Miracle-dz/UniFAR-FTUs huggingface dataset:
Structured crowdsourcing enables convolutional segmentation of histology images

Abstract Motivation While deep-learning algorithms have demonstrated outstanding performance in semantic image segmentation tasks, large annotation datasets are needed to create accurate models. Annotation of histology images is challenging due to the effort and experience required to carefully delineate tissue structures, and difficulties related to sharing and markup of whole-slide images. Results We recruited 25 participants, ranging in experience from senior pathologists to medical students, to delineate tissue regions in 151 breast cancer slides using the Digital Slide Archive. Inter-participant discordance was systematically evaluated, revealing low discordance for tumor and stroma, and higher discordance for more subjectively defined or rare tissue classes. Feedback provided by senior participants enabled the generation and curation of 20 000+ annotated tissue regions. Fully convolutional networks trained using these annotations were highly accurate (mean AUC=0.945), and the scale of annotation data provided notable improvements in image classification accuracy. Availability and Implementation Dataset is freely available at: https://goo.gl/cNM4EL. Supplementary information Supplementary data are available at Bioinformatics online.
Maximum vs minimum harmonization: what to expect from the institutional and legal battles in the EU on gene editing technologies

Abstract New plant‐breeding technologies (NPBTs), including gene editing, are widely used and drive the development of new crops. However, these new technologies are disputed, creating uncertainty in how their application for agricultural and food uses will be regulated. While in North America regulatory systems respond with a differentiated approach to NPBTs, the Court of Justice of the European Union (EU) has in effect made most if not all NPBT subject to the same regulatory regime as genetically modified organisms (GMOs). This paper discusses from a law and economics point of view different options that are available for the EU's multi‐level legal order. Using an ex‐ante regulation versus ex‐post liability framework allows the economic implications of different options to be addressed. The results show that under current conditions, some options are more expensive than others. The least costly option encompasses regulating new crops derived from NPBTs similar to those used in ‘conventional’ breeding. The current regulatory situation in the EU, namely making the use of NPBTs subject to the same conditions as GMOs, is the most costly option. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Generation of Infectious Recombinant Human Rotaviruses from Just 11 Cloned cDNAs Encoding the Rotavirus Genome

Human group A rotavirus (HuRVA) is a leading pathogen causing severe diarrhea in young children worldwide. In this paper, we describe the generation of recombinant HuRVA (strain KU) from only 11 cloned cDNAs encoding the HuRVA genome by reverse genetics. The growth properties of the recombinant HuRVA were similar to those of the parental RVA, providing a powerful tool for better understanding of HuRVA replication and pathogenesis. Furthermore, the ability to manipulate the genome of HuRVAs “to order” will be useful for next-generation vaccine production for this medically important virus and for the engineering of clinical vectors expressing any foreign genes. ABSTRACT The generation of recombinant group A rotaviruses (RVAs) entirely from cloned cDNAs has been described only for a single animal RVA strain, simian SA11-L2. We recently developed an optimized RVA reverse genetics system based on only RVA cDNAs (11-plasmid system), in which the concentration of cDNA plasmids containing the NSP2 and NSP5 genes is 3- or 5-fold increased in relation to that of the other plasmids. Based on this approach, we generated a recombinant human RVA (HuRVA)-based monoreassortant virus containing the VP4 gene of the simian SA11-L2 virus using the 11-plasmid system. In addition to this monoreassortant virus, authentic HuRVA (strain KU) was also generated with the 11-plasmid system with some modifications. Our results demonstrate that the 11-plasmid system involving just RVA cDNAs can be used for the generation of recombinant HuRVA and recombinant HuRVA-based reassortant viruses. IMPORTANCE Human group A rotavirus (HuRVA) is a leading pathogen causing severe diarrhea in young children worldwide. In this paper, we describe the generation of recombinant HuRVA (strain KU) from only 11 cloned cDNAs encoding the HuRVA genome by reverse genetics. The growth properties of the recombinant HuRVA were similar to those of the parental RVA, providing a powerful tool for better understanding of HuRVA replication and pathogenesis. Furthermore, the ability to manipulate the genome of HuRVAs “to order” will be useful for next-generation vaccine production for this medically important virus and for the engineering of clinical vectors expressing any foreign genes.
Hepatic glutamine synthetase augmentation enhances ammonia detoxification

