Miracle-dz/UniFAR-FTUs huggingface dataset:
Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex

An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action–outcome expectations. In a separate experiment, we blocked action–outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action–outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences. SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action–outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.
Computation Offloading in JVM-based Dataflow Engines

: State-of-the-art dataflow engines, such as Apache Spark and Apache Flink scale out on large clusters for a variety of data-processing tasks, including machine learning and data mining algorithms. However, being based on the JVM, they are unable to apply optimizations supported by modern CPUs. On the contrary, specialized data processing frameworks scale up by exploiting modern CPU characteristics. The goal of this thesis is to find the sweet spot between scale-out and scale-up systems by offloading computation from dataflow engines to specialized systems. We propose two computation offloading methods, reason about their applicability, and implement a prototype based on Apache Spark. Our evaluation shows that for compute-intensive tasks, computation offloading leads to performance improvements of up to a factor of 2.5x. For certain UDF scenarios, computation offloading performs worse by up to a factor of 3x: our microbenchmarks show that 80% of the time is spent on serialization operations. By employing data exchange without serialization, computation offloading achieves performance improvements by up to 10x.
Interleukin 2 (IL-2) variants engineered for increased IL-2 receptor α-subunit affinity exhibit increased potency arising from a cell surface ligand reservoir effect

Proliferation of activated T cells and CD56 bright natural killer (Cytokine Growth Factor Rev 13:169-183, 1995) cells caused by interleukin-2 (IL-2) has been exploited in IL-2-based therapies for the treatment of metastatic renal cell carcinoma and melanoma (J Clin Oncol 13:688-696, 1995; J Clin Oncol 17: 2105-2116, 1999). In this study, we demonstrate the potentially improved therapeutic value of IL-2 variants engineered to gain 15- to 30-fold increased affinity for the IL-2 receptor alpha-subunit (IL-2Ralpha). A novel pulsed bioassay was used to more closely approximate the rapid systemic clearance pharmacokinetics of cytokines such as IL-2, compared with conventional static bioassays. In this assay, mutants with increased affinity for IL-2Ralpha exhibit significantly increased activity for T-cell proliferation, whereas static bioassays not only fail to reveal the increased activity resulting from enhanced IL-2Ralpha affinity (false negatives), but also suggest improved activity for another mutant without enhanced activity in the pulsed assay (false positive). Our studies on the mechanism leading to increased activity of IL-2 mutants with increased IL-2Ralpha affinity suggest that cell-surface IL-2Ralpha acts as a ligand reservoir for the IL-2 mutants. This leads to increased cell-surface persistence of the IL-2 mutants with increased IL-2Ralpha affinity in cell-surface ligand reservoirs and consequently increased integrated growth signal. Furthermore, a mathematical model predicts increased persistence of cell surface-bound IL-2 in vivo for enhanced IL-2Ralpha-binding IL-2 mutants, suggesting potentially improved therapeutic value of allowing cellular capture of ligands in persistent cell-surface reservoirs. Finally, our findings emphasize the critical choice of appropriate bioassays to evaluate engineered proteins and other drugs.
Interferon-Stimulated Genes—Mediators of the Innate Immune Response during Canine Distemper Virus Infection

The demyelinating canine distemper virus (CDV)-leukoencephalitis represents a translational animal model for multiple sclerosis. The present study investigated the expression of type I interferon (IFN-I) pathway members in CDV-induced cerebellar lesions to gain an insight into their role in lesion development. Gene expression of 110 manually selected genes in acute, subacute and chronic lesions was analyzed using pre-existing microarray data. Interferon regulatory factor (IRF) 3, IRF7, signal transducer and activator of transcription (STAT) 1, STAT2, MX protein, protein kinase R (PKR), 2′-5′-oligoadenylate synthetase (OAS) 1 and interferon-stimulated gene (ISG) 15 expression were also evaluated using immunohistochemistry. Cellular origin of STAT1, STAT2, MX and PKR were determined using immunofluorescence. CDV infection caused an increased expression of the antiviral effector proteins MX, PKR, OAS1 and ISG15, which probably contributed to a restricted viral replication, particularly in neurons and oligodendrocytes. This increase might be partly mediated by IRF-dependent pathways due to the lack of changes in IFN-I levels and absence of STAT2 in astrocytes. Nevertheless, activated microglia/macrophages showed a strong expression of STAT1, STAT2 and MX proteins in later stages of the disease, indicating a strong activation of the IFN-I signaling cascade, which might be involved in the aggravation of bystander demyelination.
The Relation of Inflammaging With Skeletal Muscle Properties in Elderly Men

Aging is associated with a progressive decline of muscle mass and/or the qualitative impairment of the muscle tissue. There is growing evidence of the prominent role of low-grade chronic inflammation in age-related changes in the neuromuscular system. The purpose of the study was to identify the inflammatory mediators responsible for deficit in functional fitness and to explain whether inflammation is related to changes in body composition and the decline of muscle strength in older men. Thirty-three old-aged males (73.5 ± 6.3 years) and twenty young-aged males (21.2 ± 1.3 years) participated in the study. The body composition (bioelectrical impedance analysis), functional capacity (6-min walking test) and knee extension strength (isokinetic test) were estimated. In serum, circulating inflammatory markers H2O2, IL-1β, TNFα, and hsCRP as well as growth factors IGF-I and PDGFBB concentrations were determined (immunoenzymatic methods). The concentrations of H2O2, IL-1β, TNFα, and hsCRP were significantly higher in older than young men. The growth factors IGF-I and PDGFBB were twofold lower and related to high levels of IL-1β and TNFα in the elderly. The changes in cytokines and growth factors levels were correlated with age and peak torque (TQ at 60°/s and 180°/s) in the knee extension. The result of the 6-min walking test was inversely correlated with fat mass index (FMI, r = −.983; p < .001). The generation of inflammatory mediators in older men was related to changes in body composition, maximum strength muscle, and age-related changes in skeletal muscle properties responsible for deficit in functional fitness.
Refining the Analysis of Mechanism–Outcome Relationships for Anxiety Treatment: A Preliminary Investigation Using Mixed Models

Although efficacious treatments exist for anxiety disorders, issues remain regarding how best to conceptualize and measure purported change processes in clinical research. In the current study, we examined the relationship between treatment-specific (exposure therapy, attention bias modification [ABM]) as well as more general change processes with symptoms within a transdiagnostic sample using mixed models. Results indicated that slope of self-efficacy across treatment and between-session habituation across identical exposures was associated with slope of symptom change. Although slope of anxiety ratings within session was not associated with slope of symptom change, it did interact with other candidate exposure processes to predict symptoms. Purported ABM change processes were not associated with outcome. Our use of mixed models exemplifies an emerging trend in this research aimed at minimizing loss of data through aggregation, and our results highlight the utility of integrating treatment-specific as well as more general change processes in mechanistic research.
Cardiac amyloidosis as a rare cause of heart failure

Rationale: Cardiac amyloidosis is a rare condition that is difficult to diagnose, because the clinical manifestations are often varied and nonspecific. The presence and degree of cardiac involvement are the main prognosis determinants, with a median survival of 6 months expected when presented with heart failure. Moreover, the optimal treatment for cardiac amyloidosis is still unclear. Patient concerns: We report a case of a 50-year-old man who was admitted with evolution of progressive dyspnea. Two months before the present admission, the patient was diagnosed with bacterial pneumonia complicated by bilateral parapneumonic effusion that required drainage. Diagnosis: Electrocardiography demonstrated poor R-wave progression in leads V1-V3 with right axis deviation and low voltage criteria. Echocardiography revealed diffuse left ventricular hypertrophy with normal ventricular cavity size, severe diastolic dysfunction, and sparkling and granular texture of the ventricle wall. Serum free light-chain analysis showed an altered kappa/lambda ratio of 0.01 with lambda light chains greatly elevated. A periumbilical fat aspirate sample confirmed amyloidosis. Bone marrow examination confirmed benign monoclonal gammopathy with 8.5% plasma cells, and biopsy stained for Congo red was negative. Intervention: A combination of bortezomib with cyclophosphamide and dexamethasone treatment was initiated. Outcome: Unfortunately, 5 days after the second therapy with bortezomib, the patient died. Lessons: Cardiac amyloidosis should be seriously considered in any adult with signs or nonspecific symptoms of cardiac distress, most notably congestive heart failure due to underlying restrictive cardiomyopathy.
Neural responses for evaluating self and mother traits in adolescence depend on mother–adolescent relationships

Abstract An important task in adolescence is to achieve autonomy while preserving a positive relationship with parents. Previous fMRI studies showed largely overlapping activation in medial prefrontal cortex (mPFC) for evaluating self and close-other traits but separable activation for self and non-close other. Possibly, more similar mPFC activation reflects closeness or warmth in relationships. We investigated neural indicators of the mother–adolescent relationship in adolescents between 11 and 21 years (N = 143). Mother–adolescent relationship was measured using (i) mothers’ and adolescents’ trait evaluations about each other, (ii) observations of warmth, negativity and emotional support in mother–adolescent conversation and (iii) similarity in adolescents’ neural activation for evaluating self vs mother traits. Results showed relatively more similar mPFC activation in adolescents who evaluated their mothers’ traits more positively, suggesting that this is possibly a neural indicator of mother–adolescent relationship quality. Furthermore, mid-adolescence was characterized by more negative mother–adolescent interaction compared to early and late adolescence. This effect co-occurred with mid-adolescent peaks in dorsal striatum, dorsal anterior cingulate cortex and superior temporal sulcus activation in evaluating traits of self vs mother. These results suggest more negative relationships and stronger self-focus in mid-adolescence.
Myxoma virus M013 protein antagonizes NF-κB and inflammasome pathways via distinct structural motifs

