bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human clinical study of an intranasal spray of a cocktail containing two synergetic antibodies neutralizes Omicron BA.4/5
Authors: Zhang Xinghai , Luo Feiyang , Zhang Huajun , Guo Hangtian , Zhou Junhui , Li Tingting , Chen Shaohong , Song Shuyi , Shen Meiying , Wu Yan , Gao Yan , Han Xiaojian , Wang Yingming , Hu Chao , Zhao Xiaodong , Guo Huilin , Zhang Dazhi , Lu Yuchi , Wang Wei , Wang Kai , Tang Ni , Jin Tengchuan , Ding Menglu , Luo Shuhui , Lin Cuicui , Lu Tingting , Lu Bingxia , Tian Yang , Yang Chengyong , Cheng Guofeng , Yang Haitao , Jin Aishun , Ji Xiaoyun , Gong Rui , Chiu Sandra , Huang Ailong 
Published: March 2023

AbstractNeutralizing monoclonal antibodies (NAbs) with prophylactic and therapeutic efficacy have demonstrated fundamental importance in the control of SARS-CoV-2 transmission. However, their wide application has been largely limited by high cost and inconvenience in administration. Here, we developed an intranasal spray containing two synergetic human NAbs that could broadly neutralize the emerging Omicron variants in vitro. A unique synergetic neutralizing mechanism was identified that the two NAbs bound to exclusive epitopes on the RBD and structurally compensate each other in blocking the Spike-ACE2 interaction. Importantly, when given at low dosages for three consecutive days through the intranasal mucosal route, this cocktail showed significant improvement in the emergency preventive and therapeutic effects in hamsters challenged with authentic Omicron BA.1. Further, we performed an investigator-initiated trail in healthy volunteers (ChiCTR2200066525) to study the safety and pharmacokinetics of the antibody cocktail administrated as nasal spray. The nasal spray is generally safe and well tolerated without treatment related severe abnormal effects. The antibody cocktail nasal spray demonstrated nasal concentrations higher than the IC90of neutralization activity against Omicron BA.4/5 even at 24 hours post dosing. Furthermore, nasal samples from the study subjects demonstrated potent neutralization activity against Omicron BA.4/5 in an ex vivo pseudovirus neutralization assay. Together, we provide a novel approach for NAb regimens, a potentially highly effective product with broad applicable perspective in depressing the infection risk of new epidemic variant and ameliorating the heavy medical burden of hospital.One Sentence SummaryAn intranasal spray of two synergetic antibodies cocktail neutralizing Omicron BA.4/5 and an initial clinical evaluation in healthy volunteers.
A syntelog-based pan-genome provides insights into rice domestication and de-domestication
Authors: Dongya Wu , Xie Lingjuan , Sun Yanqing , Huang Yujie , Jia Lei , Dong Chenfeng , Shen Enhui , Ye Chu-Yu , Qian Qian , Fan Longjiang 
Published: March 2023

AbstractAsian rice is one of the world’s most widely cultivated crops. Large-scale resequencing analyses have been undertaken to explore the domestication and de-domestication genomic history of Asian rice, but the evolution of rice is still under debate. Here, we construct a syntelog-based rice pan-genome by integrating and merging 74 high-accuracy genomes based on long-read sequencing, encompassing all ecotypes and taxa ofOryza sativaandOryza rufipogon. Analyses of syntelog groups illustrate subspecies divergence in gene presence-and-absence and haplotype composition and identify massive genomic regions putatively introgressed from ancient Geng/japonicato ancient Xian/indicaor its wild ancestor, including almost all well-known domestication genes and a 4.5-Mb centromere-spanning block, supporting a single domestication event in rice. Genomic comparisons between weedy and cultivated rice highlight the contribution from wild introgression to the emergence of de-domestication syndromes in weedy rice. This work highlights the significance of inter-taxa introgression in shaping diversification and divergence in rice evolution and provides an exploratory attempt by utilizing the advantages of pan-genomes in evolutionary studies.
Molecular understanding of anthocyanin biosynthesis activated by PAP1 in engineered redArtemisia annuacells and regulation of 2, 4-dichlorophenoxyacetic acid
Authors: Dong Yilun , Li Mingzhuo , Cruz Bryanna , Ye Emily , Zhu Yue , Li Lihua , Xu Zhengjun , Xie De-Yu 
Published: March 2023

