Sample-efficient Multi-objective Molecular Optimization with GFlowNets

Many crucial scientific problems involve designing novel molecules with desired properties, which can be formulated as a black-box optimization problem over the discrete chemical space. In practice, multiple conflicting objectives and costly evaluations (e.g., wet-lab experiments) make the diversity of candidates paramount. Computational methods have achieved initial success but still struggle with considering diversity in both objective and search space. To fill this gap, we propose a multi-objective Bayesian optimization (MOBO) algorithm leveraging the hypernetwork-based GFlowNets (HN-GFN) as an acquisition function optimizer, with the purpose of sampling a diverse batch of candidate molecular graphs from an approximate Pareto front. Using a single preference-conditioned hypernetwork, HN-GFN learns to explore various trade-offs between objectives. We further propose a hindsight-like off-policy strategy to share high-performing molecules among different preferences in order to speed up learning for HN-GFN. We empirically illustrate that HN-GFN has adequate capacity to generalize over preferences. Moreover, experiments in various real-world MOBO settings demonstrate that our framework predominantly outperforms existing methods in terms of candidate quality and sample efficiency. The code is available at https://github.com/violet-sto/HN-GFN.Comment: NeurIPS 202

Paternal chromosome elimination of inducer triggers induction of double haploids in Brassica napus

A synthetic octoploid rapeseed, Y3380, induces maternal doubled haploids when used as a pollen donor to pollinate plant. However, the mechanism underlying doubled haploid formation remains elusive. We speculated that double haploid induction occurs as the inducer line’s chromosomes pass to the maternal egg cell, and the zygote is formed through fertilization. In the process of zygotic mitosis, the paternal chromosome is specifically eliminated. Part of the paternal gene might have infiltrated the maternal genome through homologous exchange during the elimination process. Then, the zygote haploid genome doubles (early haploid doubling, EH phenomenon), and the doubled zygote continues to develop into a complete embryo, finally forming doubled haploid offspring. To test our hypothesis, in the current study, the octoploid Y3380 line was back bred with the 4122-cp4-EPSPS exogenous gene used as a marker into hexaploid Y3380-cp4-EPSPS as paternal material to pollinate three different maternal materials. The fertilization process of crossing between the inducer line and the maternal parent was observed 48 h after pollination, and the fertilization rate reached 97.92% and 98.72%. After 12 d of pollination, the presence of cp4-EPSPS in the embryo was detected by in situ PCR, and at 13–23 d after pollination, the probability of F1 embryos containing cp4-EPSPS gene was up to 97.27%, but then declined gradually to 0% at 23–33 d. At the same time, the expression of cp4-EPSPS was observed by immunofluorescence in the 3rd to 29th day embryo. As the embryos developed, cp4-EPSPS marker genes were constantly lost, accompanied by embryonic death. After 30 d, the presence of cp4-EPSPS was not detected in surviving embryos. Meanwhile, SNP detection of induced offspring confirmed the existence of double haploids, further indicating that the induction process was caused by the loss of specificity of the paternal chromosome. The tetraploid-induced offspring showed infiltration of the induced line gene loci, with heterozygosity and homozygosity. Results indicated that the induced line chromosomes were eliminated during embryonic development, and the maternal haploid chromosomes were synchronously doubled in the embryo. These findings support our hypothesis and lay a theoretical foundation for further localization or cloning of functional genes involved in double haploid induction in rapeseed

Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: <it>PKD1 </it>(16p13.3) and <it>PKD2 </it>(4q21). Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of <it>PKD1 </it>gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both <it>PKD1 </it>and <it>PKD2 </it>genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC).</p> <p>Methods</p> <p>Both <it>PKD1 </it>and <it>PKD2 </it>genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources.</p> <p>Results</p> <p>A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication) were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65). About 69% (20/29) of the mutations are first reported with a recurrent mutation rate of 31%.</p> <p>Conclusions</p> <p>Mutation study of <it>PKD1 </it>and <it>PKD2 </it>genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.</p

