bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ornithine Transcarbamylase Deficiency Presenting with Symptoms of Mania in a Young Adult Male
Authors: Pentz Jonathan , Igboeli Blessing , Niedermier Julie 
Published: May 2021

AbstractStudy ObjectiveThe purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with acute behavior changes in the setting of undiagnosed ornithine transcarbamylase deficiency (OTCD)MethodThis case study involves a 19-year-old male with a psychiatric history of depression and one previous suicide attempt, who presented to a large midwestern university hospital emergency department after being found by police naked in a neighbor’s yard. He displayed manic signs and symptoms, including euphoria, lack of sleep for five days, and attempting to purchase a new car and three large screen TVs. Family reported the patient uncharacteristically announced three weeks earlier that he was vegetarian and stopped eating his frequent customary cheeseburgers. Due to increased anxiety and inability to sleep, the patient received lorazepam 2 mg in the emergency department. Upon transfer to the psychiatric unit, therapy was initiated with aripiprazole 5 mg daily and valproate 1000 mg nightly on Day 1 of treatment. The patient refused medications on hospital Day 2, then received this combination again on Day 3. The next morning, the patient complained of lethargy, headache, nausea, and vomiting.ResultsThe patient’s ammonia level was found to be 204 micromol/L with ALT and AST of 714 and 647 IU/L respectively. Tests for infectious hepatitis were negative. Medical consultation recommended discontinuation of current medications, vigorous hydration, and further work up. On further investigation, the patient was found to have low plasma citrulline level of 8 micromol/L, undetectable plasma arginine, and high urinary orotic acid. The laboratory data showed a biochemical phenotype consistent with a diagnosis of partial OTCD, an X-linked urea cycle disorder resulting in toxic hyperammonemia. The patient was treated with a low protein diet modification as well as a combination of sodium benzoate and sodium phenylbutyrate to reduce serum ammonia concentration. With treatment the patient’s laboratory values normalized, and mental status improved.ConclusionsIn conclusion, partial ornithine transcarbamylase deficiency may manifest with psychiatric symptoms in early adulthood. In young patients with elevated ammonia and mental status change, OTCD is an important diagnosis to consider, as it is the most common inherited cause of hyperammonemia.
The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance
Authors: Cronin Ryan , Brooke Greg N. , Prischi Filippo 
Published: May 2021

AbstractProstate cancer (PCa) is the second most commonly occurring cancer in men, with over a million new cases every year worldwide. Tumor growth and disease progression is mainly dependent on the Androgen Receptor (AR), a ligand dependent transcription factor. Standard PCa therapeutic treatments include androgen-deprivation therapy and AR signaling inhibitors. Despite being successful in controlling the disease in the majority of men, the high frequency of disease progression to aggressive and therapy resistant stages (termed castrate resistant prostate cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSK1-4) family is a group of highly conserved Ser/Thr kinases that holds promise as a novel target. RSKs are effector kinases that lay downstream of the Ras/Raf/MEK/ERK signaling pathway, and aberrant activation or expression of RSKs has been reported in several malignancies, including PCa. Despite their structural similarities, RSK isoforms have been shown to perform nonredundant functions and target a wide range of substrates involved in regulation of transcription and translation. In this article we review the roles of the RSKs in proliferation and motility, cell cycle control and therapy resistance in PCa, highlighting the possible interplay between RSKs and AR in mediating disease progression. In addition, we summarize the current advances in RSK inhibitor development and discuss their potential clinical benefits.
Stainless steel corrosion via direct iron-to-microbe electron transfer by Geobacter species
Authors: Tang Hai-Yan , Yang Chuntian , Ueki Toshiyuki , Pittman Conor C , Xu Dake , Woodard Trevor L , Holmes Dawn E , Gu Tingyue , Wang Fuhui , Lovley Derek R 
Published: May 2021

