bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis
Authors: Curtis David 
Published: June 2022

Objective
The SCHEMA consortium has identified 10 genes in which protein-truncating variants (PTVs) confer a substantial risk of schizophrenia. This study aimed to determine whether carrying these PTVs was associated with neuropsychiatric impairment in the general population.

Methods
Phenotype fields of exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment.

Results
Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than that had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia, one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1.

Conclusion
Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well. This research has been conducted using the UK Biobank Resource.
DEVELOPMENT OF A COMPLEX INTERVENTION PACKAGE FOR DENGUE PREVENTION
Authors: Rajapaksha R. M. Nayani Umesha , Abeysena Chrishantha , Balasuriya Aindralal , Hetti Nimalka Pannila , Alagiyawanna Ajith , Manilgama Suranga 
Published: June 2022

ABSTRACTIntroductionComplex interventions are widely used in public health practices. Communication for Behavioural Impact (COMBI) is an effective method in planning for dengue control. The aim was to develop an intervention package to change behaviour to prevent dengue in a dengue endemic area of Sri Lanka.MethodsDevelopment of the intervention package was formulated according to two-phases including ‘Theoretical phase’ and ‘Modelling phase’ using a framework. World Health Organization 10 key steps in planning COMBI were followed in order to develop the present intervention package. A Situational-Market-Analysis-for-Communication-Keys (SMACK) was conducted in highest dengue endemic area in Kurunegala district to identify the Specific Behavioural Objectives (SBOO), which was conducted using mixed methodological approach followed by other steps of COMBI planning.ResultsThe overall goal was to decrease morbidity and mortality due to dengue illness. The SBOO for the plan were to improve the proper waste management practices according to the ‘3R concept’ (Reduce-Reuse-Re-cycling) and to improve the dengue prevention practices by 30 minutes of weekly cleaning. The strategies were to conduct a community empowerment program to improve waste management and weekly practices on dengue prevention by conducting administrative mobilization and public-relationship, public-advocacy, community mobilization, personal selling, advertising, and point of service promotion. The plan was finalized after taking expert opinion with the participation of stakeholders by the management team.ConclusionDeveloping a COMBI plan for an area after the identification of SBOO would be feasible to implement in order to empower the community to prevent dengue and improve community health services.
Persistent inflammation promotes endocannabinoid release and presynaptic cannabinoid 1 receptor desensitization
Authors: Bouchet Courtney A. , Janowsky Aaron , Ingram Susan L. 
Published: June 2022

SummaryPain therapies targeting the cannabinoid system are increasing with expansion of cannabis legalization but adaptations in the endogenous cannabinoid system during inflammatory pain could limit their efficacy. Presynaptic inhibition of GABA release mediated by cannabinoid 1 receptor (CB1R) agonists in the ventrolateral periaqueductal gray (vlPAG) is markedly reduced in male and female Sprague Dawley rats after persistent inflammation induced by Complete Freund’s Adjuvant (CFA). Inflammation results in increased endocannabinoid (eCB) synthesis and desensitization of presynaptic CB1Rs that is reversed by a GRK2/3 inhibitor, Compound 101. Despite CB1R desensitization, eCB activation of CB1Rs is maintained after inflammation. Depolarization-induced suppression of inhibition (DSI) in naïve animals is rapid and transient, but is prolonged in recordings after inflammation. Prolonged DSI is mediated by 2-arachidonoylglycerol (2-AG) indicating reduced monoacylglycerol lipase (MAGL) activity. These adaptations within the endogenous cannabinoid system have important implications for the development of future pain therapies targeting CB1Rs or MAGL.
SARS-CoV-2 breakthrough infection during the Delta-dominant epidemic and neutralizing antibodies against Omicron in comparison with the third dose of BNT162b2: a matched analysis
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Oshiro Yusuke , Inamura Natsumi , Mizoue Tetsuya , Konishi Maki , Takeuchi Junko S. , Horii Kumi , Ozeki Mitsuru , Sugiyama Haruhito , Mitsuya Hiroaki , Sugiura Wataru , Ohmagari Norio 
Published: June 2022

AbstractBackgroundLongitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron.MethodsParticipants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naïve and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during the follow-up. One control matched to each case was randomly selected from those who completed the booster vaccine and those who were unboosted by the follow-up. We used the generalized estimating equation model to compare live-virus NAb against Wuhan, Delta, and Omicron across groups.ResultsPersons who experienced breakthrough infection showed marked increases in NAb titers against Wuhan (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than that against Wuhan and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. In contrast, these titers largely decreased (Wuhan, Delta) or remained undetected (Omicron) at follow-up in infection-naïve and unboosted persons.ConclusionsSymptomatic breakthrough infection during the Delta predominant wave was associated with significant increases in NAb against Wuhan, Delta, and Omicron, similar to the third BNT162b2 vaccine. Given the much lower cross-NAb against Omicron than other virus types, however, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.Key pointsSymptomatic, not asymptomatic, SARS-CoV-2 breakthrough infection after the second BNT162b2 vaccination during the Delta-predominant wave enhanced neutralizing antibodies against Wuhan, Delta, and Omicron comparable to the three vaccine doses, although immunity against Omicron was much lower than Wuhan and Delta.
De Novo, Post-Zygotic, Inter-Tissue Mosaicism of Cell Autonomous ADNP Mutations in Autistic Individuals: Restricted Environmental Contribution
Authors: Mohiuddin Mohiuddin , Marusic Zlatko , Anicic Mirna , Anke Van Dijck , Cappuyns Elisa , Ludovico Rizzuti , Vitriolo Alessandro , Kleiman Gal Hacohen , Grigg Iris , Testa Giuseppe , Gozes Illana , Kooy R. Frank , Pearson Christopher E. 
Published: June 2022

ABSTRACTMany neurodevelopmental disorders, including autism, are caused by de novo mutations, that might arise as early as in the parental germline, during embryonic, fetal development, or as late as post-natal aging. Intra-tissue mutation-load variations could impact clinical presentation. One of the most common causes of autism is de novo mutations in ADNP. We developed an ultra-sensitive, highly-quantitative droplet digital PCR assay to determine ADNP mutation levels in patient tissues, including blood, teeth, hair, and 24 different tissues from a post-mortem de novo ADNP-mutated child (∼6-years old), including a transplanted liver from a non-mutant donor (retained for 22 months). Striking variations of ADNP mosaicism arose between tissues of the same individual. Mutation load differences were evident between post-mortem tissues, but not in the transplanted liver — supporting a cell autonomous genetic vulnerability to de novo mutations, arguing against a transferable environmentally-sensitive DNA damage/mutation predisposition. Variations between tissues suggest a developmental timing of the mutations. Most individuals showed at least one tissue with less than heterozygous mutations, where the presence of the homozygous non-mutant cells indicates that de novo ADNP mutations arose post-zygotically. Highly variable ADNP mosaicism between tissues, that within an individual can be less than heterozygous or approach homozygosity, indicate rapid ongoing post-zygotic, and possibly post-natal, somatic mutations, contributing to clinical variability.
Persistent Salmonella infections in humans are associated with mutations in the BarA/SirA regulatory pathway
Authors: Grote Alexandra , Piscon Bar , Manson Abigail L. , Livny Jonathan , Earl Ashlee M. , Gal-Mor Ohad 
Published: June 2022

ABSTRACTThe bacterial pathogen Salmonella enterica is able to establish persistent infections, evading antibiotics and the host immune system and providing a reservoir for recrudescence and transmission to new hosts. Non-typhoidal serovars (NTS) of S. enterica can establish and maintain symptomatic and asymptomatic long term human infections that may predispose carriers to inflammatory bowel diseases and cancer. Defining the adaptations and host-pathogen interactions enabling these persistent infections is key to devising more effective strategies to combat and prevent persistent bacterial infections. Using comparative genomics of 639 Salmonella NTS isolates belonging to 49 serovars that were longitudinally obtained from 256 salmonelosis patients during different stages of infection, we identified numerous genetic variations accruing over time in strains isolated from the same patient. Many of these changes were found in the same gene across multiple patients and serovars. Among these variant loci, genes encoding global transcriptional regulators were found to be the most commonly mutated between early and late same-patient isolates. Genetic changes in the SirA/BarA two-component regulatory system were particularly frequent, with mutations identified in 24 independent patients. Comparative RNA-Seq analysis revealed that distinct mutations in sirA/barA that arose independently in late isolates of multiple patients lead to significantly diminished expression of virulence-associated genes encoded in the Salmonella Pathogenicity Islands (SPIs) 1 and 4, many of which are known to be critical for host cell invasion and the production of enteritis. Using the salmonellosis mouse model we showed that these mutations in sirA/barA genes confer attenuated virulence in-vivo. Taken together, these data suggest that selection of mutations in the SirA/BarA pathway facilitates persistent Salmonella infection in humans, possibly by attenuating Salmonella virulence and its ability to cause inflammation.
Molecular atlas reveals the tri-sectional spinning mechanism of spider dragline silk
Authors: Hu Wenbo , Jia Anqiang , Ma Sanyuan , Zhang Guoqing , Wei Zhaoyuan , Lu Fang , Luo Yongjiang , Zhang Zhisheng , Sun Jiahe , Yang Tianfang , Xia TingTing , Li Qinhui , Yao Ting , Zheng Jiangyu , Jiang Zijie , Xia Qingyou , Wang Yi 
Published: June 2022

