bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrosteatotic Allografts and Obese Recipients Have Nearly Equal Negative Impact on Liver Transplant Survival
Authors: Northup Patrick G. , Intagliata Nicolas M. , Davis Jessica P.E. , Argo Curtis K. , Pelletier Shawn J. 
Published: October 2019

Background.
Our aim was to evaluate liver transplant outcomes involving donors with high macrosteatosis grafts in the obese modern liver transplant recipient population.

Methods.
A high-steatosis graft was defined as donor graft macrosteatosis ≥30% on biopsy. Recipient obesity was defined as body mass index (BMI) >35 adjusted for ascites. Raw and adjusted recipient liver transplant survival were evaluated and compared between 4 cohorts: (1) high-steatosis graft in high-BMI recipient; (2) low-steatosis graft in high-BMI recipient; (3) high-steatosis graft in normal-BMI recipient; and (4) low-steatosis graft in normal-BMI recipient.

Results.
After adjustment for multiple factors, recipient high-BMI remained an independent predictor of posttransplant mortality at 30 days (P < 0.0001) and persisted at 1 year (P = 0.009). A high-steatosis graft was the strongest independent predictor of mortality at 30 days (hazard ratio 2.05, 1.66–2.53; P < 0.0001) and that effect was diminished but persistent at 1 year (1.27, 1.10–1.46; P = 0.001).

Conclusions.
Recipient high-BMI and a high-steatosis graft are both significant independent and equally powerful predictors of mortality after modern liver transplant. High-steatosis grafts transplanted into obese recipients have the highest mortality. The increase in mortality associated with a high-steatosis graft into a normal-BMI recipient is similar in magnitude to a low-steatosis graft placed into a high-BMI recipient.
Progress in rare central nervous system tumors
Authors: Penas-Prado Marta , Armstrong Terri S. , Gilbert Mark R. 
Published: October 2019

Purpose of review
Although all primary central nervous system (CNS) tumors are rare, certain tumor types each represent less than 2% of the total and an annual incidence of about 1000 patients or less. Most of them are disproportionally diagnosed in children and young adults, but older adults can also be affected and are rarely recruited to clinical trials. Recent new molecular techniques have led to reclassification of some of these tumors and discovery of actionable molecular alterations.

Recent findings
We review recent progress in the molecular understanding and therapeutic options of selected rare CNS tumors, with a focus on select clinical trials (temozolomide and lapatinib for recurrent ependymoma; vemurafenib for BRAFV600E-mutated tumors), as well as tumor-agnostic approvals (pembrolizumab, larotrectinib) and their implications for rare CNS tumors.

Summary
Although rare CNS tumors are a very small fraction of the total of cancers, they represent a formidable challenge. There is a need for dedicated clinical trials with strong correlative component in patients of all ages with rare CNS tumors. Critical research questions include relevance of the selected target for specific tumor types, persistence of the actionable biomarker at recurrence, blood–brain barrier penetration, and analysis of mechanisms of primary and acquired resistance.
Complications associated with immunotherapy for brain metastases
Authors: Tran Thuy T. , Jilaveanu Lucia B. , Omuro Antonio , Chiang Veronica L. , Huttner Anita , Kluger Harriet M. 
Published: October 2019

Purpose of review
Median survival after the diagnosis of brain metastases has historically been on the order of months. With the recent development of immune checkpoint inhibitors, intracranial activity and durable responses have been observed in brain metastases on multiple phase 2 clinical trials, which have primarily been conducted in patients with melanoma. Immune-related adverse events related to checkpoint inhibitor therapy of brain metastasis can present unique challenges for the clinician and underscore the need for a multidisciplinary team in the care of these patients. The goal of this review is to address the current knowledge, limitations of understanding, and future directions in research regarding immune therapy trials and neurologic toxicities based on retrospective, prospective, and case studies.

Recent findings
Immune therapy has the potential to exacerbate symptomatic edema and increase the risk of radiation necrosis in previously irradiated lesions. Neurologic toxicities will likely increase in prevalence as more patients with brain metastatic disease are eligible for immune therapy.

