bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting the impact of Schistosoma mansoni regulating mechanisms on transmission dynamics using SchiSTOP, a novel modelling framework
Authors: Malizia Veronica , de Vlas Sake J. , Roes Kit C.B. , Giardina Federica
Published: February 2024

Background The transmission cycle of Schistosoma is remarkably complex, including sexual reproduction in the human hosts and asexual reproduction in the intermediate host (freshwater snails). Patterns of rapid recrudescence after treatment and stable low transmission are often observed, hampering the achievement of control targets. Current mathematical models commonly assume regulation of transmission to occur at worm level through density-dependent egg production. However, conclusive evidence on this regulating mechanism is weak, especially for S. mansoni. In this study, we explore the interplay of different regulating mechanisms and their ability to explain observed patterns in S. mansoni epidemiology. Methodology/Principal findings We developed SchiSTOP: a hybrid stochastic agent-based and deterministic modelling framework to reproduce S. mansoni transmission in an age-structured human population. We implemented different models with regulating mechanisms at: i) worm-level (density-dependent egg production), ii) human-level (anti-reinfection immunity), and iii) snail-level (density-dependent snail dynamics). Additionally, we considered two functional choices for the age-specific exposure to water bodies. We compared the ability of each model to reproduce observed epidemiological patterns pre- and post-control, and we compared the successful models in their predictions of the impact of school-based and community-wide treatment. Simulations confirmed that assuming at least one regulating mechanism is required to reproduce a stable endemic equilibrium. Snail-level regulation was necessary to explain stable low transmission. Only models combining snail- and human-level regulation with an age-exposure function informed with water contact data were successful in reproducing observed patterns. However, the predicted probability of reaching the control targets varied across successful models. Conclusions/Significance The choice of regulating mechanisms in schistosomiasis dynamics largely determines the model-predicted feasibility to reach control targets. Overall, the models that successfully explained observed patterns for S. mansoni suggest that reaching the control targets may be more challenging than currently thought. Conclusions highlight the importance of regulating mechanisms to be included in transmission models used for policy.
Personality correlates of past-year alcohol use in individuals with severe alcohol use disorder and a lifetime history of involvement in Alcoholics Anonymous
Authors: Lannoy Severine , Svikis Dace , Stephenson Mallory , Polak Kathryn , Kendler Kenneth , Edwards Alexis
Published: February 2024

Background: Alcohol Use Disorder (AUD) is a highly impairing condition with important public health impacts. Despite the availability of treatment options for AUD, research shows that few people receive treatment, and even fewer can maintain abstinence/low drinking levels. This study investigated the role of personality traits in current alcohol use among individuals with severe AUD who ever attended Alcoholics Anonymous (AA), a widespread and easily accessible self-help group for alcohol problems. Methods: Univariable and multivariable regressions were performed separately in females and males with alcohol consumption as an outcome. Socioeconomic factors, genetic liability, and psychopathology were included as covariates. Results: Results from the multivariable model indicated that in females who attended AA, higher alcohol use was related to both positive and negative urgency as well as low sensation seeking, while in males, higher alcohol use was related to positive urgency. Results also indicated an important role of younger age and lower educational levels in higher alcohol use in both sexes. Moreover, single males and those with lower AUD severity were at higher risk of using alcohol in the past year. Conclusions: These findings highlighted sex-specific correlates of drinking in individuals with AUD who engaged in self-help groups. Findings may be useful to improve treatment options, as personality encompasses modifiable traits that can be targeted in psychological interventions.
HLA-A*03:01 is associated with visceral leishmaniasis development in people living with HIV in Ethiopia
Authors: de Vrij Nicky , Vandoren Romi , Ramadan Kadrie , Van Hul Anke , Kassa Mekibib , Melkamu Roma , Yeshanew Arega , Bogale Tadfe , Beyene Hailemariam , Sisay Kasaye , Kibret Aderajew , Mersha Dagnew , Cuypers Wim L. , Vogt Florian , van Henten Saskia , Ritmeijer Koert , Pham Thao-Thy , Meysman Pieter , Laukens Kris , Cuypers Bart , Diro Ermias , Mohammed Rezika , van Griensven Johan , Adriaensen Wim
Published: February 2024

Human immunodeficiency virus (HIV) co-infection is a major challenge for visceral leishmaniasis (VL) control, particularly in Ethiopia where the incidence of both pathogens is high. VL-HIV often leads to high rates of antileishmanial treatment failure and recurrent VL disease relapses. Considering the high prevalence of HIV and Leishmania in the Ethiopian population, preventing the progression of asymptomatic Leishmania infection to disease would be a valuable asset to VL disease control and to the clinical management of people living with HIV (PLWH). However, such a strategy requires good understanding of risk factors for VL development. In immunocompetent individuals living in Brazil, India, or Iran, the Human Leukocyte Antigen (HLA) gene region has been associated with VL development. We used NanoTYPE, an Oxford Nanopore Technologies sequencing-based HLA genotyping method, to detect associations between HLA genotype and VL development by comparing 78 PLWH with VL history and 46 PLWH that controlled a Leishmania infection, all living in a VL endemic region of North-West Ethiopia. We identified a strong association between HLA-A*03:01 and increased risk of VL development (OR = 3.89). These data provide candidate HLA alleles that can be further explored for inclusion in a potential Leishmania screen-and-treat strategy in VL endemic regions.
Adiposity and cancer: meta-analysis, mechanisms, and future perspectives
Authors: Watts Eleanor , Moore Steven C , Gunter Marc , Chatterjee Nilanjan
Published: February 2024

Obesity is a recognised risk factor for many cancers and with rising global prevalence, has become a leading cause of cancer. Here we summarise the current evidence from both population-based epidemiologic investigations and experimental studies on the role of obesity in cancer development. This review presents a new meta-analysis using data from 40 million individuals and reports positive associations with 19 cancer types. Utilising major new data from East Asia, the meta-analysis also shows that the strength of obesity and cancer associations varies regionally, with stronger relative risks for several cancers in East Asia. This review also presents current evidence on the mechanisms linking obesity and cancer and identifies promising future research directions. These include the use of new imaging data to circumvent the methodological issues involved with body mass index and the use of omics technologies to resolve biologic mechanisms with greater precision and clarity.
Neuroradiological findings in GAA-FGF14ataxia (SCA27B): more than cerebellar atrophy
Authors: Chen Shihan , Ashton Catherine , Sakalla Rawan , Clement Guillemette , Planel Sophie , Bonnet Céline , Lamont Phillipa , Kulanthaivelu Karthik , Nalini Atchayaram , Houlden Henry , Duquette Antoine , Dicaire Marie-Josée , Iruzubieta Agudo Pablo , Ruiz Martinez Javier , Marco de Lucas Enrique , Sutil Berjon Rodrigo , Infante Ceberio Jon , Indelicato Elisabetta , Boesch Sylvia , Synofzik Matthis , Bender Benjamin , Danzi Matt C. , Zuchner Stephan , Pellerin David , Brais Bernard , Renaud Mathilde , La Piana Roberta
Published: February 2024

Background

GAA-FGF14ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of theFGF14gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA-FGF14ataxia is now needed to provide supportive diagnostic features and earlier disease recognition.

Methods

We performed a retrospective review of the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) to assess the presence of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles (SCPs) involvement, we verified its presence in 54 GAA-FGF14ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we performed quantitative cerebellar segmentation in 5 affected subjects with available 3D T1-weighted images and matched controls.

Results

Cerebellar atrophy was documented in 33 subjects (94.3%). We observed SCP involvement in 22 subjects (62.8%) and confirmed this finding in 30/54 (55.6%) subjects from the validation cohorts. Cerebellar segmentation showed reduced mean volumes of lobules X and IV in the 5 affected individuals.

Conclusions

Cerebellar atrophy is a key feature of GAA-FGF14ataxia. The frequent SCP involvement observed in different cohorts may facilitate the diagnosis. The predominant involvement of lobule X correlates with the frequently observed downbeat nystagmus.
Microvascular insulin resistance associates with enhanced muscle glucose disposal in CD36 deficiency.
Authors: Shibao Cyndya A , Peche Vivek S. , Williams Ian M. , Samovski Dmitri , Pietka Terri A. , Abumrad Naji N. , Gamazon Eric , Goldberg Ira , Wasserman David , Abumrad Nada A.
Published: February 2024

Dysfunction of endothelial insulin delivery to muscle associates with insulin resistance. CD36, a fatty acid transporter and modulator of insulin signaling is abundant in endothelial cells, especially in capillaries. Humans with inherited 50% reduction in CD36 expression have endothelial dysfunction but whether it is associated with insulin resistance is unclear. Using hyperinsulinemic/euglycemic clamps in Cd36-/- and wildtype mice, and in 50% CD36 deficient humans and matched controls we found that Cd36-/- mice have enhanced systemic glucose disposal despite unaltered transendothelial insulin transfer and reductions in microvascular perfusion and blood vessel compliance. Partially CD36 deficient humans also have better glucose disposal than controls with no capillary recruitment by insulin. CD36 knockdown in primary human-derived microvascular cells impairs insulin action on AKT, endothelial nitric oxide synthase, and nitric oxide release. Thus, insulin resistance of microvascular function in CD36 deficiency paradoxically associates with increased glucose utilization, likely through a remodeling of muscle gene expression.
Differential connectivity of frontolimbic circuit induced by individualized disorder-specific stimuli in distinct symptom profiles of obsessive-compulsive disorder
Authors: Thatikonda Navya Spurthi , Narayanaswamy Janardhanan C , Venkatasubramanian Ganesan , Y C Janardhan Reddy , Arumugham Shyam Sundar
Published: February 2024