Neutrino Physics with JUNO

The Jiangmen Underground Neutrino Observatory (JUNO), a 20 kton multi-purposeunderground liquid scintillator detector, was proposed with the determinationof the neutrino mass hierarchy as a primary physics goal. It is also capable ofobserving neutrinos from terrestrial and extra-terrestrial sources, includingsupernova burst neutrinos, diffuse supernova neutrino background, geoneutrinos,atmospheric neutrinos, solar neutrinos, as well as exotic searches such asnucleon decays, dark matter, sterile neutrinos, etc. We present the physicsmotivations and the anticipated performance of the JUNO detector for variousproposed measurements. By detecting reactor antineutrinos from two power plantsat 53-km distance, JUNO will determine the neutrino mass hierarchy at a 3-4sigma significance with six years of running. The measurement of antineutrinospectrum will also lead to the precise determination of three out of the sixoscillation parameters to an accuracy of better than 1\%. Neutrino burst from atypical core-collapse supernova at 10 kpc would lead to ~5000inverse-beta-decay events and ~2000 all-flavor neutrino-proton elasticscattering events in JUNO. Detection of DSNB would provide valuable informationon the cosmic star-formation rate and the average core-collapsed neutrinoenergy spectrum. Geo-neutrinos can be detected in JUNO with a rate of ~400events per year, significantly improving the statistics of existing geoneutrinosamples. The JUNO detector is sensitive to several exotic searches, e.g. protondecay via the $p\to K^++\bar\nu$ decay channel. The JUNO detector will providea unique facility to address many outstanding crucial questions in particle andastrophysics. It holds the great potential for further advancing our quest tounderstanding the fundamental properties of neutrinos, one of the buildingblocks of our Universe

High Cycle Fatigue Performance of Inconel 718 Alloys with Different Strengths at Room Temperature

In this paper, the high cycle fatigue performance of solid solution state and aged Inconel 718 superalloys was studied at room temperature. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to analyze the original structural features and fatigue deformation features of two kinds of alloys. SEM, laser scanning confocal microscopy, and electron backscatter diffraction (EBSD) were used to analyze the secondary fracture features of the fatigue fracture morphology and fatigue fracture profile. The results showed that the aging treatment significantly affected the strength and plasticity of the alloy, which in turn affected the fatigue performance of the alloy. After the aging treatment, the yield strength &sigma;s and the tensile strength &sigma;b of the Inconel 718 alloy increased by 152% and 65.9%, respectively, compared with those of the solid solution state, but the rate of elongation &delta; and rate of contraction in the cross-section area &phi; decreased by 63.7% and 52.3%, respectively. The fatigue limit of the aged state was lower than that of the solid solution state by 6.3%. The quadratic function relationship between the high cycle fatigue limit &sigma;&minus;1 and the tensile strength &sigma;b of the Inconel 718 superalloy at room temperature was &sigma;&minus;1 = &sigma;b &middot; (0.869&minus;3.67 &times; 10&minus;4 &middot; &sigma;b). An analysis of the fatigue fracture mechanism showed that the fatigue fractures before and after aging were all initiated in the grains oriented relatively unfavorably on the surface of the sample, with a mixture of intergranular and transgranular propagation after the transgranular propagation of several grains. The higher plasticity of the solid solution state Inconel 718 alloy resulted in a large number of slip deformation zones under high cycle fatigue loads, and the plastic deformation was relatively uniform. The lengths of the secondary fractures were as high as 120 &mu;m, which formed the single-source plastic fatigue fracture that promoted an increase in the fatigue limit. After aging treatment, the higher strength of the Inconel 718 alloy made dislocation slip difficult under high cycle fatigue loads, and the plasticity compatible deformation capability was poor. When local dislocations slipped to the intragranular &gamma;&rdquo; phase, &gamma;&rsquo; phase, or interfaces with nonmetallic compounds (NMCs), plugging occurred. The degree of stress concentration increased, causing the initiation of fatigue fracture; the secondary fracture was approximately 20 &mu;m. Brittle cleavage due to multiple sources significantly reduced the fatigue limit

Presplitting Blasting the Roof Strata to Control Large Deformation in the Deep Mine Roadway