The urea cycle and glutamine synthetase (GS) are the two main pathways for waste nitrogen removal and their deficiency results in hyperammonemia. Here, we investigated the efficacy of liver‐specific GS overexpression for therapy of hyperammonemia. To achieve hepatic GS overexpression, we generated a helper‐dependent adenoviral (HDAd) vector expressing the murine GS under the control of a liver‐specific expression cassette (HDAd‐GS). Compared to mice injected with a control vector expressing an unrelated reporter gene (HDAd‐alpha‐fetoprotein), wild‐type mice with increased hepatic GS showed reduced blood ammonia levels and a concomitant increase of blood glutamine after intraperitoneal injections of ammonium chloride, whereas blood urea was unaffected. Moreover, injection of HDAd‐GS reduced blood ammonia levels at baseline and protected against acute hyperammonemia following ammonia challenge in a mouse model with conditional hepatic deficiency of carbamoyl phosphate synthetase 1 (Cps1), the initial and rate‐limiting step of ureagenesis. In summary, we found that upregulation of hepatic GS reduced hyperammonemia in wild‐type and Cps1‐deficient mice, thus confirming a key role of GS in ammonia detoxification. These results suggest that hepatic GS augmentation therapy has potential for treatment of both primary and secondary forms of hyperammonemia.
Virulence Traits of a Serogroup C Meningococcus and Isogenic cssA Mutant, Defective in Surface-Exposed Sialic Acid, in a Murine Model of Meningitis

In serogroup C Neisseria meningitidis, the cssA (siaA) gene codes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-d-glucosamine into N-acetyl-d-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. ABSTRACT In serogroup C Neisseria meningitidis, the cssA (siaA) gene codes for an UDP-N-acetylglucosamine 2-epimerase that catalyzes the conversion of UDP-N-acetyl-α-d-glucosamine into N-acetyl-d-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. In this study, we have used a reference serogroup C meningococcal strain and an isogenic cssA knockout mutant to investigate the pathogenetic role of surface-exposed sialic acids in a model of meningitis based on intracisternal inoculation of BALB/c mice. Results confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The 50% lethal dose (LD50) of the wild-type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild-type strain, the ability of this mutant to replicate in brain and spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral hemorrhages in mice infected with the mutant in comparison with the levels in those challenged with the wild-type strain. Histological analysis showed the typical features of bacterial meningitis, including inflammatory cells in the subarachnoid, perivascular, and ventricular spaces especially in animals infected with the wild type. Noticeably, 80% of mice infected with the wild-type strain presented with massive bacterial localization and accompanying inflammatory infiltrate in the corpus callosum, indicating high tropism of meningococci exposing sialic acids toward this brain structure and a specific involvement of the corpus callosum in the mouse model of meningococcal meningitis.
Unified Classification of Molecular, Network, and Endocrine Features of Hypothalamic Neurons.

Peripheral endocrine output relies on either direct or feed-forward multi-order command from the hypothalamus. Efficient coding of endocrine responses is made possible by the many neuronal cell types that coexist in intercalated hypothalamic nuclei and communicate through extensive synaptic connectivity. Although general anatomical and neurochemical features of hypothalamic neurons were described during the past decades, they have yet to be reconciled with recently discovered molecular classifiers and neurogenetic function determination. By interrogating magnocellular as well as parvocellular dopamine, GABA, glutamate, and phenotypically mixed neurons, we integrate available information at the molecular, cellular, network, and endocrine output levels to propose a framework for the comprehensive classification of hypothalamic neurons. Simultaneously, we single out putative neuronal subclasses for which future research can fill in existing gaps of knowledge to rationalize cellular diversity through function-determinant molecular marks in the hypothalamus. Expected final online publication date for the Annual Review of Physical Chemistry Volume 70 is April 20, 2019. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Alcohol Use Problems, Posttraumatic Stress Disorder, and Suicide Risk Among Trauma-Exposed Firefighters

