Overfitting in Synthesis: Theory and Practice (Extended Version)

In syntax-guided synthesis (SyGuS), a synthesizer's goal is to automatically generate a program belonging to a grammar of possible implementations that meets a logical specification. We investigate a common limitation across state-of-the-art SyGuS tools that perform counterexample-guided inductive synthesis (CEGIS). We empirically observe that as the expressiveness of the provided grammar increases, the performance of these tools degrades significantly. We claim that this degradation is not only due to a larger search space, but also due to overfitting. We formally define this phenomenon and prove no-free-lunch theorems for SyGuS, which reveal a fundamental tradeoff between synthesizer performance and grammar expressiveness. A standard approach to mitigate overfitting in machine learning is to run multiple learners with varying expressiveness in parallel. We demonstrate that this insight can immediately benefit existing SyGuS tools. We also propose a novel single-threaded technique called hybrid enumeration that interleaves different grammars and outperforms the winner of the 2018 SyGuS competition (Inv track), solving more problems and achieving a $5\times$ mean speedup.Comment: 24 pages (5 pages of appendices), 7 figures, includes proofs of theorem

Public Attitudes Toward Psychiatric Hospitals: A Rural-Urban Comparative Public Survey in Odisha State, India

Background: Integration of psychiatric care with public health services and offering mental health care services to patients from lower socioeconomic status remains a global challenge. Scarcity of funds and professional workforce in psychiatric hospitals contribute to this situation. However, negative attitudes in the population are also a known impediment to patients seeking mental health services. This study aimed to assess the attitudes toward psychiatric hospitals among the urban and rural population in India. Subjects and Methods: The study was carried out amongst the general population in Odisha, India. The total sample (n = 988) includes 496 respondents from an urban-setting, and 492 respondents from rural parts of the district. Participants were selected by using simple random-sampling from the Asian Institute of Public Health (AIPH) data base. A standardized seven-item questionnaire was adopted, with responses indicated on a 5-point Likert-scale. Interviews were fully structured and conducted face-to-face. Results: Level of education (B = -0.192, ss = -0.320, p < 0.000) and urban-rural comparison (B = -0.272, ss = -0.189, p < 0.000) significantly influenced attitudes toward psychiatric hospitals. Gender, age, and religious beliefs did not show any significant effect on attitudes toward psychiatric hospitals. Individuals in rural areas and those with lower education levels showed more negative attitudes toward psychiatric hospitals. Conclusion: Negative attitudes toward psychiatric hospitals from those living in rural areas as well as those with lesser education may be reflective of the lack of availability, accessibility, affordability, and credibility of such mental health services. The Mental Health Care Act in India is a progressive legislation which might improve the situation of the provided services and, consequently, reduce negative attitudes in the years to come

Impaired tissue homing by the Ikzf3N159S variant is mediated by interfering with Ikaros function

AIOLOS, encoded by IKZF3, is a member of the IKZF family of proteins that plays an important role in regulating late B-cell differentiation. Human individuals heterozygous for the AIOLOS p.N160S variant displayed impaired humoral immune responses as well as impaired B and T cell development. We have previously reported that a mouse strain harboring an Ikzf3N159S allele that corresponds to human IKZF3N160S recapitulated immune-deficient phenotypes, such as impaired B cell development and loss of CD23 expression. In this study, we investigated the effect of the Ikzf3N159S variant and found that B1a cell development was impaired in Ikzf3N159S/N159S mice. In addition, CD62L expression was severely decreased in both B and T lymphocytes by the Ikzf3N159S mutation, in a dose-dependent manner. Mixed bone marrow chimera experiments have revealed that most immunodeficient phenotypes, including low CD62L expression, occur in intrinsic cells. Interestingly, while Ikzf3N159S/N159S lymphocytes were still present in the spleen, they were completely outcompeted by control cells in the lymph nodes, suggesting that the capacity for homing or retention in the lymph nodes was lost due to the Ikzf3N159S mutation. The homing assay confirmed severely decreased homing abilities to lymph nodes of Ikzf3N159S/N159S B and T lymphocytes but selective enrichment of CD62L expressing Ikzf3N159S/N159S lymphocytes in lymph nodes. This finding suggests that impaired CD62L expression is the major reason for the impaired homing capacity caused by the Ikzf3N159S mutation. Interestingly, an excess amount of Ikaros, but not Aiolos, restored CD62L expression in Ikzf3N159S/N159S B cells. Together with the loss of CD62L expression due to Ikaros deficiency, the AiolosN159S mutant protein likely interferes with Ikaros function through heterodimerization, at least in activating the Sell gene encoding CD62L expression. Thus, our results revealed that AiolosN159S causes some immunodeficient phenotypes via the pathogenesis referred to as the heterodimeric interference as observed for AiolosG158R variant