Abstract
Microbial corrosion of iron-based materials is a substantial economic problem. A mechanistic understanding is required to develop mitigation strategies, but previous mechanistic studies have been limited to investigations with relatively pure Fe(0), which is not a common structural material. We report here that the mechanism for microbial corrosion of stainless steel, the metal of choice for many actual applications, can be significantly different from that for Fe(0). Although H2 is often an intermediary electron carrier between the metal and microbes during Fe(0) corrosion, we found that H2 is not abiotically produced from stainless steel, making this corrosion mechanism unlikely. Geobacter sulfurreducens and Geobacter metallireducens, electrotrophs that are known to directly accept electrons from other microbes or electrodes, extracted electrons from stainless steel via direct iron-to-microbe electron transfer. Genetic modification to prevent H2 consumption did not negatively impact on stainless steel corrosion. Corrosion was inhibited when genes for outer-surface cytochromes that are key electrical contacts were deleted. These results indicate that a common model of microbial Fe(0) corrosion by hydrogenase-positive microbes, in which H2 serves as an intermediary electron carrier between the metal surface and the microbe, may not apply to the microbial corrosion of stainless steel. However, direct iron-to-microbe electron transfer is a feasible route for stainless steel corrosion.
Diversity and distribution of viruses inhabiting the deepest ocean on Earth
Authors: Jian Huahua , Yi Yi , Wang Jiahua , Hao Yali , Zhang Mujie , Wang Siyuan , Meng Canxing , Zhang Yue , Jing Hongmei , Wang Yinzhao , Xiao Xiang 
Published: May 2021

Abstract
As the most abundant biological entities on the planet, viruses significantly influence the overall functioning of marine ecosystems. The abundance, distribution, and biodiversity of viral communities in the upper ocean have been relatively well studied, but our understanding of viruses in the hadal biosphere remains poor. Here, we established the oceanic trench viral genome dataset (OTVGD) by analysing 19 microbial metagenomes derived from seawater and sediment samples of the Mariana, Yap, and Kermadec Trenches. The trench viral communities harbored remarkably high novelty, and they were predicted to infect ecologically important microbial clades, including Thaumarchaeota and Oleibacter. Significant inter-trench and intra-trench exchange of viral communities was proposed. Moreover, viral communities in different habitats (seawater/sediment and depth-stratified ocean zones) exhibited distinct niche-dependent distribution patterns and genomic properties. Notably, microbes and viruses in the hadopelagic seawater seemed to preferably adopt lysogenic lifestyles compared to those in the upper ocean. Furthermore, niche-specific auxiliary metabolic genes were identified in the hadal viral genomes, and a novel viral D-amino acid oxidase was functionally and phylogenetically characterized, suggesting the contribution of these genes in the utilization of refractory organic matter. Together, these findings highlight the genomic novelty, dynamic movement, and environment-driven diversification of viral communities in oceanic trenches, and suggest that viruses may influence the hadal ecosystem by reprogramming the metabolism of their hosts and modulating the community of keystone microbes.
Randomised Phase 1b/2 trial of tepotinib vs sorafenib in Asian patients with advanced hepatocellular carcinoma with MET overexpression
Authors: Ryoo Baek-Yeol , Cheng Ann-Li , Ren Zhenggang , Kim Tae-You , Pan Hongming , Rau Kun-Ming , Choi Hye Jin , Park Joong-Won , Kim Jee Hyun , Yen Chia Jui , Lim Ho Yeong , Zhou Dongli , Straub Josef , Scheele Juergen , Berghoff Karin , Qin Shukui 
Published: May 2021

Abstract
Background
This open-label, Phase 1b/2 study evaluated the highly selective MET inhibitor tepotinib in systemic anticancer treatment (SACT)-naive Asian patients with advanced hepatocellular carcinoma (aHCC) with MET overexpression.

Methods
In Phase 2b, tepotinib was orally administered once daily (300, 500 or 1,000 mg) to Asian adults with aHCC. The primary endpoints were dose-limiting toxicities (DLTs) and adverse events (AEs). Phase 2 randomised SACT-naive Asian adults with aHCC with MET overexpression to tepotinib (recommended Phase 2 dose [RP2D]) or sorafenib 400 mg twice daily. The primary endpoint was independently assessed time to progression (TTP).

Results
In Phase 1b (n = 27), no DLTs occurred; the RP2D was 500 mg. In Phase 2 (n = 90, 45 patients per arm), the primary endpoint was met: independently assessed TTP was significantly longer with tepotinib versus sorafenib (median 2.9 versus 1.4 months, HR = 0.42, 90% confidence interval: 0.26–0.70, P = 0.0043). Progression-free survival and objective response also favoured tepotinib. Treatment-related Grade ≥3 AE rates were 28.9% with tepotinib and 45.5% with sorafenib.

Conclusions
Tepotinib improved TTP versus sorafenib and was generally well tolerated in SACT-naive Asian patients with aHCC with MET overexpression.

