Mingxia , Fan Baozhen , Liu Jieying , Lin Ninghua , Wang Xin , Li Li , Zhao Shengtian , Gong Yongfeng 
Published: March 2022

AbstractAlthough mature podocytes lack tight junctions, tight junction integral membrane protein claudin-5 (CLDN5) is predominantly expressed on plasma membranes of podocytes under normal conditions. Using podocyte-specific Cldn5 knockout mice, we identify CLDN5 as a crucial regulator of podocyte function and reveal that Cldn5 deletion exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, followed by transcriptional downregulation of WNT inhibitory factor-1 (WIF1) expression, which leads to activation of WNT signaling pathway. Podocyte-derived WIF1 also plays paracrine roles in tubular epithelial cells, as evidenced by the finding that animals with podocyte-specific deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction than littermate controls. Systemic delivery of WIF1 suppresses the progression of diabetic nephropathy and ureteral obstruction-induced renal fibrosis. These findings establish a function for podocyte CLDN5 in restricting WNT signaling in kidney.
Superfast precipitation of energetic electrons in the radiation belts of the Earth
Authors: Zhang Xiao-Jia , Artemyev Anton , Angelopoulos Vassilis , Tsai Ethan , Wilkins Colin , Kasahara Satoshi , Mourenas Didier , Yokota Shoichiro , Keika Kunihiro , Hori Tomoaki , Miyoshi Yoshizumi , Shinohara Iku , Matsuoka Ayako 
Published: March 2022

AbstractEnergetic electron precipitation from Earth’s outer radiation belt heats the upper atmosphere and alters its chemical properties. The precipitating flux intensity, typically modelled using inputs from high-altitude, equatorial spacecraft, dictates the radiation belt’s energy contribution to the atmosphere and the strength of space-atmosphere coupling. The classical quasi-linear theory of electron precipitation through moderately fast diffusive interactions with plasma waves predicts that precipitating electron fluxes cannot exceed fluxes of electrons trapped in the radiation belt, setting an apparent upper limit for electron precipitation. Here we show from low-altitude satellite observations, that ~100 keV electron precipitation rates often exceed this apparent upper limit. We demonstrate that such superfast precipitation is caused by nonlinear electron interactions with intense plasma waves, which have not been previously incorporated in radiation belt models. The high occurrence rate of superfast precipitation suggests that it is important for modelling both radiation belt fluxes and space-atmosphere coupling.
Functional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation
Authors: Wang Liang-Jie , Chen Chie-Pein , Lee Yun-Shien , Ng Pui-Sze , Chang Geen-Dong , Pao Yu-Hsuan , Lo Hsiao-Fan , Peng Chao-Hsiang , Cheong Mei-Leng , Chen Hungwen 
Published: March 2022

AbstractThe combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.
Intratumoral in vivo staging of breast cancer by multi-tracer PET and advanced analysis
Authors: Griessinger Jennifer , Schwab Julian , Chen Qian , Kühn Anna , Cotton Jonathan , Bowden Gregory , Preibsch Heike , Reischl Gerald , Quintanilla-Martinez Leticia , Mori Hidetoshi , Dang An Nguyen , Kohlhofer Ursula , Aina Olulanu H. , Borowsky Alexander D. , Pichler Bernd J. , Cardiff Robert D. , Schmid Andreas M. 
Published: March 2022

AbstractThe staging and local management of breast cancer involves the evaluation of the extent and completeness of excision of both the invasive carcinoma component and also the intraductal component or ductal carcinoma in situ. When both invasive ductal carcinoma and coincident ductal carcinoma in situ are present, assessment of the extent and localization of both components is required for optimal therapeutic planning. We have used a mouse model of breast cancer to evaluate the feasibility of applying molecular imaging to assess the local status of cancers in vivo. Multi-tracer positron emission tomography (PET) and magnetic resonance imaging (MRI) characterize the transition from premalignancy to invasive carcinoma. PET tracers for glucose consumption, membrane synthesis, and neoangiogenesis in combination with a Gaussian mixture model-based analysis reveal image-derived thresholds to separate the different stages within the whole-lesion. Autoradiography, histology, and quantitative image analysis of immunohistochemistry further corroborate our in vivo findings. Finally, clinical data further support our conclusions and demonstrate translational potential. In summary, this preclinical model provides a platform for characterizing multistep tumor progression and provides proof of concept that supports the utilization of advanced protocols for PET/MRI in clinical breast cancer imaging.
Sticky-MARTINI as a reactive coarse-grained model for molecular dynamics simulations of silica polymerization
Authors: Carvalho André P. , Santos Sérgio M. , Pérez-Sánchez Germán , Gouveia José D. , Gomes José R. B. , Jorge Miguel 
Published: March 2022