As the mining depth increases, under the influence of high ground stress, the surrounding rock of deep mine roadways shows soft rock characteristics. Under the influence of mining disturbance at the working face, large deformation of the roadway has occurred. To control the large deformation of the roadway, many mines have adopted the form of combined support, which has continuously increased the support strength and achieved a certain effect. However, since the stress environment of the surrounding rock of the roadway has not been changed, large deformation of the roadway still occurs in many cases. Based on the theoretical basis of academician Manchao He’s “short cantilever beam by roof cutting,” this paper puts forward the plan of “presplitting blasting + combined support” to control the large deformation of the deep mine roadways. Without changing the original support conditions of the roadway, presplitting blasting the roof strata of the roadway, by cutting off the mechanical connection of the roof strata between the roadway and gob, improves the stress distribution of the roadway to control the large deformation. Through field tests, the results show that after presplitting blasting the roadway roof, the roadway roof subsidence is reduced by 47.9%, the ribs displacement is reduced by 45.7%, and the floor heave volume is reduced by 50.8%. The effect is significant

Key parameters of gob-side entry retaining by roof cutting in close-distance seam group

Abstract During the process of close-distance seam group mining, the coal pillar in the upper coal seam is a stress-concentrated area, which leads to a loss of stability of the roadway during mining of the lower coal seam. This lack of stability introduces great safety hazards to coal mines. To solve the problem of stress concentration of coal pillars, the method of gob-side entry retaining by roof cutting is proposed to remove the coal pillar. In this study, FLAC3D was used to analyze the depth and angle of pre-split blasting. LS-DYNA was used to analyze the spacing of the blasthole. Using the methods of theoretical analysis and numerical simulation, we determined that the optimal depth of the pre-split blasting was 6 m, the optimal angle for pre-split blasting was 15°, and the optimal spacing of the blasthole was 500 mm. A field test was carried out in the 1010201 ventilation roadway of the Yuwang Coal Mine, China. The on-site peeping results showed that when the spacing of the blasthole is 500 mm, connecting cracks can form under the action of blasting stress. After the working surface is mined, the roof strata could collapse and fill the gob over time when the depth and angle of the pre-split blasting are 6 m and 15°, respectively

Efficient Defense Decision-Making Approach for Multistep Attacks Based on the Attack Graph and Game Theory

In the multistep attack scenario, each rational attack-defense player tries to maximize his payoff, but the uncertainty about his adversary prevents him from taking the favorable actions. How to select the best strategy from the candidate strategies to maximize the defense payoff becomes the core issue. For this purpose, the paper innovatively designs a game theory model from the point of network survivability in combination with the attribute attack graph. The attack graph is created based on the network connectivity and known vulnerabilities using the MulVAL toolkit, which gives the full view of all the known vulnerabilities and their interdependence. Then, we use the attack graph to extract attack-defense actions, candidate attack-defense strategies, attack-defense payoffs, and network states, as well as other game modeling elements. Afterwards, the payoffs of attack-defense strategies are quantified by integrating attack-defense strength and network survivability. In addition, we input the above elements into the game model. Through repeated learning, deduction, and improvement, we can optimize the layout of defense strategies. Finally, the efficient strategy selection approach is designed on the tradeoff between defense cost and benefit. The simulation of attack-defense confrontation in small-scale LAN shows that the proposed approach is reliable and effective

Research on the Key Technology of Gob-Side Entry Retaining by Roof Cutting for Thick and Hard Sandstone Roofs

In order to ensure the application of gob-side entry retaining by roof cutting for thick and hard sandstone roofs, the key technology of pre-split blasting was studied. The LS-DYNA was used to analyze the blasting effect of the energy-gathering pipe. Using the methods of theoretical analysis and numerical simulation, it was determined that the optimal cutting height was 16 m and the optimal cutting angle was 15&deg;. The effect of pressure relief by roof cutting was verified by FLAC3D. It is proposed to use deep-hole loosening blasting to solve the problem of the sandstone with a thick hard roof being difficult to collapse. A group of loose blasting holes was designed to be arranged every 20 m in the gob-side roadway. The depth of the #1 blasthole was 47 m, and the angle to the horizontal direction was 20&deg;; the depth of the #2 blasthole was 65 m, and the angle to the horizontal direction was 15&deg;. A field test was carried out in the 7135 ventilation roadway of Qidong Coal Mine China. The on-site peeping results showed that the blasting with the energy-gathering pipe had a good effect of directional slitting. After deep-hole loosening blasting, the thick hard sandstone roof collapsed and filled the gob in time. The monitoring curves of the hydraulic support showed that the hydraulic support resistance of the working face in the side with roof cutting was much smaller than that of the side without roof cutting, and the effect of pressure relief by roof cutting was good