Background: Emotional processing deficits in obsessive-compulsive disorder (OCD) are reportedly caused by an aberrant frontolimbic circuit activation with inconsistent evidence, possibly due to symptom heterogeneity. We compared the activation and connectivity patterns of the frontolimbic structures during symptom provocation between patients with distinct symptom profiles of OCD. Methods: We recruited 37 symptomatic OCD subjects categorized based on predominant symptom profiles, i.e., 19 with contamination/washing symptoms (OCD-C) and 18 with taboo thoughts (OCD-T), along with 17 healthy controls (HC). All subjects were evaluated with comprehensive clinical assessments and functional magnetic resonance imaging (fMRI) while appraising personalized disorder-specific visual stimuli with contrasting neutral stimuli as part of an individualized symptom provocation (ISP) task. Results: OCD-C subjects had decreased task-dependent mean activation of left amygdala and right hippocampus compared to the other groups during symptom induction. Task-modulated functional connectivity analyses during ISP task revealed that HC had increased connectivity between right hippocampus and bilateral supplementary motor cortex, right insula and left cerebellum, left insula and inferior temporal gyrus than OCD-C. OCD-T subjects had greater connectivity between right insula and left cerebellum than OCD-C and increased connectivity of medial frontal cortex with right lateral occipital cortex than HC. Conclusions: Contamination-related symptoms had decreased activation and altered connectivity of frontolimbic circuit during emotional provocation. Replicating these findings on larger samples with other symptom profiles might help develop personalized, targeted interventions for this heterogeneous disorder.
Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease
Authors: Wiesman Alex I , Madge Victoria , Fon Edward A , Dagher Alain , Collins D. Louis , Baillet Sylvain ,   PREVENT-AD Research Group,   Quebec Parkinson Network
Published: February 2024

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the impact of reduced LC norepinephrine signaling on brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8 - 12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is also stronger in fronto-motor cortices, which are regions with high densities of norepinephrine transporters in the healthy brain, and where alpha activity is negatively related to attention scores. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15 - 29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity reflects dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.
Feasibility study to assess the delivery of a novel isometric exercise intervention for people with high blood pressure in a healthcare setting
Authors: Wiles Jonathan D. , Santer Ellie , Rees-Roberts Melanie , Borthwick Rachel , Doulton Timothy , Swift Pauline A. , Pellatt-Higgins Tracy , Saxby Katie L. , Mills Ashley , Gousia Katerina , MacInnes Douglas , O'Driscoll Jamie M. , West Alan , Darby John , Short Vanessa , Farmer Christopher
Published: February 2024

BACKGROUND: Hypertension affects 1:4 adults and increases the risk of CV disease. Management aims to reduce blood pressure to a level that minimizes risk; up to 50% of people don't achieve blood pressure targets often due to insufficient treatment or poor adherence. Exercise has a role to play in the management of hypertension. The impact of isometric exercise on hypertension in healthcare settings is poorly understood. METHODS: Randomized controlled open-label multicentre feasibility study of isometric exercise compared to standard care in unmedicated hypertensives. Participants received an individualised isometric wall squat prescription and performed 4 x 2-minute bouts thrice weekly for 6-months. We assessed recruitment, deliverability, attrition, adherence, and variance in blood pressure change. RESULTS: 41 participants (56 +/- 15 years), 59% women, were randomized. Isometric exercise was found to be easily deliverable to all participants. At 6-months 34% withdrew, of those who completed isometric exercise 87% of their sessions were at the correct intensity. Variance in blood pressure change was 14.4 mmHg. The study was not powered to show a difference in blood pressure between groups, however blood pressure reductions were seen in the intervention group at all study time points compared to baseline. CONCLUSIONS: The results have allowed us to calculate a sample size (n=542) for a full randomised controlled trial. The results demonstrate good acceptability and adherence rates to the treatment protocol. Our results show a signal towards a consistent systolic blood pressure reduction in the isometric exercise group compared to baseline. REGISTRATION:NCT04936022https://classic.clinicaltrials.gov/ct2/show/NCT04936022cond=isometric+exercise&draw=2&rank=7 Registry Identifier: ISRCTN:13472393
Prohibiting Babel - A call for professional remote interpreting services in pre-operation anaesthesia information
Authors: Gerger Gernot , Graf Nikolaus , Klager Elisabeth , Doppler Klara , Langauer Armin , Albrecht Verena , Bilir Aylin , Willschke Harald , Baron David M. , Kletecka-Pulker Maria
Published: February 2024

Introduction: Language barriers within clinical settings pose a threat to patient safety. As a potential impediment to understanding, they hinder the process of obtaining informed consent. This study investigates the impact of the current use of interpreters, with a particular focus on the efficacy of engaging laypersons as interpreters, rather than professional interpreters. A further objective is to explore the validity and reliability of phone-based telemedicine. Methods: In three groups (N per group = 30), we compared how using lay or professional interpreters affected non-German speaking patients’ subjectively perceived understanding (understood vs. not understood) and recollection (recollected vs. not recollected) of information about general anaesthesia. Fluent German speaking patients served as the control group. Statistical analyses (χ2 tests and binomial) were calculated to show differences between and within the groups.  Results: All three groups indicated similar, high self-reported levels of having understood the medical information provided. This was in stark contrast to the assessed objective recollection data. In the lay interpreter group, recollection of anaesthesia facts was low; only around half of participants recalled specific facts. For patients supported by professional interpreters, their recollection of facts about anaesthesia was significantly enhanced and elevated to the same level of the control group (fluent in German). Moreover, for these patients, providing information by means of  phone-based telemedicine before anaesthesia yielded high levels of understanding and recollection of anaesthesia facts. Conclusion: Phone-based telemedicine is a safe and reliable method of communication in the professional interpreter group and German speaking control group, but not in the lay interpreter group. Compared to lay interpreters, professional interpreters significantly improve patients’ uptake of critical information about general anaesthesia, thus highlighting the importance of professional interpreters for patient safety and informed consent.
Non-Consensual Sex among Japanese Women in the COVID-19 Pandemic: A Large-Scale Nationwide Survey-Based Study
Authors: Suzuki Tomoya , Kaneda Yudai , Kotera Yasuhiro , Tanimoto Tetsuya , Ozaki Akihiko , Bhandari Divya , Horiuchi Sayaka , Tabuchi Takahiro
Published: February 2024

Background: Non-consensual sex including rape and sexual assault has been a global concern and may have been influenced by the COVID-19 pandemic, however the information on this topic is limited. Therefore, our objective was to survey the incidence rate of non-consensual sex among Japanese women aged 15-79 years between April to September 2020, following the COVID-19 pandemic in Japan.   Materials and Methods: We utilized the data obtained from a nationwide, cross-sectional internet survey conducted in Japan between August and September 2020. Sampling weights were applied to calculate national estimates, and multivariable logistic regression was performed to identify factors associated with non-consensual sex. Data was extracted from a cross-sectional, web-based, self-administered survey of approximately 2.2 million individuals from the general public, including in men and women.   Results: Excluding men and responses with inconsistencies, the final analysis included 12,809 women participants, with 138 (1.1%) reporting experiencing non-consensual sex within a five-month period. Being aged 15–29 years and having a worsened mental or economic status were associated with experiencing non-consensual sex.   Conclusions: Early intervention to prevent individuals from becoming victims of sexual harm should be extended to economically vulnerable and young women, especially during times of societal upheaval such as the COVID-19 pandemic. Additionally, Japan should prioritize the implementation of comprehensive education on the concept of sexual consent.
Inflammatory pain resolution by mouse serum-derived small extracellular vesicles
Authors: Lin Zhucheng , Luo Xuan , Wickman Jason R , Reddy Deepa , Pande Richa , Tian Yuzhen , Triana Vivian , Lee Jingyun , Furdui Cristina M , Pink Desmond , Sacan Ahmet , Ajit Seena K
Published: February 2024

Chronic pain is a significant public health issue. Current treatments have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs) to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can carry RNAs, proteins, and lipid mediators to recipient cells via circulation. sEVs can be beneficial or harmful depending on their source and contents. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naive control or spared nerve injury (SNI) model donor mice were injected intrathecally into naive recipient mice. Basal mechanical thresholds transiently increased in recipient mice. This effect was mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. A single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice delayed mechanical allodynia in SNI model mice and accelerated recovery from inflammatory pain after complete Freund's adjuvant (CFA) injection. ChipCytometry of spinal cord and dorsal root ganglion (DRG) from sEV treated mice showed that prophylactic sEV treatment reduced the number of natural killer (NK) and NKT cells in spinal cord and increased CD206+ anti-inflammatory macrophages in (DRG) after CFA injection. Further characterization of sEVs showed the presence of immune markers suggesting that sEVs can exert immunomodulatory effects in recipient mice to promote the resolution of inflammatory pain. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.
Genome sequences of three Konjac mosaic virus (KoMV) variants
Authors: Breit Timo M , de Leeuw Wim C , van Olst Marina F , Ensink Wim A , van Leeuwen Selina M , Jonker Martijs J , Dekker Rob J
Published: February 2024

This study explores the genomic diversity of three novel Konjac mosaic virus (KoMV) variants, originating from distinct Zantedeschia (calla lily) commercial cultivars. Virus-derived small RNA sequencing was performed and the complete KoMV variant genome sequences were determined by de novo assembly of short reads. All KoMV variants showed substantial nucleotide, as well as protein differences as compared to the KoMV RefSeq sequence.
MRI economics: Balancing sample size and scan duration in brain wide association studies
Authors: Ooi Leon Qi Rong , Orban Csaba , Zhang Shaoshi , Nichols Thomas E. , Tan Trevor Wei Kiat , Kong Ru , Marek Scott , Dosenbach Nico U.F. , Laumann Timothy , Gordon Evan M , Yap Kwong Hsia , Ji Fang , Chong Joanna Su Xian , Chen Christopher , An Lijun , Franzmeier Nicolai , Roemer Sebastian Niclas , Hu Qingyu , Ren Jianxun , Liu Hesheng , Chopra Sidhant , Cocuzza Carrisa V. , Baker Justin T. , Zhou Juan Helen , Bzdok Danilo , Eickhoff Simon B. , Holmes Avram J. , Yeo B. T. Thomas ,   Alzheimer’s Disease Neuroimaging Initiative
Published: February 2024

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan time given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan time per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan time are broadly interchangeable up to 20-30 min of data. However, the returns of scan time diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed overhead costs associated with each participant (e.g., recruitment, non-imaging measures), prediction accuracy in many small-scale and some large-scale BWAS might benefit from longer scan time than typically assumed. These results generalize across phenotypic domains, scanners, acquisition protocols, racial groups, mental disorders, age groups, as well as resting-state and task-state functional connectivity. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations maximize sample size, at the expense of scan time, which can result in sub-optimal prediction accuracies and inefficient use of resources. Our empirically informed reference is available for future study design: WEB_APPLICATION_LINK
Transcriptional profiling during infection of potato NLRs and Phytophthora infestans effectors using cDNA enrichment sequencing
Authors: Kaur Amanpreet , Singh Vikrant , Byrne Stephen L , Armstrong Miles , Adams Thomas M , Harrower Brian , Mullins Ewen , Hein Ingo
Published: February 2024

An accurate assessment of host and pathogen gene expression during infection is critical for understanding the molecular aspects of host-pathogen interactions. Often, pathogen-derived transcripts are difficult to ascertain at early infection stages owing to the unfavourable transcript representation compared to the host genes. In this study, we compare two sequencing techniques, RNAseq and enrichment sequencing (RenSeq and PenSeq) of cDNA, to investigate gene expression patterns in the doubled monoploid potato (DM) infected with the late blight pathogen Phytophthora infestans. Our results reveal distinct advantages of cDNA RenSeq and PenSeq over traditional RNAseq in terms of target gene representation and transcriptional quantification at early infection stages. Throughout the infection time course, cDNA enrichment sequencing enables transcriptomic analyses for more targeted host and pathogen genes. For highly expressed genes that were sampled in parallel by both cDNA enrichment and RNAseq, a high level of concordance in expression profiles is observed, indicative of at least semi-quantitative gene expression representation following enrichment.
Structural insights into IMP2 dimerization and RNA binding
Authors: Zorc Stephen , Munoz-Tello Paola , O'Leary Timothy , Yu Xiaoyu , Nag Mithun , Hansel-Harris Althea , Forli Stefano , Griffin Patrick R. , Kojetin Douglas J. , Roy Raktim N. , Janiszewska Michalina
Published: February 2024

IGF2BP2 (IMP2) is an RNA-binding protein that contributes to cancer tumorigenesis and metabolic disorders. Structural studies focused on individual IMP2 domains have provided important mechanistic insights into IMP2 function; however, structural information on full-length IMP2 is lacking but necessary to understand how to target IMP2 activity in drug discovery. In this study, we investigated the behavior of full-length IMP2 and the influence of RNA binding using biophysical and structural methods including mass photometry, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), and small angle x-ray scattering (SAXS). We found that full-length IMP2 forms multiple oligomeric states but predominantly adopts a dimeric conformation. Molecular models derived from SAXS data suggest the dimer is formed in a head-to-tail orientation by the KH34 and RRM1 domains. Upon RNA binding, IMP2 forms a pseudo-symmetric dimer different from its apo/RNA-free state, with the KH12 domains of each IMP2 molecule forming the dimer interface. We also found that the formation of IMP2 oligomeric species, which includes dimers and higher-order oligomers, is sensitive to ionic strength and RNA binding. Our findings provide the first insight into the structural properties of full-length IMP2, which may lead to novel opportunities for disrupting its function with more effective IMP2 inhibitors.
Filamin A mediates embryonical palatal fusion by linking mechanotransduction with β-Catenin/Smad2
Authors: Wang Ziyi , Hayano Satoru , Weng Yao , Mu Xindi , Ono Mitsuaki , Piña Jeremie Oliver , D'Souza Rena N. , Yamashiro Takashi , Oohashi Toshitaka , Kamioka Hiroshi
Published: February 2024

To decipher potential mechanisms underlying cleft palate (CP), we used advanced bioinformatic integrated with literature mining and genome-wide association study (GWAS). Re-analysis of RNA-seq data (GSE45568, GSE185279) combined with literature mining highlighted the roles of Filamin A (Flna) and Epithelial-Mesenchymal Transition (EMT) in palatal development. Immunofluorescence of in vivo palatal shelves showed increased Flna in medial edge epithelial (MEE) cells and EMT cells located in an epithelial triangle. Inhibition of TGF-β or RhoA and mechanical stimuli impacted Flna expression in ex vivo cultured palatal shelves. Re-analysis of scRNA-seq data (GSE155928) highlighted a correlation between Flna and Ctnnb1 in EMT cells. Flna knockdown affected β-catenin/Smad2 expression in cultured palatal shelves and HaCaT cells. Epithelium-specific knockout of Flna delayed palatal fusion in female mice but not males. Mendelian randomization analysis suggested that parental habitual physical activity (HPA) was causally associated with lower risk of CP in their offspring. Together, these findings suggested that parental HPA could benefit their offspring's palatal development through Flna by linking mechanotransduction with the Wnt/TGF-β/Smad signaling pathways during palatal fusion.
CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner
Authors: Ching Ma. Enrica Angela , Hoyeck Myriam P , Basu Lahari , Merhi Rayanna , van Zyl Erin , Crawley Angela M , Bruin Jennifer E
Published: February 2024

Aims/hypothesis: The aryl hydrocarbon receptor (AhR) pathway is involved in cellular responses to a broad range of external stressors, making it an excellent candidate for understanding the interaction between environmental factors and type 2 diabetes risk. Studies suggest deleting or downregulating AhR protects against metabolic dysfunction in high-fat diet (HFD) fed mice; however, the contribution of downstream AhR targets in driving this phenotype remains unexamined. Cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) are canonical AhR targets that encode xenobiotic metabolism enzymes. Interestingly, we have demonstrated that HFD feeding increases Cyp1a1 expression in mouse islets, which suggests CYP1A enzymes are involved in the response to metabolic stress. Since CYP1A1/1A2 activity can produce reactive oxygen intermediates, we hypothesized that chronic activation of these enzymes in tissues critical for regulating glucose homeostasis (e.g., liver, adipose, islets) will contribute to metabolic dysfunction following HFD feeding. Methods: At 29 to 31 weeks of age, male and female global Cyp1a1/1a2 knockout (CypKO) and wildtype littermate control (CypWT) mice were fed either a 45% HFD or standard rodent chow for 14 weeks. Metabolic assessments were conducted throughout the study. Results: CypKO females were partially protected from HFD-induced glucose intolerance compared to CypWT females, but both genotypes exhibited similar levels of insulin resistance. CypKO females also had lower plasma insulin levels in vivo and suppressed insulin secretion in isolated islets ex vivo compared to CypWT females. Gene expression patterns in female islets were generally similar across genotype and diet groups. In contrast, CypWT males became hyperinsulinemic and insulin resistant within 2 weeks of HFD feeding, while CypKO males maintained normal plasma insulin levels and insulin sensitivity. HFD feeding upregulated Cyp1a1 in CypWT male islets and this was accompanied by elevation of other islet stress genes. Interestingly, HFD feeding did not induce these stress gene responses in CypKO male islets, suggesting the islet stress response is mediated by activation of CYP1A1. We expected the global deletion of Cyp1a1/1a2 to have pronounced effects in the liver, but surprisingly, changes in liver pathology were predominantly driven by diet and not genotype in both sexes. Similarly, overall adiposity and adipose tissue inflammation were not affected by genotype. Conclusions: Our study highlights a novel role of islet Cyp1a1/1a2 in shaping the systemic metabolic response to HFD feeding. Our data suggest that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and the islet stress response. Importantly, the effects of Cyp1a1/1a2 deletion are sex-dependent.
Aspergillus dsRNA virus drives fungal fitness and pathogenicity in the mammalian host
Authors: Shlezinger Neta , Lerer Vanda , Rocha Marina , Adeoye John , Hayby Hilla
Published: February 2024

Fungal pathogens pose a significant threat to global health. Aspergillus fumigatus accounts for approximately 65% of all invasive fungal infections in humans, with mortality rates from aspergillosis reaching nearly 50%. Fungal virulence in plant pathogenic fungi can be modified by mycoviruses, viruses that infect fungi. However, their impact on fungal pathogenesis in mammals has remained largely unexplored. Here, utilizing an A. fumigatus strain naturally infected with Aspergillus fumigatus polymycovirus-1M (AfuPmV-1M), we found that the mycovirus confers a significant survival advantage to the fungus under conditions of oxidative stress, heat stress, and within the murine lung. Thus, AfuPmV-1M modulates fungal fitness, resulting in increased virulence and the progression of exacerbated fungal disease. Moreover, antiviral treatment reverses the exacerbated virus-mediated virulence, representing a promising "antipathogenicity" therapy against virus-bearing pathogenic fungi. Taken together, these data suggest that mycoviruses play a significant role as "backseat drivers" in human fungal diseases, presenting critical clinical implications.
Expanding the phage galaxy: Isolation and characterization of five novel Streptomyces siphoviruses Ankus, Byblos, DekoNeimoidia, Mandalore, and Naboo
Authors: Erdrich Sebastian , Luthe Tom , Kever Larissa , Badia Roige Biel , Arsova Borjana , Davoudi Eva , Frunzke Julia
Published: February 2024

Key features of the actinobacterial genusStreptomycesare multicellular, filamentous growth and production of a broad portfolio of bioactive molecules. These characteristics appear to play an important role in phage-host interactions and are modulated by phages during infection. To accelerate research of such interactions and the investigation of novel immune systems in multicellular bacteria, phage isolation, sequencing, and characterization are needed. This is a prerequisite for establishing systematic collections that appropriately cover phage diversity for comparative analyses. As part of a public outreach programme within the priority programme SPP 2330, involving local schools, we describe the isolation and characterization of five novelStreptomycessiphoviruses infectingS. griseus,S. venezuelae, andS. olivaceus. All isolates are virulent members of two existing genera and, additionally, establish a new genus in theStanwilliamsviridaefamily. In addition to an extensive set of tRNAs and proteins involved in phage replication, about 80% of phage genes encode hypothetical proteins, underlining the yet underexplored phage diversity and genomic dark matter still found in bacteriophages infecting actinobacteria. Taken together, phages Ankus, Byblos, DekoNeimoidia, Mandalore, and Naboo expand the phage diversity and contribute to ongoing research in the field ofStreptomycesphage-host interactions.
Genes required for the formation of virulence-provoking bacterial sphingolipids
Authors: Olea-Ozuna Roberto Jhonatan , Poggio Sebastian , Bergström Ed , Osorio Aurora , ELUFISAN TEMIDAYO OLUYOMI , Padilla-Gómez Jonathan , Martínez-Aguilar Lourdes , López-Lara Isabel M , Thomas-Oates Jane , Geiger Otto
Published: February 2024

Sphingolipids are ubiquitous in membranes of eukaryotes and are associated with important cellular functions. Although sphingolipids occur scarcely in bacteria, for some of them they are essential and, in other bacteria, they contribute to fitness and stability of the outer membrane, such as in the well-studied α-proteobacteriumCaulobacter crescentus. We previously defined five structural genes for ceramide synthesis inC. crescentus. However, other mutants affected in genes of this same genomic region show cofitness with a mutant deficient in serine palmitoyltransferase. Here we show that at least two phospho-sphingolipids are produced inC. crescentusand that at least another six gene products are needed for the decoration of ceramide upon phospho-sphingolipid formation. All eleven genes participating in phospho-sphingolipid formation are also required inC. crescentusfor membrane stability and for displaying sensitivity towards the antibiotic polymyxin B. The genes for the formation of complex phospho-sphingolipids are also required forC. crescentusvirulence onGalleria mellonellainsect larvae.
Developing Hybrid Systems to Address O2Uncoupling in Multi-Component Rieske Oxygenases
Authors: Runda Michael E. , Miao Hui , de Kok Niels A. W. , Schmidt Sandy
Published: February 2024

Rieske non-heme iron oxygenases (ROs) are redox enzymes that are essential for microbial biodegradation and natural product synthesis. These enzymes utilize molecular oxygen for oxygenation reactions, making them very useful in applied enzymology due to their broad reaction scope and high selectivities. The mechanism of oxygen activation in ROs involves electron transfers between redox centers of associated protein components, forming an electron transfer chain (ETC). Although the ETC is essential for electron replenishment, it carries the risk of reactive oxygen species (ROS) formation due to electron loss during oxygen activation. Our previous study linked ROS formation to O2uncoupling in the flavin-dependent reductase of the three-component cumene dioxygenase (CDO). In the present study, we extend this finding by investigating the effects of ROS formation on the multi-component CDO system in a cell-free environment. In particular, we focus on the effects of hydrogen peroxide (H2O2) formation in the presence of a NADH cofactor regeneration system on the efficiency of CDO catalytic efficacy in vitro. Based on this, we propose the implementation of hybrid systems with alternative (non-native) redox partners for CDO, which are highly advantageous in terms of reduced H2O2formation and increased product formation. The hybrid system consisting of the RO-reductase from phthalate dioxygenase (PDR) and CDO proved to be the most promising for the oxyfunctionalization of indene, showing a 4-fold increase in product formation (20 mM) over 24 h at a 3-fold increase in production rate compared to CDO-WT.
Alternative translation initiation produces synaptic organizer proteoforms with distinct localization and functions
Authors: Lee Paul Jongseo , Soares Alexa R , Sun Yu , Fai Caroline , Picciotto Marina , Guo Junjie U
Published: February 2024