Summary
An improved understanding and heightened awareness of the unique neurologic toxicities that impact this patient group is vital for mitigating treatment-related morbidity and mortality.
New metabolic imaging tools in neuro-oncology
Authors: Corbin Zachary A. 
Published: October 2019

Purpose of review
The current treatment of gliomas dovetails results of decades-old clinical trials with modern trends in chemotherapy. Molecular characterization now plays a pivotal role, and IDH mutations are key characteristics and the subject of active debate. IDH-mutant tumors produce the ‘onco-metabolite’, 2-hydroxyglutarate. Metabolic changes have become central to the understanding of tumor biology, and tumors display a fundamental metabolic change called the Warburg Effect. The Warburg Effect represents a preference for glycolysis, as opposed to oxidative phosphorylation. The present review details the clinical context and discusses clinical and preclinical metabolic imaging tools to characterize the Warburg Effect.

Recent findings
A clinical Warburg Index is proposed, defined as the lactate concentration measured by 1H-MRSI over the SUV measured by FDG-PET, to measure the Warburg Effect. A preclinical technique called deuterium metabolic imaging has successfully imaged the Warburg Effect in vivo in glioblastoma.

Summary
Metabolic imaging provides an opportunity to measure the Warburg Effect and other metabolic changes in brain tumors. An increased understanding of metabolic shifts integral to brain cancer has the potential to address multiple contemporary debates on glioma pathophysiology and treatment. Metabolic imaging tools thus have the potential to advance research findings, clinical trial development, and clinical care.
Decoding the neural dynamics of free choice in humans
Authors: Thiery Thomas , Saive Anne-Lise , Combrisson Etienne , Dehgan Arthur , Bastin Julien , Kahane Philippe , Berthoz Alain , Lachaux Jean-Philippe , Jerbi Karim 
Published: October 2019

SummaryHow do we choose a particular action among equally valid alternatives? Non-human primate findings have shown that decision-making implicates modulations in unit firing rates and local field potentials (LFPs) across frontal and parietal cortices. Yet the electrophysiological brain mechanisms that underlie free choice in humans remain ill defined. Here, we address this question using rare intracerebral EEG recordings in surgical epilepsy patients performing a delayed oculomotor decision task. We find that the temporal dynamics of high gamma (HG, 60-140 Hz) neural activity in distinct frontal and parietal brain areas robustly discriminate free choice from instructed saccade planning at the level of single trials. Classification analysis was applied to the LFP signals to isolate decision-related activity from sensory and motor planning processes. Compared to instructed saccades, free choice trials exhibited delayed and longer-lasting HG activity. The temporal dynamics of these sustained decision-related responses distinguished deliberation-related from working memory processes. Taken together, these findings provide the first direct electrophysiological evidence in humans for the role of sustained high-frequency neural activation in fronto-parietal cortex in mediating the intrinsically driven process of freely choosing among competing behavioral alternatives.HighlightsFirst intracerebral recordings in humans performing an oculomotor decision-making taskMachine learning analytics unravel underlying spectral and temporal brain dynamicsFree choice trials exhibit sustained fronto-parietal high gamma (HG) activity during the delayMaking a decision and maintaining it in working memory are associated with distinct sustained HG dynamics
All-atom Molecular Dynamics model for mycobacterial plasma membrane
Authors: Scaini João L. R. , Werhli Adriano V. , de Lima Vânia R. , da Silva Pedro E. A. , Bordin José Rafael , Machado Karina S. 
Published: October 2019

AbstractPhosphatidyl-myo-inositol mannosides (PIMs) are an essential component of the cell envelope and the most predominant at the inner membrane (IM) ofM. tuberculosis. In this work, we propose an Molecular Dynamics (MD)M. tuberculosisIM model composed of PIM2lipids. The study was divided in three parts: influence of the temperature in the PIM2membrane stability, self-assembly abilities of the PIM2lipid and the behavior when a trans membrane protein is inserted in PIM2membrane. Our results show that the model is able to reproduce the gel phase observed at 310 K and the transition to a fluid phase at 328.15 K. Also, the spontaneous self-assembly of randomly distributed lipids in a vesicular aggregate was observed. Finally, we observe that the PIM2membrane is more stable than DPPC membranes when a Tap protein is inserted. Once Tap eflux pump is related to multidrug resistance ofM. tuberculosis, this result indicated that the use of the proper lipid model is essential to the proper depiction and modeling of these systems.Graphical TOC Entry
Ictal recruitment of anterior nucleus of thalamus in human focal epilepsy
Authors: Toth Emilia , Chaitanya Ganne , Pizarro Diana , Kumar Sachin S , Ilyas Adeel , Romeo Andrew , Riley Kristen , Vlachos Ioannis , David Olivier , Balasubramanian Karthi , Pati Sandipan 
Published: October 2019