AbstractWe performed the first molecular atlas of natural spider dragline silk production using genome assembly for the golden orb-web spider Trichonephila clavata and multiomics defining for the segmented major ampullate (Ma) gland: Tail, Sac, and Duct. We uncovered a hierarchical biosynthesis of spidroins, organic acids, lipids, and chitin in the sectionalized Ma gland dedicated to fine silk constitution. The ordered secretion of spidroins was achieved by the synergetic regulation of epigenetic and ceRNA signatures for genomic group-distributed spidroin genes. Single-cellular and spatial RNA profiling identified ten cell types with partitioned functional division determining the tri-sectional organization of the Ma gland. Convergent evolution and genetic manipulation analyses further validated that this tri-sectional architecture of the silk gland was analogous in silk-spinning animals and inextricably linked with silk formation. Our study provided multiple levels of data that significantly expand the knowledge of spider dragline silk generation and may eventually benefit spider-inspired fiber innovations.
Nuclear auxin signaling is essential for organogenesis but not for cell survival in the liverwort Marchantia polymorpha
Authors: Suzuki Hidemasa , Kato Hirotaka , Iwano Megumi , Nishihama Ryuichi , Kohchi Takayuki 
Published: June 2022

AbstractAuxin plays pleiotropic roles in plant development via gene regulation upon perception by the receptors TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX (TIR1/AFBs). This nuclear auxin signaling (NAS) originated in the common ancestor of land plants. Although complete loss of TIR1/AFBs causes embryonic lethality in Arabidopsis thaliana, it is unclear whether the requirement for TIR1-mediated auxin perception in cell viability can be generalized. The model liverwort Marchanita polymorpha has a minimal NAS system with only a single TIR1/AFB, MpTIR1. Here we show by genetic, biochemical, and transcriptomic analyses that MpTIR1 functions as an evolutionarily conserved auxin receptor. Null mutants and conditionally knocked-out mutants of MpTIR1 were viable but incapable of forming any organs and grew as cell masses. Principal component analysis performed using transcriptomes at various developmental stages indicated that MpTIR1 is involved in the developmental transition from spores to organized thalli, during which apical notches containing stem cells are established. In Mptir1 cells, stem-cell- and differentiation-related genes were up- and down-regulated, respectively. Our findings suggest that, in M. polymorpha, NAS is dispensable for cell division but essential for three-dimensional body plans by establishing pluripotent stem cells for organogenesis, a derived trait of land plants.
High-resolution cross-species transcriptomic atlas of dorsal root ganglia reveals species-specific programs for sensory function
Authors: Jung Min , Dourado Michelle , Maksymetz James , Jacobson Amanda , Baca Miriam , Foreman Oded , Hackos David H. , Riol-Blanco Lorena , Kaminker Joshua S. 
Published: June 2022

ABSTRACTSensory neurons of the dorsal root ganglion (DRG) play a crucial role in maintaining tissue homeostasis by sensing and initiating responses to stimuli. While most preclinical studies of DRGs are conducted in rodents, much less is known about the mechanisms of sensory perception in primates. We generated a transcriptome atlas of mouse, guinea pig, cynomolgus monkey, and human DRGs using a framework that implements a common laboratory workflow and multiple data-integration approaches to generate high-resolution cross-species mappings of sensory neuron subtypes. Using our atlas, we identified conserved core modules highlighting subtype-specific biological processes related to inflammatory response. We also identified divergent expression of key genes involved in DRG function, suggesting species-specific adaptations. Among these, we validated that Tafa4, a member of the druggable genome, was expressed in distinct populations of DRG neurons across species, highlighting species-specific programs that are critical for therapeutic development.
The role of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis: GWAS perspective
Authors: Smieszek Sandra P. , Carlin Jesse L. , Xiao Changfu , Polymeropoulos Christos M. , Birznieks Gunther , Polymeropoulos Mihael H. 
Published: June 2022

AbstractGastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system are likely central to the pathogenesis of gastroparesis. Thus far, little is known about the underlying genetic risk factors for gastroparesis. To ascertain these genetic risk factors for gastroparesis we conducted the first large whole-genome sequencing genome-wide association study (GWAS) analysis of gastroparesis patients.The GWAS focused on idiopathic and diabetic gastroparesis cases as compared to matched controls as well as compared idiopathic versus diabetic cases. Amongst the top variants, we report a novel genetic risk variant for idiopathic gastroparesis - genetic association of the Solute Carrier Family 15 (SLC15) locus. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. SLC15A4 was shown to mediate M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress. The risk variant carriers have a significantly higher nausea score at baseline. We also delineated a number of statistically significant loci including novel ones as well as previously known loci such as HLA-DQB1 - rs9273363, variant associated with Type 1 diabetes..The GWAS picture that is emerging implicates the role of the machinery of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis. We suggest that macrophage polarization fate could lead to the destruction of the interstitial cells of Cajal which effectively leads to abnormal gastric emptying.
Mouse genomic rewriting and tailoring: synthetic Trp53 and humanized ACE2
Authors: Zhang Weimin , Golynker Ilona , Brosh Ran , Wudzinska Aleksandra M. , Zhu Yinan , Carrau Lucia , Damani-Yokota Payal , Khairallah Camille , Chalhoub Noor , Huang Emily , Ashe Hannah , Khanna Kamal M. , Maurano Matthew T. , Kim Sang Yong , tenOever Benjamin R. , Boeke Jef D. 
Published: June 2022

AbstractGenetically Engineered Mouse Models (GEMMs) aid in understanding human pathologies and developing new therapeutics, yet recapitulating human diseases authentically in mice is challenging to design and execute. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences controlling spatiotemporal gene expression patterns and splicing to human diseases. It is thus apparent that including regulatory genomic regions during the engineering of GEMMs is highly preferable for disease modeling, with the prerequisite of large-scale genome engineering ability. Existing genome engineering methods have limits on the size and efficiency of DNA delivery, hampering routine creation of highly informative GEMMs. Here, we describe mSwAP-In (mammalian Switching Antibiotic resistance markers Progressively for Integration), a method for efficient genome rewriting in mouse embryonic stem cells. We first demonstrated the use of mSwAP-In for iterative genome rewriting of up to 115 kb of the Trp53 locus, as well as for genomic humanization of up to 180 kb ACE2 locus in response to the COVID-19 pandemic. Second, we showed the hACE2 GEMM authentically recapitulated human ACE2 expression patterns and splicing, and importantly, presented milder symptoms without mortality when challenged with SARS-CoV-2 compared to the K18-ACE2 model, thus representing a more authentic model of infection.
Single-base precision design of CRISPR-Cas13b enables systematic silencing of oncogenic fusions
Authors: Hu Wenxin , Kumar Amit , Qi Shijiao , Sadras Teresa , Casan Joshua ML , Ma David , Brown Lauren M , Haber Michelle , Voskoboinik Ilia , Trapani Joseph A , Ekert Paul G , Fareh Mohamed 
Published: June 2022

ABSTRACTPrecision oncology programs can rapidly identify oncogenic gene fusions in individual patients1–3. However, despite their established oncogenic status, the vast majority of gene fusions remain ‘undruggable’ due to the lack of specific inhibitory molecules4, 5. Here, we establish PspCas13b, a poorly characterized programmable RNA nuclease, as a versatile tool to silence various oncogenic fusion transcripts. Our Single-Base Tiled crRNA screens (SiBTil), unbiased computational analysis, and comprehensive spacer-target mutagenesis revealed key determinants of PspCas13b activity. De novo design of crRNAs harbouring basepaired or mismatched guanosine bases at key spacer positions greatly enhances the silencing efficacy of otherwise inefficient crRNAs, expanding the targeting spectrum of this enzyme. We also reveal the interface between mismatch tolerance and intolerance, which unlocks an unexpected single-base precision targeting capability of this RNA nuclease. Notably, our de novo design principles enable potent and selective silencing of various gene fusion transcripts and their downstream oncogenic networks, without off-targeting of non-translocated variants that share extensive sequence homology. We demonstrate that PspCas13b targeting the breakpoint of fusion transcripts enables efficient suppression of ancestral and single-nucleotide mutants (e.g. BCR-ABL1 T315I) that often drive clinical cancer relapse. Collectively, this study provides new design principles for PspCas13b programming to specifically recognise and degrade any ‘undruggable’ fusion oncogenic transcript, thus providing a new conceptual framework for personalized oncology.
Controlling stomatal aperture, a potential strategy for managing plant bacterial disease
Authors: Sakata Nanami , Ino Taiki , Hayashi Chinatsu , Ishiga Takako , Ishiga Yasuhiro 
Published: June 2022

AbstractBacterial blight of crucifers caused by Pseudomonas cannabina pv. alisalensis (Pcal) inflicts great damage on crucifer production. To explore efficient and sustainable strategies for Pcal disease control, we here investigated and screened for amino acids with reduced disease development. We found that exogenous foliar application with multiple amino acids reduced disease symptoms and bacterial populations in cabbage after spray-inoculation, but not syringe-inoculation. These results indicate that these amino acids showed a protective effect before Pcal entered plants. Therefore, we observed stomatal responses, which is a main gateway for Pcal entry into the apoplast, after amino acid treatments, and found several amino acids induce stomatal closure. Moreover, our findings demonstrated that reducing stomatal aperture width can limit bacterial entry into plants, leading to reduced disease symptoms. Therefore, managing stomatal aperture can be a new powerful strategy for controlling bacterial disease.