While previous studies suggest that many mRNAs contain more than one translation initiation site (TIS), the biological significance of most alternative TISs and their corresponding protein isoforms (proteoforms) remains undetermined. Here we show that alternative translation initiation at a CUG and an AUG TIS in neuronal pentraxin receptor (NPR) mRNA produces two proteoforms, and their relative abundance is regulated by both neuronal activity as well as an adjacent RNA secondary structure. Downstream AUG initiation transforms the N-terminal transmembrane domain into a signal peptide, thereby converting NPR to a secreted factor sufficient to promote synaptic clustering of AMPA-type glutamate receptors. Changing the relative proteoform ratio, but not the overall NPR abundance reduces AMPA receptor in parvalbumin (PV)-positive interneurons and induces changes in learning behaviors in mice. In addition to NPR, N-terminal extensions of C1q-like synaptic organizers, mediated by upstream AUU start codons, anchor these otherwise secreted factors to the membrane. Thus, our results uncovered the plasticity of N-terminal signal sequences regulated by alternative TIS usage as a widespread mechanism to diversify protein localization and functions.
Identification of novel Bromodomain inhibitors ofTrypanosoma cruziBromodomain Factor 2 (TcBDF2) using a fluorescence polarization-base high-throughput assay
Authors: Serra Esteban Carlos , Tavernelli Luis , Alonso Victoria Lucia , Peña Imanol , Rodríguez Araya Elvio , Manarin Romina , Cantizani Juan , Martin Julio , Salamanca Juan , Bamborough Paul , Calderón Felix , Gabarro Raquel
Published: February 2024

Bromodomains are structural folds present in all eukaryotic cells that bind to other proteins recognizing acetylated lysines. Most proteins with bromodomains are part of nuclear complexes that interact with acetylated histone residues and participate in regulating DNA replication, transcription, and repair through chromatin structure remodeling. Bromodomain inhibitors are small molecules that bind to the hydrophobic pocket of bromodomains, interfering with the interaction with acetylated histones. Using a fluorescent probe, we have developed an assay to select inhibitors of the bromodomain factor 2 ofTrypanosoma cruzi(TcBDF2) using fluorescence polarization. Initially, a library of 28,251 compounds was screened in an endpoint assay. The top 350 ranked compounds were further analyzed in a dose-response assay. From this analysis, 7 compounds were obtained that had not been previously characterized as bromodomain inhibitors. Although these compounds did not exhibit significative trypanocidal activity, all showedbona fideinteraction withTcBDF2 with dissociation constants between 1 and 3 uM validating these assays to search for bromodomain inhibitors.
Lytic transglycosylase repertoire diversity enables daughter cell separation and antibiotic resistance inEscherichia coliunder acidic stress
Authors: Lee Chang-Ro , Son Ji Eun , Park Si Hyoung , Choi Umji
Published: February 2024

Peptidoglycan (PG) is an indispensable architectural element that imparts physical toughness and rigidity to the bacterial envelope. It is also a dynamic structure that undergoes continuous turnover or autolysis.Escherichia colipossesses redundant autolytic enzymes responsible for PG turnover; however, the rationale behind the existence of numerous autolytic enzymes remains incompletely understood. In this study, we elucidated the physiological roles of MltE and MltC, members of the lytic transglycosylase (LTG) family that catalyze the cleavage of glycosidic bonds between disaccharide subunits within PG strands. MltE and MltC are acidic LTGs that exhibit increased enzymatic activity and protein levels under acidic pH conditions, respectively. Deletion of these two LTGs results in a pronounced growth defect and elevated membrane permeability at acidic pH. Furthermore, these two LTGs are crucial for resistance against various antibiotics, particularly vancomycin. Intriguingly, inactivation of these LTGs induces a chaining morphology, indicative of daughter cell separation defects, only under acidic pH conditions. Simultaneous deletion of PG amidases, the known contributors to daughter cell separation, exacerbates the chaining phenotype at acidic pH. This suggests that the two LTGs may participate in the cleavage of glycan strands between daughter cells that cannot be resolved by PG amidases under acidic pH conditions. Collectively, our findings highlight the role of LTG repertoire diversity in facilitating bacterial survival and antibiotic resistance under stressful conditions.
A General Mechanism for Initiating the General Stress Response in Bacteria
Authors: Baral Rishika , Ho Kristin , Kumar Ramasamy P. , Hopkins Jesse B. , Watkins Maxwell B. , LaRussa Salvatore , Caban-Penix Suhaily , Calderone Logan A. , Bradshaw Niels
Published: February 2024

The General Stress Response promotes survival of bacteria in adverse conditions, but how sensor proteins transduce species-specific signals to initiate the response is not known. The serine/threonine phosphatase RsbU initiates the General Stress Response inB. subtilisupon binding a partner protein (RsbT) that is released from sequestration by environmental stresses. We report that RsbT activates RsbU by inducing otherwise flexible linkers of RsbU to form a short coiled-coil that dimerizes and activates the phosphatase domains. Importantly, we present evidence that related coiled-coil linkers and phosphatase dimers transduce signals from diverse sensor domains to control the General Stress Response and other signaling across bacterial phyla. This coiled-coil linker transduction mechanism additionally suggests a resolution to the mystery of how shared sensory domains control serine/threonine phosphatases, diguanylate cyclases and histidine kinases. We propose that this provides bacteria with a modularly exchangeable toolkit for the evolution of diverse signaling pathways.