bluuebunny/crossref_metadata_2025_split huggingface dataset:
Source Characteristics and Along‐Strike Variations of Shallow Very Low Frequency Earthquake Swarms on the Nankai Trough Shallow Plate Boundary
Authors: Takemura Shunsuke , Baba Satoru , Yabe Suguru , Emoto Kentaro , Shiomi Katsuhiko , Matsuzawa Takanori 
Published: May 2022

AbstractWe detected shallow very low frequency earthquakes (VLFEs) off the Cape Muroto and Kii Channel in the Nankai subduction zone and estimated their moment rate functions. Combining the new and previously estimated catalogs, we obtained the comprehensive catalog of shallow VLFE moment rate functions along the Nankai Trough. We defined the shallow VLFE swarms and investigated the scaling relationships of their cumulative moments, activity area, and durations in each region. Detected swarms were considered candidates for shallow slow slip events. A similar scaling relationship was observed between the cumulative moments and activity areas, irrespective of regions. It indicates similar stress drops in each region. However, the relationship between the cumulative moments and durations varied. This difference was explained by the along‐strike variations in the faulting conditions of shallow slow earthquakes, such as material or hydrological properties.
Inhibitory role of proguanil on the growth of bladder cancer via enhancing EGFR degradation and inhibiting its downstream signaling pathway to induce autophagy
Authors: Xiao Di , Hu Xin , Peng Mei , Deng Jun , Zhou Sichun , Xu Simeng , Wu Jingtao , Yang Xiaoping 
Published: May 2022

AbstractA major reason for the high mortality of patients with bladder cancer (BC) is that chemotherapy and surgery are only effective for very limited patients. Thus, developing novel treatment options becomes an urgent need for improving clinical outcomes and the quality of life for BC patients. Here, we demonstrated that proguanil significantly inhibited the growth of BC in vitro and in vivo. Importantly, our results indicated that the sensitivity of BC cells to proguanil is positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, proguanil specifically targeted EGFR and promoted EGFR binding to Caveolin-1, enhanced its endocytosis in a Clathrin-independent manner, and then recruited c-Cbl to promote EGFR ubiquitination and degradation through the lysosomal pathway. Further studies suggested that proguanil induced autophagy by destabilizing EGFR and inhibiting its downstream signaling pathway. Thus, this study reveals the novel mechanism of proguanil on anticancer activity and implies the potential benefits of this drug in the treatment of BC.
Blocking STAT3 signaling augments MEK/ERK inhibitor efficacy in esophageal squamous cell carcinoma
Authors: Zheng Zhen-Yuan , Chu Man-Yu , Lin Wan , Zheng Ya-Qi , Xu Xiu-E , Chen Yang , Liao Lian-Di , Wu Zhi-Yong , Wang Shao-Hong , Li En-Min , Xu Li-Yan 
Published: May 2022

AbstractEsophageal squamous cell carcinoma (ESCC) is one of the world’s leading causes of death, and its primary clinical therapy relies on surgical resection, chemotherapy, radiotherapy, and chemoradiotherapy. Although the genomic features and clinical significance of ESCC have been identified, the outcomes of targeted therapies are still unsatisfactory. Here, we demonstrate that mitogen-activated protein kinase (MAPK) signaling is highly activated and associated with poor prognosis in patients with ESCC. Mitogen-activated protein kinase kinase (MEK) inhibitors efficiently blocked the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in ESCC, while signal transducer and activator of transcription 3 (STAT3) signaling was rapidly activated. Combined STAT3 inhibition prevented the emergence of resistance and enhanced MEK inhibitor-induced cell cycle arrest and senescence in vitro and in vivo. Mechanistic studies revealed that the suppressor of cytokine signaling 3 (SOCS3) was downregulated, resulting in an increase in STAT3 phosphorylation in MEK-inhibited cells. Furthermore, chromatin immunoprecipitation showed that ELK1, which was activated by MEK/ERK signaling, induced SOCS3 transcription. These data suggest that the development of combined MEK and STAT3 inhibition could be a useful strategy in ESCC targeted therapy.
Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions
Authors: Brandolini Laura , d’Angelo Michele , Novelli Rubina , Castelli Vanessa , Giorgio Cristina , Sirico Anna , Cocchiaro Pasquale , D’Egidio Francesco , Benedetti Elisabetta , Cristiano Claudia , Bugatti Antonella , Ruocco Anna , Amendola Pier Giorgio , Talarico Carmine , Manelfi Candida , Iaconis Daniela , Beccari Andrea , Quadros Andreza U. , Cunha Thiago M. , Caruso Arnaldo , Russo Roberto , Cimini Annamaria , Aramini Andrea , Allegretti Marcello 
Published: May 2022

AbstractChemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms—in terms of cold and mechanical allodynia—and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.
An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients
Authors: Almeida Ligia S. , Pereira Catarina , Aanicai Ruxandra , Schröder Sabine , Bochinski Tomasz , Kaune Anett , Urzi Alice , Spohr Tania C. L. S. , Viceconte Nikenza , Oppermann Sebastian , Alasel Mohammed , Ebadat Saeedeh , Iftikhar Sana , Jasinge Eresha , Elsayed Solaf M. , Tomoum Hoda , Marzouk Iman , Jalan Anil B. , Cerkauskaite Agne , Cerkauskiene Rimante , Tkemaladze Tinatin , Nadeem Anjum Muhammad , El Din Mahmoud Iman Gamal , Mossad Fawzia Amer , Kamel Mona , Selim Laila Abdel , Cheema Huma Arshad , Paknia Omid , Cozma Claudia , Juaristi-Manrique Carlos , Guatibonza-Moreno Pilar , Böttcher Tobias , Vogel Florian , Pinto-Basto Jorge , Bertoli-Avella Aida , Bauer Peter 
Published: May 2022

AbstractTo present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.
Dynamic stiffening of the flagellar hook
Authors: Nord Ashley L. , Biquet-Bisquert Anaïs , Abkarian Manouk , Pigaglio Théo , Seduk Farida , Magalon Axel , Pedaci Francesco 
Published: May 2022

AbstractFor many bacteria, motility stems from one or more flagella, each rotated by the bacterial flagellar motor, a powerful rotary molecular machine. The hook, a soft polymer at the base of each flagellum, acts as a universal joint, coupling rotation between the rigid membrane-spanning rotor and rigid flagellum. In multi-flagellated species, where thrust arises from a hydrodynamically coordinated flagellar bundle, hook flexibility is crucial, as flagella rotate significantly off-axis. However, consequently, the thrust applies a significant bending moment. Therefore, the hook must simultaneously be compliant to enable bundle formation yet rigid to withstand large hydrodynamical forces. Here, via high-resolution measurements and analysis of hook fluctuations under dynamical conditions, we elucidate how it fulfills this double functionality: the hook shows a dynamic increase in bending stiffness under increasing torsional stress. Such strain-stiffening allows the system to be flexible when needed yet reduce deformation under high loads, enabling high speed motility.
Targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer
Authors: Yuan Kai , Li Zhaoxing , Kuang Wenbin , Wang Xiao , Ji Minghui , Chen Weijiao , Ding Jiayu , Li Jiaxing , Min Wenjian , Sun Chengliang , Ye Xiuquan , Lu Meiling , Wang Liping , Ge Haixia , Jiang Yuzhang , Hao Haiping , Xiao Yibei , Yang Peng 
Published: May 2022

AbstractProstate cancer (PCa) is one of the most prevalent cancers in men worldwide, and hormonal therapy plays a key role in the treatment of PCa. However, the drug resistance of hormonal therapy makes it urgent and necessary to identify novel targets for PCa treatment. Herein, dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is found and confirmed to be highly expressed in the PCa tissues and cells, and knock-down of DYRK2 remarkably reduces PCa burden in vitro and in vivo. On the base of DYRK2 acting as a promising target, we further discover a highly selective DYRK2 inhibitor YK-2-69, which specifically interacts with Lys-231 and Lys-234 in the co-crystal structure. Especially, YK-2-69 exhibits more potent anti-PCa efficacy than the first-line drug enzalutamide in vivo. Meanwhile, YK-2-69 displays favorable safety properties with a maximal tolerable dose of more than 10,000 mg/kg and pharmacokinetic profiles with 56% bioavailability. In summary, we identify DYRK2 as a potential drug target and verify its critical roles in PCa. Meanwhile, we discover a highly selective DYRK2 inhibitor with favorable druggability for the treatment of PCa.
Long COVID after breakthrough SARS-CoV-2 infection
Authors: Al-Aly Ziyad , Bowe Benjamin , Xie Yan 
Published: May 2022

AbstractThe post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—also referred to as Long COVID—have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.
An effective detection approach for phishing websites using URL and HTML features
Authors: Aljofey Ali , Jiang Qingshan , Rasool Abdur , Chen Hui , Liu Wenyin , Qu Qiang , Wang Yang 
Published: May 2022

