Miracle-dz/UniFAR-FTUs huggingface dataset:
Reconstruction of molecular network evolution from cross‐sectional omics data

Cross‐sectional studies may shed light on the evolution of a disease like cancer through the comparison of patient traits among disease stages. This problem is especially challenging when a gene–gene interaction network needs to be reconstructed from omics data, and, in addition, the patients of each stage need not form a homogeneous group. Here, the problem is operationalized as the estimation of stage‐wise mixtures of Gaussian graphical models (GGMs) from high‐dimensional data. These mixtures are fitted by a (fused) ridge penalized EM algorithm. The fused ridge penalty shrinks GGMs of contiguous stages. The (fused) ridge penalty parameters are chosen through cross‐validation. The proposed estimation procedures are shown to be consistent and their performance in other respects is studied in simulation. The down‐stream exploitation of the fitted GGMs is outlined. In a data illustration the methodology is employed to identify gene–gene interaction network changes in the transition from normal to cancer prostate tissue.
Correlation Between Standardized Uptake Value in Preneoadjuvant and Postneoadjuvant Chemoradiotherapy and Tumor Regression Grade in Patients With Locally Advanced Esophageal Cancer

Purpose: To investigate whether positron emission tomography/computed tomography (PET/CT) initial and restaging imaging predicts for pathologic response measured by tumor regression grade (TRG) after preoperative chemoradiotherapy (CRT) in patients with locally advanced esophageal cancer. Methods: A retrospective review of 220 patients with stage II-III esophageal cancer treated with neoadjuvant CRT followed by surgery was performed. In total, 187 patients were eligible for statistical analysis. Pretreatment and posttreatment PET/CT scans were reviewed. Maximum standard uptake value (SUV) at the site of the primary tumor was recorded before and 6 weeks after neoadjuvant therapy. Upon completion of surgery, TRG was determined by a specialized site-specific gastrointestinal pathologist. Spearman correlation was used to compare pre, post, and change in maximum SUV, TRG, and overall survival. Results: The median follow-up was 24 months. Although no significant correlation was found between pretreatment SUV and TRG (r=0.073, P=0.32), post-CRT SUV, however, showed a significant positive correlation with TRG (r=0.374, P<0.01). There was no significant correlation between the absolute change in fluorodeoxyglucose uptake after CRT and TRG (r=0.057, P=0.44); however, the rate of SUV change showed a significant correlation with TRG (r=0.178, P=0.017). Similar to previous studies, our study showed a significant difference in overall survival between TRG groups (log-rank test, P=0.019). Patients with TRG 3 showed prominently worse survival with median survival of 27.4 months. Patients with favorable pathologic responses were those whose scans demonstrated a metabolic response defined as a decrease in SUV≥70%. Conclusions: Changes in SUV uptake on PET/CT scans after CRT have prognostic value in predicting pathologic response of esophageal cancer after neoadjuvant therapy. Further studies are needed to validate the integration of PET/CT as a decision-making tool.
Use of patient-reported outcomes and satisfaction for quality assessments.

OBJECTIVES Recent focus on patient-reported outcomes (PROs) has created a new challenge as we learn how to integrate these outcomes into practice along with other quality metrics. We investigated the relationship between PROs and satisfaction among spine surgery patients. We hypothesized that there would be significant disparities between patient satisfaction and PROs at the 1-year postoperative time point. STUDY DESIGN Retrospective cohort study of adults undergoing elective lumbar spine surgery at 12 hospitals participating in the Spine Surgical Care and Outcomes Assessment Program. METHODS Satisfaction, pain, and function scores were collected at 1 year post operation, along with clinical information, to determine the relationship between PROs and satisfaction at the patient level. RESULTS Among 520 patients (mean age = 63 ± 13 years; 47% male), the majority of patients (82%) reported being satisfied with surgery. Satisfaction was associated with both improvement in pain (odds ratio [OR], 1.33; 95% CI, 1.17-1.51) and function (OR, 1.06; 95% CI, 1.04-1.08). However, even among patients who did not improve in pain or function, more than half (59%) reported being satisfied. CONCLUSIONS Overall, patients undergoing elective lumbar spine surgery reported being satisfied with outcomes, but the reported responses in PROs were much more variable. As the expectations increase to include PRO measures as valid quality indicators, it is necessary to dedicate time and consideration to understanding the relationships among these measures to support meaningful translations into healthcare policy.
Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory ‘milieu’ initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD.
Memory effect in a molecular quantum dot with strong electron-vibron interaction

•Polaron theory of tunneling through a molecular quantum dot ~MQD! with strong electron-vibron interactions and attractive electron-electron correlations is developed. The dot is modeled as a d-fold-degenerate energy level weakly coupled to the leads. The effective attractive interaction between polarons in the dot results in a ‘‘switching’’ phenomenon in the current-voltage characteristics when d.2, in agreement with the results for the phenomenological negative-U model. The degenerate MQD with strong electron-vibron coupling has two stable current states in a certain interval of the bias voltage below some critical temperature.
Spatiotemporal correlation of spinal network dynamics underlying spasms in chronic spinalized mice