AbstractWe report a molecular modeling paradigm to describe silica polymerization reactions in aqueous solutions at conditions that are representative of realistic experimental processes like biosilicification or porous silica synthesis – i.e. at close to ambient temperatures and over a wide range of pH. The key point is to describe the Si-O-Si chemical bond formation and breakage processes through a continuous potential with a balance between attractive and repulsive interactions between suitably placed virtual sites and sticky particles. The simplicity of the model, its applicability in standard parallelized molecular dynamics codes, and its compatibility with the widely used MARTINI coarse-grained force-field allows for the study of systems containing millions of atoms over microsecond time scales. The model is calibrated to match experimental results for the temporal evolution of silica polymerization in aqueous solution close to the isoelectric point, and can describe silica polymerization and self-assembly processes during encapsulation of a surfactant micelle.
Seawater desalination concentrate—a new frontier for sustainable mining of valuable minerals
Authors: Sharkh Basel Abu , Al-Amoudi Ahmad A. , Farooque Mohammed , Fellows Christopher M. , Ihm Seungwon , Lee Sangho , Li Sheng , Voutchkov Nikolay 
Published: March 2022

AbstractThe ocean has often been announced as a sustainable source of important materials for civilization. Application of the same extraction processes to desalination concentrate, rather than to unconcentrated seawater, will necessarily be more energetically favorable, so the expansion of seawater desalination in recent decades brings this dream closer to reality. However, there is relatively little concrete commercial development of ‘concentrate mining’. This review assesses the technical and economic prospects for utilization of commercially viable products from seawater. The most important technologies for economic use of products from desalination plant concentrate are technologies for more economic separation and technologies for more economic concentration. The most promising separation technologies are those, such as nanofiltration, which separate brine into streams enriched/depleted in entire classes of constituents with minimal input of energy and reagents. Concentration is becoming more economic due to rapid advances in Osmotically-Assisted RO technology. Despite very active research on many aspects of desalination concentrate utilization, it is likely that commercial development of the non-NaCl components of desalination brine will depend on the available market for NaCl, as the challenges and costs of extracting the other mineral components from bitterns in which they are highly enriched are so much less than those faced in direct treatment of brines.
Experimental photonic quantum memristor
Authors: Spagnolo Michele , Morris Joshua , Piacentini Simone , Antesberger Michael , Massa Francesco , Crespi Andrea , Ceccarelli Francesco , Osellame Roberto , Walther Philip 
Published: March 2022

AbstractMemristive devices are a class of physical systems with history-dependent dynamics characterized by signature hysteresis loops in their input–output relations. In the past few decades, memristive devices have attracted enormous interest in electronics. This is because memristive dynamics is very pervasive in nanoscale devices, and has potentially groundbreaking applications ranging from energy-efficient memories to physical neural networks and neuromorphic computing platforms. Recently, the concept of a quantum memristor was introduced by a few proposals, all of which face limited technological practicality. Here we propose and experimentally demonstrate a novel quantum-optical memristor (based on integrated photonics) that acts on single-photon states. We fully characterize the memristive dynamics of our device and tomographically reconstruct its quantum output state. Finally, we propose a possible application of our device in the framework of quantum machine learning through a scheme of quantum reservoir computing, which we apply to classical and quantum learning tasks. Our simulations show promising results, and may break new ground towards the use of quantum memristors in quantum neuromorphic architectures.
A portrait of obstructive sleep apnea risk factors in 27,210 middle-aged and older adults in the Canadian Longitudinal Study on Aging
Authors: Thompson Cynthia , Legault Julie , Moullec Gregory , Baltzan Marc , Cross Nathan , Dang-Vu Thien Thanh , Martineau-Dussault Marie-Ève , Hanly Patrick , Ayas Najib , Lorrain Dominique , Einstein Gillian , Carrier Julie , Gosselin Nadia 
Published: March 2022

AbstractDetermining the prevalence and characteristics of individuals susceptible to present with obstructive sleep apnea (OSA) is essential for developing targeted and efficient prevention and screening strategies. We included 27,210 participants aged ≥45 years old (50.3% women) from the Canadian Longitudinal Study on Aging. Using the STOP questionnaire combined to the percentage of body fat (%BF), we estimated the prevalence of individuals at high-risk for OSA in a sex and age-specific manner, and tested the relation with comorbidities, menopause and systemic inflammation. The prevalence was 17.5%, and was lower in women (13.1%) than in men (21.9%). A high level of high-sensitivity C-reactive protein was the strongest factor associated with OSA risk and this association was 1.3–2.3 times higher in women than in men. OSA risk increased with age, cardiovascular diseases, diabetes mellitus, anxio-depressive symptoms, asthma and arthritis. In women, post-menopausal status was associated with a high OSA risk. Nearly 1 adult out of 5 older than 45 is at risk for OSA in Canada. Comorbidities, menopause and systemic inflammation, more than age, explain increased OSA prevalence. Considering this high prevalence and associations with medical and mental comorbidities, health care practitioners should incorporate systematic OSA screening in their clinical procedures.
Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer
Authors: Hirano Hidekazu , Abe Yuichi , Nojima Yosui , Aoki Masahiko , Shoji Hirokazu , Isoyama Junko , Honda Kazufumi , Boku Narikazu , Mizuguchi Kenji , Tomonaga Takeshi , Adachi Jun 
Published: March 2022

AbstractPhosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.
Shear creep mechanical properties and damage model of mudstone in open-pit coal mine
Authors: Li Guanghe , Wang Yanting , Hu Yiming , Wang Dong , Yang Xiaoxu , Li Yanfei , Zhou Zhiwei , Zhang Shipeng 
Published: March 2022

AbstractClarifying the shear creep characteristics of rock and scientifically analyzing its creep deformation law is the key to solving the problem of safe construction and long-term stability analysis of the open-pit coal slope rock mass. Shear creep tests were carried out on mudstone from an open-pit coal mine in Eastern Mongolia to reveal the creep characteristics of mudstone under different normal and shear stresses. Based on the classical Nishihara model, a new composite six-element nonlinear shear creep damage model is established by introducing nonlinear elastomers. Using the least square method, model verification and parameter identification are carried out on the variable test data. At the same time, the influence law of the model parameters on the rock creep deformation is analyzed according to the theoretical curve. The study results showed that the nonlinear shear creeps damage model could better describe the creep characteristics of rock different normal stress and shear stress levels, significantly the non-linear both the strain and time of attenuation creep and accelerated creep. The creep characteristics of the accelerated creep stage described by this model are better than those described by the classical Nishihara model. The model curve is consistent with the changing trend of the experimental data, and the degree of agreement is very high. The correlation coefficients are all above 0.98, which verifies the accuracy and rationality of the model. The influence law of creep parameters is analyzed. The parameters b and c increase nonlinearly with creep. The increase of λ accelerates the process of rock attenuation creep stage; the increase of η10 slows down the progress of rock decay creep stage; with the increase of α, the deformation and creep rate of rock in accelerated creep stage gradually increase. When η2 increases, the deformation in the acceleration stage decreases gradually. The research results can provide important theoretical support for the safe construction and long-term stability analysis of open-pit coal slope rock masses.
Cortical activation during cooperative joint actions and competition in children with and without an autism spectrum condition (ASC): an fNIRS study
Authors: Su Wan-Chun , Culotta McKenzie , Tsuzuki Daisuke , Bhat Anjana 
Published: March 2022

AbstractChildren with an Autism Spectrum Condition (ASC) have social communication and perceptuomotor difficulties that affect their ability to engage in dyadic play. In this study, we compared spatio-temporal errors and fNIRS-related cortical activation between children with and without an ASC during a Lincoln Log dyadic game requiring them to play leader or follower roles, move in synchrony or while taking turns, and move cooperatively or competitively with an adult partner. Children with an ASC had greater motor, planning, and spatial errors and took longer to complete the building tasks compared to typically developing (TD) children. Children with an ASC had lower superior temporal sulcus (STS) activation during Turn-take and Compete, and greater Inferior Parietal Lobe (IPL) activation during Lead and Turn-take compared to TD children. As dyadic play demands increased, TD children showed greater STS activation during Turn-take (vs. Synchrony) and Compete (vs. Cooperate) whereas children with an ASC showed greater IPL activation during Lead and Compete (vs. Cooperate). Our findings suggest that children with an ASC rely on self-generated action plans (i.e., increased IPL activation) more than relying on their partner’s action cues (i.e., reduced STS activation) when engaging in dyadic play including joint actions and competition.