AbstractToday's growing phishing websites pose significant threats due to their extremely undetectable risk. They anticipate internet users to mistake them as genuine ones in order to reveal user information and privacy, such as login ids, pass-words, credit card numbers, etc. without notice. This paper proposes a new approach to solve the anti-phishing problem. The new features of this approach can be represented by URL character sequence without phishing prior knowledge, various hyperlink information, and textual content of the webpage, which are combined and fed to train the XGBoost classifier. One of the major contributions of this paper is the selection of different new features, which are capable enough to detect 0-h attacks, and these features do not depend on any third-party services. In particular, we extract character level Term Frequency-Inverse Document Frequency (TF-IDF) features from noisy parts of HTML and plaintext of the given webpage. Moreover, our proposed hyperlink features determine the relationship between the content and the URL of a webpage. Due to the absence of publicly available large phishing data sets, we needed to create our own data set with 60,252 webpages to validate the proposed solution. This data contains 32,972 benign webpages and 27,280 phishing webpages. For evaluations, the performance of each category of the proposed feature set is evaluated, and various classification algorithms are employed. From the empirical results, it was observed that the proposed individual features are valuable for phishing detection. However, the integration of all the features improves the detection of phishing sites with significant accuracy. The proposed approach achieved an accuracy of 96.76% with only 1.39% false-positive rate on our dataset, and an accuracy of 98.48% with 2.09% false-positive rate on benchmark dataset, which outperforms the existing baseline approaches.
The relevance of late MSA mandibles on the emergence of modern morphology in Northern Africa
Authors: Bergmann Inga , Hublin Jean-Jacques , Ben-Ncer Abdelouahed , Sbihi-Alaoui Fatima Zohra , Gunz Philipp , Freidline Sarah E. 
Published: May 2022

AbstractNorth Africa is a key area for understanding hominin population movements and the expansion of our species. It is home to the earliest currently known Homo sapiens (Jebel Irhoud) and several late Middle Stone Age (MSA) fossils, notably Kébibat, Contrebandiers 1, Dar-es-Soltane II H5 and El Harhoura. Mostly referred to as “Aterian” they fill a gap in the North African fossil record between Jebel Irhoud and Iberomaurusians. We explore morphological continuity in this region by quantifying mandibular shape using 3D (semi)landmark geometric morphometric methods in a comparative framework of late Early and Middle Pleistocene hominins (n = 15), Neanderthals (n = 27) and H. sapiens (n = 145). We discovered a set of mixed features among late MSA fossils that is in line with an accretion of modern traits through time and an ongoing masticatory gracilization process. In Northern Africa, Aterians display similarities to Iberomaurusians and recent humans in the area as well as to the Tighenif and Thomas Quarry hominins, suggesting a greater time depth for regional continuity than previously assumed. The evidence we lay out for a long-term succession of hominins and humans emphasizes North Africa’s role as source area of the earliest H. sapiens.
Impact of obesity on cervical ossification of the posterior longitudinal ligament: a nationwide prospective study
Authors: Mori Kanji , Yoshii Toshitaka , Egawa Satoru , Sakai Kenichiro , Kusano Kazuo , Tsutsui Shunji , Hirai Takashi , Matsukura Yu , Wada Kanichiro , Katsumi Keiichi , Koda Masao , Kimura Atsushi , Furuya Takeo , Maki Satoshi , Nagoshi Narihito , Nishida Norihiro , Nagamoto Yukitaka , Oshima Yasushi , Ando Kei , Nakashima Hiroaki , Takahata Masahiko , Nakajima Hideaki , Murata Kazuma , Miyagi Masayuki , Kaito Takashi , Yamada Kei , Banno Tomohiro , Kato Satoshi , Ohba Tetsuro , Inami Satoshi , Fujibayashi Shunsuke , Katoh Hiroyuki , Kanno Haruo , Taneichi Hiroshi , Imagama Shiro , Kawaguchi Yoshiharu , Takeshita Katsushi , Matsumoto Morio , Yamazaki Masashi , Okawa Atsushi 
Published: May 2022

AbstractPositive association between ossification of the posterior longitudinal ligament of the spine (OPLL) and obesity is widely recognized; however, few studies focused on the effects of obesity on treatment of cervical OPLL. The effects of obesity on surgical treatment of cervical OPLL were investigated by a Japanese nationwide, prospective study. Overall, 478 patients with cervical myelopathy due to OPLL were prospectively enrolled. To clarify the effects of obesity on the surgical treatment for cervical OPLL, patients were stratified into two groups, non-obese (< BMI 30.0 kg/m2) and obese (≥ BMI 30.0 kg/m2) groups. The mean age of the obese group was significantly younger than that of non-obese group. There were no significant differences between the two groups in other demographic information, medical history, and clinical and radiographical findings. Alternatively, the obese group had a significantly higher rate of surgical site infection (SSI) than that of non-obese group. Approach-specific analyses revealed that the SSI was significantly higher in the obese group than in the non-obese group. A logistic regression analysis revealed that age, BMI, and duration of symptoms were significant factors affecting the postoperative minimum clinically important difference success. The result of this study provides useful information for future cervical OPLL treatment.
Effect of adjuvant therapy with teriparatide in patients with thoracolumbar osteoporotic vertebral fractures who underwent vertebroplasty with posterior spinal fusion
Authors: Shibuya Yohei , Katsumi Keiichi , Ohashi Masayuki , Tashi Hideki , Makino Tatsuo , Yamazaki Akiyoshi , Hirano Toru , Sawakami Kimihiko , Kikuchi Ren , Kawashima Hiroyuki , Watanabe Kei 
Published: May 2022

AbstractTeriparatide (TPTD) administration has a potent osteogenic action and promotes the healing of osteoporotic vertebral fractures (OVFs). We aimed to investigate the outcomes of vertebroplasty with posterior spinal fusion (VP + PSF) and determine the impact of perioperative TPTD administration. We included 73 patients (18 male and 55 female patients; mean age: 78 years) with thoracolumbar OVFs who underwent VP + PSF and were followed-up for at least 2 years. Twenty-three patients who received TPTD perioperatively for > 3 months were included in the TPTD group, and the remaining 50 patients were included in the non-TPTD group. Radiographic findings regarding sagittal alignment and clinical outcomes in both groups were compared. The mean duration of TPTD administration was 17.5 ± 5.0 months (range 4–24 months). The mean loss of correction of local kyphosis angle in the TPTD group (4.0°) was lesser than that in the non-TPTD group (7.5°; p < 0.05); however, no significant differences were observed between the groups regarding global sagittal alignment, the occurrence of subsequent vertebral fractures, pedicle screw loosening and treatment-efficacy rates of clinical outcomes. Local kyphosis correction in patients who underwent VP + PSF for OVFs could be maintained through perioperative TPTD administration; however, TPTD administration had little effect on clinical outcomes.
Noninvasive assessment of foot perfusion in cholesterol-fed rabbits using dynamic volume perfusion CT with an upslope method
Authors: Min Hooney Daniel , Hur Saebeom , Lee Jae Hwan , Yoon Chang Jin , Choi Won Seok , Lee Seunghyun 
Published: May 2022

AbstractTo evaluate the feasibility of dynamic foot volume CT with the upslope method and to demonstrate macrovascular reactivity and microvascular perfusion during cuff-induced reactive hyperemia state in cholesterol-fed rabbits. 30 New Zealand male rabbits were divided into 2 groups: dietary hypercholesterolemia (n = 10) and normal diet control (n = 20). To measure for macrovascular reactivity, perfusion parameters of the left posterior tibial artery was measured at baseline and at reactive hyperemia state. For the evaluation of microvascular perfusion, color-coded perfusion map of the plantar dermis was generated for perfusion CT scan by an in-house developed dedicated analysis software based on upslope method. Dermal perfusion values were measured and analyzed before and after cuff-induced reactive hyperemia. Foot dynamic volume CT with the upslope method demonstrated significant impairment of both macrovascular reactivity and microvascular perfusion in cholesterol-fed rabbits without significant macrovascular lesions during cuff-induced reactive hyperemia (CRH) state. Arterial time-to-peak of cholesterol-fed rabbits failed to show acceleration while chow-fed rabbits showed significant decrease in time. Microvascular perfusion calculated by perfusion value (P < 0.01) and perfusion ratio (P = .014) showed decreased microvascular perfusion in cholesterol-fed rabbits compared to chow-fed rabbits during CRH state. Post-CT pathologic examination revealed decreased endothelial cell density in cholesterol-fed rabbits (P < 0.001). Foot perfusion CT using upslope method provides perfusion parameters for large arteries and a perfusion map of the foot during cuff-induced reactive hyperemia in cholesterol-fed rabbits. It may be a useful tool to assess microvascular reactivity in patients with peripheral artery disease but no apparent macrovascular lesions.