bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of Human Frontal Midline Theta by Neurofeedback: A Systematic Review and Quantitative Meta-Analysis
Authors: Pfeiffer Maria , Kübler Andrea , Hilger Kirsten
Published: November 2023

Human brain activity consists of different frequency bands associated with varying functions. Oscillatory activity of frontal brain regions in the theta range (4-8Hz) is linked to cognitive processing and can be modulated by neurofeedback - a technique where participants receive real-time feedback about their brain activity and learn to modulate it. However, criticism of this technique evolved, and high heterogeneity of study designs complicates a valid evaluation of its effectiveness. This meta-analysis provides the first systematic overview over studies attempting to modulate frontal midline theta with neurofeedback in healthy human participants. Out of 1431 articles screened, 14 studies were eligible for systematic review and 11 for quantitative meta-analyses. Studies were evaluated following the DIAD model and the PRISMA guidelines. A significant across-study effect of medium size (Hedges’g= .66; 95%-CI [−0.62, 1.73]) with substantial between-study heterogeneity (Q(16) = 167.43,p< .0001) was observed and subanalysis revealed effective frontal midline theta upregulation. We discuss moderators of effect sizes and provide guidelines for future research in this dynamic field.
Restoration of Cone Circuit Functionality in the Regenerating Adult Zebrafish Retina
Authors: Abraham Evelyn , Hartmann Hella , Yoshimatsu Takeshi , Baden Tom , Brand Michael
Published: November 2023

Unlike humans, teleosts like zebrafish exhibit robust retinal regeneration after injury from endogenous stem cells. However, understanding the functional recovery of the regenerated retina remains a challenge. In particular, it is unclear if regenerating cone-photoreceptors can regain physiological function and integrate correctly into post-synaptic circuits. To bridge this gap, we employed two-photon calcium imaging of living retina, focusing on photoreceptor responses before and after an intense light-induced lesion in the adult zebrafish retina. To assess the functional recovery of cones and their downstream circuits, we exploited the colour opponency in adult zebrafish cones. We find that UV cones exhibit an intrinsic Off-response to short-wavelength blue light, but an On-response to longer-wavelength green light, which depends on feedback signals from outer retinal circuits. Accordingly, we examined the presence and quality of Off-versus On-responses, to assess the functional recovery of cones and their correct integration into outer retinal circuits. We find that regenerated UV cones regain both Off-responses to short-wavelength and On-responses to long-wavelength within 3 months after light lesion. Hence, physiological circuit functionality is restored in regenerated cone photoreceptors, suggesting that inducing endogenous regeneration is a promising strategy for human retinal repair.

Graphical abstract
scLongTree: an accurate computational tool to infer the longitudinal tree for scDNAseq data
Authors: Khan Rituparna , Mallory Xian
Published: November 2023

A subclonal tree that depicts the evolution of cancer cells is of interest in understanding how cancer grows, prognosis and treatment of cancer.

Longitudinal single-cell DNA sequencing data (scDNA-seq) is the single-cell DNA sequencing data sequenced at different time points. It provides more knowledge of the order of the mutations than the scDNA-seq taken at only one time point, and thus facilitates the inference of the subclonal tree. There is only one existing tool LACE that can infer a subclonal tree based on the longitudinal scDNA-seq, and it is limited in accuracy and scale.

We presented scLongTree, a computational tool that can accurately infer the longitudinal subclonal tree based on the longitudinal scDNA-seq. ScLongTree can be scalable to hundreds of mutations, and outper-formed state-of-the-art methods SCITE, SiCloneFit and LACE on a comprehensive simulated dataset. The test on a real dataset SA501 showed that scLongTree can more accurately interpret the progres-sive growth of the tumor than LACE. ScLongTree is freely available onhttps://github.com/compbio-mallory/sclongitudinal infer.
The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons
Authors: Jones-Tabah Jace , He Kathy , Senkevich Konstantin , Karpilovsky Nathan , Deyab Ghislaine , Cousineau Yuting , Nikanorova Daria , Goldsmith Taylor , Pellitero Esther del Cid , Chen Carol X-Q. , Luo Wen , You Zhipeng , Abdian Narges , Pietrantonio Isabella , Goiran Thomas , Ahmad Jamil , Ruskey Jennifer A. , Asayesh Farnaz , Spiegelman Dan , Waters Cheryl , Monchi Oury , Dauvilliers Yves , Dupré Nicolas , Miliukhina Irina , Timofeeva Alla , Emelyanov Anton , Pchelina Sofya , Greenbaum Lior , Hassin-Baer Sharon , Alcalay Roy N. , Milnerwood Austen , Durcan Thomas M. , Gan-Or Ziv , Fon Edward A.
Published: November 2023

Variants in theCTSBgene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specificCTSBvariants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previousin vitrostudies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rareCTSBvariants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded byGBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction ofCTSBgene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereasCTSBgene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.
Synthetic Echocardiograms Generation Using Diffusion Models
Authors: Pellicer Alexandre Olive , Singh Yadav Amit Kumar , Bhagtani Kratika , Xiang Ziyue , Pizlo Zygmunt , Gradus-Pizlo Irmina , Delp Edward J.
Published: November 2023

An echocardiogram is a video sequence of a human heart captured using ultrasound imaging. It shows heart structure and motion and helps in diagnosis of cardiovascular diseases. Deep learning methods, which require large amounts of training data have shown success in using echocardiograms to detect cardiovascular disorders such as valvular heart disease. Large datasets of echocardiograms that can be used for machine learning training are scarce. One way to address this problem is to use modern machine learning generative methods to generate synthetic echocardiograms that can be used for machine learning training. In this paper, we propose a video diffusion method for the generation of echocardiograms. Our method uses a 3D selfattention mechanism and a super-resolution model. We demonstrate that our proposed method generates echocardiograms with higher resolution and with lesser artifacts, compared to existing echocardiogram generation methods.
Conversational Chemistry: A Novel Approach to Chemical Search and Property Prediction
Authors: Ben-Joseph JJ , Oates Tim
Published: November 2023

We have developed an approach to train a chemical property prediction model using both English and the SELFIES chemical language describing the structure of small, drug-like molecules. This model generates chemical embedding vectors, which we then use to train classification models. Our straightforward softmax classification model surpasses the commonly-used message passing neural network architecture in certain chemical property prediction tasks. Moreover, these chemical embedding vectors can be employed in other applications, such as building a chemical search engine that enables users to find new drugs with natural language queries (e.g., “low toxicity blood brain barrier permeable drug that inhibits HIV replication”).
Identification of genes with oscillatory expression in glioblastoma – The paradigm ofSOX2
Authors: Fu R.Z , Cottrell O , Cutillo L , Rowntree A , Zador Z , Wurdak H , Papalopulu N , Marinopoulou E.
Published: November 2023

Quiescence, a reversible state of cell-cycle arrest, is an important state during both normal development and cancer progression. For example, in glioblastoma (GBM) quiescent glioblastoma stem cells (GSCs) play an important role in re-establishing the tumour, leading to relapse. While most studies have focused on identifying differentially expressed genes between proliferative and quiescent cells as potential drivers of this transition, recent studies have shown the importance of protein oscillations in controlling the exit from quiescence of neural stem cells. Here, we have undertaken a genome-wide bioinformatic inference approach to identify genes whose expression oscillates and which may be good candidates for controlling the transition to and from the quiescent cell state in GBM. Our analysis identified, among others, a list of important transcription regulators as potential oscillators, including the stemness geneSOX2, which we verified to oscillate in quiescent GSCs. These findings expand on the way we think about gene regulation and introduce new candidate genes as key regulators of quiescence.
Functional brain networks are associated with both sex and gender in children
Authors: Dhamala Elvisha , Bassett Dani S. , Yeo B.T. Thomas , Homes Avram J.
Published: November 2023

Sex and gender are associated with human behavior throughout the lifespan and across health and disease, but whether they are associated with similar or distinct neural phenotypes is unknown. Here, we demonstrate that, in children, sex and gender are uniquely reflected in the intrinsic functional connectivity of the brain. Unimodal networks are more strongly associated with sex while heteromodal networks are more strongly associated with gender. These results suggest sex and gender are irreducible to one another not only in society but also in biology.
Emergence of the Novel Infectious bursal disease viruse Variant in Vaccinated Poultry Flocks in Egypt
Authors: Shahein Momtaz A. , Sultan Hesham A. , Zanaty Ali , Adel Amany , Mosaad Zienab , Said Dalia , Erfan Ahmed , Samy Mohamed , Selim Abdullah , Selim Karim , Naguib Mahmoud M. , Hassan Heba , Shazly Osama El , El-badiea Zeinab A. , Moawad Mahmoud K. , Samir Abdelhafez , Shahaby Mohamed El , Farghaly Eman , Eid Samah , Abdelaziz Mohamed N , Hamoud Mohamed M , Mehana Osama , Hagag Naglaa M. , Samy Ahmed
Published: November 2023

