bluuebunny/crossref_metadata_2025 huggingface dataset:
Ephaptic coupling enables action potential conduction
Authors: Waaben J. , Hofgaard J.P. , Pick G.L. , Loisel C. , Engstrøm T. , Holstein-Rathlou N.H. , Poelzing S. , Nielsen M.S.
Published: November 2024

Background

Cardiac action potentials are believed to propagate solely by electrotonic transmission via gap junctions. In the alternative theory of ephaptic transmission, changes in extracellular electrical fields and ion concentrations may enable a cardiomyocyte to activate its neighbors. The involvement of ephaptic mechanisms remain highly disputed and has been discounted due to the reported inability of an isolated cardiomyocyte to activate another.

Methods

Isolated rat cardiomyocytes were subjected to whole cell patch clamp. Transmission of action potentials was tested in current clamp in isolated cardiomyocytes pushed together and in native cardiomyocyte pairs. Sodium channel activation and inactivation was tested in voltage clamp.

Results

Isolated cardiomyocytes were pushed together end-to-end and one stimulated to fire an action potential. In 10 attempts, 2 pairs showed successful transmission of action potentials, showing that ephaptic transmission is possible. In native pairs, subthreshold depolarization was transferred between cardiomyocytes of native electrically coupled pairs, however, only after a delay, which is not be explained from electrotonic theory. Once action potentials were elicited in one cardiomyocyte of a native pair, the neighbor was activated with delays under 2 msec. The activation delay did not correlate with gap junctional coupling, again suggesting the presence of an alternative mechanism. In voltage clamp of native cardiomyocyte pairs, one cardiomyocyte was held at -90 mV while depolarizing pulses were applied to its neighbor. Consistently, activation of sodium channels in the depolarized cell led to activation of sodium channels in the hyperpolarized cell, which fits well with ephaptic but not electrotonic theory. Ephaptic transmission requires a shielded local domain. To separate this, we measured steady state inactivation in native pairs. As expected, all channels inactivated at -40 mV. However, when maintaining a potential of – 40 mV for an extended period, sodium current elicited at 0 mV re-emerged by de-inactivation. The de-inactivation at -40 mV support that a shielded domain exists where potassium currents can hyperpolarize the local potential.

Conclusions

We show for the first time that ephaptic transmission is possible, that it is most likely in operation, also in the presence of gap junctional coupling, and finally our study suggests that data obtained in single cells may fail to reproduce key features of the electrophysiology of cardiomyocytes that interact with neighboring cardiomyocytes.
Whole-brain causal connectivity during decoded neurofeedback: a meta study
Authors: Arab Fahimeh , Ghassami AmirEmad , Jamalabadai Hamidreza , Peters Megan A. K. , Nozari Erfan
Published: November 2024

Decoded Neurofeedback (DecNef) represents a pioneering approach in human neuroscience that enables modulation of brain activity patterns without subjective conscious awareness through the combination of real-time fMRI with multivariate pattern analysis. While this technique holds significant potential for clinical and cognitive applications, the causal mechanisms underlying successful DecNef regulation and the neural dynamics that distinguish successful learners from those who struggle remain poorly understood. To address this question, we conducted a meta-study across functional magnetic resonance imaging (fMRI) data from five DecNef experiments, each with multiple fMRI sessions, to reveal causal network dynamics associated with individual differences in neurofeedback performance. Using the newly proposed CaLLTiF causal discovery method, we computed causal maps to identify causal network patterns that distinguish DecNef regulation from baseline and account for variations in neurofeedback success. We found that enhanced connectivity within the bilateral control network--particularly stronger connections involving the posterior cingulate and precuneus cortex--predicted neurofeedback success across all five studies. Whole-brain causal connectivity during DecNef further exhibited distinct network reorganizations, characterized by reduced average path lengths and increased right-limbic nodal degrees. Further, comparisons across cognition- and perception-targeted DecNef revealed a remarkable separation in connections to and from the somatomotor network, where connections between somatomotor and control-default-attention networks are larger during cognitive neurofeedback while causal effects between somatomotor and subcortical-visual-limbic networks are larger during perceptive DecNef. This is despite the fact that none of the involved studies targeted or involved motor activity. Overall, our results demonstrated the key role of bilateral medial control network in successful DecNef regulation regardless of the DecNef targets, a clear separation in somatomotor involvement between cognitive and perceptive DecNef, and general promise of whole-brain causal discovery in understanding complex neural processes such as decoded neurofeedback.
Contribution of ammonia oxidizers to inorganic carbon fixation in the dark ocean
Authors: Bayer Barbara , Kitzinger Katharina , Paul Nicola L. , Albers Justine B. , Saito Mak A. , Wagner Michael , Carlson Craig A. , Santoro Alyson E.
Published: November 2024

