bluuebunny/crossref_metadata_2025 huggingface dataset:
The level of HAND1 controls the specification of multipotent cardiac and extraembryonic progenitors
Authors: Lynch Adam T , Phillips Naomi , Douglas Megan , Dorgnach Marta , Lin I-Hsuan , Adamson Antony D , Darieva Zoulfia , Whittle Jessica , Hanley Neil A , Bobola Nicoletta , Birket Matthew J
Published: August 2024

Diverse sets of progenitors contribute to the development of the embryonic heart, but the mechanisms of their specification have remained elusive. Here, using a human pluripotent stem cell (hPSC) model, we deciphered cardiac and non-cardiac lineage trajectories in differentiation and identified transcription factors underpinning cell specification, identity and function. We discovered a concentration-dependent, fate determining function in mesodermal progenitors for the basic helix-loop-helix transcription factor HAND1 and uncovered its gene regulatory network. At low level, HAND1 directs differentiation towards multipotent juxta-cardiac field progenitors able to make cardiomyocytes and epicardial cells, whereas at high level it promotes the development of extraembryonic mesoderm. Importantly, HAND1-low progenitors can be propagated in their multipotent state. This detailed mechanistic insight into human development will accelerate the delivery of effective disease modelling, including for congenital heart disease, and cell therapy-based regenerative medicine.
Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone
Authors: Catto Francesca , Dadgar-Kiani Ehsan , Kirschenbaum Daniel , Economides Athena E. , Reuss Anna Maria , Trevisan Chiara , Caredio Davide , Mirzet Delic , Frick Lukas , Weber-Stadlbauer Ulrike , Litvinov Sergey , Koumoutsakos Petros , Hyung Lee Jin , Aguzzi Adriano
Published: August 2024

A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aβ plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.
The genetic landscape of antibiotic sensitivity in Staphylococcus aureus
Authors: Li Wan , Liu Menghan , Oikonomou Panos , Blattman Sydney B , Hettleman Julia , Gonzalez Joseph , Chen Howe , Tavazoie Saeed , Jiang Wenyan
Published: August 2024

Despite the critical importance of essential genes, systems-level investigations of their contribution to antibiotic sensitivity have been limited. Using CRISPR Adaptation-mediated Library Manufacturing (CALM), we generated ultra-dense CRISPR interference (CRISPRi) libraries in methicillin-sensitive and -resistant strains of Staphylococcus aureus, which allowed us to quantify gene fitness on a global scale across ten clinically relevant antibiotics. This led to the identification of a comprehensive set of known and novel biological processes modulating bacterial fitness in the antibiotics. Notably, we found that essential genes from diverse processes dominated antibiotic-gene interactions, including a large number of synergistic interactions between bactericidal antibiotics and processes such as cell wall synthesis/cell division (CC), DNA replication/DNA recombination (DD), protein export, and coenzyme A biosynthesis. Simultaneous genetic perturbations of diverse CC and DD processes aggravated bacterial fitness, revealing a widespread synergy between the two highly coordinated processes. In contrast, perturbation of transcriptional, translational, and select energy processes antagonized the effects of bactericidal antibiotics. Finally, we show that small molecule inhibitors recapitulated synergistic antibiotic-gene interactions, providing a rational foundation for developing novel combinatorial antimicrobial therapies.
IdentifiHR: predicting homologous recombination deficiency in high-grade serous ovarian carcinoma using gene expression
Authors: Weir Ashley L. , Lee Samuel C. , Li Mengbo , Tan Chin Wee , Ramus Susan J. , Davidson Nadia M.
Published: August 2024

Background

Approximately half of all high-grade serous ovarian carcinomas (HGSCs) have a therapeutically targetable defect in the homologous recombination (HR) DNA repair mechanism. While there are genomic and transcriptomic methods, developed for other cancer types, to identify HR deficient (HRD) samples, there are no gene expression-based tools to predict HR repair status in HGSC specifically. We have built the first HGSC-specific model to predict HR repair status using gene expression.

Methods

We separated The Cancer Genome Atlas (TCGA) cohort of HGSCs (n = 361) into training (n = 288) and testing (n = 73) sets and labelled each case as HRD or HR proficient (HRP) based on the clinical standard for classification, being a score of HRD genomic damage. Using the training set, we performed differential gene expression analysis between HRD and HRP cases. The 2604 significantly differentially expressed genes were then used to tune and train a penalised logistic regression model.

Results

IdentifiHR is an elastic net penalised logistic regression model that uses the expression of 209 genes to predict HR status in HGSC. These genes capture known regions of HR-specific copy number alteration, which impact gene expression levels, and preserve the genomic damage signal. IdentifiHR has an accuracy of 85% in the TCGA test set and of 91% in an independent cohort of 99 samples, collected from primary tumours before (n = 74/99) and after autopsy (n = 6/99), in addition to ascites (n = 12/99) and normal fallopian tube samples (n = 7/99). Further, IdentifiHR is 84% accurate in pseudobulked single-cell HGSC sequencing from 37 patients and outperforms existing gene expression-based methods to predict HR status, being BRCAness, MutliscaleHRD and expHRD.

Conclusions

IdentifiHR is an accurate model to predict HR status in HGSC using gene expression alone, that is available as an R package fromhttps://github.com/DavidsonGroup/IdentifiHR.
Distinct evolutionary trajectories following loss of RNA interference inCryptococcus neoformans
Authors: Huang Jun , Larmore Connor J. , Priest Shelby J. , Xu Ziyan , Dietrich Fred S. , Yadav Vikas , Magwene Paul M. , Sun Sheng , Heitman Joseph
Published: August 2024

While increased mutation rates typically have negative consequences in multicellular organisms, hypermutation can be advantageous for microbes adapting to the environment. Previously, we identified two hypermutatorCryptococcus neoformansclinical isolates that rapidly develop drug resistance due to transposition of a retrotransposon, Cnl1. Cnl1-mediated hypermutation is caused by a nonsense mutation in the gene encoding a novel RNAi component, Znf3, combined with a tremendous transposon burden. To elucidate adaptative mechanisms following RNAi loss, two bioinformatic pipelines were developed to identify RNAi loss-of-function mutations in a collection of 387 sequencedC. neoformansisolates. Remarkably, several RNAi-loss isolates were identified that are not hypermutators and have not accumulated transposons. To test if these RNAi loss-of-function mutations can cause hypermutation, the mutations were introduced into a non-hypermutator strain with a high transposon burden, which resulted in a hypermutator phenotype. To further investigate if RNAi-loss isolates can become hypermutators,in vitropassaging was performed. Although no hypermutators were found in twoC. neoformansRNAi-loss strains after short-term passage, hypermutation was observed in a passagedC. deneoformansstrain with increased transposon burden. Consistent with a two-step evolution, when an RNAi-loss isolate was crossed with an isolate containing a high Cnl1 burden, F1 hypermutator progeny inheriting a high transposon burden were identified. In addition to Cnl1 transpositions, insertions of a novel gigantic DNA transposon KDZ1 (∼11 kb), contributed to hypermutation in the progeny. Our results suggest that RNAi loss is relatively common (7/387, ∼1.8%) and enables distinct evolutionary trajectories: hypermutation following transposon accumulation or survival without hypermutation.

Significance Statement

There is a dearth of antifungal drugs available to treatCryptococcus neoformans, a human fungal pathogen of global impact. We previously identified natural hypermutators with a loss-of-function mutation in the RNAi machinery and transposon expansion. Here, we identified several novel natural isolates with RNAi defects, none of which are hypermutators or have undergone transposon expansion. Furthermore, we demonstrate that these isolates can lie on a pathway to hypermutation following introduction of a transposon burden. In addition, a novel DNA transposon class was discovered that contributes to antifungal drug resistance. These findings highlight the importance of transposons in driving rapid adaptation in the absence of RNAi and reveal distinct evolutionary trajectories following RNAi loss, a relatively common event inC. neoformans.
Instruction-tuned large language models misalign with natural language comprehension in humans
Authors: Gao Changjiang , Ma Zhengwu , Chen Jiajun , Li Ping , Huang Shujian , Li Jixing
Published: August 2024

Transformer-based language models have significantly advanced our understanding of meaning representation in the human brain. Prior research utilizing smaller models like BERT and GPT-2 suggests that “next-word prediction” is a computational principle shared between machines and humans. However, recent advancements in large language models (LLMs) have highlighted the effectiveness of instruction tuning beyond next-word prediction. It remains to be tested whether instruction tuning can further align the model with language processing in the human brain. In this study, we evaluated the self-attention of base and finetuned LLMs of different sizes against human eye movement and functional magnetic resonance imaging (fMRI) activity patterns during naturalistic reading. Our results reveal that increases in model size significantly enhance the alignment between LLMs and brain activity, whereas instruction tuning does not. These findings confirm a scaling law in LLMs’ brain-encoding performance and suggest that “instruction-following” may not mimic natural language comprehension in humans.
Tat_BioV: Tattoo ink exposure and biokinetics of selected tracers in a short-term clinical study of 24 subjects
Authors: Kochs Susanne , Schiewe Sandra , Foerster Milena , Hillmann Kathrin , Blankenstein Claudia , Meinke Martina C. , Kugler Josephine , Kocovic David , Luch Andreas , Blume-Peytavi Ulrike , Schreiver Ines
Published: August 2024

Background

About one-fifth of people in industrialised countries are tattooed, potentially putting them at risk of exposure to possible carcinogenic or otherwise harmful substances. Health risks are directly correlated with the amounts of substances introduced, yet reliable data on the systemic exposure to tattoo inks are lacking.

Objectives

This study aims to determine the exposure to soluble tattoo ink ingredients and their excretion within 24 hours after tattooing. Comparativein vivoandin vitroexperiments were conducted to determine the change in metabolite exposure between tattooing and oral exposure.

Methods

In a clinical study, 24 subjects were tattooed with black or red tattoo ink to which the tracer substances potassium iodide, 4-aminobenzoic acid (PABA) and 2-phenoxyethanol (PEtOH) had been added to mimic known hazardous substances found in tattoo inks. Tracers and their metabolites were quantified in blood, urine, ink, and consumables pre- and post-tattooing. Tattooed skin area was determined using picture analysis. PABA metabolism upon tattooing was compared to peroral administration. Skin fibroblasts and macrophages were testedin vitrofor their ability to metabolise PABA.