Trial registration
ClinicalTrials.gov NCT01988493.
M2 macrophage-derived exosomal long non-coding RNA AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing microRNA-296 and elevating NOTCH2
Authors: Zhang Fuquan , Sang Yonghua , Chen Donglai , Wu Xuejie , Wang Xiaofan , Yang Wentao , Chen Yongbing 
Published: May 2021

AbstractLong noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.
Predictive performance of international COVID-19 mortality forecasting models
Authors: Friedman Joseph , Liu Patrick , Troeger Christopher E. , Carter Austin , Reiner Robert C. , Barber Ryan M. , Collins James , Lim Stephen S. , Pigott David M. , Vos Theo , Hay Simon I. , Murray Christopher J. L. , Gakidou Emmanuela 
Published: May 2021

AbstractForecasts and alternative scenarios of COVID-19 mortality have been critical inputs for pandemic response efforts, and decision-makers need information about predictive performance. We screen n = 386 public COVID-19 forecasting models, identifying n = 7 that are global in scope and provide public, date-versioned forecasts. We examine their predictive performance for mortality by weeks of extrapolation, world region, and estimation month. We additionally assess prediction of the timing of peak daily mortality. Globally, models released in October show a median absolute percent error (MAPE) of 7 to 13% at six weeks, reflecting surprisingly good performance despite the complexities of modelling human behavioural responses and government interventions. Median absolute error for peak timing increased from 8 days at one week of forecasting to 29 days at eight weeks and is similar for first and subsequent peaks. The framework and public codebase (https://github.com/pyliu47/covidcompare) can be used to compare predictions and evaluate predictive performance going forward.
MyD88 TIR domain higher-order assembly interactions revealed by microcrystal electron diffraction and serial femtosecond crystallography
Authors: Clabbers Max T. B. , Holmes Susannah , Muusse Timothy W. , Vajjhala Parimala R. , Thygesen Sara J. , Malde Alpeshkumar K. , Hunter Dominic J. B. , Croll Tristan I. , Flueckiger Leonie , Nanson Jeffrey D. , Rahaman Md. Habibur , Aquila Andrew , Hunter Mark S. , Liang Mengning , Yoon Chun Hong , Zhao Jingjing , Zatsepin Nadia A. , Abbey Brian , Sierecki Emma , Gambin Yann , Stacey Katryn J. , Darmanin Connie , Kobe Bostjan , Xu Hongyi , Ve Thomas 
Published: May 2021

AbstractMyD88 and MAL are Toll-like receptor (TLR) adaptors that signal to induce pro-inflammatory cytokine production. We previously observed that the TIR domain of MAL (MALTIR) forms filaments in vitro and induces formation of crystalline higher-order assemblies of the MyD88 TIR domain (MyD88TIR). These crystals are too small for conventional X-ray crystallography, but are ideally suited to structure determination by microcrystal electron diffraction (MicroED) and serial femtosecond crystallography (SFX). Here, we present MicroED and SFX structures of the MyD88TIR assembly, which reveal a two-stranded higher-order assembly arrangement of TIR domains analogous to that seen previously for MALTIR. We demonstrate via mutagenesis that the MyD88TIR assembly interfaces are critical for TLR4 signaling in vivo, and we show that MAL promotes unidirectional assembly of MyD88TIR. Collectively, our studies provide structural and mechanistic insight into TLR signal transduction and allow a direct comparison of the MicroED and SFX techniques.
Dipolar-stabilized first and second-order antiskyrmions in ferrimagnetic multilayers
Authors: Heigl Michael , Koraltan Sabri , Vaňatka Marek , Kraft Robert , Abert Claas , Vogler Christoph , Semisalova Anna , Che Ping , Ullrich Aladin , Schmidt Timo , Hintermayr Julian , Grundler Dirk , Farle Michael , Urbánek Michal , Suess Dieter , Albrecht Manfred 
Published: May 2021

AbstractSkyrmions and antiskyrmions are topologically protected spin structures with opposite vorticities. Particularly in coexisting phases, these two types of magnetic quasi-particles may show fascinating physics and potential for spintronic devices. While skyrmions are observed in a wide range of materials, until now antiskyrmions were exclusive to materials with D2d symmetry. In this work, we show first and second-order antiskyrmions stabilized by magnetic dipole–dipole interaction in Fe/Gd-based multilayers. We modify the magnetic properties of the multilayers by Ir insertion layers. Using Lorentz transmission electron microscopy imaging, we observe coexisting antiskyrmions, Bloch skyrmions, and type-2 bubbles and determine the range of material properties and magnetic fields where the different spin objects form and dissipate. We perform micromagnetic simulations to obtain more insight into the studied system and conclude that the reduction of saturation magnetization and uniaxial magnetic anisotropy leads to the existence of this zoo of different spin objects and that they are primarily stabilized by dipolar interaction.
Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data
Authors: Pintacuda Greta , Lassen Frederik H. , Hsu Yu-Han H. , Kim April , Martín Jacqueline M. , Malolepsza Edyta , Lim Justin K. , Fornelos Nadine , Eggan Kevin C. , Lage Kasper 
Published: May 2021