Abstract Alcohol use problems are associated with suicidal desire and may provide an avenue to suicidal ideation and behavior. However, the influence of posttraumatic stress disorder (PTSD) on the nature of the relationship between alcohol use problems and suicide risk is not well understood. In particular, the potential for PTSD to moderate the association between alcohol use problems and suicide risk remains unexplored. The present study investigated the main and interactive effects of alcohol use problems (Alcohol Use Disorders Identification Test) and PTSD symptoms (PTSD Checklist for DSM-5) on suicide risk (Suicide Behaviors Questionnaire-Revised) in a sample of 632 trauma-exposed firefighters (93.5% men; Mage = 38.44 years, SD = 8.59). Hierarchical logistic regression analyses evaluated whether the main and interactive effects of PTSD symptom severity and alcohol use disorders were significantly related to suicide risk, above and beyond age and cumulative trauma. The main effects of PTSD symptom severity (odds ratio, 1.76; p < 0.001) and alcohol use problems (odds ratio, 1.37; p = 0.391) significantly positively predicted suicide risk; however, PTSD symptoms did not moderate an association between alcohol use problems and suicide risk after accounting for these main effects (p > 0.05). A secondary, exploratory aim demonstrated that all PTSD symptom clusters significantly positively predicted suicide risk (p's < 0.001), although none of these clusters interacted with alcohol use problems to predict suicide risk (p's > 0.05). Theoretical and clinical implications are discussed as they relate to the importance of screening for PTSD and alcohol use disorder among firefighter populations.
Poverty and Racial Disparities in Kidney Disease: The REGARDS Study

There are pronounced disparities among black compared to white Americans for risk of end-stage renal disease. This study examines whether similar relationships exist between poverty and racial disparities in chronic kidney disease (CKD) prevalence. Methods: We studied 22,538 participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study. We defined individual poverty as family income below USD 15,000 and a neighborhood as poor if 25% or more of the households were below the federal poverty level. Results: As the estimated glomerular filtration rate (GFR) declined from 50–59 to 10–19 ml/min/ 1.73 m2, the black:white odds ratio (OR) for impaired kidney function increased from 0.74 (95% CI 0.66, 0.84) to 2.96 (95% CI 1.96, 5.57). Controlling for individual income below poverty, community poverty, demographic and comorbid characteristics attenuated the black:white prevalence to an OR of 0.65 (95% CI 0.57, 0.74) among individuals with a GFR of 59–50 ml/min/1.73 m2 and an OR of 2.21 (95% CI 1.25, 3.93) among individuals with a GFR between 10 and 19 ml/min/ 1.73 m2. Conclusion: Household, but not community poverty, was independently associated with CKD and attenuated but did not fully account for differences in CKD prevalence between whites and blacks.
Prevalence and possible predictors of sexual dysfunction and self-reported needs related to the sexual life of advanced cancer patients

Abstract Background: Sexual dysfunction and problems are common late effects after treatment of cancer. However, little is known about the prevalence and risk factors for sexual dysfunction in patients with advanced cancer. The aim of this study was to investigate the prevalence and predictors of sexual problems and needs in a large sample of Danish patients with advanced cancer. Methodology: The data derived from a representative cross-sectional study of patients with advanced cancer. Patients who had been in contact with 1 of 54 hospital departments were invited to fill out a questionnaire on symptoms and problems. Five items asked about sexuality. Ordinal logistic regression was used to identify variables associated with sexual functioning in explorative analyses. Results: A total of 1,447 patients completed the questionnaire and of those, 961 patients (66%) completed the sexuality items. More than half of the patients (60%) had not been sexually active within the previous month, despite a high prevalence of desire for sexual intimacy (62%). More than half of the patients (57%) experienced that their physical condition or treatment had impaired their sex life. Of those, 52% experienced an unmet need for help with sexual problems from the health care system. Older patients were less likely to report sexual problems than younger patients. Having prostate or gynecologic cancer was associated with the feeling that one’s sexual life was negatively influenced. Conclusion: Sexual problems are common among patients with advanced cancer and should be addressed by the health care system.
Strategies to enhance access to diagnosis and treatment for Chagas disease patients in Latin America

