bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning insights into distinct patterns of polygenic adaptation across human populations
Authors: Tripathi Devashish , Bhattacharyya Chandrika , Basu Analabha
Published: November 2024

Response to spatiotemporal variation in selection gradients resulted in signatures of polygenic adaptation in human genomes. We introduce RAISING, a two-stage deep learning framework that optimizes neural network architecture through hyperparameter tuning before performing feature selection and prediction tasks. We tested RAISING on published and newly designed simulations that incorporate the complex interplay between demographic history and selection gradients. RAISING outperformed Phylogenetic Generalized Least Squares (PGLS), ridge regression and DeepGenomeScan, with significantly higher true positive rates (TPR) in detecting genetic adaptation. It reduced computational time by 60-fold and increased TPR by up to 28% compared to DeepGenomeScan on published data. In more complex demographic simulations, RAISING showed lower false discoveries and significantly higher TPR, up to 17-fold, compared to other methods. RAISING demonstrated robustness with least sensitivity to demographic history, selection gradient and their interactions. We developed a sliding window method for genome-wide implementation of RAISING to overcome the computational challenges of high-dimensional genomic data. Applied to African, European, South Asian and East Asian populations, we identified multiple genomic regions undergoing polygenic selection. Notably, ∼70% of the regions identified in Africans are unique, with broad patterns distinguishing them from non-Africans, corroborating the Out of Africa dispersal model.
Efficient suppression of premature termination codons with alanine by engineered chimeric pyrrolysine tRNAs
Authors: Awawdeh Aya , Tapia Alejandro , Alshawi Sarah A , Dawodu Olabode , Gaier Sarah A , Specht Caitlin , Beaudoin Jean-Denis , Tharp Jeffery M , Vargas-Rodriguez Oscar
Published: November 2024

Mutations that introduce premature termination codons (PTCs) within protein-coding genes are associated with incurable and severe genetic diseases. Many PTC-associated disorders are life-threatening and have no approved medical treatment options. Suppressor transfer RNAs (sup-tRNAs) with the capacity to translate PTCs represent a promising therapeutic strategy to treat these conditions; however, developing novel sup-tRNAs with high efficiency and specificity often requires extensive engineering and screening. Moreover, these efforts are not always successful at producing more efficient sup-tRNAs. Here we show that a pyrrolysine (Pyl) tRNA (tRNAPyl), which naturally translates the UAG stop codon, offers a favorable scaffold for developing sup-tRNAs that restore protein synthesis from PTC-containing genes. We created a series of rationally designed Pyl tRNAScaffold Suppressor-tRNAs (PASS-tRNAs) that are substrates of bacterial and human alanyl-tRNA synthetase. Using a PTC-containing fluorescent reporter gene, PASS-tRNAs restore protein synthesis to wild-type levels in bacterial cells. In human cells, PASS-tRNAs display robust and consistent PTC suppression in multiple reporter genes, including pathogenic mutations in the tumor suppressor gene BRCA1 associated with breast and ovarian cancer. Moreover, PTC suppression occurred with high codon specificity and no observed cellular dysregulation. Collectively, these results unveil a new class of sup-tRNAs with encouraging potential for tRNA-based therapeutic applications.
scCancerExplorer: a comprehensive database for interactively exploring single-cell multi-omics data of human pan-cancer
Authors: Huang Changzhi , Liu Zekai , Guo Yunlei , Wang Wanchu , Yuan Zhen , Guan Yusheng , Pan Deng , Hu Zhibin , Sun Linhua , Fu Zan , Bian Shuhui
Published: November 2024

Genomic, epigenomic and transcriptomic alterations are hallmarks of cancer cells, and are closely connected. Especially, epigenetic regulation plays a critical role in tumorigenesis and progression. The growing single-cell epigenome data in cancer research provide new opportunities for data mining from a more comprehensive perspective. However, there is still a lack of databases designed for interactively exploring the single-cell multi-omics data of human pan-cancer, especially for the single-cell epigenome data. To fill in the gap, we developed scCancerExplorer, a comprehensive and user-friendly database to facilitate the exploration of the single-cell genome, epigenome (chromatin accessibility and DNA methylation), and transcriptome data of 50 cancer types. Five major modules were provided to explore those data interactively, including ‘Integrated multi-omics analysis’, ‘Single-cell transcriptome’, ‘Single-cell epigenome’, ‘Single-cell genome’ and ‘TCGA analysis’. By simple clicking, users can easily investigate gene expression features, chromatin accessibility patterns, transcription factor activities, DNA methylation states, copy number variations and TCGA survival analysis results. Taken together, scCancerExplorer is distinguished from previous databases with rich and interactive functions for exploring the single-cell multi-omics data of human pan-cancer. It bridges the gap between single-cell multi-omics data and the end-users, and will facilitate progress in the field of cancer research. scCancerExplorer is freely accessible via https://bianlab.cn/scCancerExplorer.
Long-term outcomes of IgA nephropathy in China
Authors: Shen Xue , Chen Pei , Liu Muqing , Liu Lijun , Shi Sufang , Zhou Xujie , Lv Jicheng , Zhang Hong
Published: November 2024

Background

The long-term prognosis of immunoglobulin A nephropathy (IgAN) and the optimal target for proteinuria treatment remain controversial. This study, utilizing a large prospective cohort from China, aims to assess the long-term outcomes of IgAN and to explore the definition of proteinuria remission.

Methods

We enrolled 2141 patients with biopsy-proven IgAN, all with at least 12 months of follow-up, from a prospective IgAN cohort at Peking University First Hospital. We utilized Kaplan–Meier analysis, Cox regression and an estimated glomerular filtration rate (eGFR) slope calculated via a linear mixed model to investigate kidney outcomes.

Results

The median (Q1, Q3) baseline proteinuria was 1.26 (0.65, 2.40) g/day, and the eGFR was 80 (52, 103) mL/min/1.73 m2. After a mean follow-up of 5.8 (±4.4) years, 509 (24%) patients progressed to end-stage kidney disease (ESKD). The median kidney survival time was 12.4 years, the annual event rate of ESKD was 41.1 per 1000 person-years and the 15-year kidney survival rate was 40%. Time-averaged proteinuria level was strongly associated with kidney failure (adjusted hazard ratio 1.76, 95% confidence interval 1.65 to 1.88). Restriction cubic spline analysis indicated that the risk of ESKD increases rapidly when time-average proteinuria exceeded 0.5 g/day. There was no significant difference in long-term kidney survival between patients with proteinuria <0.3 g/day and those with 0.3–0.5 g/day, with both groups demonstrating a better prognosis.

Conclusion

The long-term outcomes for patients with IgAN under current treatment strategies remain poor, with most progressing to ESKD within 15 years. Patients with time-averaged proteinuria ≥0.5 g/day experience worse kidney outcomes, challenging the previous view that proteinuria <1.0 g/day was associated with a low risk of kidney failure.
Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma
Authors: Dewdney Brittany , Miranda Panimaya Jeffreena , Kuchibhotla Mani , Palanisamy Ranjith , Richworth Caitlyn , Milligan Carol J , Ng Zi Ying , Ursich Lauren , Petrou Steve , Fletcher Emily V , Daly Roger J , Lim Kam Sian Terry C C , Valvi Santosh , Endersby Raelene , Johns Terrance G
Published: November 2024

Background

Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.

Methods

Seventy-two ion channel inhibitors were screened in patient-derived glioblastoma cells, and cell viability was determined using the ViaLight Assay. Cell cycle and apoptosis analysis were determined with flow cytometry using PI and Annexin V staining, respectively. Protein and phosphoprotein expression was determined using mass spectrometry and analyzed using gene set enrichment analysis. Kaplan-Meier survival analyses were performed using intracranial xenograft models of GBM6 and WK1 cells.

Results

The voltage-gated sodium channel modulator, DPI-201-106, was revealed to reduce glioblastoma cell viability in vitro by inducing cell cycle arrest and apoptosis. Phosphoproteomics indicated that DPI-201-106 may impact DNA damage response (DDR) pathways. Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice.

Conclusions

DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.
Real Clinical Effectiveness of Molnupiravir Against 30-day Mortality Among 74 541 SARS-CoV-2–Positive Patients: A Nationwide Cohort Study From the Czech Republic
Authors: Pavlík Tomáš , Jarkovský Jiří , Šanca Ondřej , Koziar Vašáková Martina , Dlouhý Pavel , Černý Vladimír , Štourač Petr , Válek Vlastimil , Dušek Ladislav
Published: November 2024

Background

We examined the clinical effectiveness of molnupiravir in reducing deaths in a real-world cohort of adult patients with COVID-19 during the Omicron outbreak.

Methods

This was a population-wide retrospective cohort study in the Czech Republic. We analyzed all 74 541 patients with an officially registered diagnosis of SARS-CoV-2 infection between 1 January and 31 December 2022, aged 18 years or older, treated with molnupiravir. The primary outcome was 30-day all-cause mortality; the secondary outcome was 30-day COVID-19-related mortality. Hazard ratios (HRs) were estimated using stratified Cox regression and the Fine-Gray model.

Results

The use of molnupiravir in adult SARS-CoV-2 positive patients was associated with a lower risk of both 30-day all-cause mortality: adjusted HR 0.58 (95% confidence interval, 0.53–0.64; P < .001) and 30-day COVID-19–related mortality: adjusted HR 0.50 (95% confidence interval, 0.42–0.58; P < .001). The effect of molnupiravir was highly significant regardless of sex, Deyo-Charlson Comorbidity Index score, hospitalization status, COVID-19 vaccination status, and patients older than age 65 years.

Conclusions

In this cohort study, early initiation of molnupiravir was associated with a significant reduction in 30-day all-cause and COVID-19–related mortality in adult SARS-CoV-2 positive patients.
Community Approaches to Archaeology, Heritage, and Museums
Authors: Apaydin Veysel
Published: November 2024

This chapter explores the ways in which the fields of archaeology, heritage, and museums developed in relation to communities from a historical perspective. On the one hand, the emergence and development of these fields was based on colonialist and nationalist perspectives that not only excluded communities from heritage, archaeological, and museum research and work through their top-down approaches, but also appropriated the material culture and intellectual property of the local and Indigenous communities. On the other hand, the last quarter of the twentieth century witnessed an emergence of ethical and people-centered approaches and methods that aim to include communities in research, heritage, and museum work and decision-making processes. This chapter critically examines the changing attitudes of archaeology, heritage, and museums towards communities from a historical perspective.
A Mean Value Theorem for General Dirichlet Series
Authors: Broucke Frederik , Hilberdink Titus
Published: November 2024