Infectious bursal disease viruses (IBDVs) have a profound impact on poultry production worldwide, directly causing mortality rates of up to 100%, and indirectly through their immunosuppressive effects. Since the emergence of the antigenically modified very virulent IBDV (vvIBDV) in Egypt in late 1999, the country has experienced recurrent outbreaks with high mortality rates and typical vvIBDV gross lesions. However, a notable shift occurred in 2023, characterized by a substantial increase in reported subclinical IBDV cases exhibiting atrophied bursa and associated immunosuppression. To assess the field situation, we examined samples from 21 farms in 2023 and 18 farms from 2021 and 2022, all of which experienced IBD outbreaks based on clinical diagnosis. These samples were submitted to our laboratory for confirmatory testing and subsequently subjected to VP2-HVR sequencing. Phylogenetic analysis revealed that all samples collected in 2021 and 2022 clustered with classical virulent strains and very virulent IBDV. In 2023, one sample clustered with the Egyptian vvIBDV, while one sample clustered with classic virulent IBDV, and the remaining 2023 samples clustered with the Chinese novel variant IBDV (nVarIBDV). The alignment of deduced amino acid sequences for VP2 revealed that all Egyptian classic virulent strains were similar to the Winterfield or Leukert strains. In contrast, vvIBDV strains exhibited two out of the three typical residues found in Egyptian antigenically atypical vvIBDV, namely Y220F and G254S, but not A321T, and one sample was identical to the European vvIBDV (emerged in 1989). Meanwhile, all variant strains recognized in the present study exhibited typical residues found in variant IBDV, in addition to the three conserved amino acid residues found only in Chinese variant IBDVs. However, all Egyptian variant strains showed a mutation at position 321 (321V), which represents the most exposed part of the capsid and is known to have a massive impact on IBDV antigenicity, with the exception of one sample that had 318G instead. This report highlights the emergence of a new variant IBDV clustered with the Chinese new variant in Egypt, causing bursa atrophy and spreading subclinically in broiler farms over a wide geographic distance, resulting in massive economic losses due to immunosuppression.
SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1αin pulmonary epithelial and endothelial cells
Authors: Ambrożek-Latecka Magdalena , Kozlowski Piotr , Hoser Grażyna , Bandyszewska Magdalena , Hanusek Karolina , Nowis Dominika , Gołąb Jakub , Grzanka Małgorzata , Piekiełko-Witkowska Agnieszka , Schulz Luise , Hornung Franziska , Deinhardt-Emmer Stefanie , Kozlowska Ewa , Skirecki Tomasz
Published: November 2023

Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger cell death and IL-1αrelease from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1αand IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1αas a potential novel component driving the pulmonary immunothromobosis in COVID-19.
Identifying genetic variants that influence the abundance of cell states in single-cell data
Authors: Rumker Laurie , Sakaue Saori , Reshef Yakir , Kang Joyce B. , Yazar Seyhan , Alquicira-Hernandez Jose , Valencia Cristian , Lagattuta Kaitlyn A , Mah-Som Annelise , Nathan Aparna , Powell Joseph E. , Loh Po-Ru , Raychaudhuri Soumya
Published: November 2023

Introductory Paragraph

To understand genetic mechanisms driving disease, it is essential but difficult to map how risk alleles affect the composition of cells present in the body. Single-cell profiling quantifies granular information about tissues, but variant-associated cell states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce GeNA (Genotype-Neighborhood Associations), a statistical tool to identify cell state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of scRNA-seq peripheral blood profiling from 969 individuals,1GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (p=1.96×10-11) associates with increased abundance of NK cells expressing TNF-α response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-TNF treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk.
Continuous evolution of user-defined genes at 1-million-times the genomic mutation rate
Authors: Rix Gordon , Williams Rory L. , Spinner Hansen , Hu Vincent J. , Marks Debora S. , Liu Chang C.
Published: November 2023

When nature maintains or evolves a gene’s function over millions of years at scale, it produces a diversity of homologous sequences whose patterns of conservation and change contain rich structural, functional, and historical information about the gene. However, natural gene diversity likely excludes vast regions of functional sequence space and includes phylogenetic and evolutionary eccentricities, limiting what information we can extract. We introduce an accessible experimental approach for compressing long-term gene evolution to laboratory timescales, allowing for the direct observation of extensive adaptation and divergence followed by inference of structural, functional, and environmental constraints for any selectable gene. To enable this approach, we developed a new orthogonal DNA replication (OrthoRep) system that durably hypermutates chosen genes at a rate of >10−4substitutions per basein vivo. When OrthoRep was used to evolve a conditionally essential maladapted enzyme, we obtained thousands of unique multi-mutation sequences with many pairs >60 amino acids apart (>15% divergence), revealing known and new factors influencing enzyme adaptation. The fitness of evolved sequences was not predictable by advanced machine learning models trained on natural variation. We suggest that OrthoRep supports the prospective and systematic discovery of constraints shaping gene evolution, uncovering of new regions in fitness landscapes, and general applications in biomolecular engineering.
ESMBind and QBind: LoRA, QLoRA, and ESM-2 for Predicting Binding Sites and Post Translational Modification
Authors: Schreiber Amelie
Published: November 2023