AbstractArtemisia annuais an effective antimalarial medicinal crop. We have established anthocyanin-producing red cell cultures from this plant with the overexpression ofProduction of Anthocyanin Pigment 1(PAP1) encoding a R2R3MYB transcription factor. To understand the molecular mechanism by which PAP1 activated the entire anthocyanin pathway, we mined the genomic sequences ofA. annuaand obtained eight promoters of the anthocyanin pathway genes. Sequence analysis identified four types of AC cis-elements from six promoters, the MYB response elements (MRE) bound by PAP1. In addition, six promoters were determined to have at least one G-Box cis-element. Eight promoters were cloned for activity analysis. Duel luciferase assays showed that PAP1 significantly enhanced the promoting activity of seven promoters, indicating that PAP1 turned on the biosynthesis of anthocyanins via the activation of these pathway gene expression. To understand how 2,4-dichlorophenoxyacetic acid (2,4-D), an auxin, regulates the PAP1-activated anthocyanin biosynthesis, five different concentrations (0, 0.05, 0.5, 2.5, and 5 μM) were tested to characterize anthocyanin production and profiles. The resulting data showed that the concentrations tested decreased the fresh weight of callus growth, anthocyanin levels, and the production of anthocyanins per petri dish. HPLC-qTOF-MS/MS based profiling showed that these concentrations did not alter anthocyanin profiles. Real time RT-PCR was completed to characterize the expressionPAP1and four representative pathway genes. The results showed that the five concentrations reduced the expression levels of the constitutivePAP1transgene and three pathway genes significantly and eliminated chalcone synthase gene in expression either significantly or slightly. These data indicate that the constitutivePAP1expression depends on gradients added in the medium. Based on these findings, the regulation of 2,4-D is discussed for anthocyanin engineering in red cells ofA. annua.ConclusionPromoters of eight anthocyanin pathway genes were cloned. Four types of AC cis-elements were identified from six promoters and G-Box elements were also determined from six promoters. PAP1 enhanced the activity of eight promoters. 2,4-D downregulated the expression of the constitutive PAP1 transgene leading to the decrease the biosynthesis of anthocyanins.
Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients
Authors: Abul-Husn Noura S. , Marathe Priya N. , Kelly Nicole R. , Bonini Katherine E. , Sebastin Monisha , Odgis Jacqueline A. , Abhyankar Avinash , Brown Kaitlyn , Di Biase Miranda , Gallagher Katie M. , Guha Saurav , Ioele Nicolette , Okur Volkan , Ramos Michelle A. , Rodriguez Jessica E. , Rehman Atteeq U. , Thomas-Wilson Amanda , Edelmann Lisa , Zinberg Randi E. , Diaz George A. , Greally John M. , Jobanputra Vaidehi , Suckiel Sabrina A. , Horowitz Carol R. , Wasserstein Melissa P. , Kenny Eimear E. , Gelb Bruce D. 
Published: March 2023

AbstractPurposeAdoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions.MethodsProbands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design.Results645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P< .001). Yield was greater for GSvs. TGPs in Hispanic/Latino(a) (17.2%vs. 9.5%,P< .001) and White/European American (19.8%vs. 7.9%,P< .001), but not in Black/African American (11.5%vs. 7.7%,P= .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%)vs. White/European American (47.6%;P= .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS.ConclusionGS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.
Evidence of reduced inhibition in older adults with a history of repetitive brain trauma. A transcranial magnetic stimulation study
Authors: Pearce Alan J , Kidgell Dawson J , Fraser Ashlyn K , Rist Billymo , Tallent Jamie 
Published: March 2023

