COOL, a Context Outlooker, and its Application to Question Answering and other Natural Language Processing Tasks

Vision outlookers improve the performance of vision transformers, which implement a self-attention mechanism by adding outlook attention, a form of local attention. In natural language processing, as has been the case in computer vision and other domains, transformer-based models constitute the state-of-the-art for most processing tasks. In this domain, too, many authors have argued and demonstrated the importance of local context. We present and evaluate an outlook attention mechanism, COOL, for natural language processing. COOL adds, on top of the self-attention layers of a transformer-based model, outlook attention layers that encode local syntactic context considering word proximity and consider more pair-wise constraints than dynamic convolution operations used by existing approaches. A comparative empirical performance evaluation of an implementation of COOL with different transformer-based approaches confirms the opportunity of improvement over a baseline using the neural language models alone for various natural language processing tasks, including question answering. The proposed approach is competitive with state-of-the-art methods

Towards Assessing Compliant Robotic Grasping from First-Object Perspective via Instrumented Objects

Grasping compliant objects is difficult for robots - applying too little force may cause the grasp to fail, while too much force may lead to object damage. A robot needs to apply the right amount of force to quickly and confidently grasp the objects so that it can perform the required task. Although some methods have been proposed to tackle this issue, performance assessment is still a problem for directly measuring object property changes and possible damage. To fill the gap, a new concept is introduced in this paper to assess compliant robotic grasping using instrumented objects. A proof-of-concept design is proposed to measure the force applied on a cuboid object from a first-object perspective. The design can detect multiple contact locations and applied forces on its surface by using multiple embedded 3D Hall sensors to detect deformation relative to embedded magnets. The contact estimation is achieved by interpreting the Hall-effect signals using neural networks. In comprehensive experiments, the design achieved good performance in estimating contacts from each single face of the cuboid and decent performance in detecting contacts from multiple faces when being used to evaluate grasping from a parallel jaw gripper, demonstrating the effectiveness of the design and the feasibility of the concept.Comment: Under review for RA-

Analysis of monitoring results of food microbial pathogenic factors in Zhoushan City from 2017 to 2019

Objective To understand the contamination status of microorganisms and pathogenic factors in 19 kinds of food in Zhoushan City, so as to provide basic data for food safety risk monitoring and early warning. Methods A total of 1 246 food samples were collected from 2017 to 2019 according to the requirements of the national risk monitor manual of food contamination and harmful factors from 2017 to 2019. The samples were tested for food microbial pathogenic factors. Results A total of 243 pathogenic factors were detected and the total detection rate was 19.50% (243/1 246). The detection rate of Salmonella in raw meat was 41.67% (30/72), the detection rate of Vibrio parahaemolyticus in bivalve shellfish was 31.58% (48/152), the detection rate of Anisakid in fresh marine fish was 27.00% (27/100), and the detection rate of Staphylococcus aureus in cold-made pastry was 16.25% (13/80). The detection rate of microorganism and its pathogenic factors in bulk food was higher than that in pre-packaged food. The difference was statistically significant (χ2=92.333, P<0.05). In different sampling locations, the highest detection rate of pathogenic factors was found in farmers’ markets (32.54%, 150/461), followed by online stores (25.44%, 29/114) and small restaurants (23.88%, 16/67). Conclusion From 2017 to 2019, 19 types of food on sale in Zhoushan City were contaminated by microorganisms and pathogenic factors at varying degrees. The contamination of microorganisms and pathogenic factors in take-out meals, raw animal meat and bivalve shellfish products was relatively serious. It is suggested to strengthen hygiene supervision on these types of food to prevent the occurrence of foodborne diseases