In this study we discuss the viability of applying protein language models to the problem of predicting bindings sites of protein sequences from single sequences alone using Low Rank Adaptation (LoRA) and Quantized Low Rank Adaptation (QLoRA). No Multiple Sequence Alignment (MSA) or structural information for the proteins was used. Moreover, using LoRA and QLoRA shows improved performance over vanilla full finetuning, and significantly helps in mitigating overfitting. Also, due to the efficiency of LoRA and QLoRA, we are able to train the larger ESM-2 models on modest hardware, making the method very attractive and accessible. We also note that this technique serves as an important regularization technique and serves to improve generalization of models on unseen data.
Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades
Authors: Dadonaite Bernadeta , Brown Jack , McMahon Teagan E , Farrell Ariana G , Asarnow Daniel , Stewart Cameron , Logue Jenni , Murrell Ben , Chu Helen Y. , Veesler David , Bloom Jesse D
Published: November 2023

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties that contribute to viral fitness such as ACE2 receptor binding and cell entry. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning to measure how >9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry, or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully impacted ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456, and 473—however, the antigenic impacts of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.
Neonatal Autonomic Regulation as a Predictor of Autism Spectrum Disorder in Very Preterm Infants
Authors: Bradshaw Jessica , O’Reilly Christian , Everhart Kayla C. , Dixon Elizabeth , Vinyard Amy , Tavakoli Abbas , Iskersky Victor , Dail Robin B.
Published: November 2023

Infants born preterm are at a significantly higher likelihood of having autism spectrum disorder (ASD). Preterm birth and ASD are both associated with neurological differences, notably autonomic nervous system (ANS) dysfunction, pointing to preterm ANS dysfunction as a potential pathway to ASD, particularly in VPT infants. In this study, a subset of very preterm (VPT) infants enrolled in a large, multisite clinical trial were enrolled in this study at birth (N=20). Continuous measures of minute-by-minute thermal gradients, defined by the difference between central and peripheral temperatures, and hour-by-hour abnormal heart rate characteristics (HRCs) were collected from birth-28 days (>40,000 samples/infant). Following NICU discharge, standardized measures of cognition, language, and motor skills were collected at adjusted ages 6, 9, and 12 months. At 12 months, assessments of social communication and early ASD symptoms were administered. Results suggest significant ASD concerns for half of the sample by 12 months of age. Neonatal abnormal HRCs were strongly associated with 12-month ASD symptoms (r=0.81, p<.01), as was birth gestational age (GA), birth weight (BW), and abnormal negative thermal gradients. ANS measures collected in the first month of neonatal life, more than a year prior to the ASD evaluation, were surprisingly strong predictors of ASD. This study highlights complementary ANS measures that describe how ANS dysfunction, likely resulting from an imbalance between the parasympathetic and sympathetic systems, may impact very early regulatory processes for neonates who later develop ASD. This finding offers a promising avenue for researching ANS-related etiological mechanisms and biomarkers of ASD.
Fibrosis and liver inflammation are key regulators of α1-acid glycoprotein fucosylation
Authors: Oltmanns Carlos , Bremer Birgit , Kusche Laura , Stål Per , Zenlander Robin , Tauwaldt Jan , Rydén Ingvar , Påhlsson Peter , Cornberg Markus , Wedemeyer Heiner
Published: November 2023

Background and Aims

There is an urgent need for new high-quality markers in the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2-bound α1-acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated S2-bound AGP for a predictive advantage in the early detection of HCC.

Methods

In a retrospective case-control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral agents (n=93), we measured S2-bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at treatment start, end of treatment and follow-up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). 31 patients chronically infected with HCV developed HCC after sustained virological response while 62 did not. In addition, samples of HBV, MASLD and HCC from different etiologies patients were measured.

Results

S2-bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2-bound AGP in early detection of HCC during treatment and follow-up. Interestingly, S2-bound AGP levels correlated with aspartate aminotransferase (ρ=0.56, p=9.5×10-15) and liver elastography (ρ=0.67, p=2.2×10-16). Of note, S2-bound AGP decreased in patients chronically infected with HCV after treatment-induced clearance of HCV.

Conclusion

Fibrosis and liver inflammation are key regulators in the fucosylation of AGP. The potential role of S2-bound AGP as a novel tumor marker requires further investigation.