Mechanisms of Loss of Functions of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Background: Mutations in the coding region of angiogenin (ANG) gene have been found in patients suffering from Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration results from the loss of angiogenic ability of ANG (protein coded by ANG). In this work, we performed extensive molecular dynamics (MD) simulations of wild-type ANG and disease associated ANG variants to elucidate the mechanism behind the loss of ribonucleolytic activity and nuclear translocation activity, functions needed for angiogenesis. Methodology/Principal Findings: MD simulations were carried out to study the structural and dynamic differences in the catalytic site and nuclear localization signal residues between WT-ANG (Wild-type ANG) and six mutants. Variants K17I, S28N, P112L and V113I have confirmed association with ALS, while T195C and A238G single nucleotide polymorphisms (SNPs) encoding L35P and K60E mutants respectively, have not been associated with ALS. Our results show that loss of ribonucleolytic activity in K17I is caused by conformational switching of the catalytic residue His114 by 99u. The loss of nuclear translocation activity of S28N and P112L is caused by changes in the folding of the residues 31 RRR 33 that result in the reduction in solvent accessible surface area (SASA). Consequently, we predict that V113I will exhibit loss of angiogenic properties by loss of nuclear translocation activity and L35P by loss of both ribonucleolytic activity and nuclear translocation activity. No functional loss was inferred for K60E. The MD simulation results were supported by hydrogen bond interactio

How Does Arbidol Inhibit the Novel Coronavirus SARS-CoV-2? Atomistic Insights from Molecular Dynamics Simulations

The COVID-19 pandemic is spreading at an alarming rate, posing an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) treatment. China\u27s prevention and treatment guidelines suggest the use of an anti-influenza drug, Arbidol, for the clinical treatment of COVID-19. Reports indicate that Arbidol could neutralize the SARS-CoV-2. Monotherapy with Arbidol is found superior to Lopinavir-Ritonavir or Favipiravir in the treatment of COVID-19. In the SARS-CoV-2, Arbidol acts upon interfering in virus binding to host cells. However, the detailed understanding of Arbidol induced inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the Arbidol-induced SARS-CoV-2 membrane fusion inhibition and propose a model of inhibition. Molecular dynamics (MD) simulation-based analyses demonstrate that Arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between RBD and ACE2 in the Arbidol-bound RBD/ACE2 complex, suggesting that Arbidol could generate favorable interactions between them. Based on our MD simulation results, we propose that the binding of Arbidol induced structural rigidity in the virus glycoprotein resulting in restriction of the conformational rearrangements associated with membrane attachment and virus entry.Further, key residues of RBD and ACE2 that interacted with Arbidol were identified, opening the doors for the development of therapeutic strategies and higher efficacy Arbidol derivatives or lead drug candidates.</p

A Stochastic Feedback Model to Simulate Saccadic Eye Movement Variability

Variability is an important behavioral signature of biological movements that can be used as a tool to understand motor control. This study has modeled the inter-trial variability of very rapid eye movements called saccades by using a stochastic feedback model. The proposed model represents the brainstem saccade generation system with noise in the loop. Three types of noise signal namely visual noise, premotor noise and motor noise are considered in this model. The model can predict the inter-trial variability in the angular displacement of saccade trajectories. The accuracy of the predictions of the model has been verified using experimental data of horizontal saccades. It is observed that the presence of all the three noise components is important for the prediction of the dynamic evolution of the inter trial variability during eye movement. This work provides a way to better understand the control of the saccadic system. (C) 2017, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved

Characterization of Pulse-step Input for Saccadic Eye Movements

The understanding of the neuronal firing input to the motor neurons innervating oculomotor muscles is vital in studying control of eye-movements. The firing rate of the motor neurons which causes rapid eye movements called saccades has been characterized here using a Gaussian function. Using experimental horizontal saccade data, the parameters of the Gaussian function are estimated by least square minimization. These parameters, peak firing rate and time-to-peak of the input firing rate were observed to be functions of the saccade amplitude. Their relationship is quantified using a least square curve fit. The peak firing rate is found to be linearly varying with saccade amplitude and time-to-peak varies as a quadratic function of saccade amplitude. The model can predict the input firing rate of motor neurons for all saccade amplitudes independent of the availability of data. This work provides a method that can be extended for predicting the neural firing rates to be generated by the motor neurons at the oculomotor muscles for producing different classes of eye movements

A Stochastic Feedback Model to Simulate Saccadic Eye Movement Variability

Variability is an important behavioral signature of biological movements that can be used as a tool to understand motor control. This study has modeled the inter-trial variability of very rapid eye movements called saccades by using a stochastic feedback model. The proposed model represents the brainstem saccade generation system with noise in the loop. Three types of noise signal namely visual noise, premotor noise and motor noise are considered in this model. The model can predict the inter-trial variability in the angular displacement of saccade trajectories. The accuracy of the predictions of the model has been verified using experimental data of horizontal saccades. It is observed that the presence of all the three noise components is important for the prediction of the dynamic evolution of the inter trial variability during eye movement. This work provides a way to better understand the control of the saccadic system. (C) 2017, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved

Interface-based Design of the Favipiravir-binding Site in SARS-CoV-2 RNA-dependent RNA Polymerase Reveals Mutations Conferring Resistance to Chain Termination

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19. Accumulation of mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RdRp may facilitate antigenic drift, generating favipiravir resistance. Focussing on the chain-termination mechanism utilized by favipiravir, we used high-throughput interface-based protein design to generate \u3e 100 000 designs of the favipiravir-binding site of RdRp and identify mutational hotspots. We identified several single-point mutants and designs having a sequence identity of 97%–98% with wild-type RdRp, suggesting that SARS-CoV-2 can develop favipiravir resistance with few mutations. Out of 134 mutations documented in the CoV-GLUE database, 63 specific mutations were already predicted as resistant in our calculations, thus attaining ˜ 47% correlation with the sequencing data. These findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir