bluuebunny/crossref_metadata_2025 huggingface dataset:
Purifying selection and intraspecies recombination may drive the speciation in Crassostrea: evidence from complete mitochondria sequence ofCrassostrea hongkongensisand comparative genomic analysis
Authors: Sahu Basanta Pravas , Fazil Mohamed Madhar , Panda Subhasmita , Thiyagarajan Vengatesen
Published: April 2024

Repeat dynamics and recombination play a crucial role during the evolution of the mitochondrial genome in plants and animals. However, this phenomenon has got less attention within Crassostrea, a complex marine species found worldwide having high commercial value as well as efficient carbon neutralizer. During this study, we characterized the whole mitochondrial genomes ofC. hongkongensisretrieved from transcriptome data (GenBank acc. no. MZ073671). The current mitochondrial genome (18,616 bp) was composed of a non-coding control region (D-loop region), 2 ribosomal RNA (rRNA genes), 12 protein-coding genes (PCGs), and 23 transfer RNA (tRNA). Furthermore, comparative genomics analysis revealed that the present isolate is closely related to the Chinese isolate (NC_011518) with 99.82% similarity. Microsatellite analysis within the mitochondrial genome revealed its bias towards mononucleotide repeat A/T, di-nucleotide AG followed by AT and AC, trinucleotide AAT followed by AAG, ATC, and ATG. The recombination analysis deciphered the lack of interspecific recombination, but the presence of intraspecific recombination within ND1, ND2, and ND4L of Crassostrea species. Selection pressure analysis revealed the presence of purifying selection within maximum genes which drive the evolution of the species.
Complex-based Ligand-Binding Proteins Redesign by Equivariant Diffusion-based Generative Models
Authors: Nguyen Viet Thanh Duy , Nguyen Nhan , Hy Truong Son
Published: April 2024

Proteins, serving as the fundamental architects of biological processes, interact with ligands to perform a myriad of functions essential for life. The design and optimization of ligand-binding proteins are pivotal for advancing drug development and enhancing therapeutic efficacy. In this study, we introduce ProteinReDiff, a novel computational framework designed to revolutionize the redesign of ligand-binding proteins. Distinguished by its utilization of Equivariant Diffusion-based Generative Models and advanced computational modules, ProteinReDiff enables the creation of high-affinity ligand-binding proteins without the need for detailed structural information, leveraging instead the potential of initial protein sequences and ligand SMILES strings. Our thorough evaluation across sequence diversity, structural preservation, and ligand binding affinity underscores ProteinReDiff's potential to significantly advance computational drug discovery and protein engineering. Our source code is publicly available at https://github.com/HySonLab/Protein_Redesign
Harmonization of the fastest and densest responses embodies the humanlike reaction time of mice
Authors: Kim Chan Hee
Published: April 2024

Reaction time (RT) is important in evaluating delayed latency in behavior. Unlike that of humans, the RT of animals, in which the stimulus–response relationship is not one-to-one due to repeated responses per trial, may exhibit two peaks of the fastest and densest responses in a distribution of responses. We determined whether the two peak latencies are aligned for a single RT by controlling stimulus duration. In delay conditioning with mice using sound cues of 10, 5, and 2s, the 2s group exhibited the strongest positive correlations between the two peaks, as well as responses’ number and accuracy rate, suggesting coupling of the fastest and densest responses, and a one-to-one relationship between stimulus and response, respectively. We propose the use of harmonization of the two peaks, elicited by stimuli that induce minimal responses, as a criterion for designing animal experiments to mimic humanlike RT.
Selective attention and sensitivity to auditory disturbances in a virtually-real Classroom: Comparison of adults with and without AD(H)D
Authors: Levy Orel , Libman Hackmon Shirley , Zvilichovsky Yair , Korisky Adi , Bidet-Caulet Aurelie , Schweitzer Julie B. , Zion Golumbic Elana
Published: April 2024

Many people, and particularly individuals with Attention Deficit (Hyperactivity) Disorder (AD(H)D), find it difficult to maintain attention during classroom learning. However, traditional paradigms used to evaluate attention do not capture the complexity and dynamic nature of real-life classrooms. Using a novel Virtual Reality platform, coupled with measurement of neural activity, eye-gaze and skin conductance, here we studied the neurophysiological manifestations of attention and distractibility, under realistic learning conditions. Individuals with AD(H)D exhibited higher neural responses to irrelevant sounds and reduced speech tracking of the teacher, relative to controls. Additional neurophysiological measures, such the power of alpha-oscillations and frequency of gaze-shifts away from the teacher, contributed to explaining variance in self-reported AD(H)D symptoms across the sample. These ecologically-valid findings provide critical insight into the neurophysiological mechanisms underlying individual differences in the capacity for sustained attention and the proneness to distraction and mind-wandering, experienced in real-life situations.
scCaT: an explainable capsulating architecture for sepsis diagnosis transferring from single-cell RNA sequencing
Authors: Zheng Xubin , Meng Dian , Chen Duo , Wong Wan-Ki , To Ka-Ho , Zhu Lei , Wu JiaFei , Liang Yining , Leung Kwong-Sak , Wong Man-Hon , Cheng Lixin
Published: April 2024

Sepsis is a life-threatening condition characterized by an exaggerated immune response to pathogens, leading to organ damage and high mortality rates in the intensive care unit. Although deep learning has achieved impressive performance on prediction and classification tasks in medicine, it requires large amounts of data and lacks explainability, which hinder its application to sepsis diagnosis. We introduce a deep learning framework, called scCaT, which blends the capsulating architecture with Transformer to develop a sepsis diagnostic model using single-cell RNA sequencing data and transfers it to bulk RNA data. The capsulating architecture effectively groups genes into capsules based on biological functions, which provides explainability in encoding gene expressions. The Transformer serves as a decoder to classify sepsis patients and controls. Our model achieves high accuracy with an AUROC of 0.93 on the single-cell test set and an average AUROC of 0.98 on seven bulk RNA cohorts. Additionally, the capsules can recognize different cell types and distinguish sepsis from control samples based on their biological pathways. This study presents a novel approach for learning gene modules and transferring the model to other data types, offering potential benefits in diagnosing rare diseases with limited subjects.

Author summary

Deep learning models used in disease diagnosis usually suffer from insufficient data for training and the lack of explainability, especially in rare diseases. These shortages hinder their application to sepsis diagnosis. Here we propose a diagnostic framework name scCaT(https://github.com/Kimxbzheng/CaT), which transfers knowledge learned from single-cell RNA-seq, for diseases with insufficient bulk data. The framework uses capsulating architecture to group genes into capsules and provide explainability to the deep learning model for sepsis diagnosis. ScCaT achieves robust and outstanding performance for sepsis diagnosis in both scRNA-seq and bulk RNA datasets. This architecture offers potential approaches in diagnosing rare diseases with limited subjects with explainability.
Dental Caries Prevalence and Prevention Behaviour Related Factors among Adolescents in Nigeria: A Systematic Review and Meta-analysis
Authors: Afolabi Adebukunola O. , Ehizele Adebola O. , Nnawuihe Ukachi Chiwendu , Nwaokorie Francisca O. , Nwaozuru Ucheoma , Owotade Foluso , Lusher Joanne , Eleje George Uchenna , Alade Omolola T. , Akinsolu Folahanmi T. , Ezechi Oliver C. , Folayan Morenike O.
Published: April 2024

Background

Adolescence is a critical period of life that has implications for oral health and wellbeing, however, the oral health profile of adolescents in Nigeria is undocumented. This systematic review and meta-analysis determined the prevalence of caries and identified the caries prevention behaviours among adolescents in Nigeria.

Methods

In August 2023, a literature search was conducted across PubMed, Google Scholar, Academic Info, Cochrane and Refseek databases to identify studies on dental caries prevalence and caries prevention behaviour among adolescents aged 10 to 19 years in Nigeria. Two reviewers used an independent and double-blind approach to extract data, with discrepancies resolved by a third reviewer. Heterogeneity was assessed using I2percentages, and a funnel plot was constructed to assess the potential for publication bias. The meta-analysis employed a random effects model to ascertain the prevalence of dental caries. Subgroup analysis was conducted to explore the variation in caries prevalence by sex. The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework guidelines while the Joanna Briggs Institute Critical Appraisal Checklist was used to critically appraise the quality and integrity of the included studies. Registration of this systematic review was completed on PROSPERO CRD42024458849.

Results

Sixteen studies met the eligibility criteria. The pooled caries prevalence among adolescents in Nigeria was 23.0% (95% CI: 16, 30) with a pooled prevalence of 16.0% (p < 0.00001, 95% CI: 9 - 23) for males, and a pooled prevalence of 22.0% (p < 0.00001, 95% CI= 11 - 32) for females. The commonest caries prevention practices reported were daily tooth brushing, use of fluoride containing toothpastes and dental service utilization. Factors associated with caries among adolescents were a history of dental service utilization, poor oral hygiene practices and consumption of refined carbohydrates in-between-meals.

Conclusion

The high prevalence of dental caries among adolescents in Nigeria warrants programmatic attention with an emphasis on improving oral hygiene practices and controlling the consumption of refined carbohydrates in-between-meals. Dental service utilization for caries prevention needs to be encouraged.
Improved Lymphangiogenesis around Vascularized Lymph Node Flaps by Periodic Injection of Hyaluronidase in a Rodent Model
Authors: Cheon Hwayeong , Chen Linhai , Kim Sang-Ah , Gelvosa Ma Nessa , Hong Joon Pio , Jeon Jae Yong , Suh Hyunsuk Peter
Published: April 2024

Background

Vascularized lymph node transfer (VLNT) is an advanced surgical approach for secondary lymphedema (SLE) treatment, but tissue fibrosis around the lymph node flap (VLNF) inhibiting lymphangiogenesis is the biggest challenge undermining its therapeutic efficacy. Hyaluronidase (HLD), which is an enzyme that breaks down hyaluronic acid, may have the efficacy of reducing fibrosis and increasing the chance of lymphangiogenesis in the injury site.

Materials and methods

52 Sprague–Dawley rats with VLNF were divided into a group injected periodically with HLD and a control group and followed up. A follow-up study was performed for 13 weeks starting 1 week after model formation was examined. The limb volume and dermal backflow pattern were observed to evaluate the degree of lymphedema. The real-time ICG fluorescence intensity changes were measured to evaluate the degree of lymphatic drainage to the flap. Lastly, the number of regenerative lymphatic vessels and the degree of fibrosis were investigated.

Results

In the group injected with HLD periodically (VLNF+HLD group), swelling reduction and dermal backflow pattern recovery occurred rapidly in the 3rd week of follow-up compared to the only VLNF group. Moreover, the efficiency of lymphatic drainage into the flap was also improved in the VLNF+HLD group. They significantly had more newly formed lymphatic vessels along with a decrease in collagen fiber decomposition in the tissue around the VLNF by up to 26%.

Conclusion

These encouraging results pave the way for developing a combination strategy for SLE treatment involving HLD and VLNT. Furthermore, this finding may guide future research on the development of new drugs that could enhance the efficacy of VLNT surgery for SLE patients.

Graphic abstract
Lgr5+ductal cells of von Ebner’s glands are stem cells for turnover of posterior tongue taste buds
Authors: Harrison Theresa A. , Downs Anthony M. , Slepian Alexandria J. , van Es Johan H. , Clevers Hans , Defoe Dennis M.
Published: April 2024

Taste bud cells have a limited lifespan and must be continuously replaced along with the papilla epithelium in which they reside. Previous work has shown that expression of leucine- rich G protein-coupled receptor 5 (Lgr5), a Wnt pathway agonist, serves as a marker of adult stem/progenitor cells for taste buds located in posterior tongue (circumvallate and foliate), but not anterior tongue (fungiform), taste papillae. However, the specific location/niche of theLgr5-expressing cells supporting renewal and their phenotypic properties have not been fully explored. To address this, the genesis and fate of Lgr5+cells were examined in developing and adult mice using genetic reporter strains. Evidence fromLgr5-lacZandLgr5-GFPmice shows that, whileLgr5is broadly expressed in the epithelium of nascent circumvallate papillae and their trenches during embryonic development, it becomes concentrated within the ducts of adjacent von Ebner’s salivary glands during the first postnatal week, co-incident with the appearance of differentiated taste buds. In posterior tongue taste papillae of adult animals, sites of highestLgr5expression are found in excretory ducts, restricted to the outer (basal) layer of the bi-layered excretory zone. These Lgr5+cells are immunoreactive for keratin 14, like cells in the basal layer of extragemmal taste epithelium, and for Sox9, a marker of exocrine gland duct cells. Lineage tracing experiments with anLgr5-EGFP-IRES-CreERT2;R26-mTmGreporter show that Lgr5+ductal cells become labeled one day following Cre induction, prior to the appearance of descendent cells in taste buds and extragemmal epithelium. These data support a role for Lgr5+ductal cells as stem cells and suggest that a cooperative interaction exists between posterior taste epithelium and its associated salivary glands in taste cell turnover.
Enforced MYC expression selectively redirects transcriptional programs during human plasma cell differentiation
Authors: Vardaka Panagiota , Page Eden , Care Matthew A , Stephenson Sophie , Kemp Ben , Umpierrez Michelle , O’Callaghan Eleanor , Mabbutt Adam , Owen Roger , Hodson Daniel J , Doody Gina M , Tooze Reuben M
Published: April 2024

MYC provides a rheostat linking cell growth and division during plasma cell (PC) differentiation. Precise control of MYC is central to the network controlling differentiation. Deregulation of MYC drives transformation in aggressive B-cell neoplasms and is often accompanied by apoptotic protection conferred by BCL2. We assess how MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. Under permissive conditions for PC differentiation we find such deregulation does not transform cells. While driving loss of normal PC surface phenotype, MYC deregulation has little impact on components of regulatory circuitry controlling B-cell identity. This contrasts with profound impact on initiation of secretory output and secretory reprogramming, coupled to dampening ofXBP1and immunoglobulin gene enhancement and a shift toward distinct metabolic programs. The establishment of this aberrant state depends on MYC homology boxes (MB0 and MBII). Dependence on MBII is profound and resolves to residue W135.
A scoping review of evidence of naturally occurring Japanese encephalitis infection in vertebrate animals other than humans, ardeid birds and pigs
Authors: Levesque Zoë A. , Walsh Michael , Webb Cameron , Zadoks Ruth , Brookes Victoria J.
Published: April 2024

Japanese encephalitis virus (JEV) is the leading cause of human encephalitis in Asia. JEV is a vector-borne disease, mainly transmitted byCulexmosquitoes, withArdeidaebirds as maintenance hosts and pigs as amplifying hosts. Other vertebrate animal hosts have been suggested to play a role in the epidemiology of JEV. This scoping review followed PRISMA guidelines to identify species in which evidence of naturally occurring JEV infection was detected in vertebrates other than ardeid birds, pigs and people. Following systematic searches, 4372 records were screened, and data were extracted from 62 eligible studies. Direct evidence (virus, viral antigen or viral RNA) of JEV infection was identified in a variety of mammals and birds (not always identified to the species level), including bats, passerine birds (family Turdidae), livestock (cattle [Bos taurus] and a goat [Capra hircus]), carnivores (two meerkats [Suricata suricatta]), and one horse (Equus caballus). Bat families included Pteropodidae, Vespertilionidae, Rhinolophidae, Miniopteridae, Hipposideridae. Indirect evidence suggestive of JEV infection (antibodies) was detected in several mammalian and avian orders, as well as reported in two reptile species. However, a major limitation of the evidence of JEV infection identified in this review was diagnostic test accuracy, particularly for serological testing. Studies generally did not report diagnostic sensitivity or specificity. Although we hypothesise that bats and passerine birds could play an underappreciated role in JEV epidemiology, development of diagnostic tests to differentiate JEV from other orthoflaviviruses will be critical for effective surveillance in these, as well as the companion and livestock species that could be used to evaluate JEV control measures in currently endemic regions.
Genetic purging of strongly deleterious mutations underlies black-necked crane’s unusual escape from an extinction vortex
Authors: Cui Ning , Ma Xuntao , Wu Heqi , Chen Xiaocheng , Hung Chih-Ming , Zhang Lixun , Lei Fumin , Yang Le , Yan Dao , Yang Xiaojun , Dong Feng
Published: April 2024

Many species are undergoing rapid demographic declines, necessitating an examination of the resulting genetic impacts. The prevailing small population paradigm posits an elevated genetic load and extinction risk. However, instances of fast recovery from severe population bottlenecks suggest alternative outcomes. To investigate this issue, we performed a population genomic analysis on the black-necked crane, analyzing 42 modern and 11 historical genomes. This study revealed substantial evidence of large-effect allele purging underlying the unexpectedly rapid population recovery following an abrupt bottleneck during the 1980s. Nevertheless, forward simulations supposing a prolonged bottleneck (e.g., five generations) predicted a reversion with negative prospects, implying that rapid population recovery served as both the cause and consequence of the species escaping from an extinction vortex. These findings shed light on a potential positive microevolutionary response to current widespread population collapses and underscore the urgency of implementing active and effective conservation strategies to reverse this trend before it becomes irreversible.
Dynamic modelling of signalling pathways when ODEs are not feasible
Authors: Rachel Timo , Brombacher Eva , Wöhrle Svenja , Groß Olaf , Kreutz Clemens
Published: April 2024

Motivation

Mathematical modelling plays a crucial role in understanding inter- and intracellular signalling processes. Currently, ordinary differential equations (ODEs) are the predominant approach in systems biology for modelling such pathways. While ODE models offer mechanistic interpretability, they also suffer from limitations, including the need to consider all relevant compounds, resulting in large models difficult to handle numerically and requiring extensive data.

Results

In previous work, we introduced theretarded transient function (RTF)as an alternative method for modelling temporal responses of signalling pathways. Here, we extend the RTF approach to integrate concentration or dose-dependencies into the modelling of dynamics. With this advancement, RTF modelling now fully encompasses the application range of ordinary differential equation (ODE) models, which comprises predictions in both time and concentration domains. Moreover, characterizing dose-dependencies provides an intuitive way to investigate and characterize signalling differences between biological conditions or cell-types based on their response to stimulating inputs. To demonstrate the applicability of our extended approach, we employ data from time- and dose-dependent inflammasome activation in bone-marrow derived macrophages (BMDMs) treated with nigericin sodium salt. Our results show the effectiveness of the extended RTF approach as a generic framework for modelling dose-dependent kinetics in cellular signalling. The approach results in intuitively interpretable parameters that describe signal dynamics and enables predictive modelling of time- and dose-dependencies even if only individual cellular components are quantified.

Availability

The presented approach is available within the MATLAB-basedData2Dynamicsmodelling toolbox athttps://github.com/Data2Dynamicsandhttps://zenodo.org/records/14008247and as R code athttps://github.com/kreutz-lab/RTF.

Contact

clemens.kreutz@uniklinik-freiburg.de
Multiple endocrine defects in adult-onset Sprouty1/2/4 triple knockout mice
Authors: Altés Gisela , Olomí Anna , Perramon-Güell Aida , Hernández Sara , Casanovas Anna , Pérez Aurora , Díaz-Tocados Juan Miguel , Valdivielso José Manuel , Megino Cristina , Navaridas Raúl , Matias-Guiu Xavier , Klein Ophir D. , Egea Joaquim , Dolcet Xavi , Yeramian Andrée , Encinas Mario
Published: April 2024

Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinases, especially of Ret and the FGF receptors. As such, they play distinct and overlapping roles in embryo morphogenesis and are considered to be tumor suppressors in adult life. Genetic experiments in mice have defined in great detail the role of these genes during embryonic development, however their function in adult mice is less clearly established. Here we generate adult-onset, whole body Spry1/2/4 triple knockout mice. Tumor incidence in triple mutant mice is comparable to that of wild type littermates of up to one year of age, indicating that Sprouty loss per se is not sufficient to initiate tumorigenesis. On the other hand, triple knockout mice do not gain weight as they age, show less visceral fat, and have lower plasma glucose levels than wild type littermates, despite showing similar food intake and slightly reduced motor function. They also show alopecia, eyelid inflammation, and mild hyperthyroidism. Finally, triple knockout mice present phosphaturia and hypophosphatemia, suggesting exacerbated signaling downstream of FGF23. In conclusion, triple knockout mice develop a series of endocrine abnormalities but do not show increased tumor incidence.
Myosin II actively regulatesDrosophilaproprioceptors
Authors: Guan Chonglin , Nishi Kengo , Kreis Christian T. , Bäumchen Oliver , Göpfert Martin C. , Schmidt Christoph F.
Published: April 2024

Auditory receptors can be motile to actively amplify their mechanical input. Here we describe a novel and different type of motility that, residing in supporting cells, shapes physiological responses of mechanoreceptor cells. InDrosophilalarvae, supporting cap cells transmit mechanical stimuli to proprioceptive chordotonal neurons. We found that the cap cells are strongly pre-stretched at rest to twice their relaxed length. The tension in these cells is modulated by non-muscle myosin-II motors. Activating the motors optogenetically causes contractions of the cap cells. Cap-cell-specific knockdown of the regulatory light chain of myosin-II alters mechanically evoked receptor neuron responses, converting them from phasic to more tonic, impairing sensory adaptation. Hence, two motile mechanisms seem to operate in concert in insect chordotonal organs, one in the sensory receptor neurons, based on dynein, and the other in supporting cells, based on myosin.

One Sentence Summary

Myosin II motors in contractile cells pre-stretchDrosophilastretch receptors.
Long-read sequencing and structural variant characterization in 1,019 samples from the 1000 Genomes Project
Authors: Schloissnig Siegfried , Pani Samarendra , Rodriguez-Martin Bernardo , Ebler Jana , Hain Carsten , Tsapalou Vasiliki , Söylev Arda , Hüther Patrick , Ashraf Hufsah , Prodanov Timofey , Asparuhova Mila , Hunt Sarah , Rausch Tobias , Marschall Tobias , Korbel Jan O.
Published: April 2024

Structural variants (SVs) contribute significantly to human genetic diversity and disease1–4. Previously, SVs have remained incompletely resolved by population genomics, with short-read sequencing facing limitations in capturing the whole spectrum of SVs at nucleotide resolution5–7. Here we leveraged nanopore sequencing8to construct an intermediate coverage resource of 1,019 long-read genomes sampled within 26 human populations from the 1000 Genomes Project. By integrating linear and graph-based approaches for SV analysis via pangenome graph-augmentation, we uncover 167,291 sequence-resolved SVs in these samples, considerably advancing SV characterization compared to population-wide short-read sequencing studies3,4. Our analysis details diverse SV classes—deletions, duplications, insertions, and inversions—at population-scale. LINE-1 and SVA retrotransposition activities frequently mediate transductions9,10of unique sequences, with both mobile element classes transducing sequences at either the 3′- or 5′-end, depending on the source element locus. Furthermore, analyses of SV breakpoint junctions suggest a continuum of homology-mediated rearrangement processes are integral to SV formation, and highlight evidence for SV recurrence involving repeat sequences. Our open-access dataset underscores the transformative impact of long-read sequencing in advancing the characterisation of polymorphic genomic architectures, and provides a resource for guiding variant prioritisation in future long-read sequencing-based disease studies.
Suppression of bacterial cell death underlies the antagonistic interaction between ciprofloxacin and tetracycline inEscherichia coli
Authors: Broughton James , Fraisse Achille , Karoui Meriem El
Published: April 2024

Antibiotic combinations are an attractive strategy to maximise the efficiency of drug treatment and minimise resistance evolution, but we still lack a full understanding of their effect on bacterial cells. The interaction between DNA-targeting antibiotics, such as ciprofloxacin, and translation inhibitors, such as tetracycline, is antagonistic, resulting in a weaker effect on bacterial growth than expected from the effect of each single drug. This antagonism has been analysed in detail at the population level, but we lack a single-cell understanding of its effect and how it depends on nutrient availability. Here, we used a microfluidic device to quantify the antagonism between ciprofloxacin and tetracycline at the single-cell level in three nutrient conditions. We showed that improved growth is due to increased survival of cells under the drug combination compared to ciprofloxacin alone. This effect is growth-dependent, with better suppression in rich nutrient conditions. Quantification of the DNA damage response (SOS response) revealed two sub-populations among the cells that die upon ciprofloxacin treatment, with some cells reaching a very high level of SOS while others had a lower level of SOS, similar to surviving cells. The low-SOS cells were more frequent in fast growth conditions and showed increased survival under the drug combination but the high-SOS cells were hardly rescued by the drug combination. This result explains the stronger antagonistic effect of tetracycline on ciprofloxacin in fast growth compared to slow growth. Our results underscore the importance of single-cell quantification in understanding the bacterial response to antibiotic combinations and devising new treatment strategies.
Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity
Authors: Xie Qiqi , Du Yuanning , Ghosh Sugata , Rajendran Saranya , Cohen-Gadol Aaron A. , Baizabal José-Manuel , Nephew Kenneth P. , Han Leng , Shen Jia
Published: April 2024

Histone H3 Lysine 9 dimethylation or trimethylation (H3K9me2 or H3K9me3) marks more than half of the human genome, particularly in heterochromatin regions and specific genes within euchromatic regions. Enzymes catalyzing the methylation of H3K9 have individually been associated with the modulation of gene expression patterns involved in cancer progression, including suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, euchromatic histone-lysine N-methyltransferase 1 and 2 (EHMT1/2). However, a comprehensive comparison and understanding of the characteristics and mechanisms of these chromatin-modifying enzymes in cancers remains incompletely understood. In this study, we demonstrated that these six H3K9 methyltransferases differentially expressed in tumors and correlated expression with somatic copy number variations (CNVs) and DNA methylation patterns. Through integrative multi-omics analyses, we identified SUV39H1, SUV39H2, and SETDB1 as the key players among the six H3K9 methyltransferases that exhibited the most significant associations with cancer phenotypes. By incorporating SUV39H1, SUV39H2, and SETDB1, we developed a novel signature termed “H3K9me3 MtSig” (H3K9me3 methyltransferases signature). H3K9me3 MtSig was unique for various tumor types, had prognostic implications and was linked to significant signaling pathways, particularly in glioblastoma (GBM). Furthermore, elevated H3K9me3 MtSig was confirmed in GBM patient-derived cells and tissues. In addition, single-cell expression analysis of H3K9me3 MtSig in GBM tissues demonstrated a pattern related to the G2/M cell cycle and was negatively correlated with immune responses. H3K9me3-mediated repetitive sequence silencing by H3K9me3 MtSig, determined using ChIP-sequencing, contributed to these phenotypes, and inhibiting H3K9me3 MtSig in patient-derived GBM cells suppressed proliferation and increased immune responses. Translationally, H3K9me3 MtSig performed as an independent prognostic factor in a clinical prediction model, and drug susceptibility screening integrating H3K9me3 MtSig identified potential biomarkers and therapeutics for GBM. In summary, H3K9me3 MtSig has the potential to elucidate novel prognostic markers, therapeutic targets, and predictors of treatment response in GBM and other cancer types for clinical intervention.

Significance

Differential expressions of H3K9 methyltransferases across cancers correlates with clinical outcomes; in GBM, an H3K9me3 methyltransferase signature links to G2/M cell cycle, immune response pathways, and prognosis, aiding biomarker and treatment development.
Elevated DNA Damage without signs of aging in the short-sleeping Mexican Cavefish
Authors: Lloyd Evan , Xia Fanning , Moore Kinsley , Zertuche Carolina , Rastogi Aakriti , Kozol Rob , Kenzior Olga , Warren Wesley , Appelbaum Lior , Moran Rachel L. , Zhao Chongbei , Duboue Erik , Rohner Nicolas , Keene Alex C.
Published: April 2024

Dysregulation of sleep has widespread health consequences and represents an enormous health burden. Short-sleeping individuals are predisposed to the effects of neurodegeneration, suggesting a critical role for sleep in the maintenance of neuronal health. While the effects of sleep on cellular function are not completely understood, growing evidence has identified an association between sleep loss and DNA damage, raising the possibility that sleep facilitates efficient DNA repair. The Mexican tetra fish,Astyanax mexicanusprovides a model to investigate the evolutionary basis for changes in sleep and the consequences of sleep loss. Multiple cave-adapted populations of these fish have evolved to sleep for substantially less time compared to surface populations of the same species without identifiable impacts on healthspan or longevity. To investigate whether the evolved sleep loss is associated with DNA damage and cellular stress, we compared the DNA Damage Response (DDR) and oxidative stress levels betweenA. mexicanuspopulations. We measured markers of chronic sleep loss and discovered elevated levels of the DNA damage marker γH2AX in the brain, and increased oxidative stress in the gut of cavefish, consistent with chronic sleep deprivation. Notably, we found that acute UV-induced DNA damage elicited an increase in sleep in surface fish but not in cavefish. On a transcriptional level, only the surface fish activated the photoreactivation repair pathway following UV damage. These findings suggest a reduction of the DDR in cavefish compared to surface fish that coincides with elevated DNA damage in cavefish. To examine DDR pathways at a cellular level, we created an embryonic fibroblast cell line from the two populations ofA. mexicanus. We observed that both the DDR and DNA repair were diminished in the cavefish cells, corroborating thein vivofindings and suggesting that the acute response to DNA damage is lost in cavefish. To investigate the long-term impact of these changes, we compared the transcriptome in the brain and gut of aged surface fish and cavefish. Strikingly, many genes that are differentially expressed between young and old surface fish do not transcriptionally vary by age in cavefish. Taken together, these findings suggest that cavefish have developed resilience to sleep loss, despite possessing cellular hallmarks of chronic sleep deprivation.
Dependence of Contextual Modulation in Macaque V1 on Interlaminar Signal Flow
Authors: Zhu Shude , Oh Yu Jin , Trepka Ethan B. , Chen Xiaomo , Moore Tirin
Published: April 2024

In visual cortex, neural correlates of subjective perception can be generated by modulation of activity from beyond the classical receptive field (CRF). In macaque V1, activity generated by nonclassical receptive field (nCRF) stimulation involves different intracortical circuitry than activity generated by CRF stimulation, suggesting that interactions between neurons across V1 layers differ under CRF and nCRF stimulus conditions. Using Neuropixels probes, we measured border ownership modulation within large, local populations of V1 neurons. We found that neurons in single columns preferred the same side of objects located outside of the CRF. In addition, we found that cross-correlations between pairs of neurons situated across feedback/horizontal and input layers differed between CRF and nCRF stimulation. Furthermore, independent of the comparison with CRF stimulation, we observed that the magnitude of border ownership modulation increased with the proportion of information flow from feedback/horizontal layers to input layers. These results demonstrate that the flow of signals between layers covaries with the degree to which neurons integrate information from beyond the CRF.
hyve, a compositional visualisation engine for brain imaging data
Authors: Ciric Rastko , Xu Anna , Poldrack Russell A.
Published: April 2024

Visualisations facilitate the interpretation of geometrically structured data and results. However, heterogeneous geometries—such as volumes, surfaces, and networks—have traditionally mandated different software approaches. We introducehyve, a Python library that uses a compositional functional framework to enable parametric implementation of custom visualisations for different brain geometries. Under this framework, users compose a reusable visualisation protocol fromgeometricprimitives for representing data geometries,inputprimitives for common data formats and research objectives, andoutputprimitives for producing interactive displays or configurable snapshots.hyvealso writes documentation for user-constructed protocols, automates serial production of multiple visualisations, and includes an API for semantically organising an editable multi-panel figure. Through the seamless composition of input, output, and geometric primitives,hyvesupports creating visualisations for a range of neuroimaging research objectives.
Matrix Vesicles from Osteoblasts Promote Atherosclerotic Calcification
Authors: Wang Xiaoli , Ren Jie , Zhang Zhen , Fang Fei , Wang Erxiang , Li Jianwei , He Weihong , Shen Yang , Liu Xiaoheng
Published: April 2024

Backgrounds

Vascular calcification often occurs with osteoporosis, a contradictory association known as “the calcification paradox”. Osteoblast-derived matrix vesicles (Ost-MVs) have been implicated in bone mineralization, and also have a potential role in ectopic vascular calcification. Herein, we aim to investigate the contributions that Ost-MVs make to the bone–vascular calcification paradox and the underlying mechanisms.

Methods and Results

Hyperlipidemia-induced atherosclerotic calcification in mice was accompanied with bone mineral loss, as evidenced by reduced deposition of Ost-MVs in the bone matrix and increased release of Ost-MVs into the circulation. Intravenous injection of fluorescent DiІ-labeled Ost-MVs revealed a marked fluorescence accumulation in the aorta of atherogenic mice, whereas no fluorescence signals were observed in normal controls. Using proteomics to analyze proteins in non-matrix bound Ost-MVs and mineralized SMC-derived MVs (SMC-MVs), we found Lamp1 was specifically expressed in SMC-MVs, and Nid2 was exclusively expressed in Ost-MVs. We further demonstrated that both Lamp1 and Nid2 were co-localized with Collagen І within calcific plaques, indicating the involvement of both Ost-MVs and SMC-MVs in atherosclerotic calcification. Mechanistically, LPS-induced vascular injury facilitated the transendothelial transport of Ost-MVs. The recruitment of circulating Ost-MVs was regulated by remodeled Collagen І during calcification progression. Furthermore, the phenotypic transition of SMCs determined the endocytosis of Ost-MVs. Finally, we demonstrated that either recruited Ost-MVs or resident SMC-MVs accelerated atherosclerotic calcification, depending on the Ras-Raf-ERK signaling.

Conclusion

Atherosclerotic calcification-induced Ost-MVs are released into circulation, facilitating the transport from bone to plaque lesions and exacerbating artery calcification progression. The mechanisms of Ost-MVs recruitment include vascular injury allowing transendothelial transport of Ost-MVs, collagen І remodeling promoting Ost-MVs aggregation, and SMC phenotypic switch to facilitate Ost-MVs uptake. Our results further revealed that both recruited Ost-MVs and calcifying SMC-MVs aggravate calcification through the Ras-Raf-ERK pathway.
Lipid-dependent conformational dynamics of bacterial ATP-binding cassette transporter Sav1866
Authors: Badiee Shadi A , Hettige Jeevapani , Moradi Mahmoud
Published: April 2024

Sav1866, a bacterial ATP-binding cassette (ABC) exporter, plays a crucial role in cellular processes by facilitating the efflux of a diverse range of substrates, including drugs, chemotherapeutic agents, peptides, and lipids. This efflux activity significantly impacts the effectiveness of various therapies against bacterial infections. In our recent investigation, we focused on understanding the conformational dynamics of Sav1866 within different lipid environments. Specifically, we explored its behavior in environments composed of DMPC and POPE lipids, which exhibit crucial distinctions not only in their headgroup polarity but also in the length and saturation of their hydrophobic tails. Our extensive set of equilibrium microsecond-level all-atom molecular dynamics (MD) simulations revealed significant distinctions in transporter behavior influenced by these lipid compositions. We observed a rapid transition to an occluded-inward-facing (IF-occ) conformation in POPE environments, contrasting with a channel-like behavior in DMPC environments, deviating from the expected alternating access mechanism (AAM). These findings underscore the significant impact of lipid compositions on ABC transporter function, offering new perspectives on membrane transport mechanisms.
RiboDiffusion: Tertiary Structure-based RNA Inverse Folding with Generative Diffusion Models
Authors: Huang Han , Lin Ziqian , He Dongchen , Hong Liang , Li Yu
Published: April 2024

RNA design shows growing applications in synthetic biology and therapeutics, driven by the crucial role of RNA in various biological processes. A fundamental challenge is to find functional RNA sequences that satisfy given structural constraints, known as the inverse folding problem. Computational approaches have emerged to address this problem based on secondary structures. However, designing RNA sequences directly from 3D structures is still challenging, due to the scarcity of data, the non-unique structure-sequence mapping, and the flexibility of RNA conformation. In this study, we propose RiboDiffusion, a generative diffusion model for RNA inverse folding that can learn the conditional distribution of RNA sequences given 3D backbone structures. Our model consists of a graph neural network-based structure module and a Transformer-based sequence module, which iteratively transforms random sequences into desired sequences. By tuning the sampling weight, our model allows for a trade-off between sequence recovery and diversity to explore more candidates. We split test sets based on RNA clustering with different cut-offs for sequence or structure similarity. Our model outperforms baselines in sequence recovery, with an average relative improvement of 11% for sequence similarity splits and 16% for structure similarity splits. Moreover, RiboDiffusion performs consistently well across various RNA length categories and RNA types. We also apply in-silico folding to validate whether the generated sequences can fold into the given 3D RNA backbones. Our method could be a powerful tool for RNA design that explores the vast sequence space and finds novel solutions to 3D structural constraints.
Spatial mapping reveals unique cellular interactions and enhanced tertiary lymphoid structures in responders to anti-PD-1 therapy in mucosal head and neck cancers
Authors: Ferguson A.L. , Beddow T. , Patrick E. , Willie E. , Elliott M.S. , Low T.H. , Wykes J. , Hui M.H. , Palme C.E. , Boyer M. , Clark J.R. , Lee J.H. , Palendira U. , Gupta R.
Published: April 2024

Survival in recurrent/metastatic head and neck mucosal squamous cell carcinoma (HNmSCC) remains poor. Anti-programmed death (PD)-1 therapies have demonstrated improved survival with lower toxicity when compared to standard chemotherapy. However, response to anti-PD-1 therapy remains modest, at 13-17%.

We evaluated the tumor microenvironment (TME) using Imaging Mass Cytometry (IMC) on 27 tumor specimens from 24 advanced HNmSCC patients prior to receiving anti-PD-1 based treatment. We show significantly increased central memory T cells and B cells in responders (n=8) when compared to non-responders (n=16). Spatial mapping identified interactions between phenotypically distinct malignant squamous cells with CD8+ T cells, CD4+ Tregs and endothelial cells in responders, and avoidance of these cells in non-responders. Importantly, regional analysis shows responders have more abundant tertiary lymphoid structures (TLS), with TLS proportion >20% also associated with longer progression free survival. Together these findings define the immune landscape associated with response to anti-PD-1 treatment in HNmSCCs.
Manuscript Title: Facility-based HIV self-testing as an additional testing option in health facilities: A systematic review and meta-analysis
Authors: McGee Kathleen , Jamil Muhammad S. , Siegfried Nandi , Radebe Busisiwe Msimanga , Barr-DiChiara Magdalena , Baggaley Rachel , Johnson Cheryl
Published: April 2024

Facility-based HIV self-testing (FB-HIVST) has been used across settings to improve testing accessibility and achieve global testing and treatment targets by 2030. The effectiveness of FB-HIVST remains uncertain; thus, we conducted a review to assess the risk and benefits of FB-HIVST to inform global guidance. We searched across nine electronic databases covering the period up to February 01, 2022, and included publications that directly compared FB-HIVST to standard HIV testing services (SOC) or no intervention. Meta-analysis was conducted on comparable outcomes using random-effects model for relative risks (RR) and 95% confidence intervals. Other outcomes were summarized descriptively. Risk of bias was assessed using Cochrane’s Risk of Bias tool. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). After screening 2,203 articles, 11 studies were found eligible, including 4 randomized controlled trials (RCT), 2 cohort studies, 3 economic evaluations, and 2 qualitative studies. Meta-analyses of four RCTs demonstrated that FB-HIVST may increase testing uptake (RR=2.47; 95% CI= 0.96, 6.33) and may lead to greater HIV diagnosis (RR=3.77; 95% CI=0.81, 17.44). Overall GRADE certainty was low. Trials found FB-HIVST as acceptable and feasible to many users, with minimal risk of social harm. A single RCT reported on linkage to care and observed that, among total enrolled, FB-HIVST compared to SOC may increase linkage to care threefold (RR= 3.26; 95% CI: 0.68, 15.62; low-certainty evidence). FB-HIVST was found to be cost-effective in a high-burden outpatient department, but determined to be quite variable. FB-HIVST is safe and may be an effective method to increase testing coverage and the diagnoses, particularly in high-burden HIV settings or sites with limited staff and resources. Findings from this review informed WHO’S guideline development process and its recommendation that FB-HIVST be offered as an additional testing option at facilities.

PROSPERO Number: CRD42022302619
Baseline functional connectivity predicts who will benefit from neuromodulation: evidence from primary progressive aphasia
Authors: Wang Zeyi , Gallegos Jessica , Tippett Donna , Onyike Chiadi U , Desmond John E , Hillis Argye E , Frangakis Constantine E , Caffo Brian , Tsapkini Kyrana
Published: April 2024

Background

Identifying the characteristics of individuals who demonstrate response to an intervention allows us to predict who is most likely to benefit from certain interventions. Prediction is challenging in rare and heterogeneous diseases, such as primary progressive aphasia (PPA), that have varying clinical manifestations. We aimed to determine the characteristics of those who will benefit most from transcranial direct current stimulation (tDCS) of the left inferior frontal gyrus (IFG) using a novel heterogeneity and group identification analysis.

Methods

We compared the predictive ability of demographic and clinical patient characteristics (e.g., PPA variant and disease progression, baseline language performance) vs. functional connectivity alone (from resting-state fMRI) in the same cohort.

Results

Functional connectivity alone had the highest predictive value for outcomes, explaining 62% and 75% of tDCS effect of variance in generalization (semantic fluency) and in the trained outcome of the clinical trial (written naming), contrasted with <15% predicted by clinical characteristics, including baseline language performance. Patients with higher baseline functional connectivity between the left IFG (opercularis and triangularis), and between the middle temporal pole and posterior superior temporal gyrus, were most likely to benefit from tDCS.

Conclusions

We show the importance of a baseline 7-minute functional connectivity scan in predicting tDCS outcomes, and point towards a precision medicine approach in neuromodulation studies. The study has important implications for clinical trials and practice, providing a statistical method that addresses heterogeneity in patient populations and allowing accurate prediction and enrollment of those who will most likely benefit from specific interventions.