Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulatory Forum Commentary*

International regulatory and pharmaceutical industry scientists are discussing revision of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S1 guidance on rodent carcinogenicity assessment of small molecule pharmaceuticals. A weight-of-evidence approach is proposed to determine the need for rodent carcinogenicity studies. For compounds with high human cancer risk, the product may be labeled appropriately without conducting rodent carcinogenicity studies. For compounds with minimal cancer risk, only a 6-month transgenic mouse study (rasH2 mouse or p53+/− mouse) or a 2-year mouse study would be needed. If rodent carcinogenicity testing may add significant value to cancer risk assessment, a 2-year rat study and either a 6-month transgenic mouse or a 2-year mouse study is appropriate. In many cases, therefore, one rodent carcinogenicity study could be sufficient. The rasH2 model predicts neoplastic findings relevant to human cancer risk assessment as well as 2-year rodent models, produces fewer irrelevant neoplastic outcomes, and often will be preferable to a 2-year rodent study. Before revising ICH S1 guidance, a prospective evaluation will be conducted to test the proposed weight-of-evidence approach. This evaluation offers an opportunity for a secondary analysis comparing the value of alternative mouse models and 2-year rodent studies in the proposed ICH S1 weight-of-evidence approach for human cancer risk assessment.
Learning Neural Trans-Dimensional Random Field Language Models with Noise-Contrastive Estimation

Trans-dimensional random field language models (TRF LMs) where sentences are modeled as a collection of random fields, have shown close performance with LSTM LMs in speech recognition and are computationally more efficient in inference. However, the training efficiency of neural TRF LMs is not satisfactory, which limits the scalability of TRF LMs on large training corpus. In this paper, several techniques on both model formulation and parameter estimation are proposed to improve the training efficiency and the performance of neural TRF LMs. First, TRFs are reformulated in the form of exponential tilting of a reference distribution. Second, noise-contrastive estimation (NCE) is introduced to jointly estimate the model parameters and normalization constants. Third, we extend the neural TRF LMs by marrying the deep convolutional neural network (CNN) and the bidirectional LSTM into the potential function to extract the deep hierarchical features and bidirectionally sequential features. Utilizing all the above techniques enables the successful and efficient training of neural TRF LMs on a 40x larger training set with only 1/3 training time and further reduces the WER with relative reduction of 4.7% on top of a strong LSTM LM baseline.
Beta Human Papillomavirus E6 Expression Inhibits Stabilization of p53 and Increases Tolerance of Genomic Instability

ABSTRACT Infections with the beta genus of human papillomaviruses (β-HPVs) may contribute to the development of nonmelanoma skin cancers. However, β-HPV genomes are found at too low a copy number in tumors for the virus to be necessary for tumor maintenance. Instead, they are hypothesized to destabilize the host genome by allowing the persistence of mutations that can drive tumorigenesis independently of the viral genome. Supporting this premise is our previous finding that the expression of some β-HPV E6 proteins can attenuate p53 signaling in response to DNA damage. We show that β-HPV E6 proteins can prevent the stabilization of p53 in response to two types of genome-destabilizing events, aberrant mitosis and dysregulated centrosome duplication. The inability to stabilize p53 in response to these stimuli allows cells expressing HPV5, HPV8, or HPV38 E6 to remain proliferatively active, leading to further genome deterioration in a proportion of these cells. These phenotypes are lost by the introduction of a mutation into the p300 binding domain of HPV8 E6 or by the transfection of mutated p300 that is resistant to the degradation mediated by HPV5 or HPV8 E6. These findings expand the understanding of the role played by p300 in promoting the faithful resolution of mitotic figures as well as proper centrosome duplication. Finally, we describe a phenomenon by which binucleated cells are resolved via cytokinesis into two cells, each with one nucleus. These data support the hypothesis that β-HPV infections may promote tumorigenesis via genome destabilization. IMPORTANCE The work described in this report provides support for the hypothesis that β-HPV infections may contribute to nonmelanoma skin cancer by increasing the likelihood that tumorigenic mutations are introduced into the host cell's genome. We demonstrate that expression of the E6 proteins from some of these viruses increases the tolerance of two genome-destabilizing events, aberrant cell division and dysregulated centrosome duplication. Typically, these mutagenic occurrences elicit the stabilization of the tumor suppressor p53, which prevents further propagation of cells containing these errors. We show that the expression of β-HPV E6 restricts this stabilization of p53, leading not only to continued cellular proliferation but also to further accumulation of similar mutagenic events. Finally, in addition to supporting a role for β-HPV infections in certain skin cancers, we present studies with a mutated β-HPV E6 protein suggesting that the histone acetyltransferase p300 plays a role in promoting genome stability during replication.
RF9 Powerfully Stimulates Gonadotrophin Secretion in the Ewe: Evidence for a Seasonal Threshold of Sensitivity

GPR147 and its endogenous ligands, RFRPs, are emerging as important actors in hypothalamic‐pituitary axis control. The role of this system would be to inhibit gonadotrophin secretion. However, data on the subject are contradictory. The discovery of RF9 (adamantanecarbonyl‐RF‐2‐NH2), a GPR147 antagonist, prompted us to use this new tool to further investigate this system in the ewe. Accordingly, we tested the effect of i.c. v. administration of RF9 on gonadotrophin secretion in the ewe during anoestrous and the breeding season. Intracerebroventricular injections of RF9 (from 50–450 nmol) caused a clear elevation in peripheral blood plasma luteinising hormone (LH) concentrations. The effect of RF9 on LH was more pronounced during the anoestrous season. Furthermore, peripheral administration of RF9 as a bolus (2.1, 6.2 and 12.4 μmol per ewe) or as a constant i.v. infusion (2.1, 6.2, 12.4 and 18.6 μmol/h per ewe) to anoestrous acyclic ewes induced a sustained increase in LH plasma concentrations. A pharmacokinetic study showed that RF9 (12.4 μmol bolus i.v.) has an effective half life of 5.5 h in the plasma. Conversely, RF9 is not detectable in the cerebrospinal fluid, suggesting that it does not cross the blood–brain barrier. The increase in LH plasma concentrations induced by RF9 was blocked by previous administration of 1.3 μmol per ewe of gondotrophin‐releasing hormone (GnRH) antagonist Teverelix. This suggests that GnRH is involved in the stimulatory effect of RF9 on gonadotrophin secretion. Finally, no variation in LH plasma concentrations could be detected in ovariectomised ewes injected either i.c. v. or i.v. with RFRP3 (VPNLPQRF‐NH2). The lack of effect of RFRP3 in our experimental setting suggests that the mechanisms involved in RF9 action are probably more complex than previously assumed. Our results indicate that delivery of RF9 in the ewe greatly increases gondadotrophin secretion in both the oestrus and anoestrus season, suggesting a potential new way of controlling reproduction in mammals.
Correlation between subjective visual horizontal test and ocular vestibular-evoked myogenic potential test

Abstract Conclusion: The static subjective visual horizontal (SVH) test correlates with the dynamic ocular vestibular-evoked myogenic potential (oVEMP) test in healthy and pathological ears, and further confirms that both tests may, at least in part, share the same utricular reflex pathway. Objective: This study correlated the SVH test results with those of the oVEMP and cervical VEMP (cVEMP) tests to investigate their relationships. Methods: Twenty healthy subjects underwent the SVH test at a view pattern angle of 30° or 70° horizontal tilt under various background distractions to establish the optimal stimulation mode for SVH test. Thereafter, 20 patients with unilateral Meniere's disease underwent the SVH test using the optimal mode. In addition, oVEMP and cVEMP tests were performed in all subjects. Results: The preliminary study in 20 healthy subjects at a view pattern angle of 70° under counterclockwise square background distraction revealed that the mean deviation degree of the SVH test was –0.61 ± 1.17°. Based on the criteria, abnormal percentages of SVH in 20 Meniere's patients were 40%. All healthy subjects had normal oVEMPs and cVEMPs. In contrast, eight patients (40%) showed abnormal oVEMPs and nine (45%) revealed abnormal cVEMPs. The SVH test results correlated significantly with oVEMP results, but not with cVEMP results.
Escherichia coli HIyT protein, a transcriptional activator of haemolysin synthesis and secretion, is encoded by the rfaH (sfrB) locus required for expression of sex factor and lipopolysaccharide genes

Synthesis and secretion of the 110kDa haemolysin toxin of Escherichia coli and other pathogenic Gram‐negative bacteria are governed by the four genes of the hly operon. We have identified, by transposon mutagenesis, an E. coli cellular locus, hlyT, required for the synthesis and secretion of haemolysin encoded in trans by intact hly operons carrying the hly upstream regulatory region. Mutation of the hlyT locus specifically reduced the level of hlyA structural gene transcript 20‐100‐fold and thus markedly lowered both intracellular and extracellular levels of the HlyA protein. Genetic and structural analysis of the hlyT locus mapped it at co‐ordinate 3680 kbp (minute 87) on the chromosome adjacent to the fadBA operon, and identified it specifically as the rfaH (sfrB) locus which is required for transcription of the genes encoding synthesis of the sex pilus and also the lipopolysaccharide core for attachment of the O‐antigen of E. coli and Salmonella. Expression of the hly operon in the E. coli hlyT mutant was restored in trans by both the hlyT and rfaH genes, suggesting that the rfaH gene is an important activator of regulon structures that are central to the fertility and virulence of these pathogenic bacteria. DNA sequencing of the hlyT locus identifies the HlyT/RfaH transcriptional activator as a protein of 162 amino acids (Mr 18325) which shows no identity to characterized transcription factors.
The CCR2 3′UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis

ABSTRACT Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co-regulate each other's expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is implicated in cancer progression. However, we found that a higher CCR2 mRNA level is remarkably associated with prolonged survival of breast cancer patients. These conflicting results prompted us to study the non-coding function of CCR2 mRNA. We found that the CCR2 3′ untranslated region (UTR) inhibited MDA-MB-231 and MCF-7 cell metastasis by repressing epithelial–mesenchymal transition (EMT) in vitro, and suppressed breast cancer metastasis in vivo. Mechanistically, the CCR2 3′UTR modulated the expression of the RhoGAP protein STARD13 via acting as a STARD13 ceRNA in a microRNA-dependent and protein coding-independent manner. The CCR2 3′UTR blocked the activation of RhoA–ROCK1 pathway, which is the downstream effector of STARD13, and thus decreased the phosphorylation level of myosin light chain 2 (MLC2) and formation of F-actin. Additionally, the function of the CCR2 3′UTR was dependent on STARD13 expression. In conclusion, our results confirmed that the CCR2 3′UTR acts as a metastasis suppressor by acting as a ceRNA for STARD13 and thus inhibiting RhoA–ROCK1–MLC–F-actin pathway in breast cancer cells. This article has an associated First Person interview with the first author of the paper. Summary: The CCR2 3′UTR acts as a metastasis suppressor by acting as a competing endogenous RNA for STARD13 and thus inhibiting activation of the RhoA–ROCK1–MLC–F-actin pathway in breast cancer cells.
Seroprevalence of Helicobacter pylori Infection in Large Series of Patients in an Urban Area of Saudi Arabia.

BACKGROUND/AIMS Helicobacter pylori is present worldwide but few large population studies exist on the epidemiology of the infection in Saudi Arabia. This is an urban based study which was undertaken to determine the prevalence of H. pylori infection among outpatients suffering from gastrointestinal symptoms attending large hospital in Riyadh, Saudi Arabia. METHODS A validated enzyme-linked immunosorbent assay (ELISA) was used for this study with 5782 samples collected from the outpatients population suffering from gastrointestinal (dyspeptic) symptoms, aged 2 to 82 years. RESULTS H. pylori seroprevalence was 67% increasing with age. Female shows higher prevalence of H. pylori infection than male. H. pylori infection was more common in patients suffering from epigastric pain. CONCLUSIONS The seroprevalence rate was higher in female than male. This study shows a high prevalence of H. pylori infection in a large series of patients in an urban area of Saudi Arabia.
Immune System Stimulation by Probiotic Microorganisms

Probiotic organisms are claimed to offer several functional properties including stimulation of immune system. This review is presented to provide detailed informations about how probiotics stimulate our immune system. Lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Bifidobacterium animalis Bb-12, Lactobacillus johnsonii La1, Bifidobacterium lactis DR10, and Saccharomyces cerevisiae boulardii are the most investigated probiotic cultures for their immunomodulation properties. Probiotics can enhance nonspecific cellular immune response characterized by activation of macrophages, natural killer (NK) cells, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in strain-specific and dose-dependent manner. Mixture and type (gram-positive and gram-negative) of probiotic organisms may induce different cytokine responses. Supplementation of probiotic organisms in infancy could help prevent immune-mediated diseases in childhood, whereas their intervention in pregnancy could affect fetal immune parameters, such as cord blood interferon (IFN)-γ levels, transforming growth factor (TGF)-β1 levels, and breast milk immunoglobulin (Ig)A. Probiotics that can be delivered via fermented milk or yogurt could improve the gut mucosal immune system by increasing the number of IgA+ cells and cytokine-producing cells in the effector site of the intestine.
Sex differences in pain: a tale of two immune cells

Abstract Substantial evidence has implicated microglia in neuropathic pain. After peripheral nerve injury, microglia in the spinal cord proliferate and increase cell-surface expression of the purinergic receptor P2X4. Activation of P2X4 receptors results in release of brain-derived neurotrophic factor, which acts on neurons to produce disinhibition of dorsal horn neurons which transmit nociceptive information to the brain. Disinhibition of these neurons produces pain hypersensitivity, a hallmark symptom of neuropathic pain. However, elucidating this microglia-neuronal signalling pathway was based on studies using only male rodents. Recent evidence has shown that the role of microglia in pain is sexually dimorphic. Despite similar microglia proliferation in the dorsal horn in both sexes, females do not upregulate P2X4Rs and use a microglia-independent pathway to mediate pain hypersensitivity. Instead, adaptive immune cells, possibly T cells, may mediate pain hypersensitivity in female mice. This profound sex difference highlights the importance of including subjects of both sexes in preclinical pain research.
Motor skill impairment in SIV‐infected rhesus macaques with rapidly and slowly progressing disease

Abstract: A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to further characterize the rhesus macaque infected with neurovirulent SIV as a model of neuroAIDS. Using a motor skill task, our objective was to detect SIV‐related movement impairments in behaviorally trained macaques. The motor skill task required retrieval of a food pellet from a cup in a rotating turntable across a range of speeds. Nine monkeys were infected with neurovirulent strains of SIVmac (R71/17E); four monkeys served initially as controls pre‐inoculation. Seven monkeys developed simian AIDS within 4 months of inoculation (rapid progressors), and two survived more than 18 months post‐inoculation (slow progressors). Of the rapid progressors, five exhibited significant deficits in this task, most showing a gradual decline in performance terminating in a sharp drop to severely impaired levels of performance. One slow progressor (AQ15) showed no performance declines. The other slow progressor (AQ94) showed a significant decrease in maximum speed that was concurrent with the onset of clinical signs. For AQ94, the role of sickness behavior related to late stage simian AIDS could not be ruled out. These results demonstrate that motor system impairment can be detected early in the course of SIV infection in rhesus macaques, further establishing the SIVmac‐infected macaque monkey as a viable model of neuroAIDS.
Stochastic Search Gene Suggestion: A Bayesian Hierarchical Model for Gene Mapping