AbstractCombining genetic and cell-type-specific proteomic datasets can generate biological insights and therapeutic hypotheses, but a technical and statistical framework for such analyses is lacking. Here, we present an open-source computational tool called Genoppi (lagelab.org/genoppi) that enables robust, standardized, and intuitive integration of quantitative proteomic results with genetic data. We use Genoppi to analyze 16 cell-type-specific protein interaction datasets of four proteins (BCL2, TDP-43, MDM2, PTEN) involved in cancer and neurological disease. Through systematic quality control of the data and integration with published protein interactions, we show a general pattern of both cell-type-independent and cell-type-specific interactions across three cancer cell types and one human iPSC-derived neuronal cell type. Furthermore, through the integration of proteomic and genetic datasets in Genoppi, our results suggest that the neuron-specific interactions of these proteins are mediating their genetic involvement in neurodegenerative diseases. Importantly, our analyses suggest that human iPSC-derived neurons are a relevant model system for studying the involvement of BCL2 and TDP-43 in amyotrophic lateral sclerosis.
Agricultural subsidies and global greenhouse gas emissions
Authors: Laborde David , Mamun Abdullah , Martin Will , Piñeiro Valeria , Vos Rob 
Published: May 2021

AbstractAgricultural production is strongly affected by and a major contributor to climate change. Agriculture and land-use change account for a quarter of total global emissions of greenhouse gases (GHG). Agriculture receives around US$600 billion per year worldwide in government support. No rigorous quantification of the impact of this support on GHG emissions has been available. This article helps fill the void. Here, we find that, while over the years the government support has incentivized the development of high-emission farming systems, at present, the support only has a small impact in terms of inducing additional global GHG emissions from agricultural production; partly because support is not systematically biased towards high-emission products, and partly because support generated by trade protection reduces demand for some high-emission products by raising their consumer prices. Substantially reducing GHG emissions from agriculture while safeguarding food security requires a more comprehensive revamping of existing support to agriculture and food consumption.
Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Authors: Lauterborn Julie C. , Scaduto Pietro , Cox Conor D. , Schulmann Anton , Lynch Gary , Gall Christine M. , Keene C. Dirk , Limon Agenor 
Published: May 2021

AbstractSynaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.
Unconventional singularities and energy balance in frictional rupture
Authors: Brener Efim A. , Bouchbinder Eran 
Published: May 2021

AbstractA widespread framework for understanding frictional rupture, such as earthquakes along geological faults, invokes an analogy to ordinary cracks. A distinct feature of ordinary cracks is that their near edge fields are characterized by a square root singularity, which is intimately related to the existence of strict dissipation-related lengthscale separation and edge-localized energy balance. Yet, the interrelations between the singularity order, lengthscale separation and edge-localized energy balance in frictional rupture are not fully understood, even in physical situations in which the conventional square root singularity remains approximately valid. Here we develop a macroscopic theory that shows that the generic rate-dependent nature of friction leads to deviations from the conventional singularity, and that even if this deviation is small, significant non-edge-localized rupture-related dissipation emerges. The physical origin of the latter, which is predicted to vanish identically in the crack analogy, is the breakdown of scale separation that leads an accumulated spatially-extended dissipation, involving macroscopic scales. The non-edge-localized rupture-related dissipation is also predicted to be position dependent. The theoretical predictions are quantitatively supported by available numerical results, and their possible implications for earthquake physics are discussed.
Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
Authors: Wang Feng , Morita Kiyomi , DiNardo Courtney D. , Furudate Ken , Tanaka Tomoyuki , Yan Yuanqing , Patel Keyur P. , MacBeth Kyle J. , Wu Bin , Liu Guowen , Frattini Mark , Matthews Jairo A. , Little Latasha D. , Gumbs Curtis , Song Xingzhi , Zhang Jianhua , Thompson Erika J. , Kadia Tapan M. , Garcia-Manero Guillermo , Jabbour Elias , Ravandi Farhad , Bhalla Kapil N. , Konopleva Marina , Kantarjian Hagop M. , Andrew Futreal P. , Takahashi Koichi 
Published: May 2021

AbstractAllosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.