AbstractThe thalamic nuclei play diverse roles in the initiation, propagation, and termination of temporal lobe seizures. The role of the anterior nucleus of the thalamus (ANT) - a node that is integral to the limbic network is unclear. The objective of this study was to characterize temporal and - spectral patterns of ANT ictal recruitment in drug-resistant temporal lobe epilepsy (TLE). We hypothesized that seizures localized to the temporolimbic network are likely to recruit ANT, and the odds of recruitment were higher in seizures that had altered consciousness. Ten patients undergoing stereo-electroencephalography (SEEG) were recruited prospectively to record field potentials from the ANT. Using epileptogenicity index and line length, we computed the number of seizures that recruited the ANT (recruitment ratio), the recruitment latencies between the ANT and the epileptogenic zone (EZ), and latency of ANT recruitment to clinical manifestation for seventy-nine seizures. We observed that seizures localized to mesial temporal subregions (hippocampus, amygdala, anterior cingulate) have a higher predilection for ANT recruitment, and the recruitment was faster (ranged 5-12 secs) and preceded clinical onset for seizures that impaired consciousness. Seizures that recruited ANT lasted significantly longer (t=1.795, p=0.005). Recruitment latency was inversely correlated to seizure duration (r=-0.78, p=0.004). Electrical stimulation of the EZ induced seizures, in which early recruitment of ANT was confirmed. Stimulation of ANT did not induce a seizure. Finally, we tested the hypothesis that spectral and entropy-based features extracted from thalamic field potentials can distinguish its state of ictal recruitment from other interictal states (including awake, sleep). For this, we employed classification machine learning that discriminated thalamic ictal state from other interictal states with high accuracy (92.8%) and precision (93.1%). Among the features, the emergence of the theta rhythm (4-8 Hz) maximally discriminated the endogenous ictal state from other interictal states of vigilance. These results prompt a mechanistic role for the ANT in the early organization and sustaining of seizures, and the possibility to serve as a target for therapeutic closed-loop stimulation in TLE.
High-throughput and all-solution phase African Swine Fever Virus (ASFV) detection using CRISPR-Cas12a and fluorescence based point-of-care system
Authors: He Qian , Yu Dongmei , Bao Mengdi , Korensky Grant , Chen Juhong , Shin Mingyeong , Kim Juwon , Park Myeongkee , Qin Peiwu , Du Ke 
Published: October 2019

AbstractHere we report the development of a high throughput, all-solution phase, and isothermal detection system to detect African Swine Fever Virus (ASFV). CRISPR-Cas12a programmed with a CRISPR RNA (crRNA) is used to detect ASFV target DNA. Upon ASFV DNA binding, the Cas12a/crRNA/ASFV DNA complex becomes activated and degrades a fluorescent single stranded DNA (ssDNA) reporter present in the assay. We combine this powerful CRISPR-Cas assay with fluorescence-based point-of-care (POC) system we developed for rapid and accurate virus detection. Without nucleic acid amplification, a detection limit of 1 pM is achieved within 2 hrs. In addition, the ternary Cas12a/crRNA/ASFV DNA complex is highly stable at physiological temperature and continues to cleave the ssDNA reporter even after 24 hrs of incubation, resulting in an improvement of the detection limit to 100 fM. We show that this system is very specific and can differentiate nucleic acid targets with closely matched sequences. The high sensitivity and selectivity of our system enables the detection of ASFV in femtomolar range. Importantly, this system features a disposable cartridge and a sensitive custom designed fluorometer, enabling compact, multiplexing, and simple ASFV detection, intended for low resource settings.
Regulation of transcription termination by FUS and TDP-43
Authors: Zhao Dorothy Yanling , Ni Zuyao , Pu Shuye , Zhong Guoqing , Schmitges Frank W. , Braunschweig Ulrich , Blencowe Benjamin J. , Greenblatt Jack F. 
Published: October 2019

ABSTRACTThe carboxy-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. We previously found that symmetrical dimethylation (me2s) of a CTD Arginine residue (R1810 in human) causes recruitment of the Tudor domain of SMN, which interacts with Senataxin. SMN is mutated in spinal muscular atrophy (SMA), and Senataxin is sometimes mutated in Amyotrophic Lateral Sclerosis (ALS). R1810me2s and SMN, like Senataxin, are important for resolving R-loops (DNA:RNA hybrids) at transcription terminators. FUS and TDP-43 (TARDBP) are DNA/RNA binding proteins that are sometimes mutated in ALS and FTD (Frontotemporal dementia). Here we show that TDP-43 and, to some extent, FUS are recruited by the R1810me2s-SMN pathway. Defects in FUS and TDP-43 recruitment influence RNAPII termination and R-loop accumulation, leading to elevated DNA damage at terminators that may contribute to neurodegenerative disorders like ALS and FTD.
Genetic architecture underlying changes in carotenoid accumulation during the evolution of the Blind Mexican cavefish,Astyanax mexicanus
Authors: Riddle Misty R. , Aspiras Ariel , Damen Fleur , Hutchinson John N. , Chinnapen Daniel , Tabin Clifford J. 
Published: October 2019

AbstractCarotenoids are yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and therefore limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed.Astyanax mexicanusis a species of fish with river-adapted (surface) and multiple cave-adapted populations (i.e. Tinaja, Pachón, Molino). Cavefish exhibit regressive features such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here we show that unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue (VAT). Carotenoid accumulation is not observed in Molino cavefish indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with this trait. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into un-pigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishesA. mexicanusas a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.Research HighlightsCavefish accumulate carotenoids in the visceral adipose tissue (VAT)Genetic mapping reveals candidate genes associated with yellow VATCarotenoid accumulation is linked with decreased expression of carotenoid-processing genes
Uniform Genomic Data Analysis in the NCI Genomic Data Commons
Authors: Zhang Zhenyu , Hernandez Kyle , Savage Jeremiah , Li Shenglai , Miller Dan , Agrawal Stuti , Ortuno Francisco , Staudt Lou , Heath Allison , Grossman Robert L. 
Published: October 2019

AbstractThe goal of the National Cancer Institute (NCI) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive (https://gdc.cancer.gov/).
Cleavage-furrow formation without F-actin inChlamydomonas
Authors: Onishi Masayuki , Umen James G. , Cross Frederick R. , Pringle John R. 
Published: October 2019

AbstractIt is widely believed that cleavage-furrow formation during cell division is driven by the contraction of a ring containing F-actin and type-II myosin. However, even in cells that have such rings, they are not always essential for furrow formation. Moreover, many taxonomically diverse eukaryotic cells divide by furrowing but have no type-II myosin, making it unlikely that an actomyosin ring drives furrowing. To explore this issue further, we have used one such organism, the green algaChlamydomonas reinhardtii. We found that although F-actin is concentrated in the furrow region, none of the three myosins (of types VIII and XI) is localized there. Moreover, when F-actin was eliminated through a combination of a mutation and a drug, furrows still formed and the cells divided, although somewhat less efficiently than normal. Unexpectedly, division of the largeChlamydomonaschloroplast was delayed in the cells lacking F-actin; as this organelle lies directly in the path of the cleavage furrow, this delay may explain, at least in part, the delay in cell division itself. Earlier studies had shown an association of microtubules with the cleavage furrow, and we used a fluorescently tagged EB1 protein to show that at least the microtubule plus-ends are still associated with the furrows in the absence of F-actin, consistent with the possibility that the microtubules are important for furrow formation. We suggest that the actomyosin ring evolved as one way to improve the efficiency of a core process for furrow formation that was already present in ancestral eukaryotes.
Defining relative mutational difficulty to understand cancer formation and prevention
Authors: Shan Lin , Yu Jiao , He Zhengjin , Chen Shishuang , Liu Mingxian , Ding Hongyu , Xu Liang , Zhao Jie , Yang Ailing , Jiang Hai 
Published: October 2019

SummaryMost mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Furthermore, mutational difficulty analysis also points to potential means of cancer prevention. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such parameter, we can bring new angles to understanding cancer formation and prevention.
Robustness and universality in organelle size control
Authors: Amiri Kiandokht Panjtan , Kalish Asa , Mukherji Shankar 
Published: October 2019

ABSTRACTOne of the grand challenges in quantitative cell biology is understanding the precision with which cells assemble and maintain subcellular organelles. A critical property that governs organelle function is its size. Organelle sizes must be flexible enough to allow cells to grow or shrink them as environments demand, yet be maintained within homeostatic limits. Despite identification of numerous molecular factors that regulate organelle sizes we lack insight into the quantitative principles underlying organelle size control. Here we examine organelle sizes from Saccharomyces cerevisiae and human iPS cells with mathematical theory to show that cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey a universal scaling relationship we predict theoretically, our framework suggests that organelles grow in random bursts from a limited pool of building blocks. Burst-like growth provides a general biophysical mechanism by which cells can maintain on average reliable yet plastic organelle sizes.