Summary Mapping the genes for a complex disease, such as diabetes or rheumatoid arthritis (RA), involves finding multiple genetic loci that may contribute to the onset of the disease. Pairwise testing of the loci leads to the problem of multiple testing. Looking at haplotypes, or linear sets of loci, avoids multiple tests but results in a contingency table with sparse counts, especially when using marker loci with multiple alleles. We propose a hierarchical Bayesian model for case–parent triad data that uses a conditional logistic regression likelihood to model the probability of transmission to a diseased child. We define hierarchical prior distributions on the allele main effects to model the genetic dependencies present in the human leukocyte antigen (HLA) region of chromosome 6. First, we add a hierarchical level for model selection that accounts for both locus and allele selection. This allows us to cast the problem of identifying genetic loci relevant to the disease into a problem of Bayesian variable selection. Second, we attempt to include linkage disequilibrium as a covariance structure in the prior for model coefficients. We evaluate the performance of the procedure with some simulated examples and then apply our procedure to identifying genetic markers in the HLA region that influence risk for RA. Our software is available on the website http://www.epigenetic. org/Linkage/ssgs‐public/.
Is a Picture Worth a Thousand Words? Evidence from Concept Definitions by Patients with Semantic Dementia

Nine patients with semantic dementia (the temporal lobe variant of frontotemporal dementia) were asked to define concrete concepts either from presentation of a picture of the object or from its spoken name. As expected, the patients with the most severe semantic impairment produced the least detailed definitions, and the quality of the definitions overall was significantly related to concept familiarity. Further analyses of the definitions were designed to assess two key theoretical aspects of semantic organization. (i) Do objects and their corresponding names activate conceptual information in two neuroanatomically separable (modality-specific) semantic systems? If so, then-apart from any expected commonality in performance attributable to factors such as concept familiarity-one would not predict striking item-specific similarities in a patient's picture- and word-elicited definitions. (ii) Do sensory/perceptual features and more associative/functional attributes of conceptual knowledge form two neuroanatomically separable subsystems? If so, then one would predict significant dissociations in the prominence of these two types of information in the patients' definitions. The results lead us to favor a model of the semantic system that is divided by attribute type but not by modality.
From Ischemic Conditioning to ‘Hyperconditioning’: Clinical Phenomenon and Basic Science Opportunity

Thousands of articles have been published on the topic of ischemic conditioning. Nevertheless, relatively little attention has been given to assessment of conditioning's dose-response characteristics. Specifically, the consequences of multiple conditioning episodes, what we will term “hyperconditioning”, have seldom been examined. We propose that hyperconditioning warrants investigation because it; (1) may be of clinical importance, (2) could provide insight into conditioning mechanisms, and (3) might result in development of novel models of human disease. The prevalence of angina pectoris and intermittent claudication is sufficiently high and the potential for daily ischemia-reperfusion episodes sufficiently large that hyperconditioning is a clinically relevant phenomenon. In basic science, attenuation of conditioning-mediated infarct size reduction found in some studies after hyperconditioning offers a possible means to facilitate further discernment of cardioprotective signaling pathways. Moreover, hyperconditioning's impact extends beyond cytoprotection to tissue structural elements. Several studies demonstrate that hyperconditioning produces collagen injury (primarily fiber breakage). Such structural impairment could have adverse clinical consequences; however, in laboratory studies, selective collagen damage could provide the basis for models of cardiac rupture and dilated cardiomyopathy. Accordingly, we propose that hyperconditioning represents the dark, but potentially illuminating, side of ischemic conditioning - a paradigm that merits attention and prospective evaluation.