bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of multigeneration history of suicidality on offspring’s neurodevelopment outcomes: evidence from the Adolescent Brain and Cognitive Development (ABCD) cohort
Authors: Wen Xue , Qu Diyang , Wu Guowei , Liu Dongyu , Wang Yuanyuan , Cui Zaixu , Zhang Xiaoqian , Chen Runsen 
Published: May 2022

SummaryBackgroundParent-child transmission of suicidal behaviors has been widely elucidated, while the three-generation family suicide risk paradigm remains to be explored. This longitudinal study aimed to examine the influences of family history of suicidality (FHoS) among two prior generations on offspring’s neurodevelopment.MethodsWe conducted a retrospective, longitudinal study using the Adolescent Brain Cognitive Development (ABCD) study data collected from 2016 to 2021. Participants were allocated into four groups according to their parents’ (Generation 1 [G1]) and grandparents’ (Generation 2 [G2]) history of suicidality (G1−G2−; G1+G2−; G1−/G2+; G1+/G2+). We estimated adjusted associations between FHoS and offspring’s suicide ideation (SI), psychopathology, impulsivity and brain cortical volumes while controlling for age, sex, parental education, household income and marital status.FindingsA total of 11,875 children aged 9-10 years were observed from baseline to 3-year follow-up. Compared to G1-G2-, higher odds of SI were observed for G1-G2+ (OR=1·99, 95% CI [1·54-2·56]) and G1+G2+ (2·25 [1·46-3·47]) by child-report. Higher odds of SI were also observed for G1+G2- (1·54 [1·12-2·12]), G1-G2+ (2·57 [1·89-3·48]) and G1+G2+ (2·70 [1·60-4·56]) by caregiver-report. Higher odds for psychopathology were also observed (1·47 [1·11-1·96]; 3·33 [2·57-4·33]; 5·44 [3·42-8·66]), while higher family suicide risk was associated with high impulsivity (B=1·32 [0·48-2·17]; 2·24 [1·32-3·15]; 2·26 [0·47-4·05]). Offspring in G1+G2-had higher cortical volumes in 12 brain regions, including the bilateral insula, temporal regions and occipital regions, which were also significantly associated with their lifetime SI.DiscussionA cumulative risk pattern of FHoS in two prior generations was found for offspring’s neurodevelopmental outcomes. Earlier preventive interventions are warranted to weaken the familial transmission of suicidal risk.
Segregation analysis of 17,425 population-based breast cancer families: evidence for genetic susceptibility and risk prediction
Authors: Li Shuai , MacInnis Robert J. , Lee Andrew , Nguyen-Dumont Tu , Dorling Leila , Carvalho Sara , Dite Gillian S. , Shah Mitul , Luccarini Craig , Wang Qin , Milne Roger L. , Jenkins Mark A. , Giles Graham G. , Dunning Alison M. , Pharoah Paul D.P. , Southey Melissa C. , Easton Douglas F. , Hopper John L. , Antoniou Antonis C. 
Published: May 2022

ABSTRACTRare pathogenic variants in known breast cancer susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM and TP53 using gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of pathogenic variants in known susceptibility genes and other unidentified major genes, and a normally distributed polygenic component. The proportion of familial variance explained by BRCA1, BRCA2, PALB2, CHEK2, ATM and TP53 was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessively inherited risk component with a combined genotype frequency of 1.7% (95% CI: 0.3-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38-95%) for homozygotes, and a polygenic variance of 1.27 (95% CI: 0.94-1.65) which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer susceptibility genes and improve breast cancer risk prediction, especially at a young age.
Omicron reactive multi protein specific CD4 T cells defines cellular immune response induced by inactivated virus vaccines
Authors: Lim Joey Ming Er , Hang Shou Kit , Hariharaputran Smrithi , Chia Adeline , Tan Nicole , Lee Eng Sing , Chng Edwin , Lim Poh Lian , Young Barnaby , Lye David Chien , Le Bert Nina , Bertoletti Antonio , Tan Anthony T 
Published: May 2022

SummaryUnlike mRNA vaccines based only on the Spike protein, inactivated SARS-CoV-2 vaccines should induce a diversified T cell response recognizing distinct structural proteins. Here we performed a comparative analysis of SARS-CoV-2 specific T cells in healthy individuals following vaccination with inactivated SARS-CoV-2 or mRNA vaccines. Relative to Spike mRNA vaccination, inactivated vaccines elicited a lower magnitude of Spike-specific T cells, but the combined Membrane, Nucleoprotein and Spike-specific T cell response was quantitatively comparable to the sole Spike T cell response induced by mRNA vaccines, and they efficiently tolerate the mutations characterizing the Omicron lineage. However, this multi-protein specific T cell response was not mediated by a coordinated CD4 and CD8 T cell expansion but by selected priming of CD4 T cells. These findings can help in defining the role of CD4 and CD8 T cells in the efficacy of the different vaccines to control severe COVID-19 after Omicron infection.
Adaptation delay causes a burst of mutations in bacteria responding to oxidative stress
Authors: Lagage Valentine , Chen Victor , Uphoff Stephan 
Published: May 2022