Graphical abstract
Association of Genetic Variant in MC4R (rs17782313) Gene with Obesity and Other Health Behaviors among Selected Bangladeshi Population: A Population-based Case-control Study
Authors: Jhily Nusrat Jahan , Shill Lincon Chandra , Supti Dilara Akter , Munim Md Adnan , Rashid Rumana , Yeasmin Roksana , Alam Mohammad Rahanur
Published: November 2023

Background and Aims

This study aim to investigate the influence of a gene polymorphism (rs17782313) on obesity-related traits and biochemical parameters in the Bangladeshi population and the association between this polymorphism and lifestyle-related risk factors.

Methods

The study was carried out with 320 samples of which 160 were obese and 160 were healthy people. BMI, MUAC, waist and hip circumference, systolic and diastolic blood pressure, lipid profile, and other socio-demographic and anthropometric profile were accounted for to assess the metabolic properties which are associated with obesity. The tetra-primer Amplified Refractory Mutation System Polymerase chain reaction (ARMS-PCR) was used to genotype rs17782313 in the MC4R gene by using the isolated DNA from collected peripheral blood from the selected sample.

Result

The prevalence of hypertension, heart disease, and diabetes were significantly higher among the case group (p<.05) as compared with healthy people. BMI, waist circumference, and hip circumference were significantly higher among people carrying minor allele C (p<.05). We also found a significant difference in dominant (CC vs. CT+TT), co-dominant (CC vs. CT and TT), and recessive (TT vs. CC+CT) model between case and control group (p<.05), which may indicate that rs17782313 in MC4R significantly predict obesity.

Conclusion

In conclusion, this study shows the significant association of rs17782313 in MC4R with obesity and obesity-related other health problems. The study has to be conducted further in a broad population to establish a strong association.
High-throughput screening assay for PARP-HPF1 interaction inhibitors to affect DNA damage repair
Authors: Dhakar Saurabh S. , Galera-Prat Albert , Lehtiö Lari
Published: November 2023

ADP-ribosyltransferases PARP1 and PARP2 play a major role in DNA repair mechanism by detecting the DNA damage and inducing poly-ADP-ribosylation dependent chromatin relaxation and recruitment of repair proteins. Catalytic PARP inhibitors are used as anticancer drugs especially in the case of tumors arising from sensitizing mutations. Recently, a study showed that Histone PARylation Factor (HPF1) forms a joint active site with PARP1/2. The interaction of HPF1 with PARP1/2 alters the automodification site from Aspartate, Glutamate to Serine, which has been shown to be a key ADP-ribosylation event in the context of DNA damage. Therefore disruption of PARP1/2-HPF1 interaction could be an alternative strategy for drug development to block the PARP1/2 activity. In this study, we describe a FRET based high-throughput screening assay to screen inhibitor libraries against PARP-HPF1 interaction. We optimized the conditions for FRET signal and verified the interaction by competing the FRET pair in multiple ways. The assay is robust and easy to automate. Validatory screening showed the robust performance of the assay, and we discovered two compounds, Dimethylacrylshikonin and Alkannin, with µM inhibition potency against PARP1/2-HPF1 interaction. The assay will facilitate the discovery of inhibitors against HPF1-PARP1/2 complex and to develop potentially new effective anticancer agents.
Diurnal rhythm causes metabolic crises in the cyanobacterial mutants of c-di-AMP signalling cascade
Authors: Haffner Michael , Mantovani Oliver , Spät Philipp , Maček Boris , Hagemann Martin , Forchhammer Karl , Selim Khaled A.
Published: November 2023

In nature, the photoautotrophic lifestyle of cyanobacteria has to cope with the successive diurnal changes in light supply. Light supply throughout the day enables photosynthesis and glycogen biosynthesis, while night phases require the switch to a heterotrophic-like lifestyle relying on glycogen catabolism. We previously highlighted a unique function of the carbon control protein, SbtB, and its effector molecule c-di-AMP, for the nighttime survival of cyanobacteria through the regulation of glycogen anabolism. However, the extent to which c-di-AMP and SbtB impact the cellular metabolism for day-night survivability remained elusive. To gain better understanding of cellular processes regulated by SbtB or c-di-AMP, we compared the metabolomic and proteomic landscapes of ΔsbtBand the c-di-AMP-free (ΔdacA) mutants of the model strainSynechocystissp. PCC 6803. While our results indicate that the cellular role of SbtB is restricted to carbon/glycogen metabolism, the diurnal lethality of ΔdacAseems to be a sum of dysregulation of multiple metabolic processes. These processes include photosynthesis and redox regulation, which lead to elevated levels of intracellular ROS and glutathione. Further, we show an impact of c-di-AMP on central carbon as well as on nitrogen metabolism. Effects on nitrogen metabolism are linked to reduced levels of the global nitrogen transcription regulator NtcA and highlighted by an imbalance of the glutamine to glutamate ratio as well as reduced metabolite levels of the arginine pathway. We further identified the HCO3-uptake systems, BicA and BCT1 as novel SbtB targets, in agreement with its broader role in regulating carbon homeostasis.
Primary multistep phosphorelay activation comprises both cytokinin and abiotic stress responses in Brassicaceae
Authors: Mala Katrina Leslie Nicolas , Skalak Jan , Zemlyanskaya Elena , Dolgikh Vladislav , Jedlickova Veronika , Robert-Boisivon Helene S. , Havlicková Lenka , Panzarova Klara , Trtilek Martin , Bancroft Ian , Hejatko Jan
Published: November 2023