Role of Leptin in Mood Disorder and Neurodegenerative Disease

The critical regulatory role of leptin in the neuroendocrine system has been widely reported. Significantly, leptin can improve learning and memory, affect hippocampal synaptic plasticity, exert neuroprotective efficacy and reduce the risk of several neuropsychiatric diseases. In terms of depression, leptin could modulate the levels of neurotransmitters, neurotrophic factors and reverse the dysfunction in the hypothalamic-pituitary-adrenal axis (HPA). At the same time, leptin affects neurological diseases during the regulation of metabolic homeostasis. With regards to neurodegenerative diseases, leptin can affect them via neuroprotection, mainly including Alzheimer’s disease and Parkinson’s disease. This review will summarize the mechanisms of leptin signaling within the neuroendocrine system with respect to these diseases and discuss the therapeutic potential of leptin

Selecting an Anti-Malarial Clinical Candidate from Two Potent Dihydroisoquinolones

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. RESULTS: Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. CONCLUSION: SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators

Discovery of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 μM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug

A HALP score-based prediction model for survival of patients with the upper tract urothelial carcinoma undergoing radical nephroureterectomy

The combination of hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been confirmed as an important risk biomarker in several cancers. Hence, we aimed at evaluating the prognostic value of the HALP score in patients with non-metastatic upper tract urothelial carcinoma (UTUC). We retrospectively enrolled 533 of the 640 patients from two centers (315 and 325 patients, respectively) who underwent radical nephroureterectomy (RNU) for UTUC in this study. The cutoff value of HALP was determined using the Youden index by performing receiver operating characteristic (ROC) curve analysis. The relationship between postoperative survival outcomes and preoperative HALP level was assessed using Kaplan-Meier analysis and Cox regression analysis. As a result, the cutoff value of HALP was 28.67 and patients were then divided into HALP<28.67 group and HALP≥28.67 group. Kaplan-Meier analysis and log-rank test revealed that HALP was significantly associated with overall survival (OS) (P<0.001) and progression-free survival (PFS) (P<0.001). Multivariate analysis demonstrated that lower HALP score was an independent risk factor for OS (HR=1.54, 95%CI, 1.14-2.01, P=0.006) and PFS (HR=1.44, 95%CI, 1.07-1.93, P=0.020). Nomograms of OS and PFS incorporated with HALP score were more accurate in predicting prognosis than without. In the subgroup analysis, the HALP score could also stratify patients with respect to survival under different pathologic T stages. Therefore, pretreatment HALP score was an independent prognostic factor of OS and PFS in UTUC patients undergoing RNU

The 5HT4R agonist velusetrag efficacy on neuropathic chronic intestinal pseudo-obstruction in PrP-SCA7-92Q transgenic mice

BackgroundChronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction with symptoms of intestinal blockage but without the actual mechanical obstruction. Currently, there are no drugs available to treat this disease. Herein, we report the characterization of the PrP-SCA7-92Q transgenic (Tg) line as a valuable CIPO mouse model and investigated the tolerability and efficacy of the 5-hydroxytryptamine type-4 receptor (5HT4R) agonist velusetrag as a promising pharmacological treatment for CIPO.MethodsTo test the pharmacodynamics of velusetrag, 8-week-old SCA7 Tg mice, which express human mutated Ataxin-7 gene containing 92 CAG repeats under the mouse prion protein promoter, were treated for 5 weeks by oral route with velusetrag at 1 and 3 mg/kg doses or vehicle. Body weight was monitored throughout the treatment. After sacrifice, the small intestine and proximal colon were collected for whole-mount immunostaining. Untreated, age-matched, C57BL/6J mice were also used as controls in comparison with the other experimental groups.ResultsAnalysis of SCA7 Tg mice showed tissue damage and alterations, mucosal abnormalities, and ulcers in the distal small intestine and proximal colon. Morphological changes were associated with significant neuronal loss, as shown by decreased staining of pan-neuronal markers, and with accumulation of ataxin-7-positive inclusions in cholinergic neurons. Administration of velusetrag reversed intestinal abnormalities, by normalizing tissue damage and re-establishing the normal level of glia/neuron’s count in both the small and large intestines.ConclusionWe demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease