A PRESTO-based parallel pulsar search pipeline used for FAST drift scan data

We developed a pulsar search pipeline based on PulsaR Exploration and Search TOolkit(PRESTO).This pipeline simply runs dedispersion,Fast Fourier Transform(FFT)and acceleration search in process-level parallel to shorten the processing time.With two parallel strategies,the pipeline can highly shorten the processing time in both normal searches and acceleration searches.This pipeline was first tested with Parkes Multibeam Pulsar Survery(PMPS)data and discovered two new faint pulsars.Then,it was successfully applied in processing the Five-hundred-meter Aperture Spherical radio Telescope(FAST)drift scan data with tens of new pulsar discoveries up to now.The pipeline is only CPU-based and can be easily and quickly deployed in computing nodes for testing purposes or data processing.

A GPU based single-pulse search pipeline(GSP)with database and its application to the Commensal Radio Astronomy FAST Survey(CRAFTS)

We developed a GPU based single-pulse search pipeline(GSP)with a candidate-archiving database.Largely based upon the infrastructure of the open source PulsaR Exploration and Search Toolkit(PRESTO),GSP implements GPU acceleration of the de-dispersion and integrates a candidate-archiving database.We applied GSP to the data streams from the Commensal Radio Astronomy FAST Survey(CRAFTS),which resulted in quasi-real-time processing.The integrated candidate database facilitates synergistic usage of multiple machine-learning tools and thus improves efficient identification of radio pulsars such as rotating radio transients(RRATs)and fast radio bursts(FRBs).We first tested GSP on pilot CRAFTS observations with the FAST Ultra-Wide Band(UWB)receiver.GSP detected all pulsars known from the the Parkes multibeam pulsar survey in the corresponding sky area covered by the FAST-UWB.GSP also discovered 13 new pulsars.We measured the computational efficiency of GSP to be~120 times faster than the original PRESTO and~60 times faster than an MPI-parallelized version of PRESTO.

An Arecibo follow-up study of seven pulsars discovered by Five-hundred-meter Aperture Spherical radio Telescope(FAST)

We present Arecibo 327 MHz confirmation and follow-up studies of seven new pulsars discovered by the Five-hundred-meter Aperture Spherical radio Telescope(FAST).These pulsars are discovered in a pilot program of the Commensal Radio Astronomy FAST Survey(CRAFTS)with the ultra-widebandwidth commissioning receiver.Five of them are normal pulsars and two are extreme nulling slow pulsars.PSR J2111+2132’s dispersion measure(DM:78.5 pc cm^(-3))is above the upper limits of the two Galactic free electron density models,NE2001 and YMW16,and PSR J2057+2133’s position is out of the Scutum-Crux Arm,making them uniquely useful for improving the Galactic free electron density model in their directions.We present a detailed single pulse analysis for the slow nulling pulsars.We show evidence that PSR J2323+1214’s main pulse component follows a non-Poisson distribution and marginal evidence for a sub-pulse-drift or recurrent period of 32.3±0.4 rotations from PSR J0539+0013.We discuss the implication of our finding to the pulsar radiation mechanism.

An RFI Mitigation Pipeline for CRAFTS Multi-beam Data Based on Signal Cross-Correlation Function and SumThreshold Algorithm

The increasing radio frequency interference(RFI)is a well-recognized problem in radio astronomy research.Pulsars and Fast Radio Bursts(FRBs)are high-priority science targets of the ongoing Commercial Radio Astronomy FAST Survey(CRAFTS).To improve the quality of RFI removal in searches of pulsars and FRBs based on CRAFTS multi-beam data,we here propose an intuitive but powerful RFI mitigation pipeline(CCF-ST).The“CCF-ST”is a spatial filter constructed by signal cross-correlation function(CCF)and Sum-Threshold(ST)algorithm.The RFI marking result is saved in a“mask”file,a binary format for RFI masks in PRESTO.Three known pulsars,PSR B0525-21,PSR B0621-04,and PSR J0943+2252 from CRAFTS L-band 19 beams data are used for evaluation of the performance of CCF-ST in comparison with other methods,such as PRESTO’s“rfifind”,ArPLS-ST and ArPLS-SF.The result shows that CCF-ST can reduce effective data loss rate and improves the detected signal-to-noise ratio of the pulsations by~26%and~18%respectively compared with PRESTO’s“rfifind”and ArPLS-ST.The CCF-ST also has the advantage of low computational cost,e.g.,reducing the time consumption by~40%and memory consumption by~90%compared with ArPLS-SF.We expect that the new RFI mitigation and analysis toolkit(CCF-ST)demonstrated in this paper can be applied to CRAFTS and other multi-beam telescope observations to improve the data quality and efficiency of pulsar and FRB searches.

Development and application of hepatocellular carcinoma risk prediction model based on clinical characteristics and liver related indexes

BACKGROUND Hepatocellular carcinoma(HCC)is difficult to diagnose with poor therapeutic effect,high recurrence rate and has a low survival rate.The survival of patients with HCC is closely related to the stage of diagnosis.At present,no specific serolo-gical indicator or method to predict HCC,early diagnosis of HCC remains a challenge,especially in China,where the situation is more severe.AIM To identify risk factors associated with HCC and establish a risk prediction model based on clinical characteristics and liver-related indicators.METHODS The clinical data of patients in the Affiliated Hospital of North Sichuan Medical College from 2016 to 2020 were collected,using a retrospective study method.The results of needle biopsy or surgical pathology were used as the grouping criteria for the experimental group and the control group in this study.Based on the time of admission,the cases were divided into training cohort(n=1739)and validation cohort(n=467).Using HCC as a dependent variable,the research indicators were incorporated into logistic univariate and multivariate analysis.An HCC risk prediction model,which was called NSMC-HCC model,was then established in training cohort and verified in validation cohort.RESULTS Logistic univariate analysis showed that,gender,age,alpha-fetoprotein,and protein induced by vitamin K absence or antagonist-II,gamma-glutamyl transferase,aspartate aminotransferase and hepatitis B surface antigen were risk factors for HCC,alanine aminotransferase,total bilirubin and total bile acid were protective factors for HCC.When the cut-off value of the NSMC-HCC model joint prediction was 0.22,the area under receiver operating characteristic curve(AUC)of NSMC-HCC model in HCC diagnosis was 0.960,with sensitivity 94.40%and specificity 95.35%in training cohort,and AUC was 0.966,with sensitivity 90.00%and specificity 94.20%in validation cohort.In early-stage HCC diagnosis,the AUC of NSMC-HCC model was 0.946,with sensitivity 85.93%and specificity 93.62%in training cohort,and AUC was 0.947,with sensitivity 89.10%and specificity 98.49%in validation cohort.CONCLUSION The newly NSMC-HCC model was an effective risk prediction model in HCC and early-stage HCC diagnosis.

Cryo-EM structure of cannabinoid receptor CB1-β-arrestincomplex

Dear Editor,G protein-coupled receptors(GPCRs)play a vital role in regulating almost every aspect of human physiology,making up more than one-third of marketed drug targets(Santos et al.,2017).GPCRs orchestrate their signalling through interactions with three distinct downstream protein families:G proteins,G protein-coupled receptor kinases(GRKs),and arrestins(Santos et al.,2017).While G protein-mediated signalling is initiated upon GPCR stimulation,activated GPCRs return to their basal levels through a GRK-and arrestin-regulated desensitization process(Santos et al.,2017).In addition to modulating receptor desensitization,β-arrestin also regulates downstream events that are distinct from classical G protein signalling(Ahn et al.,2020).

Generalized Einstein-Podolsky-Rosen steering paradox

Quantum paradoxes are essential means to reveal the incompatibility between quantum and classical theories,among which the Einstein–Podolsky–Rosen(EPR)steering paradox offers a sharper criterion for the contradiction between localhidden-state model and quantum mechanics than the usual inequality-based method.In this work,we present a generalized EPR steering paradox,which predicts a contradictory equality“2_(Q)=(1+δ)_(C)”(0≤δ<1)given by the quantum(Q)and classical(C)theories.For any N-qubit state in which the conditional state of the steered party is pure,we test the paradox through a two-setting steering protocol,and find that the state is steerable if some specific measurement requirements are satisfied.Moreover,our construction also enlightens the building of EPR steering inequality,which may contribute to some schemes for typical quantum teleportation and quantum key distributions.

The emerging roles of the DDX41 protein in immunity and diseases

RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box hell- cases compdse the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recant literatures on one member of the SF2 superfamily, the DEAD- box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons （IFN）. After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in Innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutetions in DDX41 gane are identified from myelodysplastic syndrome and/or acute myeloid leukemia （MDS/AML） patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survlval at all stages throughout the life cycle of the fly.

Mechanism of the Rpn13-induced activation of Uch37

Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo- dimer of Uch37, each of the catalytic domains was blocking the other＇s ubiquitin （Ub）-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combi- nation of mutagenesis, biochemical, NMR, and small- angle X-ray scattering （SAXS） techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubi- quitin-7-amino-4-methylcoumarin （Ub-AMC） of de-ubiq- uitinating enzymes. Uch37AHb＇Hc＇KEKE, a truncation removal of the C-terminal extension region （residues 256- 329） converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C （Rpn13 residues 270- 407） could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 com- plex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS （TR-SAXS） and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1：1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.

Structural biology study of human TNF receptor associated factor 4 TRAF domain

TRAF4 is a unique member of TRAF family,which is es-sential for innate immune response,nervous system and other systems.In addition to being an adaptor protein,TRAF4 was identifi ed as a regulator protein in recent studies.We have determined the crystal structure of TRAF domain of TRAF4(residues 292-466)at 2.60Åresolution by X-ray crystallography method.The trimericly assembled TRAF4 resembles a mushroom shape,containing a super helical“stalk”which is made of three right-handed intertwinedαhelixes and a C-terminal“cap”,which is divided at resi-due L302 as a boundary.Similar to other TRAFs,both intermolecular hydrophobic interaction in super helical“stalk”and hydrogen bonds in“cap”regions contribute directly to the formation of TRAF4 trimer.However,differ-ing from other TRAFs,there is an additional fl exible loop(residues 421-426),which contains a previously identifi ed phosphorylated site S426 exposing on the surface.This S426 was reported to be phosphorylated by IKKαwhich is the pre-requisite for TRAF4-NOD2 complex formation and thus to inhibit NOD2-induced NF-κB activation.Therefore,the crystal structure of TRAF4-TRAF is valuable for under-standing its molecular basis for its special function and provides structural information for further studies.

New insights into the structural basis of DNA recognition by HINa and HINb domains of IFI16

Interferon gamma-inducible protein 16(IFI16)senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear(HIN)domains,HINa and HINb,through the cooperative assembly of IFI16 filaments on double-stranded DNA(dsDNA).The role of HINa in sensing DNA is not clearly understood.Here,we describe the crystal structure of the HINa domain in complex with DNA at 2.55A°resolution and provide the first insight into the mode of DNA binding by the HINa domain.The structure reveals the presence of two oligosaccharide/nucleotide-binding(OB)folds with a unique DNA-binding surface.HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone.The dsDNA is recognized as two single strands of DNA.Interestingly,deletion of HINb compromises the ability of IFI16 to induce IFN-b,while HINa mutants impaired in DNAbinding enhance the production of IFN-b.These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.

Molecular detection of Anaplasma infections in ixodid ticks from the Qinghai-Tibet Plateau

Anaplasma species are tick-transmitted obligate intracellular bacteria that infect many wild and domestic animals and humans.The prevalence ofAnaplasma spp.in ixodid ticks of Qinghai Province is poorly understood.In this study,a total of 1104 questing adult ticks were investigated for the infection ofAnaplasma species.As a result,we demonstrated the total infection rates of 3.1,11.1,5.6,and 4.5%forA.phagocytophilum,A.bovis,A.ovis andA.capra,respectively.All of the tick samples were negative forA.marginale.The positive rates ofA.phagocytophilum,A.ovis andA.capra in different tick species were significantly different.The positive rates ofA.capra andA.bovis in the male ticks were significantly higher than that in the female ticks.Sequence analysis ofA.ovis showed 99.5-100%identity to the previous reported isolates.The sequences ofA.phagocytophilum had 100%identity to strains Ap-SHX21,JC3-3 and ZAM dog-181 from sheep,Mongolian gazelles,and dogs.Two genotypes ofA.capra were found based on 16S rRNA,citrate synthase(gltA)gene and heat shock protein(groEL)gene analysis.In conclusion,A.bovis,A.ovis,A.phagocytophilum,andA.capra were present in the ticks in Qinghai Province.Anaplasma infection is associated with tick species,gender and distribution.These data will be helpful for understanding prevalence status ofAnaplasma infections in ticks in Qinghai-Tibet Plateau.

Binding of bacterial secondary messenger molecule c di-GMP is a STING operation

Initial skirmishes between the host and pathogen result in spillage of the contents of the bacterial cell.Amongst the spillage,the secondary messenger molecule,cyclic dimeric guanosine monophosphate(c di-GMP),was recently shown to be bound by stimulator of interferon genes(STING).Binding of c di-GMP by STING activates the Tank Binding Kinase(TBK1)mediated signaling cascades that galvanize the body’s defenses for elimi-nation of the pathogen.In addition to c di-GMP,STING has also been shown to function in innate immune re-sponses against pathogen associated molecular pat-terns(PAMPs)originating from the DNA or RNA of pathogens.The pivotal role of STING in host defense is exemplified by the fact that STING-/-mice die upon infection by HSV-1.Thus,STING plays an essential role in innate immune responses against pathogens.This opens up an exciting possibility of targeting STING for development of adjuvant therapies to boost the im-mune defenses against invading microbes.Similarly,STING could be targeted for mitigating the inflamma-tory responses augmented by the innate immune sys-tem.This review summarizes and updates our current understanding of the role of STING in innate immune responses and discusses the future challenges in de-lineating the mechanism of STING-mediated responses.

Protein-protein complexation in bioluminescence

In this review we summarize the progress made towards understanding the role of protein-protein interactions in the function of various bioluminescence systems of marine organisms,including bacteria,jellyfish and soft corals,with particular focus on methodology used to detect and characterize these interactions.In some bioluminescence systems,protein-protein interactions involve an“accessory protein”whereby a stored substrate is efficiently delivered to the bioluminescent enzyme luciferase.Other types of complexation mediate energy transfer to an“antenna protein”altering the color and quantum yield of a bioluminescence reaction.Spatial structures of the complexes reveal an important role of electrostatic forces in governing the corresponding weak interactions and define the nature of the interaction surfaces.The most reliable structural model is available for the protein-protein complex of the Ca2+-regulated photoprotein clytin and green-fluorescent protein(GFP)from the jellyfish Clytia gregaria,solved by means of Xray crystallography,NMR mapping and molecular docking.This provides an example of the potential strategies in studying the transient complexes involved in bioluminescence.It is emphasized that structural studies such as these can provide valuable insight into the detailed mechanism of bioluminescence.

Crystal structure of a novel non-Pfam protein PF2046 solved using low resolution B-factor sharpening and multi-crystal averaging methods

Sometimes crystals cannot diffract X-rays beyond 3.0Åresolution due to the intrinsic flexibility associated with the protein.Low resolution diffraction data not only pose a challenge to structure determination,but also hamper interpretation of mechanistic details.Crystals of a 25.6 kDa non-Pfam,hypothetical protein,PF2046,diffracted X-rays to 3.38Åresolution.A combination of SeMet derived heavy atom positions with multiple cycles of B-factor sharpening,multi-crystal averaging,restrained refinement followed by manual inspection of electron density and model building resulted in a final model with a R value of 23.5(R_(free)=24.7).The asymmetric unit was large and consisted of six molecules arranged as a homodimer of trimers.Analysis of the structure revealed the presence of a RNA binding domain suggesting a role for PF2046 in the processing of nucleic acids.

Structural insights into the activation initiation of full-length mGlu1

Dear Editor,Glutamate is the main excitatory neurotransmitter in the human brain,and it exerts diverse responses through ionotropic glutamate receptors(iGluRs)and metabotropic glutamate receptors(mGluRs)(Nakanishi and Masu,1994).mGluRs are members of the C family of GPCRs,and are divided into three groups based on G protein coupling,sequence homology,and ligand selectivity(Stansley and Conn,2019).mGlu1 and mGlu5 belong to group I and predominantly couple to Gq/11.

Structural and functional analyses of human DDX41 DEAD domain

Dear Editor, DEAD-box proteins, which are named after the strictly con- served amino acid sequence Asp-Glu-Ala-Asp, were first identified as a distinct family in the late 1980s when alignments based on eight homologues of the yeast elF4A highlighted the presence of several conserved motifs （Linder et al., 1989）.