Spasms after spinal cord injury (SCI) are debilitating involuntary muscle contractions that have been associated with increased motor neuron excitability and decreased inhibition. However, whether spasms involve activation of premotor spinal excitatory neuronal circuits is unknown. Here we use mouse genetics, electrophysiology, imaging and optogenetics to directly target major classes of spinal interneurons as well as motor neurons during spasms in a mouse model of chronic SCI. We find that assemblies of excitatory spinal interneurons are recruited by sensory input into functional circuits to generate persistent neural activity, which interacts with both the graded expression of plateau potentials in motor neurons to generate spasms, and inhibitory interneurons to curtail them. Our study reveals hitherto unrecognized neuronal mechanisms for the generation of persistent neural activity under pathophysiological conditions, opening up new targets for treatment of muscle spasms after SCI. DOI: http://dx.doi. org/10.7554/eLife.23011. 001
Transient errors and rollback recovery in LZ compression

This paper analyzes the data integrity of one of the most widely used lossless data compression techniques, Lempel-Ziv (LZ) compression. In this algorithm, because the data reconstruction from compressed codewords relies on previously decoded results, a transient error during compression may propagate to the decoder and cause a significant corruption in the reconstructed data. To recover the system from transient faults, we designed two rollback error recovery schemes for the LZ compression hardware, the "reload-retry" and "direct-retry" schemes. Statistical analyses show that the "reload-retry" scheme can recover the LZ compression process from transient faults in one dictionary reload cycle with a small amount of hardware redundancy. The "direct-retry" scheme can recover normal operations with a shorter latency but with a small degradation in the compression ratio.
Proton pump inhibitors affect the gut microbiome

Background and aims Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome. Methods The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis. Results 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate <0.05). Multiple oral bacteria were over-represented in the faecal microbiome of PPI-users, including the genus Rothia (p=9.8×10−38). In PPI users we observed a significant increase in bacteria: genera Enterococcus, Streptococcus, Staphylococcus and the potentially pathogenic species Escherichia coli. Conclusions The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.
Key interindividual determinants in MDMA pharmacodynamics

ABSTRACT Introduction: MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.
Neutrophils diminish T-cell immunity to foster gastric cancer progression: the role of GM-CSF/PD-L1/PD-1 signalling pathway

Neutrophils are the predominant leucocytes in the blood and act as the first line of host defence against invading pathogens. Neutrophils have also been shown to play important roles in the other pathological conditions, including cancer. In the past decade, many efforts have been made to clarify the roles of neutrophils in cancer development and progression. It appears that neutrophils have both antitumour and protumour functions.1 On one hand, neutrophils can directly kill tumour cells by releasing antimicrobial and cytotoxic contents that are prestored in their granules. Neutrophils can induce apoptosis in tumour cells and reduce tumour growth when administrated into tumour-bearing animals. Neutrophils are regarded as important effector cells for monoclonal antibody (mAb)-mediated immunotherapy, where they interact with mAb through the Fc receptor, leading to antibody-dependent cell cytotoxicity. Neutrophils also have antimetastatic activity. In mouse models of cancer metastasis, neutrophils at the premetastatic site produce cytotoxic substances to eliminate tumour cells and limit their metastatic spread. In addition, neutrophils are able to regulate the activation of T cells and other immune cells to elicit antitumour immune responses. On the other hand, emerging evidence suggests that neutrophils possess protumour properties including the induction of malignant transformation, enhancement of tumour growth, establishment of premetastatic niche, stimulation of angiogenesis and promotion of immune evasion by suppression of innate and adaptive immune cells (eg, T cells and NK cells). The dual roles of neutrophils in cancer might be explained by their plasticity and the existence of distinct neutrophil subsets with differing properties within the tumours, which could be driven by signals from the tumours.2 ,3 In particular, neutrophils seem to have both stimulatory and suppressive roles in T-cell immunity. During the early phase of tumour growth, neutrophils tend to inhibit primary tumour growth by recruiting and activating CD8+ T …
Sparse ternary connect: Convolutional neural networks using ternarized weights with enhanced sparsity

Convolutional Neural Networks (CNNs) are indispensable in a wide range of tasks to achieve state-of-the-art results. In this work, we exploit ternary weights in both inference and training of CNNs and further propose Sparse Ternary Connect (STC) where kernel weights in float value are converted to 1, −1 and 0 based on a new conversion rule with the controlled ratio of 0. STC can save hardware resource a lot with small degradation of precision. The experimental evaluation on 2 popular datasets (CIFAR-10 and SVHN) shows that the proposed method can reduce resource utilization (by 28.9% of LUT, 25.3% of FF, 97.5% of DSP and 88.7% of BRAM on Xilinx Kintex-7 FPGA) with less than 0.5% accuracy loss.
Complete genome sequence of Parvibaculum lavamentivorans type strain (DS-1T)