Among the repertoire of immunoregulatory proteins encoded by myxoma virus, M013 is a viral homologue of the viral pyrin domain-only protein (vPOP) family. In myeloid cells, M013 protein has been shown to inhibit both the inflammasome and NF-κB signaling pathways by direct binding to ASC1 and NF-κB1, respectively. In this study, a three-dimensional homology model of the M013 pyrin domain (PYD) was built based on similarities to known PYD structures. A distinctive feature of the deduced surface electrostatic map of the M013 PYD is the presence of a negatively region consisting of numerous aspartate and glutamate residues in close proximity. Single-site mutations of aspartate and glutamate residues reveal their role in interactions with ASC-1. The biological significance of charge complementarity in the M013–ASC-1 interaction was further confirmed by functional assays of caspase-1 activation and subsequent secretion of cytokines. M013 also has a unique 33-residue C-terminal tail that follows the N-terminal PYD, and it is enriched in positively charged residues. Deletion of the tail of M013 significantly inhibited the interactions between M013 and NF-κB1, thus compromising the ability of the viral protein to suppress the secretion of pro-inflammatory cytokines. These results demonstrate that vPOP M013 exploits distinct structural motifs to regulate both the inflammasome and NF-κB pathways.
Epidemiological investigation of Leptospira spp. in a dairy farming enterprise after the occurrence of three human leptospirosis cases

An epidemiological investigation was conducted in an unvaccinated dairy farming enterprise in which three workers on one of the milking herds (Herd 1) were diagnosed with leptospirosis due to serovars Hardjo (H) (n = 2) and Pomona (P) (n = 1) between January and March 2015. Blood and urine samples were collected from milking cows in Herd 1 (N = 230) and Herd 2 (N = 400), rising one‐ (R1, N = 125) and rising two‐year‐old (R2, N = 130) replacement heifers, and four pigs associated with Herd 1, in March 2015. Sera were tested using the MAT for serovars H, P, Copenhageni (C), Ballum (B) and Tarassovi (T), and urine samples were tested by qPCR. Seventy‐five per cent of 109 cows in Herd 1 and 36% of 121 in Herd 2 were seropositive (≥48), predominantly to H and P, and 23% of 74 cows in Herd 1 and 1% of 90 cows in Herd 2 were qPCR positive. Fifty‐five per cent of 42 R2 heifers were seropositive to T. No R1 and 17% of 42 R2 heifers were qPCR positive. Subsequently, all cattle were vaccinated for H and P, and Herds 1 and 2 were given amoxicillin. After the booster vaccination, 7% of 91 in Herd 1, 2% of 82 in Herd 2 and 11% of 38 R1 heifers (sampled as R2) were PCR positive. After the amoxicillin treatment, no cows in Herd 1 and 5% of 62 cows in Herd 2 were urine PCR positive. Calves and pigs were seropositive to H, P, C and B. Vaccination and antibiotic treatment appeared effective in reducing the risk of exposure of workers to vaccine serovars. However, evidence of non‐vaccine serovars indicated that workers likely remain at risk of exposure to Leptospira.
Lycopene Inhibits Reactive Oxygen Species-Mediated NF-κB Signaling and Induces Apoptosis in Pancreatic Cancer Cells

Generation of excess quantities of reactive oxygen species (ROS) caused by mitochondrial dysfunction facilitates rapid growth of pancreatic cancer cells. Elevated ROS levels in cancer cells cause an anti-apoptotic effect by activating survival signaling pathways, such as NF-κB and its target gene expression. Lycopene, a carotenoid found in tomatoes and a potent antioxidant, displays a protective effect against pancreatic cancer. The present study was designed to determine if lycopene induces apoptosis of pancreatic cancer PANC-1 cells by decreasing intracellular and mitochondrial ROS levels, and consequently suppressing NF-κB activation and expression of NF-κB target genes including cIAP1, cIAP2, and survivin. The results show that the lycopene decreased intracellular and mitochondrial ROS levels, mitochondrial function (determined by the mitochondrial membrane potential and oxygen consumption rate), NF-κB activity, and expression of NF-κB-dependent survival genes in PANC-1 cells. Lycopene reduced cell viability with increases in active caspase-3 and the Bax to Bcl-2 ratio in PANC-1 cells. These findings suggest that supplementation of lycopene could potentially reduce the incidence of pancreatic cancer.
Letter to the Editor: "Genetic Link Between Gender Dysphoria and Sex Hormone Signaling."

F oreman et al. (1) tested the interesting hypothesis that transgender women (formerly called male-to-female transsexuals) have frequencies of polymorphisms in genes for several steroid metabolizing enzymes and hormone receptors that differ from those of male controls. They concluded that gender dysphoria, at least in natal males, may have a genetic basis. The evidence does not justify the conclusions drawn because, in a surprising omission for a genetics article (2), no effort was made to control the type 1 error rate (a) for multiple hypothesis testing. Two ways of doing this are the familywise error rate (FWER; the likelihood of incorrectly rejecting a single true null hypothesis among m null hypotheses, i.e., false positives), most often controlled with a Bonferroni correction (a/m). In Tables 1 and 2, polymorphisms in 12 different genes were examined. For a5 0.05, the FWER was controlled at 0.05/ 125 0.004. Thus even the smallest P value, 0.015 for the STS gene, is.0.004 and thus not significant. Similarly, in Table 3, which tests 10 hypotheses, the smallest P value, 0.009 for SULT2A1, was.0. 005 (0.05/10) and thus not significant. The P values in Table 4 cannot be interpreted without knowing howmany interactions were examined; there are 66 possible pairwise interactions between 12 genes. It is often argued that a Bonferroni correction is too stringent and thus is prone to type 2 errors (incorrectly accepting a false null hypothesis, i.e., false negatives). Therefore, many studies use the false discovery rate (FDR; the proportion of incorrectly rejected null hypotheses among all rejected null hypotheses, i.e., an FDR of 0.05 means that 5% of all positives at that statistical threshold are false positives), most often calculated via the Benjamini-Hochberg procedure (3). For a given a, that procedure ranks all P values from smallest to largest, finds the largest k such that P(k)# (k/m)*a, and rejects all null hypotheses up to and including that one. But this is not much less stringent than the FWER when there are few tests with uncorrected P , a. For the data in Tables 1 and 2 combined, there are 3/12 such tests, the highest having P 5 0.03. This is higher than the threshold of 0.05*3/12 5 0.0125. Accordingly, no association passes the Benjamini-Hochberg procedure either; the same is true for the data in Table 3. Moreover, of the three associations with the lowest P values in Tables 1 and 2, only one, Era, shows an uncorrected P, 0.05 for genotype association in Table 3. Similarly, only one of the total of four genes with associations having uncorrected P , 0.05 in Tables 1–3, SRD5A2, is one of the six genes involved in putative two-locus gene interactions in Table 4. Thus, three different ways of analyzing the same data yield inconsistent results, supporting the idea that all the identified associations are due to chance. Therefore, the data in this article do not demonstrate that any polymorphism in the examined genes, or any combination of polymorphisms, influences risk of gender dysphoria in transgender women.
What's Happened to the Price of College?: Quality-Adjusted Net Price Indexes for Four-Year Colleges

In this paper we estimate hedonic models of the (consumer) price of college to construct quality-adjusted net price indexes for U.S. four-year colleges, where the net price of college is defined as tuition and fees minus financial aid. For academic years 1990–91 to 1994–95, we find adjusting for financial aid leads to a 22 percent decline in the estimated price index for all fouryear colleges, while quality adjusting the results leads to a further, albeit smaller, decline. Nevertheless, public comprehensive colleges, perhaps an important gateway to college for students from low-income backgrounds, experienced the largest net price increases.
Retracted: Unified Framework for Efficient and Enriched Water Animation with Surface and Wave Foams

The above article from Computer Graphics Forum, published online on 28 June 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editors Min Chen and Bedrich Benes and John Wiley & Sons Ltd. The retraction has been agreed due to both authors wishing to adhere to the high professional standard for academic publications.
Pure Functional Epidemics: An Agent-Based Approach

Agent-Based Simulation (ABS) is a methodology in which a system is simulated in a bottom-up approach by modelling the micro interactions of its constituting parts, called agents, out of which the global system behaviour emerges. So far mainly object-oriented techniques and languages have been used in ABS. Using the SIR model of epidemiology, which simulates the spreading of an infectious disease through a population, we demonstrate how to use pure Functional Reactive Programming to implement ABS. With our approach we can guarantee the reproducibility of the simulation at compile time and rule out specific classes of run-time bugs, something that is not possible with traditional object-oriented languages. Also, we found that the representation in a purely functional format is conceptually quite elegant and opens the way to formally reason about ABS.