AbstractInternational concern regarding the association between repetitive neurotrauma in sport and long term concerns with ageing continues. While previous studies have reported older (i.e. over 50 years) our study describes corticomotor changes across the lifespan between retired contact sport athletes, between the ages of 30 and 70 years. Retired athletes, minimum five years retired, (n=152; 48.6±9.0 years) and age-matched controls (n=72; 47.8±9.5 years) were assessed using single and paired-pulse transcranial magnetic stimulation (TMS) for active motor threshold (aMT), motor evoked potential and cortical silent period duration (expressed as MEP:cSP ratio), and short- and long-interval intracortical inhibition (SICI and LICI). Age-matched controls showed significant moderate correlations for MEP:cSP ratios at 130% (rho=0.48), 150% (rho=0.49)and 170% aMT (rho=0.42; allp<0.001) and significant but small negative correlation for SICI (rho=-0.27;p=0.030), and moderate negative correlation for LICI (rho=-0.43;p<0.001). Further, group-wise correlation analysis shows significant stronger corelations (allp<0.05) in the control for each variable than in the retired players. This study is the first to characterise corticomotor differences between retired athletes and age matched controls across the lifespan. in those with a history of repetitive head trauma and provides a foundation for further work to utilise TMS as a prodromal marker useful in supplementing neuropsychological assessment for traumatic encephalopathy syndrome which currently lacks physiological biomarkers.
Thermodynamic and kinetic analysis of the LAO binding protein and its isolated domains reveal non-additivity in stability, folding, and function
Authors: Vergara Renan , Berrocal Tania , Mejía Eva Isela Juárez , Romero-Romero Sergio , Velázquez-López Isabel , Pulido Nancy O. , López Sanchez Haven A. , Silva Daniel-Adriano , Costas Miguel , Rodríguez-Romero Adela , Rodríguez-Sotres Rogelio , Sosa-Peinado Alejandro , Fernández-Velasco D. Alejandro 
Published: March 2023

AbstractSubstrate-binding proteins (SBP) are used by organisms from the three domains of life for transport and signaling. SBPs are composed of two domains that collectively trap ligands with high affinity and selectivity. To explore the role of the domains and the integrity of the hinge region between them in the function and conformation of SBPs, here we describe the ligand binding, conformational stability, and folding kinetics of the Lysine Arginine Ornithine binding protein (LAO) fromSalmonella thiphimuriumand constructs corresponding to its two independent domains. LAO is a class II SBP formed by a continuous and a discontinuous domain. Contrary to the expected behavior based on their connectivity, the discontinuous domain shows a stable native-like structure that binds L-arginine with moderate affinity, whereas the continuous domain is barely stable and shows no detectable ligand binding. Regarding folding kinetics, studies of the entire protein revealed the presence of at least two intermediates. While the unfolding and refolding of the continuous domain exhibited only a single intermediate and simpler and faster kinetics than LAO, the folding mechanism of the discontinuous domain was complex and involved multiple intermediates. These findings suggest that in the complete protein the continuous domain nucleates folding and that its presence funnels the folding of the discontinuous domain avoiding nonproductive interactions. The strong dependence of the function, stability, and folding pathway of the lobes on their covalent association, is most likely the result of the coevolution of both domains as a single unit.
Non-catalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia
Authors: Gonskikh Yulia , Stoute Julian , Shen Hui , Budinich Krista , Pingul Bianca , Schultz Kollin , Elashal Heidi , Marmorstein Ronen , Shi Junwei , Liu Kathy Fange 
Published: March 2023

AbstractSeveral rRNA modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18SrRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a non-catalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mis-localizes DIMT1 to the nucleoplasm, in contrast with the primarily nucleolar localization of wild-type DIMT1. Mechanistically, rRNA binding is required for DIMT1 to undergo liquid-liquid phase separation, which explains why the distinct nucleoplasm localization of the rRNA-binding deficient DIMT1. Re-expression of wild-type or a catalytically inactive mutant E85A, but not the rRNA-binding deficient DIMT1, supports AML cell proliferation. This study provides a new strategy to target DIMT1-regulated AML proliferation via targeting this essential non-catalytic region.
Dopamine neurons govern olfactory-gated infant begging behavior
Authors: Butler Julie M. , Singh Devraj , Baker Penelope , Edwards Scott V. , Summers Kyle , O’Connell Lauren A. 
Published: March 2023

AbstractAltricial young of many species beg parents for the nutrients required for healthy development. From human crying to begging chicks, young expend precious energy reserves to communicate their hunger. Despite repeated independent evolutionary origins, the neural basis of parent-directed communication by infants is unknown. Here, we examined the sensory and neural basis of begging behavior in tadpoles of the monogamous and biparental Mimetic poison frog (Ranitomeya imitator). In this species, tadpoles beg parents for egg meals by dancing. We used this robust motor display to determine that tadpoles use multimodal cues for caregiver recognition, where olfactory cues are necessary for caregiver recognition while visual cues provide an orientation goal. We found that dopamine related brain regions have higher neural activity in begging tadpoles and that dopamine signaling had opposing modulatory effects through D1 and D2 family receptors, similar to swimming behavior in other tadpole species. We then identified caudal posterior tuberculum dopamine neurons as more active during begging behavior and sensitive to caregiver olfactory cues. Projections of these dopaminergic neurons to the spinal accessory motor nucleus are required for begging displays. These findings support the idea that dopamine regulates olfactory-guided parental recognition in young and opens many avenues for studying how new communication behaviors can evolve from ancestral motor circuits.
The CARD8 inflammasome drives CD4+T-cell depletion in HIV-1 infection
Authors: Wang Qiankun , Shan Liang 
Published: March 2023

AbstractCD4+T-cell depletion is the root cause of acquired immunodeficiency syndrome (AIDS). How HIV depletes CD4+T cells in humans remains unknown because vast majority of the dying CD4+T cells in patients are uninfected. Burgeoning evidence supports the hypothesis that non-productive HIV-1 infection triggers CD4+T-cell depletion in the course of pathogenic HIV and SIV infections. Here, we report that the CARD8 inflammasome is activated immediately after HIV-1 entry by the viral protease encapsulated in the incoming HIV-1 particles. Sensing of HIV-1 protease activity by the CARD8 inflammasome leads to rapid pyroptosis of quiescent CD4+T cells without productive viral infection. In humanized mice reconstituted with a CARD8-deficient immune system, CD4+T-cell loss is delayed despite increased levels of HIV-1 replication. Our study suggests that the CARD8 inflammasome drives CD4+T-cell depletion and disease progression through rapid sensing of HIV-1 particles.
Enzymatic assay for UDP-GlcNAc and its application in the parallel assessment of substrate availability and protein O-GlcNAcylation
Authors: Sunden Marc , Upadhyay Divya , Banerjee Rishi , Sipari Nina , Fellman Vineta , Kallijärvi Jukka , Purhonen Janne 
Published: March 2023

AbstractO-linked N-acetylglucosaminylation (O-GlcNAcylation) is a ubiquitous and dynamic yet still relatively poorly understood non-canonical glycosylation of intracellular proteins. Several vital branches of metabolism converge at the hexosamine biosynthetic pathway (HBP) to produce the substrate for protein O-GlcNAcylation the uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Availability of this metabolite is considered a key regulator of O-GlcNAcylation. Yet UDP-GlcNAc concentrations are rarely reported in studies exploring the HBP and O-GlcNAcylation, most likely because the methods to measure it restrict to specialized chromatographic procedures. To overcome this limitation, we introduce here an enzymatic method to quantify cellular and tissue UDP-GlcNAc. The method is based on O-GlcNAcylation of a substrate peptide by recombinant O-linked N-acetylglucosamine transferase (OGT) and detection of the modification with a specific antibody. The assay can be performed in dot blot or microplate formats. The key to successful assay was the removal of strong inhibition of OGT by the reaction side product, uridine diphosphate (UDP). We applied the assay to provide the first systematic report of UDP-GlcNAc concentrations in mouse tissues and cultured cells. Furthermore, we show how changes in UDP-GlcNAc levels correlate with O-GlcNAcylation and the expression of OGT and O-GlcNAcase (OGA).
Effects of phase encoding direction on test-retest reliability of human functional connectome
Authors: Cao Hengyi , Barber Anita D. , Rubio Jose M. , Argyelan Miklos , Gallego Juan A. , Lencz Todd , Malhotra Anil K. 
Published: March 2023

AbstractThe majority of human connectome studies in the literature based on functional magnetic resonance imaging (fMRI) data use either an anterior-to-posterior (AP) or a posterior-to-anterior (PA) phase encoding direction. However, whether and how phase encoding direction would affect test-retest reliability of functional connectome is unclear. Here, in a sample of healthy subjects with two sessions of fMRI scans separated by 12 weeks (two runs per session, one with AP, the other with PA), we tested the influence of phase encoding direction on global and nodal connectivity in the constructed brain networks. All data underwent the state-of-the-art Human Connectome Project (HCP) pipeline to correct for phase-encoding-related distortions before entering analysis. We found that at the global level, the PA scans showed significantly higher intraclass correlation coefficients (ICCs) for global connectivity compared with AP scans, which was particularly prominent when using the Seitzman-300 atlas (versus the CAB-NP-718 atlas). At the nodal level, regions most strongly affected by phase encoding direction were consistently mapped to the cingulate cortex and temporal lobe, with significantly higher ICCs during PA scans compared with AP scans, regardless of atlas. Further, we demonstrated that the observed reliability differences between phase encoding directions may relate to a similar effect on the reliability of temporal signal-to-noise ratio (tSNR) in the same regions (that PA scans were associated with higher reliability of tSNR than AP scans). Averaging the connectivity outcome from the AP and PA scans could slightly, but overall have limited value to boost the ICCs. These results were largely replicated in an independent, public dataset from the HCP-Early Psychosis (HCP-EP) study with a similar design but a much shorter scan session interval. Our findings suggest that phase encoding direction has significant effects on the reliability of connectomic estimates in fMRI studies. We urge that these effects need to be carefully considered in future neuroimaging designs, especially in longitudinal studies such as those related to neurodevelopment or clinical intervention.
Safety and Effectiveness of SA58 Nasal Spray against SARS-CoV-2 family transmission: an exploratory single-arm trial
Authors: Wang Lianhao , Song Rui , Hu Yuansheng , Zeng Gang , Sun Keqiang , Wang Jianfeng , Bao Yafeng , Zhou Yun’ao , Cheng Long , Wu Can , Pu Junfan , Han Xing , Wu Junlan , Jin Ronghua , Gao Qiang 
Published: March 2023

ABSTRACTBackgroundThis study has assessed the protective effect of a new Anti-COVID-19 SA58 Nasal Spray (SA58 Nasal Spray) against SARS-CoV-2 infection under continuous exposure.MethodsThis is an exploratory open-label, single-arm trial. To evaluate the safety and effectiveness of SA58 against SARS-CoV-2 family transmission, SA58 was administered to all enrolled family contacts at 3∼6-hour intervals. The frequency of administration and adverse events (AEs) were self-reported by online questionnaire, and RT-PCR tests were used to diagnose SARS-CoV-2 infection. The effectiveness was assessed in comparison to a contemporaneous control group whose information was collected through three follow-up visits. Total effectiveness and single-day effectiveness were calculated.ResultsThe incidence of SARS-CoV-2 infection was 62.9% (44/70) in the experimental group and 94.8% (343/362) in the control group. Using SA58 nasal spray at least three times per day could possibly reduce the risk of household transmission of SARS-CoV-2 by 46.7%∼56.5%. The incidence of AEs was 41.4% and the severity of all AEs was mild.ConclusionEven under the scenario of continuous exposure to SARS-CoV-2, SA58 nasal spray remained effective in blocking viral transmission and was well tolerated.
Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes
Authors: Adler Nina , Bahcheli Alexander T. , Cheng Kevin , Al-Zahrani Khalid N. , Slobodyanyuk Mykhaylo , Pellegrina Diogo , Schramek Daniel , Reimand Jüri 
Published: March 2023

ABSTRACTMutational signatures represent a footprint of tumor evolution and its endogenous and exogenous mutational processes. However, their functional impact on the proteome remains incompletely understood. We analysed the protein-coding impact of single base substitution signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) were strongly enriched in the signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes affect specific trinucleotide contexts to substitute serine and glutamic acid residues with stop codons. SGMs are enriched in cancer hallmark pathways and tumor suppressors such asTP53, FAT1, andAPC. Tobacco-driven SGMs in lung cancer correlate with lifetime smoking history and highlight a preventable determinant of these harmful mutations. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes contribute to protein loss-of-function, oncogenesis, and tumor heterogeneity, providing potential translational and mechanistic insights.