ABSTRACT Introduction: Chagas disease, caused by infection with the parasite Trypanosoma cruzi, represents a huge public health problem in the Americas, where millions of people are affected. Despite the availability of two drugs against the infection (benznidazole and nifurtimox), multiple factors impede their effective usage: (1) gaps in patient and healthcare provider awareness; (2) lack of access to diagnosis; (3) drug toxicity and absence of treatment algorithms to address adverse effects; (4) failures in drug supply and distribution; and (5) inconsistent drug efficacy against the symptomatic chronic stage. Areas covered: We review new approaches and technologies to enhance access to diagnosis and treatment to reduce the disease burden. We also provide an updated picture of recently published and ongoing anti-T. cruzi drug clinical trials. Although there has been progress improving the research and development (R&D) landscape, it is unclear whether any new treatments will emerge soon. Literature search methodologies included multiple queries to public databases and the use of own-built libraries. Expert opinion: Besides R&D, there is a major need to continue awareness and advocacy efforts by patient associations, local and national governments, and international agencies. Overall, health systems strengthening is essential to ensure vector control commitments, as well as patient access to diagnosis and treatment.
The structure of genetic and environmental influences on normative personality, abnormal personality traits, and personality disorder symptoms

Abstract Background Can the structure of genetic and environmental influences on normative personality traits (NPTs), abnormal personality traits (APTs), and DSM-IV criteria for personality disorders (PD) fit a high or low congruence model positing, respectively, close or more limited etiologic continuity? Method Exploratory factor analysis was applied to transformed correlation matrices from Cholesky twin decompositions obtained in OpenMx. In 2801 adult twins from the Norwegian Institute of Public Health Twin Panel, NPTs and APTs were assessed by self-report using the Big Five Inventory (BFI) and PID-5-Norwegian Brief Form (PID-5-NBF), respectively. PDs were assessed at interview using the Structured Interview for DSM-IV Personality (SIDP-IV). Results The best model yielded three genetic and three unique environmental factors. Genetic factors were dominated, respectively, by (i) high loadings on nearly all PDs and NPT/APT neuroticism and compulsivity, (ii) negative loadings on NPT agreeableness/conscientiousness and positive loadings on APT/PD measures of antisocial traits, and (iii) negative loadings on NPT extraversion and histrionic PD, and positive loadings on APT detachment and schizoid/avoidant PD. Unique environmental factors were dominated, by (i) high loadings on all PDs, (ii) high loadings on all APT dimensions and NPT neuroticism, and (iii) negative loadings on NPT extraversion and positive loadings on NPT detachment/avoidant PD. Conclusions Two genetic and one environmental common factor were consistent with a high congruence model while one genetic and two environmental factors were more supportive of a low congruence model. The relationship between genetic and environmental influences on personality assessed by NPTs, APTs, and PDs is complex and does not fit easily into a low or high congruence model.
Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score. ” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy. Implications: In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.
Luring the Motor System: Impact of Performance-Contingent Incentives on Pre-Movement Beta-Band Activity and Motor Performance

It has been shown that when incentives are provided during movement preparation, activity in parieto-frontal regions reflects both expected value and motivational salience. Yet behavioral work suggests that the processing of rewards is faster than for punishments, raising the possibility that expected value and motivational salience manifest at different latencies during movement planning. Given the role of beta oscillations (13–30 Hz) in movement preparation and in communication within the reward circuit, this study investigated how beta activity is modulated by positive and negative monetary incentives during reach planning, and in particular whether it reflects expected value and motivational salience at different latencies. Electroencephalography was recorded while male and female humans performed a reaching task in which reward or punishment delivery depended on movement accuracy. Before a preparatory delay period, participants were informed of the consequences of hitting or missing the target, according to four experimental conditions: Neutral (hit/miss:+0/−0¢), Reward (hit/miss:+5/−0¢), Punish (hit/miss:+0/−5¢) and Mixed (hit/miss:+5/−5¢). Results revealed that beta power over parieto-frontal regions was strongly modulated by incentives during the delay period, with power positively correlating with movement times. Interestingly, beta power was selectively sensitive to potential rewards early in the delay period, after which it came to reflect motivational salience as movement onset neared. These results demonstrate that beta activity reflects expected value and motivational salience on different time scales during reach planning. They also provide support for models that link beta activity with basal ganglia and dopamine for the allocation of neural resources according to behavioral salience. SIGNIFICANCE STATEMENT The present work demonstrates that pre-movement parieto-frontal beta power is modulated by monetary incentives in a goal-directed reaching task. Specifically, beta power transiently scaled with the availability of rewards early in movement planning, before reflecting motivational salience as movement onset neared. Moreover, pre-movement beta activity correlated with the vigor of the upcoming movement. These findings suggest that beta oscillations reflect neural processes that mediate the invigorating effect of incentives on motor performance, possibly through dopamine-mediated interactions with the basal ganglia.