Multistep phosphorelay (MSP) signaling integrates hormonal and environmental signals to control plant development and adaptive responses. The type-ARESPONSE REGULATORs(RRAs), the downstream members of the MSP cascade and cytokinin primary response genes, are supposed to mediate primarily the negative feedback regulation of (cytokinin-induced) MSP signaling. However, the transcriptional data suggest the involvement ofRRAsin stress-related responses as well. By employing evolutionary conservation with the well-characterizedArabidopsis thaliana RRAs, we identified 5 and 38 novel putativeRRAsinBrassica oleraceaandBrassica napus, respectively. Our phylogenetic analysis suggests the existence of gene-specific selective pressure, maintaining the homologs ofARR3, ARR6,andARR16as singletons during the evolution ofBrassica oleraceaandBrassica rapa. We categorizedRRAsbased on the kinetics of their cytokinin-mediated upregulation and observed both similarities and specificities in this type of response across Brassicaceae. Using bioinformatic analysis and experimental data demonstrating the cytokinin responsiveness ofArabidopsis-derivedTCSv2reporter, we unveil the mechanistic conservation of cytokinin-mediated upregulation ofRRAsinBrassica rapaandBrassica napus. Notably, we identify partial cytokinin dependency of cold stress-inducedRRAtranscription, thus corroborating the role of cytokinin signaling in the crop adaptive responses.

Highlights

We identifiedBrassicahomologs ofArabidopsistype-A response regulators (RRAs), demonstrate existence of selective pressure preventing severalRRAsmultiplication during Brassicaceae evolution and describe cytokinin dependency of cold-inducedRRAsupregulation.
Trans-eQTL hotspots shape complex traits by modulating cellular states
Authors: Renganaath Kaushik , Albert Frank W.
Published: November 2023

Regulatory genetic variation shapes gene expression, providing an important mechanism connecting DNA variation and complex traits. The causal relationships between gene expression and complex traits remain poorly understood. Here, we integrated transcriptomes and 46 genetically complex growth traits in a large cross between two strains of the yeastSaccharomyces cerevisiae. We discovered thousands of genetic correlations between gene expression and growth, suggesting potential functional connections. Local regulatory variation was a minor source of these genetic correlations. Instead, genetic correlations tended to arise from multiple independenttrans-acting regulatory loci.Trans-acting hotspots that affect the expression of numerous genes accounted for particularly large fractions of genetic growth variation and of genetic correlations between gene expression and growth. Genes with genetic correlations were enriched for similar biological processes across traits, but with heterogeneous direction of effect. Our results reveal howtrans-acting regulatory hotspots shape complex traits by altering cellular states.
Comparing hormone dynamics in cereal crops via transient expression of hormone sensors
Authors: Dao Thai Q. , Drapek Colleen , Jones Alexander , Leiboff Samuel
Published: November 2023

Plant hormones are small molecules which elicit profound physiological responses. Although plant hormone biosynthesis and response genes have been critical for agricultural improvement, it has been difficult to experimentally compare hormone biology across species because of complex phenotypic outputs. We used transient expression of genetic hormone sensors and transcriptomics to quantify tissue-specific gibberellic acid (GA) and auxin responses across tissues and genotypes in cereal crops. We found that the FRET-based GPS2 biosensor detects exogenous GA treatments in maize, barley, sorghum, and wheat, in both vegetative and floral tissues. Measuring GPS2 output across GA dosages revealed tissue- and genotype-specific differences in GA sensor response. We observed marked differences in maize vs barley leaves and floral tissues and an unexpected drop in GPS2 output in the maized1GA biosynthesis mutant after GA treatment, likely reflecting differences in bioactive GA content, GA transport, and mechanisms of GA response. We then used RNAseq to measure transcriptional responses to GA treatment in leaves from maize wildtype,d1, and barley as well as floral tissues from maize and barley for a cross-tissue, cross-genotype, and cross-species GA-response comparison. After orthology prediction and analysis of within- and cross-species GO-term enrichment, we identified core sets of GA-responsive genes in each species as well as maize- barley orthogroups. Our analysis suggests that downregulation ofGA-INSENSITIVE DWARF1(GID1) and upregulation of α-Expansin1(EXPA1) orthologs comprises a universal GA-response mechanism that is independent of GA biosynthesis, and identifies F-Box proteins, hexokinase, and AMPK/SNF1 protein kinase orthologs as unexpected cross-tissue, cross-genotype, and cross-species GA-responsive genes. We then compared the transient expression of the DR5, DR5v2, and DII-mDII auxin reporters in barley and maize and find that although DR5 did not respond to exogenous auxin in barley, DR5v2 responded to auxin treatment with a similar magnitude as in maize. Both species display auxin-mediated DII degradation that requires the 26S proteasome.
Nucleus Reuniens: Modulating Negative Overgeneralization in Periadolescents with Anxiety
Authors: Rivera Núñez M. Vanessa , McMakin Dana , Mattfeld Aaron T.
Published: November 2023