ABSTRACTUnderstanding the interplay between phenotypic plasticity and genetic adaptation is a long-standing focus of evolutionary biology. In bacteria, the oxidative stress response limits the formation of mutagenic reactive oxygen species (ROS) under diverse stress conditions. This suggests that the dynamics of the oxidative stress response are closely tied to the timing of the mutation supply that fuels genetic adaptation to stress. Here, we explored how mutation rates change in real-time in Escherichia coli cells during continuous hydrogen peroxide treatment in microfluidic channels. By visualising nascent DNA replication errors, we uncovered that sudden oxidative stress causes a burst of mutations. We developed a range of single-molecule and single-cell microscopy assays to determine how these mutation dynamics arise from phenotypic adaptation mechanisms. Signalling of peroxide stress by the transcription factor OxyR rapidly induces ROS scavenging enzymes. However, an adaptation delay leaves cells vulnerable to the mutagenic and toxic effects of hydroxyl radicals generated by the Fenton reaction. Resulting DNA damage is counteracted by a spike in DNA repair activities during the adaptation delay. Prior stress exposure or constitutive OxyR induction allowed cells to avoid the burst of mutations. Similar observations for alkylation stress show that mutation bursts are a general phenomenon associated with adaptation delays.
Phylogenomic diversity elucidates mechanistic insights into Lyme borreliae host association
Authors: Combs Matthew , Marcinkiewicz Ashley L. , Dupuis Alan P. , Davis April D. , Lederman Patricia , Nowak Tristan A. , Stout Jessica L. , Strle Klemen , Fingerle Volker , Margos Gabriele , Ciota Alexander T. , Diuk-Wasser Maria A. , Kolokotronis Sergios-Orestis , Lin Yi-Pin 
Published: May 2022

ABSTRACTHost association– the selective adaptation of pathogens to specific host species – evolves through constant interactions between host and pathogens, leaving a lot yet to be discovered on immunological mechanisms and genomic determinants. The causative agents of Lyme disease (LD) are spirochete bacteria composed of multiple species of the Borrelia burgdorferi sensu lato complex, including B. burgdorferi (Bb), the main LD pathogen in North America – a useful model for the study of mechanisms underlying host-pathogen association. Host adaptation requires pathogens’ ability to evade host immune responses, such as complement, the first-line innate immune defense mechanism. We tested the hypothesis that different host adapted phenotypes among Bb strains are linked to polymorphic loci that confer complement evasion traits in a host-specific manner. We first examined the survivability of 20 Bb strains in sera in vitro and/or bloodstream and tissues in vivo from rodent and avian LD models. Three groups of complement-dependent host association phenotypes emerged. We analyzed complement-evasion genes, identified a priori among all strains and sequenced and compared genomes for individual strains representing each phenotype. The evolutionary history of ospC loci is correlated with host-specific complement-evasion phenotypes, while comparative genomics suggests several gene families and loci are potentially involved in host association. This multidisciplinary work provides novel insights into the functional evolution of host adapted phenotypes, building a foundation for further investigation of the immunological and genomic determinants of host association.IMPORTANCEHost association is the phenotype that is commonly found in many pathogens that preferential survive in particular hosts. The Lyme disease (LD) causing agent, B. burgdorferi (Bb), is an ideal model to study host association, as Bb is mainly maintained in nature through rodent and avian hosts. A widespread yet untested concept posits that host association in Bb strains is linked to Bb functional genetic variation conferring evasion to complement, an innate defense mechanism in vertebrate sera. Here, we tested this concept by grouping 20 Bb strains into three complement-dependent host association phenotypes based on their survivability in sera and/or bloodstream and distal tissues in rodent and avian LD models. Phylogenomic analysis of these strains further correlated several gene families and loci, including ospC, with host-specific complement-evasion phenotypes. Such multifaceted studies thus pave the road to further identify the determinants of host association, providing mechanistic insights into host-pathogen interaction.
INSERT-seq enables high resolution mapping of genomically integrated DNA using nanopore sequencing
Authors: Ivančić Dimitrije , Mir-Pedrol Júlia , Jaraba-Wallace Jessica , Rafel Núria , Sanchez-Mejias Avencia , Güell Marc 
Published: May 2022

AbstractComprehensive characterization of genome engineering with viral vectors, transposons, CRISPR/Cas mediated DNA integration and other DNA editors remains relevant for their development and safe use in human gene therapy. Currently, described methods for measuring DNA integration in edited cells rely on short read based technologies. Due to the repetitive nature of the human genome, short read based methods can potentially overlook insertion events in repetitive regions. We modelled the impact of read length in resolving insertion sites, which suggested a significant drop in insertion site detection with shorter read length. Based on that, we developed a method that combines targeted amplification of integrated DNA, UMI-based correction of PCR bias and Oxford Nanopore long-read sequencing for robust analysis of DNA integration in a genome. This method, called INSERT-seq, is capable of detecting events occurring at a frequency of up to 0.1%. INSERT-seq presents a complete handling of all insertions independently of repeat size. The experimental pipeline improves the number mappable insertions at repetitive regions by 7.3% and repeats larger than the long read sequencing size are processed computationally to perform a peak calling in a repeat database. INSERT-seq is a simple, cheap and robust method to quantitatively characterise DNA integration in diverse ex-vivo and in-vivo samples.
Increasing evenness and stability in synthetic microbial consortia
Authors: Choudhary Ruhi , Mahadevan Radhakrishnan 
Published: May 2022

AbstractConstruction of successful synthetic microbial consortia will harbour a new era in the field of agriculture, bioremediation, and human health. Engineering communities is a complex, multi-dimensional problem with several considerations ranging from the choice of consortia members and spatial factors to genetic circuit performances. There has been a growing number of computational strategies to aid in synthetic microbial consortia design, but a framework to optimize communities for two essential properties, evenness and stability, is missing. We investigated how the structure of different social interactions (cooperation, competition, and predation) in quorum-sensing based circuits impacts robustness of synthetic microbial communities and specifically affected evenness and stability. Our proposed work predicts engineering targets and computes their operating ranges to maximize the probability of synthetic microbial consortia to have high evenness and high stability. Our exhaustive pipeline for rapid and thorough analysis of large and complex parametric spaces further allowed us to dissect the relationship between evenness and stability for different social interactions. Our results showed that in cooperation, the speed at which species stabilizes is unrelated to evenness, however the region of stability increases with evenness. The opposite effect was noted for competition, where evenness and stable regions are negatively correlated. In both competition and predation, the system takes significantly longer to stabilize following a perturbation in uneven microbial conditions. We believe our study takes us one step closer to resolving the pivotal debate of evenness-stability relationship in ecology and has contributed to computational design of synthetic microbial communities by optimizing for previously unaddressed properties allowing for more accurate and streamlined ecological engineering.
Increased microtubule lattice spacing correlates with selective binding of kinesin-1 in cells
Authors: de Jager Leanne , Jansen Klara I. , Kapitein Lukas C. , Förster Friedrich , Howes Stuart C. 
Published: May 2022

AbstractWithin the cell cargo is transported via motor proteins walking along microtubules. The affinity of motor proteins for microtubules is controlled by various layers of regulation like tubulin isoforms, post- translational modifications and microtubule associated proteins. Recently, the conformation of the microtubule lattice has also emerged as a potential regulatory factor, but to what extent it acts as an additional layer of regulation has remained unclear. In this study, we used cryo-correlative light and electron microscopy to study microtubule lattices inside cells. We find that, while most microtubules have a compacted lattice (∼41 Å), a significant proportion of the microtubule cores have expanded lattice spacings and that these lattice spacings could be modulated by the microtubule stabilizing drug Taxol. Furthermore, kinesin-1 predominantly binds microtubules with a more expanded lattice spacing (∼41.6 Å). The different lattice spacings present in the cell can thus act as an additional factor that modulates the binding of motor proteins to specific microtubule subsets.
rRNA methylation by Spb1 regulates the GTPase activity of Nog2 during 60S ribosomal subunit assembly
Authors: Sekulski Kamil , Cruz Victor Emmanuel , Weirich Christine S. , Erzberger Jan P. 
Published: May 2022

AbstractBiogenesis of the large ribosomal (60S) subunit involves the assembly of three rRNAs and 46 proteins, a process requiring approximately 70 ribosome biogenesis factors (RBFs) that bind and release the pre-60S at specific steps along the assembly pathway. The methyltransferase Spb1 and the K-loop GTPase Nog2 are essential RBFs that engage the rRNA A-loop during sequential steps in 60S maturation. Spb1 methylates the A-loop nucleotide G2922 and a catalytically deficient mutant strain (spb1D52A) has a severe 60S biogenesis defect. However, the assembly function of this modification is currently unknown. Here, we present cryo-EM reconstructions that reveal that unmethylated G2922 leads to the premature activation of Nog2 GTPase activity and capture a Nog2-GDP-AlF4- transition state structure that shows the direct involvement of unmodified G2922 in Nog2 GTPase activation. Intragenic and dosage suppressors indicate that the biogenesis defect in the spb1D52A strain is caused by reduced initial recruitment of Nog2 to early nucleoplasmic 60S intermediates. We propose that G2922 methylation levels regulate Nog2 stability on the pre-60S near the nucleolar/nucleoplasmic phase boundary, forming a kinetic checkpoint to regulate 60S production. Because multiple K-loop GTPases are involved in the assembly of ribosomes and other RNPs, our findings provide a template to study the role of RNA trans factors in modulating the regulatory functions of this important family of enzymes.
Post-mitotic centriole disengagement and maturation leads to centrosome amplification in polyploid trophoblast giant cells
Authors: Buss Garrison , Stratton Miranda B. , Milenkovic Ljiljana , Stearns Tim 
Published: May 2022

AbstractDNA replication is normally coupled with centriole duplication in the cell cycle. Trophoblast giant cells (TGCs) of the placenta undergo endocycles resulting in polyploidy but their centriole state is not known. We used a cell culture model for TGC differentiation to examine centriole and centrosome number and properties. Prior to differentiation, trophoblast stem cells (TSCs) have either two centrioles before duplication, or four centrioles after. We find that average nuclear area increases approximately 8-fold over differentiation, but most TGCs do not have more than four centrioles. However, these centrioles become disengaged, acquire centrosome proteins, and can nucleate microtubules. In addition, some TGCs undergo further duplication and disengagement of centrioles, resulting in substantially higher numbers. Live imaging revealed that disengagement and separation are centriole autonomous and can occur asynchronously. Centriole amplification, when present, occurs by the standard mechanism of one centriole generating one procentriole. PLK4 inihibition blocks centriole formation in differentiating TGCs but does not affect endocycle progression. In summary, centrioles in TGC endocycles undergo disengagement and conversion to centrosomes. This increases centrosome number, but to a limited extent compared with DNA reduplication.
Targeted directional kilobase sequence insertion by combining prime editing with recombinases or integrases
Authors: Jillette Nathaniel , Zhu Jacqueline Jufen , Cheng Albert Wu 
Published: May 2022

AbstractTargeted insertion of exogenous sequences to genomes is useful for therapeutics and biological research. While CRISPR/Cas technologies have been very efficient in gene knockouts by double-strand breaks (DSBs) followed by indel formation through non-homologous end-joining (NHEJ) repair pathway, the precise introduction of new sequences mainly rely on inefficient homology directed repair (HDR) pathways following Cas9-induced DSBs and are restricted to dividing cells. The recent invention of Prime Editing allows short sequences to be precisely inserted at target sites without DSBs. Here, we combine Prime Editing and sequence-specific recombinases and integrases to insert kilobase sequences directionally at target sites. This technique, called PRIMAS for Prime editing, Recombinase, Integrase-mediated Addition of Sequence, will expand our genome editing toolbox for targeted insertion of long sequences up to kilobases and beyond.
The ultradian transcriptome of the human prefrontal cortex and abnormalities in schizophrenia
Authors: Scott Madeline R. , Zong Wei , Ketchesin Kyle D. , Seney Marianne L. , Tseng George C. , Zhu Bokai , McClung Colleen A. 
Published: May 2022

AbstractTwelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in the human brain. Here we identify 12 h rhythms in transcripts which either peak at sleep/wake transitions (~9 AM/PM) or static times (~3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in schizophrenia, suggesting suboptimal timing of these essential processes that may contribute to cognitive deficits commonly found in schizophrenia.
A new perspective of learning in organisations: eight strategies to develop skills and core competencies
Authors: Kapoor Bhavya 
Published: May 2022

Purpose
The post-pandemic world of work portrays a changing learning landscape that allows employees to control their learning requirements. This study aims to show how organizations can facilitate effective learning environments to suit employees’ changing needs. It points out how they can facilitate personalized learning experiences for their employees by various means.

Design/methodology/approach
This study draws on existing literature in the domain of self-directed and self-managed learning. It also extensively reviews the practical training tactics adopted by organizations and learning and development leaders.

Findings
The most significant contribution of this study is highlighting that self-directed learning is not limited to being a function or an approach adopted by employees. There are various ways by which organizations can facilitate learning, encourage and also enable their workforce to own and drive their personal development for future job roles. This study lists eight new learning and development strategies, ranging from tactical to strategic, to facilitate personalized learning in organizations in the prevailing era of flexible working environments in which organizations embrace the hybrid model and offer better work-life integration.

Practical implications
By cultivating self-directed learning via described strategies, organizations can encourage employees to share performance ownership.

Originality/value
This study is a literature review that highlights the increasing proclivity of employees toward self-directed learning. It suggests new learning and development strategies that every organization should adopt to sustain the changed world order and expand the learning opportunities for its employees.