Results

All tracers or their metabolites were identified in urine; iodide and the PABA metabolite 4-acetamidobenzoic acid (ACD) were identified in plasma. The worst-case scenario for systemic ink exposure was estimated to be 0.31 g of ink per tattoo session (75thpercentile). Peroral administration resulted in lower levels of ACD than tattooing. Fibroblasts and macrophages were capable of converting PABA into ACD.

Discussion

Our results are the first humanin vivodata on soluble tattoo ink ingredients and suggest that the overall exposure might be lower than the estimates previously used for regulatory purposes. In addition, the first-pass effect by skin metabolism leads to an altered metabolite profile compared to oral exposure. Skin metabolism might also contribute to detoxification of certain carcinogenic substances throughN-acetylation.
The prevalence among heart failure patients and clinical profiles of patients with cor pulmonale at a tertiary center in Ethiopia
Authors: Anagaw Sewale , Fentahun Netsanet , Bayih Habtamu , Tekleab Yohannes
Published: August 2024

Background

Heart failure is a complex clinical syndrome resulting from structural and functional impairment of ventricular filling or ejection of blood. Cor pulmonale is one type of this clinical syndrome. There are only a few published studies on cor pulmonale from Ethiopia. The objective of this study was to determine the prevalence among patients with heart failure and the clinical and laboratory profiles of patients with cor pulmonale who had follow up at one of the tertiary hospitals in Ethiopia

Methods

A hospital-based cross-sectional study was conducted at Felege Hiwot Referral Hospital from December 2018 to April 2019. A single population proportion formula was used to determine the number of heart failure patients that had to be included in the study to determine the prevalence of cor pulmonale. The medical records of cor pulmonale patients among the sample heart failure patients were then retrieved and data was extracted using a structured checklist. Data was entered into, cleaned, and analyzed using IBM.SPSS version 23.0. Descriptive statistics were used to report the findings.

Results

Eight percent (35) of patients with heart failure had cor pulmonale. Fifty-four point three percent (19) of the patients with cor pulmonale were males and 45.7 %(16) were females. The median age of patients with cor pulmonale was 55 years. The commonest clinical features were cough and dyspnea (91.4 % and 97.1 % respectively). All patients had right ventricular dilation on echocardiography. Pulmonary Complications post-treatment for tuberculosis were the leading causes followed by interstitial lung disease. There was no identified respiratory disease in 40% of patients with cor pulmonale

Conclusion

Cor pulmonale accounted for less than 10 % of heart failure cases. Complications post-pulmonary tuberculosis were found to be the leading respiratory conditions underlying the cor pulmonale. Programs on prevention, early detection, and treatment of pulmonary tuberculosis must be strengthened.
Deep learning-derived splenic radiomics, genomics, and coronary artery disease
Authors: Kamineni Meghana , Raghu Vineet , Truong Buu , Alaa Ahmed , Schuermans Art , Friedman Sam , Reeder Christopher , Bhattacharya Romit , Libby Peter , Ellinor Patrick T. , Maddah Mahnaz , Philippakis Anthony , Hornsby Whitney , Yu Zhi , Natarajan Pradeep
Published: August 2024

Background

Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD, but the role of a key regulating organ, spleen, is unknown. The understudied spleen is a 3-dimensional structure of the hematopoietic system optimally suited for unbiased radiologic investigations toward novel mechanistic insights.

Methods

Deep learning-based image segmentation and radiomics techniques were utilized to extract splenic radiomic features from abdominal MRIs of 42,059 UK Biobank participants. Regression analysis was used to identify splenic radiomics features associated with CAD. Genome-wide association analyses were applied to identify loci associated with these radiomics features. Overlap between loci associated with CAD and the splenic radiomics features was explored to understand the underlying genetic mechanisms of the role of the spleen in CAD.

Results

We extracted 107 splenic radiomics features from abdominal MRIs, and of these, 10 features were associated with CAD. Genome-wide association analysis of CAD-associated features identified 219 loci, including 35 previously reported CAD loci, 7 of which were not associated with conventional CAD risk factors. Notably, variants at 9p21 were associated with splenic features such as run length non-uniformity.

Conclusions

Our study, combining deep learning with genomics, presents a new framework to uncover the splenic axis of CAD. Notably, our study provides evidence for the underlying genetic connection between the spleen as a candidate causal tissue-type and CAD with insight into the mechanisms of 9p21, whose mechanism is still elusive despite its initial discovery in 2007. More broadly, our study provides a unique application of deep learning radiomics to non-invasively find associations between imaging, genetics, and clinical outcomes.
Common and rare variant analyses reveal novel genetic factors underlying Idiopathic Pulmonary Fibrosis and shared aetiology with COVID-19
Authors: Kousathanas Athanasios , Odhams Christopher A. , Cook James , Hu Yao , Klee Stephan , Erzurumluoglu A. Mesut , Ramirez Fidel , Mayr Christoph , Schäfer Dennis , Beck Lara , Christ Ingrid , Lee Taekyu , Tarr James Christopher , Fesik Steven W. ,   Boehringer Ingelheim – Global Computational Biology and Digital Sciences, Duboff James , Wirtz-Peitz Frederik , Moutsianas Loukas , Brown Matthew A. , Kriegl Jan , Okafo Goerge , Jensen Jan N , Thomas Matthew J. , Ding Zhihao
Published: August 2024

Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating respiratory disease with limited therapeutic options. We carried out genome-wide association (GWAS), post-GWAS and rare variant analyses utilising the whole genome sequencing data (WGS) from the 100,000 Genomes Project (100kGP) of a cohort of IPF participants (n=586) to identify novel associations and potential drug targets. Meta-analysis combining 100kGP and published GWASs of IPF (total 11,746 cases and 1,416,493 controls) identified a novel association signal at the 1q21.2 locus (rs16837903, OR[95%CI]=0.88[0.85, 0.92],P=9.54×10−9) which was also successfully replicated with independent data and linked to the probable effector geneMCL1. MCL1showed increased expression levels in IPF patients versus controls in alveolar epithelial type I cells. Despite its known antiapoptotic role, inhibition ofMCL1 in vitrodid not selectively deplete senescent cells, hinting at the complexity involved in targetingMCL1. Rare variant burden analysis identifiedANGPTL7, a secreted glycoprotein involved in the regulation of angiogenesis, as a novel IPF candidate gene (OR[95%CI]=28.79 [8.51-97.43],P=6.73×10−8). Transcriptome-wide association analysis (TWAS) revealed that overexpression of cell cycle regulatorSERTAD2and nuclear importerTPNO3were associated with increased IPF risk. We also investigated shared genetic mechanisms between IPF with severe COVID-19 and expanded the list of shared genetic loci with three novel colocalised signals at 1q21.2, 6p24.3 and 16p13.3 with probable effector genesMCL1,DSP and RHBDF1, implicating regulation of apoptosis, cell adhesion and epidermal growth factor signalling, respectively. By leveraging the genetic correlation between IPF and severe COVID-19 (rg[95% CI]) = 0.39 [0.25-0.53]) through multi-trait meta-analysis, we further identified and replicated an additional novel candidate IPF signal at 2p16.1 with probable effector geneBCL11A, a regulator of haematopoiesis and lymphocyte development. Based on prioritized genes across analyses, we propose mechanisms mediating IPF disease risk and shared mechanisms between IPF and severe COVID-19, thereby expanding the potential for developing common treatments.
Distinct contributions of the dorsal and ventral hippocampus to spatial working memory and spatial coding in the prefrontal cortex
Authors: Babl Susanne S. , Sigurdsson Torfi
Published: August 2024

The hippocampus (HPC) supports spatial working memory (SWM) through its interactions with the prefrontal cortex (PFC). However, it is not clear whether and how the dorsal (dHPC) and ventral (vHPC) poles of the HPC make distinct contributions to SWM and whether they differentially influence the PFC. To address this question, we optogenetically silenced the dHPC or the vHPC while simultaneously recording from the PFC of mice performing a SWM task. We found that whereas both HPC subregions were necessary during the encoding phase of the task, only the dHPC was necessary during the choice phase. Silencing of either subregion altered the spatial firing patterns of PFC neurons. However, only silencing of the vHPC affected their coding of spatial goals. These results thus reveal distinct contributions of the dorsal and ventral HPC poles to SWM and the coding of behaviorally-relevant spatial information by PFC neurons.
Shifts in vernalization and phenology at the rear edge hold insight into adaptation of temperate plants to future milder winters
Authors: Perrier Antoine , Turner Megan C. , Galloway Laura F.
Published: August 2024

Temperate plants often regulate reproduction through winter cues, such as vernalization, that may decrease under climate change. Studies of rear-edge populations, glacial relicts that persist in environments that have warmed since last glaciation, can provide insight into adaptive potential to milder winters.

We studied how rear-edge populations have adapted to shorter winters and compared them to the rest of the range in the herbCampanula americana. Using citizen science, climate data and experimental climate manipulation, we characterize variation in vernalization requirements and reproductive phenology across the range and their potential climatic drivers.

Rear-edge populations experienced little to no vernalization in nature. In climate manipulation experiments, these populations also had a reduced vernalization requirement, weaker response to changes in vernalization length, and flowered later compared to the rest of the range.

Our results suggest shifts in phenology and its underlying regulation at the rear edge to compensate for unreliable vernalization cues. Thus, future milder winters may be less detrimental to these populations than more northern ones. Furthermore, our results showcase strong adaptive shifts at the rear edge of temperate plants’ ranges, highlighting the importance of these areas in studies of predicted future climates.
Assessing white matter plasticity in a randomized controlled trial of early literacy training in preschoolers
Authors: Caffarra Sendy , Karipidis Iliana I. , Kruper John , Kubota Emily , Richie-Halford Adam , Takada Megumi , Rokem Ariel , Yeatman Jason D.
Published: August 2024

Reading is a cognitive skill that requires our brain to go through a myriad of changes during learning. While many studies have described how reading acquisition shapes children’s brain function, less is known about the impact of reading on brain structure. Here we examined short-term causal effects of reading training on preschoolers’ behavior and white matter structure. Forty-eight English-speaking preschoolers (4y10m to 6y2m) participated in a randomized controlled trial where they were randomly assigned to two training programs: the Letter training program was focused on key skills for reading (e.g., decoding and letter knowledge), while the Language training program strengthened oral language comprehension skills without exposure to text. Longitudinal behavioral data showed that only the Letter Training group increased letter knowledge and decoding skills after the two-week training. Diffusion MRI measures (FA and MD) of eighteen white matter pathways (including the left arcuate and the left inferior longitudinal fasciculus) did not reveal any statistically significant changes for either group despite high degrees of scan-rescan reliability across sessions. These findings suggest that a two- week reading training program can cause changes in preschoolers’ letter knowledge and decoding abilities, without being accompanied by measurable changes in the diffusion properties of the major white matter pathways of the reading network. We conclude highlighting possible constraints (i.e., age, training onset and duration, cognitive profile) to reading-related white matter plasticity.
Ultrahigh-throughput discovery of modified aptamers as specific and potent enzyme inhibitors
Authors: Husser Claire , Hoetzel Janis , Cubi Roger , Lebars Isabelle , Kraus Leon , Di Primo Carmelo , Baudrey Stephanie , Proschak Ewgenij , Kieffer Bruno , Suess Beatrix , Ryckelynck Michael
Published: August 2024

Enzymes are instrumental to life and key actors of pathologies, making them relevant drug targets. Most enzyme inhibitors consist of small molecules. Although efficient, their development is long, costly and can come with unwanted off-targeting. Substantial gain in specificity and discovery efficiency is possible using biologicals. Best exemplified by antibodies, these drugs derived from living systems display high specificity and their development is eased by harnessing natural evolution. Aptamers are nucleic acids sharing functional similarities with antibodies while being deprived of many of their limitations. Yet, the success rate of inhibitory aptamer discovery remained hampered by the lack of an efficient discovery pipeline. In this work, we addressed this issue by introducing an ultrahigh-throughput strategy combiningin vitroselection, microfluidic screening and bioinformatics. We demonstrate its efficiency by discovering a modified aptamer that specifically and strongly inhibits SPM-1, a beta-lactamase that remained recalcitrant to the development of potent inhibitors.

Graphical Abstract
Placental and fetal microbiota in rhesus macaque: a case study using metagenomic sequencing
Authors: Du Qiao , Liu Xu , Zhang Rusong , Hu Gang , Liu Qinghua , Ma Wen , Hu Ying , Fan Zhenxin , Li Jing
Published: August 2024

Recent evidence challenging the notion of a sterile intrauterine environment has sparked research into the origins and effects of fetal microbiota on immunity development during gestation. Rhesus macaques (RMs) serve as valuable non-human primate (NHP) models due to their similarities to humans in development, placental structure, and immune response. In this study, metagenomic analysis was applied to the placenta, umbilical cord, spleen, gastrointestinal (GI) tissues of an unborn RM fetus, and the maternal intestine, revealing the diversity and functionality of microbes in these tissues. We observed substantial microbial sharing between the mother and fetus, with the microbial composition of the placenta and umbilical cord more closely resembling that of the fetal organs than the maternal intestine. Notably, compared with other adult RMs, there was a clear convergence between maternal and fetal microbiota, alongside distinct differences between the microbiota of adults and the fetus, which underscores the unique microbial profiles in fetal environments. Furthermore, the fetal microbiota displayed a less developed carbohydrate metabolism capacity than adult RMs. It also shared antibiotic resistance genes (ARGs) with both maternal and adult RM microbiomes, indicating potential vertical transmission. Comparative analysis of the metagenomes between the RM fetus and a human fetus revealed significant differences in microbial composition and genes, yet also showed similarities in certain abundant microbiota. Collectively, our results contribute to a more comprehensive understanding of the intrauterine microbial environment in macaques.
Study of excess manganese stress response highlights the central role of manganese exporter Mnx for holding manganese homeostasis in the cyanobacteriumSynechocystis sp.PCC 6803
Authors: Reis Mara , Zenker Sanja , Viehöver Prisca , Niehaus Karsten , Bräutigam Andrea , Eisenhut Marion
Published: August 2024

Cellular levels of the essential micronutrient manganese (Mn) need to be carefully balanced within narrow boarders. In cyanobacteria, sufficient Mn supply is critical for assuring the function of the oxygen-evolving complex as central part of the photosynthetic machinery. However, Mn accumulation is fatal for the cells. The reason for the observed cytotoxicity is unclear. To understand the causality behind Mn toxicity in cyanobacteria, we investigated the impact of excess Mn on physiology and global gene expression in the model organismSynechocystissp. PCC 6803. We compared the response of the wild type and the knock-out mutant in the manganese exporter (Mnx), Δmnx,which is disabled in the export of surplus Mn and thus functions as model for toxic Mn overaccumulation. While growth and pigment accumulation in Δmnxwas severely impaired 24 h after addition of 10-fold Mn, the wild type was not affected and thus mounted an adequate transcriptional response. RNA-seq data analysis revealed that the Mn stress transcriptomes were partly resembling an iron limitation transcriptome. However, the expression of iron limitation signature genesisiABDCwas not affected by the Mn treatment, indicating that Mn excess is not accompanied by iron limitation inSynechocystis.We suggest that the Ferric uptake regulator, Fur, gets partially mismetallated under Mn excess conditions and thus interferes with an iron-dependent transcriptional response. To encounter mismetallation and other Mn-dependent problems on protein level, the cells invest into transcripts of ribosomes, proteases, and chaperones. In case of the Δmnxmutant the consequences of the disability to export excess Mn from the cytosol manifest in additionally impaired energy metabolism and oxidative stress transcriptomes with fatal outcome. This study emphasizes the central importance of Mn homeostasis and the transporter Mnx’s role in restoring and holding it.
Protective threshold of a potent neutralizing Zika virus monoclonal antibody in rhesus macaques
Authors: Nkolola Joseph P. , Hope David , Guan Ruaron , Colarusso Alessandro , Aid Malika , Carnahan Robert H. , Crowe James E. , Barouch Dan H.
Published: August 2024

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused a global pandemic in 2016-2017 with continued ongoing transmission at low levels in several countries. In the absence of an approved ZIKV vaccine, neutralizing monoclonal antibodies (mAbs) provide an option for the prevention and treatment of ZIKV infection. Previous studies identified a potent neutralizing human mAb ZIKV-117 that reduced fetal infection and death in mice following ZIKV challenge. In this study, we report exquisite potency of ZIKV-117 in a titration study in rhesus macaques to protect against ZIKV challenge. We show complete protection at a dose of 0.016 mg/kg ZIKV-117, which resulted in median serum concentrations of 0.13 µg/mL. The high potency of this mAb supports its potential clinical development as a novel biotherapeutic intervention for ZIKV.

Importance

In this study, we report the potency of the ZIKV-specific neutralizing antibody ZIKV-117 against ZIKV challenge in a titration study rhesus macaques. This high potency supports the further development of this mAb for ZIKV.
P(all-atom) Is Unlocking New Path For Protein Design
Authors: Qu Wei , Guan Jiawei , Ma Rui , Zhai Ke , Wu Weikun , Wang Haobo
Published: August 2024

We introduce Pallatom, an innovative protein generation model capable of producing protein structures with all-atom coordinates. Pallatom directly learns and models the joint distribution P(structure, seq) by focusing on P(all-atom), effectively addressing the interdependence between sequence and structure in protein generation. To achieve this, we propose a novel network architecture specifically designed for all-atom protein generation. Our model employs a dual-track framework that tokenizes proteins into residue-level and atomic-level representations, integrating them through a multi-layer decoding process with “traversing” representations and recycling mechanism. We also introduce theatom14representation method, which unifies the description of unknown side-chain coordinates, ensuring high fidelity between the generated all-atom conformation and its physical structure. Experimental results demonstrate that Pallatom excels in key metrics of protein design, including designability, diversity, and novelty, showing significant improvements across the board. Our model not only enhances the accuracy of protein generation but also exhibits excellent training efficiency, paving the way for future applications in larger and more complex systems.
Recovery of Verbal Working Memory Depends on Left Hemisphere White Matter Tracts
Authors: Martin Randi C , Ding Junhua , Alwani Ali I , Fung Steve H , Schnur Tatiana T
Published: August 2024

Researchers propose that the recovery of language function following stroke depends on the recruitment of perilesional regions in the left hemisphere and/or homologous regions in the right hemisphere. Many investigations of recovery focus on changes in gray matter regions, whereas relatively few examine white matter tracts and none address the role of these tracts in the recovery of verbal working memory (WM). The present study addressed these gaps, examining the role of left vs. right hemisphere tracts in the longitudinal recovery of phonological and semantic WM. For 24 individuals with left hemisphere stroke, we assessed WM performance within one week of stroke (acute timepoint) and at more than six months after stroke (chronic timepoint). To address whether recovery depends on the recruitment of left or right hemisphere tracts, we assessed whether changes in WM were related to the integrity of five white matter tracts in the left hemisphere which had been implicated previously in verbal WM and their right hemisphere analogues. Behavioral results showed significant improvement in semantic but not phonological WM from the acute to chronic timepoints. Improvements in semantic WM significantly correlated with tract integrity as measured by functional anisotropy in the left direct segment of the arcuate fasciculus, inferior fronto-occipital fasciculus and inferior longitudinal fasciculus. The results confirm the role of white matter tracts in language recovery and support the involvement of the left rather than right hemisphere in the recovery of semantic WM.
A Single Mutation in an Enteric Virus Alters Tropism and Sensitivity to Microbiota
Authors: Erickson Andrea K. , Sutherland Danica M. , Welsh Olivia L. , Maples Robert W. , Dermody Terence S. , Pfeiffer Julie K.
Published: August 2024

Many enteric viruses benefit from the microbiota, and depletion of the microbiota reduces infection of noroviruses and picornaviruses in mice. However,Reoviralesviruses are outliers among enteric viruses. Rotavirus infection is inhibited by bacteria, and we determined that several reovirus strains have enhanced replication following microbiota depletion. We found that an isogenic pair of reoviruses have opposing infection outcomes after microbiota depletion. Microbiota depletion reduces infection of reovirus strain T3SA+ but increases infection of strain T3SA−. These strains differ by a single amino acid polymorphism in the σ1 attachment protein, which confers sialic acid binding to T3SA+. Sialic acid binding facilitates T3SA+ infection of intestinal endothelial cells, while T3SA− inefficiently infects intestinal epithelial cells due to restriction by microbiota-driven, host-derived type III interferon responses. This study enhances an understanding of the complex interactions of enteric viruses, the microbiota, intestinal tropism, and antiviral responses.

Highlights

Microbiota enhance infection of a sialic acid (SA)-binding reovirus strain but inhibit infection of an isogenic non-SA-binding reovirus strain that differs by a single amino acid change.

SA binding facilitates viral infection of intestinal endothelial cells in a microbiota-dependent manner.

A non-SA-binding reovirus strain inefficiently infects intestinal epithelial cells due to microbiota-driven type III interferon responses.
Dissociable patterns of dopamine dynamics and causal contributions to stimulus-response behaviors across striatal subregions
Authors: Princz-Lebel Oren , Skirzewski Miguel , Rai Harleen , Panjwani Samina , Chu Anthony , Lemieux Claire A. , Palmer Daniel , Machado Meira M.F. , Prado Vania F. , Prado Marco A.M. , Saksida Lisa M. , Bussey Timothy J.
Published: August 2024

Striatal dopaminergic dynamics exhibit regional variation, yet are usually studied in isolation, with interpretations often extrapolated to the striatum as a whole. Here we used fiber photometry to characterize DA dynamics across the nucleus accumbens, dorsomedial, and dorsolateral striatum in parallel in mice performing a striatum-dependent stimulus-response (S-R) learning task. We found that transients in all regions varied dynamically across task events but differed significantly across regions in their timing of peak responding, presence of pre-choice ramping, and stability across learning. Next, manipulations of reward probability revealed that DA transients in all regions tracked reward delivery and omission, but not choice. Lastly, we used inhibitory chemogenetics to test the necessity of these signals for cognition, revealing that nigrostriatal DA, but not mesolimbic striatal DA, was necessary for the acquisition of S-R contingencies. These findings demonstrate heterogeneity of DA signals across the striatum and reveal their distinct, causal roles in cognition.
Functional investigation of a putative calcium-binding site involved in the inhibition of inositol 1,4,5-trisphosphate receptor activity
Authors: Arige Vikas , Wagner Larry E. , Malik Sundeep , Baker Mariah R. , Fan Guizhen , Serysheva Irina I. , Yule David I.
Published: August 2024

A wide variety of factors influence inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) activity resulting in modulation of intracellular Ca2+release. This regulation is thought to define the spatio-temporal patterns of Ca2+signals necessary for the appropriate activation of downstream effectors. The binding of both IP3and Ca2+are obligatory for IP3R channel opening, however, Ca2+regulates IP3R activity in a biphasic manner. Mutational studies have revealed that Ca2+binding to a high-affinity pocket formed by the ARM3 domain and linker domain promotes IP3R channel opening without altering the Ca2+dependency for channel inactivation. These data suggest a distinct low-affinity Ca2+binding site is responsible for the reduction in IP3R activity at higher [Ca2+]. We determined the consequences of mutating a cluster of acidic residues in the ARM2 and central linker domain reported to coordinate Ca2+in cryo-EM structures of the IP3R type 3. This site is termed the “CD Ca2+binding site” and is well-conserved in all IP3R sub-types. We show that the CD site Ca2+binding mutants where the negatively charged glutamic acid residues are mutated to alanine exhibited enhanced sensitivity to IP3-generating agonists. Ca2+binding mutants displayed spontaneous elemental Ca2+events (Ca2+puffs) and the number of IP3-induced Ca2+puffs was significantly augmented in cells stably expressing Ca2+binding site mutants. When measured with “on-nucleus” patch clamp, the inhibitory effect of high [Ca2+] on single channel-open probability (Po) was reduced in mutant channels and this effect was dependent on [ATP]. These results indicate that Ca2+binding to the putative CD Ca2+inhibitory site facilitates the reduction in IP3R channel activation when cytosolic [ATP] is reduced and suggest that at higher [ATP], additional Ca2+binding motifs may contribute to the biphasic regulation of IP3-induced Ca2+release.
The threat of contagious diseases: when consumers avoid human presence in product packaging
Authors: Park Jane , Kim Chaeyeong , Park Sehoon
Published: August 2024

Purpose

Postulating that individuals exposed to the threat of contagious diseases respond oversensitively toward other people, the current research aims to investigate its impact on consumers’ preferences for human images—human presence—in product packaging.

Design/methodology/approach

Five independent online and offline experiments were conducted. Studies 1, 2a, and 2b employed a three-group (threat: contagious vs. control vs. noncontagious) between-subjects design to investigate the main effect and its underlying mechanism. To further examine the moderation effects, Study 3 used a 2 (threat: contagious vs. control) × 2 (product feature: basic vs. antibacterial) between-subjects design, and Study 4 employed a 2 (threat: contagious vs. control) × 3 (human type: non–human vs. human–adult vs. human–baby) between-subjects design.

Findings

Studies 1, 2a, and 2b demonstrate that consumers facing the threat of contagious diseases tend to avoid social interaction, leading to a lower preference for products featuring human presence (vs. non-human presence). Studies 3 and 4 contribute to our hypothesized process by providing boundary conditions. Specifically, when the product incorporates an antibacterial function (Study 3) and the packaging depicts a baby (Study 4), the existing effect can be attenuated.