Background

Anxiety affects 4.4-million children in the United States with an onset between childhood and adolescence, a period marked by neural changes that impact emotions and memory. Negative overgeneralization – or responding similarly to innocuous events that share features with past aversive experiences – is common in anxiety but remains mechanistically underspecified. The nucleus reuniens (RE) has been considered a crucial candidate in the modulation of memory specificity. Our study investigated its activation and functional connectivity with the medial prefrontal cortex (mPFC) and hippocampus (HPC) as neurobiological mechanisms of negative overgeneralization in anxious youth.

Methods

As part of a secondary data analysis, we examined data from 34 participants between 9-14 years (mean age ± SD, 11.4 ± 2.0 years, 16 females) with varying degrees of anxiety severity. During the Study session participants rated images as negative, neutral, and positive. After 12-hours, participants returned for a Test session, where they performed a memory recognition test with repeated (targets) and similar (lures) images. Labeling negative relative to neutral lures as “old” (false alarms) was our operational definition of negative overgeneralization.

Results

Negative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the CA1 (at Test only). Elevated anxiety severity was associated with reductions in the RE-mPFC functional coupling for neutral relative to negative stimuli. Exploratory analyses revealed similar patterns in activation and functional connectivity with positive stimuli.

Conclusions

Our findings demonstrate the importance of the RE in the overgeneralization of memories in anxious youth.
Allosteric substrate activation of SAMHD1 shapes deoxynucleotide triphosphate imbalances by interconnecting the depletion and biosynthesis of different dNTPs
Authors: McCown Claudia , Yu Corey H. , Ivanov Dmitri N.
Published: November 2023

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism of SAMHD1 that depends on dNTP binding at allosteric sites and the concomitant tetramerization of the enzyme. The study reveals that SAMHD1 activation involves an inactive tetrameric intermediate with partial occupancy of the allosteric sites. The equilibrium between the inactive and active tetrameric states, which is coupled to cooperative binding/dissociation of at least two allosteric dNTP ligands, controls the dNTPase activity of the enzyme, which, in addition, depends on the identity of the dNTPs occupying the four allosteric sites of the active tetramer. We show how such allosteric regulation determines deoxynucleotide triphosphate levels established in the dynamic equilibria between dNTP production and SAMHD1-catalyzed depletion. Notably, the mechanism enables a distinctive functionality of SAMHD1, which we call facilitated dNTP depletion, whereby elevated biosynthesis of some dNTPs results in more efficient depletion of others. The regulatory relationship between the biosynthesis and depletion of different dNTPs sheds light on the emerging role of SAMHD1 in the biology of dNTP homeostasis with implications for HIV/AIDS, innate antiviral immunity, T cell disorders, telomere maintenance and therapeutic efficacy of nucleoside analogs.
Algal Exudates Promote Conjugation in Marine Roseobacters
Authors: Rapp Yemima Duchin , Lipsman Valeria , Yuda Lilach , Kublanov Ilya V , Matsliyah Dor , Segev Einat
Published: November 2023

Horizontal gene transfer (HGT) is a pivotal mechanism driving bacterial evolution, conferring adaptability within dynamic marine ecosystems. Among HGT mechanisms, conjugation mediated by type IV secretion systems (T4SSs) plays a central role in the ecological success of marine bacteria. However, the conditions promoting conjugation events in the marine environment are not well understood. Roseobacters, abundant marine bacteria commonly associated with algae, possess a multitude of T4SSs. Many Roseobacters are heterotrophic bacteria that rely on algal secreted compounds to support their growth. These compounds attract bacteria, facilitating colonization and attachment to algal cells. Algae and their metabolites bring bacteria into close proximity, potentially promoting bacterial HGT. Investigation across various Roseobacters revealed that algal exudates indeed enhance plasmid transfer through conjugation. While algal exudates do not influence the transcription of bacterial conjugative machinery genes, they promote bacterial attachment, potentially stabilizing proximity and facilitating HGT. Notably, under conditions where attachment is less advantageous, the impact of algal exudates on conjugation is reduced. These findings suggest that algae enhance bacterial conjugation primarily by fostering attachment and highlight the importance of studying bacterial HGT within the context of algal-bacterial interactions.
Sensorless robust control for PMSG wind energy conversion systems based on smith predictor ADRC and SMO-PLL estimation
Authors: Benrabah Abdeldjabar , Khoucha Farid , Raza Ali , Benbouzid Mohamed
Published: November 2023

Purpose

The purpose of this study is to improve the control performance of wind energy conversion systems (WECSs) by proposing a new sensorless, robust control strategy based on a Smith predictor active disturbance rejection control (SP-ADRC) associated with a speed/position estimator.

Design/methodology/approach

The estimator consists of a sliding mode observer (SMO) in combination with a phase-locked loop (PLL) to estimate the permanent magnet synchronous generator (PMSG) rotor position and speed. At the same time, the SP-ADRC is applied to the speed control loop of the variable-speed WECS control system to adapt strongly to dynamic characteristics under parameter uncertainties and disturbances.

Findings

Numerical simulations are conducted to evaluate the speed tracking performances under various wind speed profiles. The results show that the proposed sensorless speed control improves the accuracy of rotor speed and position estimation and provides better power tracking performance than a regular ADRC controller under fast wind speed variations.

Practical implications

This paper offers a new approach for designing sensorless, robust control for PMSG-based WECSs.

Originality/value

A new sensorless, robust control is proposed to improve the stability and tracking performance of PMSG-based WECSs. The SP-ADRC control attenuates the effects of parameter uncertainties and disturbances and eliminates the time-delay impact. The sensorless control design based on SMO and PLL improves the accuracy of rotor speed estimation and reduces the chattering problem of traditional SMO. The obtained results support the theoretical findings.
Turnover intention among Vietnamese millennials in the workplace
Authors: Yang Yumei , Thu Hue Hannah Mai , Takeda Sachiko
Published: November 2023

Purpose

Drawing upon the framework of social exchange theory, this study investigated the influence of work-life balance, procedural justice and distributive justice on job satisfaction and turnover intention among Vietnamese millennials.

Design/methodology/approach

Employing a quantitative research method, the authors collected a sample of 258 millennial participants in Vietnam. Utilizing the method of multiple regression analysis, the collected data were rigorously examined.

Findings

The results showed that job satisfaction is negatively related to the turnover intention of the millennial generation in Vietnam. Distributive justice is a stronger predictor of job satisfaction than procedural justice. Of particular note, the study revealed an intriguing result: work-life balance does not have a significant influence on job satisfaction among millennials.

Practical implications

Leveraging insights from national cultural theories, the authors' findings provide some insightful explanations of what drives millennials in Vietnam to consider leaving their organizations.

Social implications

The study provides some insights for policymakers in Vietnam and other similar developing countries to reform their approach at managing the millennial generation.

Originality/value

The research addresses the existing gap in literature by delving into the underlying factors driving the propensity of Vietnamese millennials to frequently switch jobs.
The impact of financial support on forestry green total factor productivity from the perspective of environmental regulation
Authors: Wu Haotian , Chen Jiancheng , Bai Wanting , Fang Yiliang
Published: November 2023

Purpose

The aim of this article is to research on forestry green total factor productivity and explore the impact of financial support on forestry green total factor productivity.

Design/methodology/approach

The methods used in this study are super efficiency SBM model of undesired output and empirical model. SBM model is a kind of Data Envelopment Analysis (DEA). The SBM model with non-expected outputs (slacks-based measure) can be used to deal with the problem of efficiency measurement with multiple input and output variables and can be used to analyze the efficiency of green development of forestry economy.

Findings

First, the overall green total factor productivity of the authors’ country's forestry has shown a trend of first decline and then an increase from 2008 to 2018, and there are significant spatiotemporal differences; second, financial support has a significant positive impact on forestry green total factor productivity; third, environmental regulation has a significant threshold effect in the process of financial support on forestry green total factor productivity, and the role of financial support shows a trend of first increasing and then decreasing.

Originality/value

Secondly, taking the data of 30 provinces and cities in the authors’ country from 2008 to 2018 as the research object, using the super-efficiency SBM-Malmquist index to measure the country's forestry green total factor productivity and analyze its temporal and spatial changes; finally, a dynamic panel model was established to explore the impact of financial support on forestry green total factors quantitative impact on productivity, and adding environmental regulation as a threshold variable to establish a dynamic threshold regression, and found that financial support has a nonlinear impact on forestry green total factor productivity.