Parvibaculum lavamentivorans DS-1T is the type species of the novel genus Parvibaculum in the novel family Rhodobiaceae (formerly Phyllobacteriaceae) of the order Rhizobiales of Alphaproteobacteria. Strain DS-1T is a non-pigmented, aerobic, heterotrophic bacterium and represents the first tier member of environmentally important bacterial communities that catalyze the complete degradation of synthetic laundry surfactants. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 3,914,745 bp long genome with its predicted 3,654 protein coding genes is the first completed genome sequence of the genus Parvibaculum, and the first genome sequence of a representative of the family Rhodobiaceae.
Validity and Reliability of the Load-Velocity Relationship to Predict the One-Repetition Maximum in Deadlift

Abstract Ruf, L, Chéry, C, Taylor, KL. Validity and reliability of the load-velocity relationship to predict the 1RM in deadlift. J Strength Cond Res 32(3): 681–689, 2018—The aim of this study was to verify the reliability and validity of using submaximal loads from the load-velocity relationship to predict the actual 1 repetition maximum (1RM) in the deadlift. Data from 11 resistance-trained athletes were analyzed performing three 1RM assessments separated by at least 3 days. Reliability was assessed by comparing predicted 1RMs of sessions 2 and 3, whereas for validity purposes, predicted 1RMs of session 3 were compared with actual 1RMs of session 2. Mean concentric velocity at 1RM (v at 1RM) was entered in individualized linear regression equations, derived from the load-velocity relationship for 3 (20–60%, 40–80%, and 60–90% of 1RM), 4 (20–80% and 40–90% of 1RM), and 5 (20–90% of 1RM) incremental loads to predict 1RMs. There were trivial changes for all predicted 1RMs between sessions with 20–90% of 1RM being the most reliable model. Similarly, the actual 1RM was very stable (effect size [ES] = 0.04, 90% confidence limit [CL] [−0.03 to 0.12], typical error of measurement [TE] = 3.4 kg [2.5–5.4], intraclass coefficient [ICC] = 0.99 [0.96–0.996], and coefficient of variation [CV] = 1.9% [1.4–3.0]), whereas the v at 1RM was unreliable between trials (ES = −0.30, 90% CL [−0.78 to 0.17], TE = 0.029 m·s−1 [0.022–0.047], ICC = 0.63 [0.19–0.86], and CV = 15.7% [11.7–26.1]). However, predicted 1RMs computed from all submaximal load ranges substantially overestimated the actual 1RM with considerable differences between athletes. Although 1RM predictions showed high reliability, they all overestimated the actual 1RM, which was stable between sessions. Therefore, it is not recommended to apply the prediction models used in this study to compute daily 1RMs.
Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations

Purpose: Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC. Experimental Design: Archival and prospectively acquired samples and matched normal DNA from N = 833 PDAC cases were analyzed using a hybridization capture–based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status. Results: MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease). Conclusions: An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients. Clin Cancer Res; 24(6); 1326–36. ©2018 AACR.
Readers' perceptions of authors' citation behaviour

Purpose – The aim of this paper is to determine the extent to which readers perceive correctly the reasons why authors cite items in scholarly texts.Design/methodology/approach – The authors of ten library and information science articles provided the reasons for citing material in their articles and these reasons were compared with those suggested independently by readers of the articles.Findings – Readers are able to perceive correctly author reasons for citation only to a very limited extent.Research limitations/implications – Limitations are a small sample of ten articles and 45 reader assessments of those articles, and the use of a single classification of reasons for citation.Practical implications – The findings call into question techniques such as citation context analysis that are based on the assumption that readers understand the reasons why authors cite material.Originality/value – This is the first attempt to compare author and reader reasons for citation and hence to validate the use of cit.
TAB1-Induced Autoactivation of p38α Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185

ABSTRACT p38α mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms to activate p38α exist. The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment. The second is by autophosphorylation of Thr180 and Tyr182 in cis, mediated by p38α binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction. Based on the crystal structure of the p38α-TAB1 complex we replaced threonine 185 of p38α with glycine (T185G) to prevent an intramolecular hydrogen bond with Asp150 from being formed. This mutation did not interfere with TAB1 binding to p38α. However, it disrupted the consequent long-range effect of this binding event on the distal activation segment, releasing the constraint on Thr180 that oriented its hydroxyl for phosphotransfer. Based on assays performed in vitro and in vivo, the autoactivation of p38α(T185G) was disabled, while its ability to be activated by upstream MAP2Ks and to phosphorylate downstream substrates remained intact. Furthermore, myocardial cells expressing p38α(T185G) were resistant to injury. These findings reveal a mechanism to selectively disable p38α autoactivation and its consequences, which may ultimately circumvent the toxicity associated with strategies that inhibit p38α kinase activity under all circumstances, such as with ATP-competitive inhibitors.