Originality/value

Despite the prevalence of experiencing epidemics and pandemics, little work has examined how threatened consumers respond to product packaging. The present research addresses this gap by exploring consumers' preferences for products featuring human presence on their packaging. Furthermore, this research contributes to the practical understanding of consumer choices by identifying product features and human types as moderating factors.
Gender-inclusive urban planning: European frameworks as a potential methodology for Arabian Gulf urban parks
Authors: Chung Ruben Yu-an , Grichting Solder Anna
Published: August 2024

Purpose

This trigger article explores established European gender-mainstreaming urban planning frameworks of urban parks to analyze and identify ways that could be applied or adapted for Arabian Gulf cities. It aims to accelerate the mainstreaming process, increasing women’s participation and inclusion in urban spaces, paving the way for future research.

Design/methodology/approach

Analytical frameworks are created by reviewing legal and policy evolution, city-issued guidelines and European cities’ case studies (Barcelona, Berlin, Paris and Vienna) engaged in gender mainstreaming in urban planning. These analytical tools are then applied to assess two Arabian Gulf parks (Al Azaiba Wadi Park, Muscat, Oman, and Dahl Al-Hamam Park, Doha, Qatar), suggesting a possible future research methodology.

Findings

Success factors in European cities include integrating female perspectives, detailed user analysis, specific planning solutions and political will. Despite differing social and cultural contexts, commonalities exist for female park users in Europe and the Arabian Gulf. This trigger article proposes a methodology for assessing the potential effective application or adaptation of European established frameworks in the Gulf context to accelerate gender mainstreaming.

Research limitations/implications

The paper proposes a methodology for future research, noting limitations such as limited input on design preparation processes in Gulf City park case studies, a lack of feedback from park users and only a brief overview of sociocultural differences. Future research should explore nuanced cultural contexts, including historical processes and gender dynamics, thorough literature review, expanded case study analysis and participatory approaches. The proposed methodology aims to demonstrate how European frameworks can guide gender-mainstreaming efforts in diverse contexts, facilitating collaborative solutions for inclusive urban planning.

Practical implications

Drawing from decades of European gender-mainstreaming activities, the paper distills urban planning principles and best practices for application or adaptation in the Arab Gulf.

Social implications

Enhancing the park experience for women through planning and design boosts gender equality in cities, benefiting their physical and social well-being.

Originality/value

An original methodology is suggested for adapting well-developed European gender-mainstreaming frameworks to Arabian Gulf parks. Authored by a male, this paper aims to advance gender issues in planning while exploring the role men can play in contributing to such.
Exploring the melodies of opportunity: do nepo babies pursue music out of genuine passion or is it a matter of engaging in musicpreneurship?
Authors: Maziriri Eugine Tafadzwa , Mabuyana Brain , Nyagadza Brighton , Dzingirai Mufaro , Maramura Tafadzwa C.
Published: August 2024

Purpose

In recent years, a number of privileged individuals have entered the music industry in Zimbabwe, either as performers or entrepreneurs. The economic challenges in the country may have prompted these individuals to invest in music as a means of diversifying their income or exploring new business opportunities. To determine whether their interest in music is driven by entrepreneurship or genuine passion, a scholarly examination was deemed necessary.

Design/methodology/approach

A qualitative research approach with semi-structured interviews was used as the data collection technique. Narrative analysis was conducted on a sample of musicology students in Gweru, Zimbabwe.

Findings

The findings revealed the nepo babies’ interest in music is driven by legacy continuation – the responsibility to carry on with the name of the parent – harsh economic conditions, capitalizing on Internet and digital opportunities and mechanisms for psychological satisfaction during hardships.

Originality/value

Although there is a wide range of literature on musicpreneurship, there are gaps in studies that have examined whether a nepo baby's interest in music is motivated by musicpreneurship or a genuine passion for it. Therefore, the aim of this research is to contribute to the existing body of literature on African musicpreneurship, with a specific focus on Zimbabwe.
Does tour quality impact tourist satisfaction? Experiences from Arunachal Pradesh, India
Authors: Tagiya Mudang , Mara Odang
Published: August 2024

Purpose

This study addresses a critical aspect of tourism in Arunachal Pradesh, India, by investigating how tour quality impacts on tourist satisfaction of domestic tourists. As one of the least explored regions of the country, Arunachal Pradesh holds immense tourism potential. Understanding the factors that contribute to tourist satisfaction, particularly the role of tour quality, is of paramount importance for enhancing the region's appeal as a sought-after travel destination.

Design/methodology/approach

The study was operationalized using survey questionnaires from domestic tourists (n = 200) visiting Ziro Valley, Arunachal Pradesh, India. A convenient sampling method was adopted for the study. Ordinary least square structural equation modeling (OLS-SEM) was used to measure the relationships.

Findings

The findings show that tourist expectations and tourist motivation influence tour quality and consequently impact the overall satisfaction of tourists.

Practical implications

This study extended the existing literature on tourist satisfaction in the domain of travel and tour by demonstrating the significance of tourist expectations and motivations on tour quality and tourist satisfaction. The findings offer insights for stakeholders seeking to enhance destinations' image, tour quality and overall tourist satisfaction.

Originality/value

This paper provides original contributions to the field of tourism by examining the effect of tour quality on tourist satisfaction. It integrates the factors, namely tourist expectations and motivations, into the analysis, offering insights into delivering customized tour experiences that meet tourists' needs.