In this paper we obtain a mean value theorem for a general Dirichlet series $f(s)= \sum_{j=1}^\infty a_j n_j^{-s}$ with positive coefficients for which the counting function $A(x) = \sum_{n_{j}\le x}a_{j}$ satisfies $A(x)=\rho x + O(x^\beta)$ for some ρ > 0 and β < 1. We prove that $\frac1T\int_0^T |\,f(\sigma+it)|^2\, dt \to \sum_{j=1}^\infty a_j^2n_j^{-2\sigma}$ for $\sigma\gt\frac{1+\beta}{2}$ and obtain an upper bound for this moment for $\beta\lt\sigma\le \frac{1+\beta}{2}$. We provide a number of examples indicating the sharpness of our results.
Development of equivalent dose assessment methodology for the lens of the eye at nuclear power plant workers
Authors: Kim Siyoung , Son Jungkwon , Kim Cheon-Woo
Published: November 2024

As the International Commission on Radiological Protection lowers the equivalent dose limit for lens of the eye of radiation workers, the importance of radiation protection for the lens of the eye has been increased. In the case of poor working condition, such as high temperatures and humid environments at nuclear power plants, wearing an eye dosemeter near the worker’s eye may interfere with work. In addition, it would not be reasonable for all workers to wear an eye dosemeter to evaluate the lens equivalent dose even in areas with an expected low exposure dose in the NPPs. Therefore, it is necessary to develop an indirect assessment method for lens equivalent dose. The purpose of this study is to develop an indirect assessment method for a lens equivalent dose using correlation factors between whole-body dose and eye. The correlation factors are calculated by MCNP simulation results.
Psychotic Experiences and Risk of Suicidal Thoughts and Behaviors: A Systematic Review and Meta-Analysis of Longitudinal Population Studies
Authors: O’Hare Kirstie , Fadiloglu Kubra , Lång Ulla , Healy Colm , Cannon Mary , DeVylder Jordan , Kelleher Ian
Published: November 2024

Background and Hypothesis

Since a prior systematic review and meta-analysis reported an association between psychotic experiences (PEs) and suicidal thoughts and behaviors, a large number of new studies have been published on the topic, including several novel studies on the association between PEs and transition from suicidal ideation to attempt.

Study Design

Two authors independently searched PubMed, Embase, CINAHL, and PsycINFO databases from inception until July 2023, conducted data extraction, and assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. Random-effects models were used to calculate pooled odds ratios (ORs) for the association of PEs and subsequent suicide ideation, suicide attempts, suicide death, and transition from suicidal ideation to attempt, first for the total population, and second stratified by age group. Secondary analyses assessed the mediating role of co-occurring psychopathology.

Study Results

Twenty studies from 18 different samples (n = 81,861) were identified. Individuals who reported PEs had increased odds of subsequent suicidal ideation (k = 12, OR = 1.90, 95% CI = 1.65-2.19), suicide attempt (k = 13, OR = 2.95, 95% CI = 2.21-3.94), transition from suicidal ideation to suicide attempt (k = 3, OR = 2.83, 95% CI = 1.60-4.99), and suicide death (k = 1, OR = 4.39, 95% CI = 1.63-11.80). This heightened risk was stable across childhood, adolescence, and adulthood. PEs predicted suicide attempts over and above co-occurring psychopathology (k = 8, OR = 2.85, 95% CI = 2.06-3.95).

Conclusions

Individuals reporting PEs are at increased risk of all types of suicidal thoughts and behaviors. In addition, PEs are particularly important risk markers for future suicidal behaviors, including in individuals already reporting suicidal ideation. This risk is in excess of what is explained by co-occurring psychopathology.
Pilonidal Disease Management in Young Adults: A Retrospective Analysis of Practices in a single tertiary centre in Bahrain
Authors: Isa Ahmed J. , Alqatari Ali , Daoud Rabbani Mahmoud , Althawadi Reem , Ali Noora Fuad , Salman Esra
Published: November 2024

Background

Pilonidal disease is a prevalent skin condition that predominantly affects young males. This study, conducted at Salmaniya Medical Complex in Bahrain, aimed to analyze the demographics, treatment methodologies, and complications associated with pilonidal disease.

Materials and Methods

We analyzed the medical records of 56 patients, comparing our practices to the American Society of Colon and Rectal Surgeons (ASCRS) guidelines. Variables collected included patient demographics (age and gender), details on preoperative and postoperative antibiotics, the type of surgical intervention performed, the closure technique used, and follow-up results at 2 months post-discharge,

Results

Our findings confirmed the high prevalence of the disease in young males (75%), with a median age at presentation being 20.5 years. Our practices showed minimal compliance (≤69%) to key recommendations. We found no documented practices for hair removal, phenol application, fibrin glue, or minimally invasive approaches. The most common surgical approach was primary closure (60%), followed by flap reconstruction (16%) and leaving wounds open (7%). The commonest complications were wound dehiscence and surgical site infection (27% each). Post-operative complications were significant, with 67.6% in patients who received pre- operative antibiotics and 63.6% in those who received post-operative antibiotics. However, no statistical link to closure type was found, likely due to our small sample size.

Conclusion

We recommend reassessing our management protocols to align with ASCRS guidelines and considering non-operative treatments to reduce morbidity. This study underscores the need for guideline adherence and the potential benefits of non-operative treatments in managing pilonidal disease.
Perspectives on the potential application of microRNAs in the diagnosis and treatment of triple-negative breast cancer
Authors: Wu Yeqin , Song Haitao , Shi Huifang , Wang Gangping
Published: November 2024

Triple-negative breast cancer (TNBC) is currently the most heterogeneous and aggressive breast cancer type. It has a high recurrence rate, poor clinical prospects, and lack of predictive markers and potential treatment options. Dysregulated microRNAs (miRNAs) are involved in various cellular processes in TNBC. Moreover, variations in the miRNA levels in TNBC may act as a dependable indicator for predicting the effectiveness and specificity of treatments. Currently, the application of miRNAs for breast cancer therapy is primarily in the preclinical stage, with a focus on identifying highly specific and sensitive miRNAs that could offer new possibilities for early diagnosis, clinical treatment, and prognostic monitoring of TNBC.
Nasoethmoidal Dermoid Cyst With Intracranial Extension. Case Presentation and Surgical Management
Authors: Giugliano Villarroel Carlos , Ortiz Araya Javiera , Carvajal Guzmán Melissa , Ghazal Mohamad Nour
Published: November 2024

Nasoethmoidal dermoid cysts are rare congenital ectodermal malformations. Unlike other dermoid cysts, those located in the midline can exhibit intracranial extension. Clinically, they may manifest with sebaceous discharge through a fistulous orifice and other morphologic alterations, occasionally presenting with complications at the onset. The authors present a clinical case of a nasoethmoidal dermoid cyst with an intracranial extension, treated with combined interdisciplinary surgical intervention. An adequate imaging evaluation before the surgical planning and complete lesion resection are crucial, considering their high recurrence rates.
Three-dimensional Visualization Technology With 3DSlicer and Laser Guidance for Deep Brain Hematoma Evacuation in Primary Hospitals: A Technical Note
Authors: Huang Jian , Fei Xi-feng , He Bao , Sun Zhixiang , Shi Lei , Cai Shi-zhong
Published: November 2024

We present a minimally invasive technique for deep brain hematoma evacuation that combines 3-dimensional visualization through 3DSlicer and laser-guided navigation, providing a practical and cost-effective alternative to traditional navigation in resource-limited settings.
Uncovering causal gene-tissue pairs and variants: A multivariable TWAS method controlling for infinitesimal effects
Authors: Yang Yihe , Lorincz-Comi Noah , Zhu Xiaofeng
Published: November 2024

Transcriptome-wide association studies (TWAS) are commonly used to prioritize causal genes underlying associations found in genome-wide association studies (GWAS) and have been extended to identify causal genes through multivariable TWAS methods. However, recent studies have shown that widespread infinitesimal effects due to polygenicity can impair the performance of these methods. In this report, we introduce a multivariable TWAS method named Tissue-Gene pairs, direct causal Variants, and Infinitesimal effects selector (TGVIS) to identify tissue-specific causal genes and direct causal variants while accounting for infinitesimal effects. In simulations, TGVIS maintains an accurate prioritization of causal gene-tissue pairs and variants and demonstrates comparable or superior power to existing approaches, regardless of the presence of infinitesimal effects. In the real data analysis of GWAS summary data of 45 cardiometabolic traits and expression/splicing quantitative trait loci (eQTL/sQTL) from 31 tissues, TGVIS is able to improve causal gene prioritization and identifies novel genes that were missed by conventional TWAS.
NERVE 2.0: boosting the New Enhanced Reverse Vaccinology Environment via artificial intelligence and a user-friendly web interface
Authors: Conte Andrea , Gulmini Nicola , Costa Francesco , Cartura Matteo , Bröhl Felix , Patanè Francesco , Filippini Francesco
Published: November 2024

Background

Vaccines development in this millennium started by the milestone work onNeisseria meningitidis B, reporting the invention of Reverse Vaccinology (RV), which allows to identify vaccine candidates (VCs) by screening bacterial pathogens genome or proteome through computational analyses. When NERVE (New Enhanced RV Environment), the first RV software integrating tools to perform the selection of VCs, was released, it prompted further development in the field. However, the problem-solving potential of most, if not all, RV programs is still largely unexploited by experimental vaccinologists that impaired by somehow difficult interfaces, requiring bioinformatic skills.

Results

We report here on the development and release of NERVE 2.0 (available at:https://nerve-bio.org) which keeps the original integrative and modular approach of NERVE, while showing higher predictive performance than its previous version and other web-RV programs (Vaxign and Vaxijen). We renewed some of its modules and added innovative ones, such asLoop Razor, to recover fragments of promising vaccine candidates orepitopepredictfor the epitope prediction binding affinities and population coverage. Along with two newly built AI (Artificial Intelligence)-based models: ESPAAN and Virulent. To improve user-friendliness, NERVE was shifted to a tutored, web-based interface, with a noSQL-database to consent the user to submit, obtain and retrieve analysis results at any moment.

Conclusions

With its redesigned and updated environment, NERVE 2.0 allows customisable and refinable bacterial protein vaccine analyses to all different kinds of users.
OPN5 and TRPV4 subserve intrinsic photosensitivity in mouse corneal epithelium
Authors: Lapajne Luka , Lakk Monika , Rudzitis Christopher N. , Vemaraju Shruti , Lang Richard A. , Hawlina Marko , Križaj David
Published: November 2024

Abstract

The ocular surface protects the eye from pathogens, mechanical impact and harmful radiation. Excessive exposure of corneal epithelial (CE) layers to ultraviolet B (UVB) photons compromises these protective functions and may be associated with inflammation, pain, vision loss and cancer. We investigated the mechanisms that translate corneal epithelial (CE) transduction of UVB photons into intracellular and inflammatory signaling. Optical imaging in dissociated CECs and intact CE sheets showed rapid, UVB-induced increases in intracellular calcium concentration [Ca2+]ithat were partially reduced by the TRPV4 antagonist HC067047, removal of extracellular Ca2+and knockdown of the Trpv4 gene, and obliterated by depletion of internal calcium stores. Knockdown of neuropsin and inhibition of phospholipase C signaling markedly reduced the amplitude of the evoked calcium signal. UVB photons promoted release of cytokines and chemokines that included interleukins, metalloproteinases and thymic stromal lymphopoietin (TSLP). CECs are thus intrinsically photosensitive, utilizing a rhabdomeric-like phototransduction pathway cou0led to cytokine release to alert trigeminal afferents and stromal keratocytes about the presence of harmful irradiation and protect the visual system from snow blindness, injury, vision loss and cancer.
From Fear to Feast: Rattlesnakes Navigate the Landscape of Fear to Optimize Foraging
Authors: Da Cunha Oceane , Dominguez Rio P , Horne L. Miles , Mead Joshua J. , Fournier Corentin , Johnson Jerry D , Seymoure Brett M
Published: November 2024

According to optimal foraging theory, mesopredators should forage in areas where their prey is abundant while avoiding high predation risk. Here, we investigate how environmental factors influence mesopredators’ abilities to minimize spatiotemporal overlap with predators while increasing spatiotemporal overlap with prey. We paired thirty western diamond-backed rattlesnake (Crotalus atrox) 3D-printed replicas with game cameras in West Texas for two years to quantify several spatiotemporal factors affecting prey availability and predation risk. Concurrently, 25Crotalus atroxwere radiotracked at the same site to gather activity and microhabitat selection data regarding free-ranging individuals. Random forest algorithms were trained using data obtained from the game camera and applied to predict the probability of predation and the probability of prey encounter for each radiotracking event. Time of day, month, vegetation structure, and concealment percentage, all had a significant association with the probability of predation and the probability of prey encounter. Our results suggest that rattlesnakes choose to be active when and where the probability of prey encounter was significantly higher than the probability of detection by predators, thus following optimal foraging theory. Our results demonstrate that mesopredators increase chances of prey capture while reducing predator detection in natural setting.
The mitochondrial methylation potential gates mitoribosome assembly
Authors: Glasgow Ruth I.C. , Singh Vivek , Peña-Pérez Lucía , Wilhalm Alissa , Moedas Marco F. , Moore David , Rosenberger Florian A. , Li Xinping , Atanassov Ilian , Saba Mira , Cipullo Miriam , Rorbach Joanna , Wedell Anna , Freyer Christoph , Amunts Alexey , Wredenberg Anna
Published: November 2024

S-adenosylmethionine (SAM) is crucial for cellular processes, primarily serving as the principal methyl group donor of the cell and playing a key role in gene regulation and translation on the ribosome. Inside mitochondria, SAM-dependent methylations occur at several steps of gene expression, but their role and significance remain unclear. Using direct long-read RNA sequencing on mouse tissue and mouse embryonic fibroblasts, we demonstrate that the mitochondrial ribosomal gene cluster is not efficiently processed without mitochondrial SAM. This results in the accumulation of unprocessed ribosomal RNA precursors. Protein profiling of ribosome fractions revealed that these precursors are associated with processing and ribosome assembly factors, indicating stalling at an early stage. Structural analysis of the mitochondrial ribosome by cryogenic electron microscopy revealed that mitochondrial SAM is required during peptidyl transferase centre formation and mitochondrial ribosome assembly. Our data thus identify a critical role for methylation at two steps during mitochondrial gene expression.
A novel rhodopsin-based voltage indicator for simultaneous two-photon optical recording with GCaMP in vivo
Authors: Villette Vincent , Yang Shang , Valenti Rosario , Macklin John J. , Bradley Jonathan , Mathieu Benjamin , Lombardini Alberto , Podgorski Kaspar , Dieudonné Stéphane , Schreiter Eric R. , Abdelfattah Ahmed S.
Published: November 2024

Genetically encoded voltage indicators (GEVIs) allow optical recording of membrane potential from targeted cellsin vivo. However, red GEVIs that are compatible with two-photon microscopy and that can be multiplexedin vivowith green reporters like GCaMP, are currently lacking. To address this gap, we explored diverse rhodopsin proteins as GEVIs and engineered a novel GEVI, 2Photron, based on a rhodopsin from the green algaeKlebsormidium nitens. 2Photron, combined with two photon ultrafast local volume excitation (ULoVE), enabled multiplexed readout of spiking and subthreshold voltage simultaneously with GCaMP calcium signals in visual cortical neurons of awake, behaving mice. These recordings revealed the cell-specific relationship of spiking and subthreshold voltage dynamics with GCaMP responses, highlighting the challenges of extracting underlying spike trains from calcium imaging.
Immunization with Plant-based Vaccine ExpressingToxoplasma gondiiSAG1 Fused to Plant HSP90 Elicits Protective Immune Response in Lambs
Authors: Campero Lucía M. , Gual Ignacio , Sander Valeria A. , Mendoza Morales Luisa F. , Ramos Duarte Victor A. , Formigo Paula M. , Sosa Emiliano , Lázaro Fermín , Scioli María Valeria , Atela Agustín , Legarralde Ariel , Hozbor Federico A. , Cantón Germán J. , Angel Sergio O. , Moore Dadín P. , Clemente Marina
Published: November 2024

Toxoplasma gondiiis a protozoan parasite causing toxoplasmosis, a principal concern for public health and livestock industries. Effective vaccination strategies are crucial for controlling toxoplasmosis, particularly in the lamb, which are significant reservoirs ofT. gondii. In addition, ovine toxoplasmosis also causes economic losses due to abortions and reproductive complications. In this study, we evaluated two immunization strategies to elucidate the immune protective potential of SAG1 fused to the plant Hsp90 adjuvant against experimental toxoplasmosis in lambs. We performed an oral administration of AtHsp81.2–SAG1HC-infiltrated fresh leaves homogenate (Plant Vaccine) and a subcutaneous administration of recombinant NbHsp90.3-SAG1HC produced inEscherichia coli(Recombinant Vaccine). Our results showed that only the Recombinant Vaccine significantly increased anti-rSAG1 total IgG values. In addition, only lambs immunized with the Plant Vaccine showed a significant increase in IFN-γ serum levels after the experimental infection (evaluated 8 days post-challenge). On the other hand, we also observed a statistically significant decrease in histopathological lesions (injury score) in challenged vaccinated lambs compared to challenged but not vaccinated animals (vehicle and control groups). Finally, to evaluateT. gondiiinfection, we choose the chimera rGra4-Gra7 as an acute phase protein marker. All lambs from the control and vehicle groups showed higher rates of serological reactivity than lambs from the vaccinated groups, concurrently with increased severity of lesions. These results suggest that both the plant-based and recombinant vaccines are promising candidates for controllingT. gondiiinfection in lambs, with potential benefits for enhancing public health and animal welfare.
Large scale capsid-mediated mobilisation of bacterial genomic DNA in the gut microbiome
Authors: Borodovich Tatiana , Wilson Jason S. , Bardy Pavol , Smith Muireann , Hill Conor , Khokhlova Ekaterina V. , Govi Bianca , Fogg Paul C.M. , Hill Colin , Shkoporov Andrey N.
Published: November 2024

Transducing bacteriophages and gene transfer agents (GTA) are constrained by their capsids’ structural properties in the length of host DNA they can package. Nanopore sequencing of intact capsid-packaged DNA molecules with full-sized reads can be used to establish the precise lengths and identity of individual packaged DNA molecules and their association with specific bacterial hosts. This approach was validated using a few well-characterised transducing systems, and then applied to study bacterial DNA encapsidation in the faecal microbiomes from three healthy human donors. Bacterial DNA encapsidation appears to be widespread in the microbiome with up to 5.4% of capsid-packaged DNA in the gut virome being of bacterial (non-prophage) origin. Generalised transduction and GTA activity are especially prevalent in the families Oscillospiraceae and Ruminococcaceae, whereas an example of lateral transduction was observed in genus Bacteroides. In addition to that, induction of prophages in a variety of highly prevalent gut bacteria was observed.
BREASTFEEDING SUPPORT BASED ON SELF-CARE FORM PERSPECTIVE PHILOSOPHY OF SCIENCE: A LITERATURE REVIEW
Authors: Pertami Sumirah Budi , Pandin Moses Glorino Rumambo , Yunitasari Esti , Triharini Mira
Published: November 2024

Introduction

Failure of the lactation process leads to decreased milk production, which is a serious problem especially regarding the health of the mother and child. Reduced milk production and failure to provide exclusive breastfeeding directly contribute to high infant morbidity.. Infants who are not breastfed can deteriorate their health and increase the risk of malnutrition and stunting. Breastfeeding mothers need the support of those closest to them, such as family members, friends, relatives and coworkers. The family, in this case the husband or parents, is considered the most capable party to influence the mother to maximize exclusive breastfeeding. Support from others or those closest to them plays a significant role in the success or failure of breastfeeding. The purpose of this study is to examine the philosophy of breastfeeding support from the perspective of the Self Care model theory.

Methods

This study used a literature review using the PICOS framework. Articles were searched from 3 databases namely Sciencedirect, Scopus, Sage. The keywords used in the literature search were breastfeeding AND support, AND self AND care AND theory AND model, AND postpartum. The search was limited to 2020-2024 publications, full articles, not review articles. The strategy used to search for articles using the PICOS framework. Then selected using the PRISMA diagram and obtained eleven articles. Quality assessment of eleven articles using the JBI Critical Appraisal tool.

Results

Eleven articles describing the theoretical application of the Dhorothy Orem Self Care Model can be used as guidelines in providing self-care to improve breastfeeding support.

Conclusion

a more efficient strategy to increase breast milk production can be developed by understanding the self-care model. In addition, the self-care model can be applied in breasfeeding support by providing self-care to improve breastfeeding practices.
Autoimmune responses to myelin-associated proteins as diagnostic and prognostic biomarkers of relapsing-remitting multiple sclerosis: associations with human herpesvirus-6 and Epstein-Barr Virus reactivation
Authors: Vojdani Aristo , Almulla Abbas F. , Vojdani Elroy , Li Jing , Zhang Yingqian , Maes Michael
Published: November 2024

Background

The pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is linked to autoimmune attacks against myelin proteins, and reactivation of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). However, the connection between viral reactivation and autoimmune biomarkers has remained unclear.

Objectives

To investigate immunoglobulin (Ig)G/IgA/IgM responses targeting myelin-related proteins in association with EBV and HHV-6 replication markers in RRMS.

Methods

We recruited 55 patients with RRMS and 63 healthy controls and assessed IgG/IgA/IgM responses against seven myelin-related components, as well as EBV nuclear antigen 1 (EBNA-1) and deoxyuridine-triphosphate nucleotidohydrolase (dUTPases). Disability was evaluated using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS).

Results

IgG/IgA/IgM levels targeting seven myelin-related proteins were significantly higher in RRMS than in controls. IgG against myelin basic protein (MBP) (IgG-MBP), IgM-myelin-associated glycoprotein (IgM-MAG)-37-60, IgA-MBP, and IgA-myelin-oligodendrocyte-glycoprotein (IgA-MOG-31-55) distinguished RRMS from controls with a predictive accuracy of 96.6% (sensitivity = 95.7%, specificity = 95.2%) and an area under the ROC curve of 0.991. A large part of the variance in the EDSS (around 75%) and MSSS score (62.8%) was explained by IgG-MBP, IgM-MBP, IgA-MOG-31-55, and IgM-MAG. Part of the variance (47.4%) in the IgG/IgA/IgM responses to myelin-related proteins was explained by immune responses to EBNA and deoxyuridine-triphosphate nucleotidohydrolases of EBV and HHV-6.

Conclusions

Autoimmune reactivities targeting myelin-related proteins are valuable biomarkers of RRMS and the severity and progression of RRMS. Reactivation of EBV and HHV-6 may trigger or maintain these autoimmune responses thereby impacting disease progression.
Quantitative guiding of developmental cell fate transitions using gene-free modelling
Authors: Hajji Ismail , Siggia Eric D. , Corson Francis , Keil Wolfgang
Published: November 2024

During development, cells gradually assume specialized fates via changes of transcriptional dynamics in thousands of genes. Terminal cell identities are then stabilized through the convergence of gene regulatory network dynamics and the accumulation of epigenetic DNA modifications. “Gene-free” (or geometric) modeling approaches for cell fate acquisition, which abstract from the underlying gene regulatory landscape and reason in phenotypic space, have been remarkably successful in explaining terminal fate outcomes. However, their implications for cellular dynamics during fate acquisition processes have so far not been testedin vivo. To do so, here we combine gene-free mathematical modeling of cell fate acquisition duringC. elegansvulval development with temporally controlled perturbations ofin vivosignaling dynamics using temperature sensitive (ts) mutant alleles of the EGF/Ras/MAPK and Notch signaling pathways. We show that gene-free modeling can quantitatively predict non-intuitive fate outcomes in a variety of ts genetic backgrounds, including pathway epistasis effects. In addition, we use gene-free modeling to infer how cell fate transitions can be guided towards specific outcomes through timed pulses of signaling activity and verify these model predictions quantitatively with temporally controlled signaling perturbations via temperature shifts in ts backgrounds. Our results highlight the predictive power of gene-free models beyond terminal fate outcomes and illustrate a new approach to quantitatively guide cell fate acquisition in a developmental context.
A nucleic acid prodrug activates mitochondrial respiration and extends lifespan
Authors: Anada Takahisa , Kawahara Michiharu , Shimada Taisei , Kuroda Ryotaro , Kage-Nakadai Eriko , Kobayashi Shingo , Tanaka Masaru
Published: November 2024

Mitochondrial dysfunction caused by aging leads to decreased energy metabolism, resulting in functional decline and increased frailty in multiple tissues. Strategies for protecting and activating mitochondria under stressful conditions are required to suppress aging and age-related diseases. However, it is challenging to develop drugs capable of boosting mitochondrial respiration and compensating for the reduced intracellular adenosine triphosphate (ATP) levels. In this study, we developed a prodrug that stimulates the metabolism of intracellular adenine nucleotides (AXP: adenosine monophosphate (AMP), adenosine diphosphate (ADP), and ATP). It enhances AMP-activated protein kinase activity, fatty acid oxidation, oxidative stress resistance, and mitochondrial respiration, thereby increasing the intracellular ATP levels. Furthermore, this prodrug markedly extended the lifespan ofCaenorhabditis elegans. The stimulation of the AXP energy metabolism (AXP stimulation) proposed in this study is expected to offer a new strategy against aging and pave the way for a novel approach in the bioenergetic molecules drug discovery.
Right posterior theta reflects human parahippocampal phase resetting by salient cues during goal-directed navigation
Authors: Güth Malte R. , Reid Andrew , Zhang Yu , Huntgeburth Sonja C. , Mill Ravi D. , Dagher Alain , Kerns Kim , Holroyd Clay B. , Petrides Michael , Cole Michael W. , Baker Travis E.
Published: November 2024

Animal and computational work indicate that phase resetting of theta oscillations (4-12 Hz) in the parahippocampal gyrus (PHG) by salient events (e.g., reward, landmarks) facilitates the encoding of goal-oriented information during navigation. Although well-studied in animals, this mechanism has not been empirically substantiated in humans. In the present article, we present data from two studies (Study 1: asynchronous EEG-MEG | Study 2: simultaneous EEG-fMRI) to investigate theta phase resetting and its relationship to PHG BOLD activation in healthy adults (aged 18-34 years old) navigating a virtual T-maze to find rewards. In the first experiment, both EEG and MEG data revealed a burst of theta power over right-posterior scalp locations following feedback onset (termed right-posterior theta, RPT), and RPT power and measures of phase resetting were sensitive to the subject’s spatial trajectory. In Experiment 2, we used probabilistic tractography data from the human connectome project to segment the anterior and posterior PHG based on differential connectivity profiles to other brain regions. This analysis resulted in a PHG subdivision consisting of four distinct anterior and two posterior PHG clusters. Next, a series of linear mixed effects models based on simultaneous EEG-fMRI data revealed that single-trial RPT peak power significantly predicted single-trial hemodynamic responses in two clusters within the posterior PHG and one in the anterior PHG. This coupling between RPT power and PHG BOLD was exclusive to trials performed during maze navigation, and not during a similar task devoid of the spatial context of the maze. These findings highlight a role of PHG theta phase resetting for the purpose of encoding salient information during goal-directed spatial navigation. Taken together, RPT during virtual navigation integrates experimental, computational, and theoretical research of PHG function in animals with human cognitive electrophysiology studies and clinical research on memory-related disorders such as Alzheimer’s disease.
Evaluation of Brain Age as a Specific Marker of Brain Health
Authors: Tan Trevor Wei Kiat , Nguyen Kim-Ngan , Zhang Chen , Kong Ru , Cheng Susan F , Ji Fang , Chong Joanna Su Xian , Chong Eddie Jun Yi , Venketasubramanian Narayanaswamy , Orban Csaba , Chee Michael W. L. , Chen Christopher , Zhou Juan Helen , Yeo B. T. Thomas ,   Alzheimer’s Disease Neuroimaging Initiative,   Australian Imaging Biomarkers and Lifestyle Study of Aging
Published: November 2024

Brain age is a powerful marker ofgeneralbrain health. Furthermore, brain age models are trained on large datasets, thus giving them a potential advantage in predictingspecificoutcomes – much like the success of finetuning large language models for specific applications. However, it is also well-accepted in machine learning that models trained to directly predict specific outcomes (i.e., direct models) often perform better than those trained on surrogate outcomes. Therefore, despite their much larger training data, it is unclear whether brain age models outperform direct models in predicting specific brain health outcomes. Here, we compare large-scale brain age models and direct models for predicting specific health outcomes in the context of Alzheimer’s Disease (AD) dementia. Using anatomical T1 scans from three continents (N = 1,848), we find that direct models outperform brain age models without finetuning. Finetuned brain age models yielded similar performance as direct models, but importantly, did not outperform direct models although the brain age models were pretrained on 1000 times more data than the direct models: N = 53,542 vs N = 50. Overall, our results do not discount brain age as a useful marker of general brain health. However, in this era of large-scale brain age models, our results suggest that small-scale, targeted approaches for extracting specific brain health markers still hold significant value.
Identification of Potential Hub Genes and Therapeutic Targets in Colorectal Cancer Using Integrated Bioinformatics Approaches
Authors: D Kamalakannan , R Manivannan , Kumar Suresh Gopal , Kumar Dilip
Published: November 2024

In this study, we took a comprehensive approach using bioinformatics to uncover potential therapeutic targets for colorectal cancer (CRC). We started by analyzing gene expression data from GEO2R to identify genes that were differentially expressed in CRC. Then, using FunRich software, we created Venn diagrams to visualize these genes. From the 191 upregulated genes we found, we focused on potential “hub genes” by looking at their network connections and strength, using the STRING database.To understand the roles of these hub genes, we performed functional analyses like Gene Ontology (GO) and pathway enrichment through the DAVID platform. This helped us pinpoint key biological processes and pathways linked to the genes we identified. We also looked at patient survival data from GEPIA, along with information on gene expression related to disease stages and metastatic progression. This helped us identify which hub genes were most relevant for CRC.In addition, we examined genetic changes and gene expression patterns in CRC patients through databases like cBioPortal and the Human Protein Atlas. This gave us more evidence supporting the involvement of these genes in the disease. Ultimately, our analysis highlighted CXCL8, FOXC1, ICOS, and MCF2 as potential hub genes with important roles in CRC. These genes may serve as useful biomarkers for both diagnosing CRC and predicting patient outcomes, and they could also help guide the development of targeted treatments to improve survival rates.