Ammonia-oxidizing archaea are the most abundant chemolithoautotrophs in the ocean, comprising up to 40% of microbial cells in deep waters, and are assumed to dominate dissolved inorganic carbon (DIC) fixation below the sunlit surface layer. Yet, the supply of reduced nitrogen from particulate organic matter flux from the surface is insufficient to support the amount of nitrification required to sustain measured DIC fixation rates in the dark ocean. The aim of this study was to quantify the contribution of ammonia oxidizers to DIC fixation in the dark ocean. We used phenylacetylene - a specific inhibitor of the ammonia monooxygenase enzyme - to selectively inhibit ammonia oxidizers during two oceanographic expeditions in the eastern tropical and subtropical Pacific Ocean spanning 35º N to 10º S. We show that ammonia oxidizers contribute only a small fraction to dark DIC fixation, accounting for 2 to 22% of the depth-integrated rates in the eastern tropical Pacific. The highest contributions were observed at the depth of the nitrification maximum, where ammonia oxidation could account for up to 50% of dark DIC fixation. Our results help to reconcile the observed discrepancies between nitrogen supply and DIC fixation at depth, and provide a new perspective on global ocean chemolithoautotrophy, revealing that the majority of DIC fixation within the lower euphotic zone and below 200 m depth is not fueled by ammonia oxidation.

Significance

Microbes in the ocean play important roles in the global carbon cycle and the ocean’s capacity to sequester carbon. Despite this importance, deciphering the contributions of different microbial metabolic processes to the oceanic carbon budget remains challenging. Particularly in the dark ocean, large discrepancies between organic matter fluxes and measured microbial metabolic rates are observed. We show that abundant chemoautotrophs – ammonia-oxidizing microbes – contribute only a small fraction to dark carbon fixation in the Pacific Ocean, challenging the current view that carbon fixation in the dark ocean is primarily sustained by nitrification. This work advances our understanding of microbial carbon processing, and offers new insights into the long-standing question of the main energy sources fueling carbon fixation in the dark ocean.
When sexual selection meets genetic drift: the coevolution of male traits and female preferences in finite populations
Authors: Xu Kuangyi
Published: November 2024

Fisher’s mechanism is central to sexual selection theories, where mate choice generates a genetic correlation between male trait and female preference alleles, driving the coevolution of the trait and preference with positive feedback. However, how Fisher’s mechanism operates in finite populations remains unclear, as sexual selection can interact with genetic drift, influencing both trait-preference correlation and allele frequencies. By using population genetic models, this study addresses the gap in our understanding of interactions between fundamental evolutionary forces. We show that more frequent recombination increases trait-preference correlations in infinitely large populations, unless a positive correlation initially exists. In finite populations, interactions between sexual selection and drift elevate trait-preference correlation when the male trait is rare but reduce the correlation when the trait is common, potentially making it negative when recombination is rare or population size is small. Also, these interactions tend to slow the spread of the male trait while promoting the evolution of preferences. These results differ from the Hill-Robertson effect under natural selection due to two key factors: mate choice generates positive linkage disequilibrium, and the strength of indirect selection on preferences increases with linkage disequilibrium. The fixation of trait and preference alleles is positively correlated. This correlation peaks at intermediate recombination rates and is often stronger in small populations than in large ones, so large population sizes tend to reduce the likelihood that both trait and preference alleles fix. We discuss how the results provide insights into the progression of sexual selection in nature.
Associations between DNA methylation and cognitive function in early-stage hormone receptor-positive breast cancer patients
Authors: Liu Shuwei , Liu Dongjing , Bender Catherine M. , Erickson Kirk I. , Sereika Susan M. , Shaffer John R. , Weeks Daniel E. , Conley Yvette P.
Published: November 2024

Background

Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF) before receiving adjuvant therapy compared with age-matched healthy controls. However, the biological mechanisms driving CF variation in the context of BC remain unclear. In this study, we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC using DNA methylation (DNAm) data, a dynamic regulator of gene activity.

Methods

Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n=109) taken at time of enrollment. Post-EWAS functional analyses were performed to enhance the understanding of the CF-related cytosine-phosphate-guanine (CpG) sites.

Results

When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 nearCTNND2(p-value= 9.65 × 10−9) and cg25906741 inMLIP(p-value= 2.01 × 10−8) were associated with processing speed and subjective CF, respectively, while regions in/nearSLC6A11,PRKG1/CSTF2T, andFAM3Bfor processing speed, and regions in/nearPI4KBandSGCE/PEG10for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients.

Conclusions

In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one at cg10331779 nearCTNND2with processing speed and the other at cg25906741 inMLIPwith subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility. These findings need replication in larger cohorts.
Phenotypic variation and weak behavioral isolation in a putative hybrid zone between AndeanAtlapetesbrushfinches (Passerellidae)
Authors: Muñoz-Quintana Gabriela , Cuervo Andrés M.
Published: November 2024

Individuals in the contact zone between hybridizing species often exhibit intermediate phenotypes that vary smoothly in a clinal fashion from one species to the other. However, many tropical hybrid zones remain poorly documented due to limited specimens, small species ranges, and logistical challenges of accessing key localities within contact zones. We investigated phenotypic variation and species recognition between two endemic Andean brushfinches that replace each other geographically along the Central Cordillera of the Colombian Andes:Atlapetes fuscoolivaceus(Dusky-headed Brushfinch) andA. flaviceps(Yellow-headed Brushfinch). We scored phenotypic traits from 111 georeferenced photographs of live individuals and 40 museum specimens. Using cline-fit analyses for two hybrid indexes (face color pattern and overall body color), we tested whether phenotypic transitions were abrupt (suggesting a barrier, or a sharp replacement) or gradual (indicating hybridization) across their contact zone. We also conducted playback experiments to assess song discrimination as an indication of potential prezygotic reproductive barrier. Plumage traits varied clinally, with a center near Inzá, Cauca (2.55°N), and with notably different cline widths between facial (12 km) and body-color traits (73 km). This difference likely reflects greater sampling density for facial traits and possibly stronger selection on face coloration. TerritorialA. flavicepsindividuals responded to songs of both species (no difference in latency); however, response duration was longer when exposed to local songs, indicating weak behavioral isolation. Our results suggest that these two ecologically equivalent brushfinches maintain a hybrid zone where their ranges meet, with a smooth transition from a pure phenotypic form to the other, which is likely facilitated by weak prezygotic behavioral barriers to reproduction. This study represents the initial step in investigating phenotypic variation, speciation genomics, behavior and interaction at the hybrid zone betweenAtlapetesbrushfinches in the Colombian Andes.
Combined SNP parental haplotyping and intensity analysis identifies meiotic and mitotic aneuploidies and frequent segmental aneuploidies in preimplantation human embryos
Authors: Handyside Alan H , Newnham Louise , Newnham Matthew , Henning Dominika , Velebny Jan , Pozdena Jan , Krmelova Jindriska , Horak Jakub
Published: November 2024

Genome-wide single nucleotide polymorphism (SNP) genotyping using microarrays and karyomapping (parental haplotyping) is a universal linkage-based method for preimplantation genetic testing of monogenic disease (PGT-M) and identification of chromosome aneuploidies, including meiotic trisomies, monosomies and deletions. Following IVF, embryos are biopsied at the blastocyst stage and several trophectoderm cells removed. Both parents, a close relative of known disease status and the biopsy samples are genotyped and parental haplotypes analysed. Here we extended the method by combining parental haplotyping with SNP intensity analysis. This enables identification of meiotic and mitotic, whole and segmental aneuploidies at high resolution. In 342 cycles of PGT-M in couples with a mean maternal age of 32.9±4.2 (SD), 37% (471/1270) of the biopsy samples were identified as aneuploid with an almost equal number of meiotic and mitotic aneuploidies. Meiotic aneuploidies were predominantly whole chromosome aneuploidies of maternal origin and increased with maternal age. Mitotic aneuploidies (with normal parental haplotype patterns) were mainly segmental imbalances. For PGT of aneuploidies (PGT-A) in infertile couples, identifying meiotic aneuploidies, which are almost all non-viable, provides a valuable option to avoid the discard of embryos with only mitotic aneuploidies of unknown clinical outcome.
Small form factor implantable neural probe with efficient flip chip μLED for in vivo optogenetics
Authors: Abrantes Mafalda , Pereira Tiago , Silva Patrícia , Falcão Margarida , Borme Jérôme , Alpuim Pedro , Jacinto Luis
Published: November 2024

Optogenetics is a widely used tool to dissect neural circuits with optical stimulation, but it requires that light is delivered to photosensitive neurons inside the brain. Implantable neural probes with microscale LEDs (μLEDs) are an emerging approach to delivering light to the brain with superior light output control. However, approaches to integrate μLEDs in neural probes depend on complex fabrication processes. Here, we developed an implantable small form factor neural probe that integrates highly efficient commercial flip chip μLEDs using only standard lithography processes in silicon and a custom automated LED mounting approach with custom 3D-printed tools on a pick-and-place machine. The probe has a cross-sectional area under 0.013 mm2but can output up to 2.3 mW of optical power with an irradiance of 175 mW/mm2. Due to the high plug efficiency of the LED and wide large interconnect lines, the neural probe has improved heat dissipation properties and can perform stimulation protocols up to 50 Hz and 90% duty cycles without surpassing hotspot temperature elevations above 1 ºC. The neural probes were validated in vivo, with brain activity in the motor cortex of transgenic optogenetic mice being reliably modulated by pulsed light emitted from the probe.
Inhibition of Notch Signaling Attenuates Epileptic Discharges in the Adolescent Rat Brain after Status Epilepticus Induction
Authors: Liu Jie , Chen Jin , Yuan Ping
Published: November 2024

Background

Notch signaling plays a critical role in neuroregeneration after injuries such as those caused by status epilepticus (SE).

Objective

To explore the effects of Notch signaling on epileptogenesis and the underlying mechanisms in adolescent rat brains in the acute phase after SE induction.

Methods

N-[N-(3,5-difluorophenacetyl)- L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), which indirectly inhibits Notch, was injected into rats during the acute phase after SE induction to inhibit Notch signaling. Electroencephalogram (EEG) was used to observe spontaneous recurrent seizures. Differences in the synaptic structures of the hippocampus were observed by transmission electron microscopy. Nissl staining and Timm staining were used to observe the loss of hippocampal neurons and sprouting of mossy fibers, respectively, in the hippocampus at 28 days after SE.

Results

EEG illustrated that DAPT treatment reduced the severity of epileptic discharges after SE induction. Transmission electron microscopy revealed reductions in the presynaptic membrane active band length and postsynaptic membrane dense matter thickness in the CA1 region of the hippocampus. Meanwhile, Nissl staining demonstrated that DAPT treatment reduced the loss of hippocampal neuronal cell degeneration, and the hippocampal structure was repaired to a certain extent. Meanwhile, Timm staining illustrated that DAPT treatment did not affect mossy fiber sprouting (MFS) after SE induction.

Conclusion

Inhibiting Notch signaling reduced EEG epileptic activity, attenuated synaptic damage, and partially restored the hippocampal neuronal structure. However, it did not alter MFS after SE induction.
Costs of dispersal evolution under larval malnutrition
Authors: Vibishan B. , Malwade Akshay , Koner Anish , Khodake Vinayak , Dey Sutirth
Published: November 2024

Dispersal is a key eco-evolutionary process, and the causes and consequences of its evolution have been well-studied. However, although dispersal depends critically on the nutritional status of organisms, it is unclear how malnutrition affects the evolution of life history and the behavior of organisms under selection for increased dispersal. To address this issue, we used four replicate laboratory populations ofDrosophila melanogasterpreviously selected for increased dispersal for 66-67 generations on a protein-poor larval diet. Compared to the unselected controls, the selected populations had lower female body weight, fecundity, male desiccation resistance and mating propensity, but greater male locomotor activity and mating latency. There were no significant differences in aggression. We also compared our results qualitatively with those from a previous study on dispersal selection under a standard larval diet. Barring desiccation resistance, locomotor activity, and rest duration, all other traits investigated responded differently to dispersal selection between the poor and the standard larval nutritional regimes. These results show that the evolution of traits associated with dispersal can differ markedly depending on the nutrition available for the dispersing populations.
Interrelations of Serum Uric Acid, Beta-Cell Function, and Insulin Resistance in Indian Cohort: A Comprehensive Analysis
Authors: Thummala Sabitha , Kruthi Nithya , Fatima Sarah , Ghori Junaid Ahmed Khan , Saikia Katherine , Balamurali AR , Ranganathan Rahul
Published: November 2024

Background

Hyperuricemia, characterised by elevated levels of serum uric acid (SUA), has been linked to an increased risk of metabolic disorders, including type 2 diabetes. Understanding the relationship between SUA, beta-cell function, and insulin resistance is crucial for elucidating the pathophysiology of these conditions, especially in the Indian population, where such data is limited.

Objective

This study aimed to explore the interrelations between serum uric acid levels, beta-cell function, and insulin resistance in an Indian cohort.

Methods

A cross-sectional study was conducted involving a representative sample of adults from an Indian population. Participants were stratified into sex-specific SUA quartiles. Key measurements included BMI, serum creatinine, lipid profiles, fasting insulin, HOMA1-B (beta-cell function), and HOMA1-IR (insulin resistance). Partial correlation coefficients were calculated to assess the associations between SUA and various metabolic parameters.

Results

Significant differences were observed across SUA quartiles in terms of age, BMI, serum creatinine, HDL cholesterol, LDL cholesterol, triglycerides, total cholesterol, fasting insulin, HOMA1-B, and HOMA1-IR (all p-values < 0.05). Higher SUA levels were associated with increased BMI, serum creatinine, triglycerides, fasting insulin, HOMA1-B, and HOMA1-IR. Additionally, partial correlation analysis revealed positive correlations between SUA and BMI (r=0.065, p=0.026), fat mass (r=0.065, p=0.026), serum creatinine (r=0.277, p<0.001), triglycerides (r=0.084, p=0.004), fasting insulin (r=0.130, p<0.001), and HOMA1-B (r=0.078, p=0.008). Negative correlations were found between SUA and vitamin B12 (r=-0.117, p=0.000071), GFR (r=-0.113, p<0.001), total cholesterol (r=-0.068, p=0.021), LDL cholesterol (r=-0.080, p=0.006), HDL cholesterol (r=-0.071, p=0.016), and HbA1c (r=-0.170, p<0.001).

Conclusions

Elevated serum uric acid levels are significantly associated with increased beta-cell function and insulin resistance among Indian adults. These findings suggest that hyperuricemia could be an early marker for metabolic dysfunction, highlighting the need for early intervention strategies in this population. Further longitudinal studies are warranted to establish causal relationships and to explore the potential benefits of uric acid-lowering therapies in preventing metabolic diseases.

Trial registration

Not applicable.
Publicly available continuously updated topic specific databases of randomised clinical trials: A scoping review
Authors: Boesen Kim , Hemkens Lars G , Janiaud Perrine , Hirt Julian
Published: November 2024

Conducting systematic reviews of clinical trials is arduous and resource consuming. One potential solution is to design databases that are continuously and automatically populated with clinical trial data from harmonised and structured datasets. We aimed to map publicly available, continuously updated, topic-specific databases of randomised clinical trials (RCTs). We systematically searched PubMed, Embase, the preprint servers medRxiv, ArXiv, and Open Science Framework, and Google. We described seven features (access model, database architecture, data input sources, retrieval methods, data extraction methods, trial presentation, and export options) and narratively summarised the results. We did not register a protocol for this review. We identified 14 continuously updated clinical trial databases, seven related to COVID-19 (first active in 2020) and seven non-COVID databases (first active in 2009). All databases, except one, were publicly funded and accessible without restrictions. They mainly employed methods similar to those from static article-based systematic reviews and retrieved data from journal publications and trial registries. The COVID-19 databases and some non-COVID databases implemented semi-automated features of data import, which combined automated and manual data curation, whereas the non-COVID databases mainly relied on manual workflows. Most reported information was metadata, such as author names, years of publication, and link to publication or trial registry. Two databases included trial appraisal information (risk of bias assessments). Six databases reported aggregate group level results, but only one database provided individual participant data on request. We identified few continuously updated trial databases, and existing initiatives mainly employ methods known from static article -based reviews. The main limitation to create truly live evidence synthesis is the access and import of machine-readable and harmonised clinical trial data.
Fractionated Potential-Guided Cryoablation Targeting Termination of Atrioventricular Nodal Reentrant Tachycardia While Avoiding the Compact Node Electrogram
Authors: Hirata Shu , Nagashima Koichi , Watanabe Ryuta , Wakamatsu Yuji , Hirata Moyuru , Kurokawa Sayaka , Otsuka Naoto , Sawada Masanaru , Okumura Yasuo
Published: November 2024

Background

Fractionated potential (FP) ablation during atrioventricular nodal reentrant tachycardia (AVNRT), is an effective strategy that minimizes redundant radiofrequency (RF) applications. This study aimed to evaluate the utility of cryoablation targeting FPs to effectively terminate AVNRT while further minimizing redundant cryoapplications. Moreover, we observed what appeared to be compact AVN (cAVN) or proximal His potentials—tiny, dull potentials (TDPs) with continuity to the His potential during sinus rhythm (SR) and AVNRT—in the anteroseptal area. The second aim of this study was to explore the significance of those potentials.

Methods

Analyzed were 53 slow-fast AVNRT patients who underwent ablation procedures. Ultra-high resolution activation maps in the triangle of Koch were obtained during SR (n=34) and AVNRT (n=46). TDPs during SR and AVNRT in the anteroseptal area were identified and annotated using the LUMIPOINT Activation Search tool.

Results

FP areas were observed in 19 patients (56%) during SR and in 46 (100%) during AVNRT. This area corresponded to the AVNRT termination and/or successful ablation site in all, with peak numbers of 8.8±1.4 during AVNRT and 5.3±1.3 during SR. The number of ablation points was 3.6±1.5 for the FP-guided cryoablation (n=32) (Bonferroni corrected P<0.05 vs. anatomical RF; and P<0.05 vs. FP-guided RF), 5.4±2.1 for the FP-guided RF ablation (n=11) (P=0.0825 vs. anatomical RF), and 8.2±3.2 for the conventional RF ablation (n=10). Transient AV block occurred in 11 patients (21%). All AV block sites overlapped with the TDP area in the phase just before the His potential during AVNRT and SR, with a confidence setting of ≥24% (35[24-60]%). Conversely, in 42 patients without AV block, no ablation was performed in this area.

Conclusion

The FP-guided cryoablation strategy targeting AVNRT termination required fewer cryoapplications than RF ablation. The RF/cryo application in the TDP area during SR and AVNRT posed a risk of AV block.
Decreased SNCA Expression in Whole-Blood RNA Analysis of Parkinson’s Disease Adjusting for Lymphocytes
Authors: Xu Kayla , Violich Ivo , Hutchins Elizabeth , Alsop Eric , Nalls Mike A. , Blauwendraat Cornelis , Gibbs J. Raphael , Cookson Mark R. , Moore Anni , Van Keuren-Jensen Kendall , Craig David W.
Published: November 2024

Blood-based RNA transcriptomics offers a promising avenue for identifying biomarkers of Parkinson’s Disease (PD) progression and may provide mechanistic insights into the systemic biological processes underlying its pathogenesis beyond the well-defined neurodegenerative features. Previous studies have indicated an age-dependent increase in neutrophil-enriched gene expression, alongside a reduction in lymphocyte counts, in individuals with PD. These immune cell changes can obscure disease-relevant transcriptomic signals. In this study, we performed differential expression (DE) analysis of whole-blood RNA sequencing data from PD cohorts, incorporating a correction for immune cell-enriched gene expression, particularly neutrophil-related pathways, to improve the resolution of PD-associated molecular changes. Using 1,254 Parkinson’s Progression Markers Initiative (PPMI) samples with complete blood count (CBC) data, we developed a predictive model to estimate neutrophil percentages in a 6,987 PPMI and Parkinson’s Disease Biomarkers Program (PDBP) samples. We mitigated the confounding effects of immune cell-enriched gene expression by integrating predicted neutrophil percentages as a covariate in DE analysis. This approach revealed a consistent and significant downregulation of SNCA across all PD cohorts, a finding previously obscured by immune cell signatures. Lowered SNCA expression was found in individuals with known predisposition genes (e.g., SNCA, GBA, LRRK2) and in non-genetic PD cohorts lacking known pathogenic mutations, suggesting it may represent a key transcriptomic hallmark of the disease.
A quantitative approach to poxvirus infection reveals general correlates of antigen presentation and immunogenicity for viral CD8+T cell epitopes
Authors: Witney Matthew J , Croft Nathan P , Wong Yik Chun , Smith Stewart A , Flesch Inge EA , Keller Erica , La Gruta Nicole L , Purcell Anthony W , Tscharke David C.
Published: November 2024

CD8+T cells are essential effectors in antiviral immunity that kill infected cells displaying viral peptide epitopes on MHC class I. The pathways underpinning antigen presentation on MHC I are well known but we lack a general understanding of the quantitative and kinetic relationships between source proteins and presented epitopes, and how these relate to immunogenicity. We used quantitative mass spectrometry to interrogate infection with vaccinia virus, the MPOX vaccine, measuring amounts of >40 viral epitopes and their source proteins multiple times after infection in four cell types. This revealed that up to 90% of the epitopes were presented as fast as their source proteins were made and that protein amounts failed to correlate with epitope levels. Further, a significant correlation between epitope levels and immunogenicity required presentation to be quantifiedex vivo, with each step away from a matched infection route and natural presenting cell eroding the association.
Mapping the Impact ofDUSP6in an ADHD iPSC derived-dopaminergic neuronal model
Authors: Namipashaki Atefeh , Hellyer Shane D. , Arnatkeviciute Aurina , Walsh Kevin , Nowell Cameron J , Polo Jose M. , Gregory Karen J , Bellgrove Mark A. , Hawi Ziarih
Published: November 2024

Although the geneDUSP6has been implicated as a risk gene for ADHD in recent GWAS studies, its functional role in the aetiology of the condition remains poorly understood.DUSP6is reported to regulate dopaminergic neurotransmission by decreasing available synaptic dopamine, suggesting a potential mechanism by whichDUSP6may confer risk to ADHD. In this study, we employed CRISPR-Cas9 to knockoutDUSP6in induced pluripotent stem cells (iPSCs) derived from an individual with ADHD. These isogenic engineered cells were then differentiated into highly homogeneous dopaminergic neurons, including both heterozygous (Het) and homozygous (Hom) knockout lines, along with parental control lines, to assess changes in dopaminergic neurotransmission at both cellular and transcriptomic levels. Enzyme Linked Immunosorbent Assay (ELISA) analyses showed a dose-dependent trend of increasing dopamine levels, at extracellular level, in the knockout lines. RNA sequencing further supported this finding, showing that downregulation ofDUSP6lead to the upregulation of differentially expressed genes (DEGs) associated with the regulation of dopamine secretion and synaptic functions critical for dopamine signalling. These DEGs appear to encode components of the synaptic machinery essential for effective dopamine transmission or act as regulators of dopaminergic neurotransmission. Additionally, RNA sequencing uncovered other potential biological mechanisms through whichDUSP6may contribute to increase the risk for ADHD, including effects on neurogenesis, extracellular matrix-associated processes, lipid metabolism, and sex-specific gene expression. Furthermore, we identified overlaps betweenDUSP6knockout DEGs and those associated with other neuropsychiatric disorders, including major depression (MDD), bipolar disorder (BD), and schizophrenia (SCZ), suggesting shared genetic pathways potentially influenced byDUSP6. Together, this study provides deeper insights into the molecular underpinnings of the role played byDUSP6in the genetic aetiology of ADHD and its broader implications across related neuropsychiatric conditions.
Dual-timescale motor circuit dynamics underlies fast head exploratory behavior and efficient locomotion
Authors: Li Pinjie , Zhang Heng , Su Yifan , Wang Jiaqi , Tao Louis , Wen Quan
Published: November 2024

Caenorhabditis elegansexhibits complex head exploratory behavior in natural environments. We quantified these movements and examined the motor circuits responsible for their intricate dynamics. Using variational mode decomposition, we distinguished between fast casts and slow bends. Slow bends backpropagate along the body, whereas fast casts show phase-specific timing and influence directional bias during forward movement. Combinatorial ablations of three types of cholinergic motor neurons, coupled with dynamical systems analysis of subsequent behaviors, revealed their distinct and overlapping roles. RMD contribute to head casts; SMD maintain bending states; SMB and SMD enable slow rhythmic bending and head-body coupling; RMD, SMD, and SMB together constitute the head central pattern generator (CPG) that drives forward locomotion. We propose a computational model with dual-timescale proprioceptive feedback to reproduce fast casts and slow bends and demonstrate how phase-specific head casts enhance roaming efficiency by optimizing movement speed. These findings highlight how different excitatory motor neurons control distinct and complementary aspects of head bending dynamics while working synergistically to maximize locomotion efficiency.
Lrif1 modulates Trim28-mediated repression of theDuxlocus in mouse embryonic stem cells
Authors: Šikrová Darina , González-Prieto Román , Vertegaal Alfred C. O. , Balog Judit , Clemens-Daxinger Lucia , van der Maarel Silvère M.
Published: November 2024

Germline mutations in SMCHD1, DNMT3B and LRIF1 can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2). FSHD is an epigenetic skeletal muscle disorder in which partial failure in heterochromatinization of the D4Z4 macrosatellite repeat causes spurious expression of the repeat-embeddedDUX4gene in skeletal muscle, ultimately leading to muscle weakness and wasting. All three proteins play a role in chromatin organization and gene silencing; however, their functional relationship has not been fully elucidated. Here, we show that knockdown ofLrif1, but not of the other two FSHD2 genes, in mouse embryonic stem cells leads to modest upregulation of the 2-cell cleavage stage transcriptional program driven by the transcription factor Dux, which is the mouse functional homologue of human DUX4. Furthermore, we show that Lrif1 interacts with Trim28, a known Dux repressor and that this interaction is independent of Cbx proteins and Smchd1. We uncover that modestDuxupregulation inLrif1knockdown mESCs coincides with decreased Trim28 occupancy at theDuxlocus. Together, our results provide evidence for a conserved function of Lrif1 in repressing an early zygotic genome activator in mice and humans.
The infant brain rapidly entrains to visual statistical regularities during stimulus exposure
Authors: Capparini Chiara , Fourdin Lauréline , Wens Vincent , Dontaine Pauline , Aeby Alec , Bertels Julie
Published: November 2024

Statistical learning (SL) has been studied quite extensively in infancy. Still, most evidence relies on post-exposure behavioural tasks whose directionality (familiarity vs. novel effects) may not be straightforward to predict nor to interpret. In addition, these tasks do not tell anything about the online learning dynamics and may be influenced by memory effects. In this work, we investigated online SL mechanisms by tracking neural entrainment to visual regularities in a group of 4- to 6-month-old infants exposed to a stream of shapes presented at 6 Hz. Shapes were either organized in doublets or presented randomly. Results revealed neural entrainment at the base frequency of 6 Hz and harmonics did not differ across conditions, confirming that infants attended to the stimuli similarly across conditions. On the other hand, entrainment at the doublet frequency of 3 Hz and harmonics varied across conditions and trials. Infants showed greater occipital entrainment to the doublet frequency in the deterministic condition than in the random one, especially over the first trials of exposure. This suggests that the brain can detect visual regularities from early infancy. Further, this sensitivity emerged early over the exposure period and did not show a learning curve. Hence, considering its time course and the brain regions involved, neural entrainment at the doublet frequency seems to reflect a bottom-up detection mechanism rather than a learning process. These findings are crucial to better understand how infants extract regularities during stimulus exposure and what neural entrainment can reveal in a visual SL task.
Reference-free Analysis of scRNA-seq Data Reveals Elevated rRNA and mtRNA Transcription during Neurogenesis in Axolotl
Authors: Zahan Ratul Md. Rownok , Karim Md. Redwanul , Hasan Samee Md. Abul , Rahman Atif
Published: November 2024

Analysis of single-cell RNA-seq data is typically performed on a gene expression matrix estimated by aligning reads to a reference transcriptome. However, this approach is difficult to apply to organisms with no or incomplete reference transcriptomes. In addition, events deviating from the reference remain undetected. Here we present a reference-free method to analyze single-cell RNA-seq data based onk-mers. We assess the performance of our method on a metastatic renal cell carcinoma dataset and find that it is largely able to capture differentially expressed genes. We then analyze a recently generated dataset to study neurogenesis in Axolotl and observe increased levels of transcription of rRNA and mtRNA during neurogenesis as well as a miRNA with previously predicted links to neuronal development. We also detect lncRNAs and intron retention in heart disease-related genes in diseased cardiomyocytes in an analysis of a congenital heart disease dataset.
Biofilm lifestyle as a common trait of ammonia-oxidizing archaea
Authors: Dreer Maximilian , Pribasnig Thomas , Hodgskiss Logan H. , Luo Zhen-Hao , Pozaric Fran , Schleper Christa
Published: November 2024

Although widespread in nature, growth in biofilms has been relatively little explored in the globally distributed ammonia oxidizing archaea (AOA). Here we investigated six representatives of three different terrestrial and marine clades of AOA in a longitudinal and quantitative study for their ability to form biofilm and studied gene expression patterns of three representatives. While all strains grew on a solid surface, soil strains exhibited the highest capacity for biofilm formation. Based on microscopic and gene expression data, two different colonization strategies could be distinguished. S-layer containing AOA (from both soil and marine habitats) initialized attachment as single cells and subsequently formed denser layers and three-dimensional structures, while the S-layer free species of theNitrosocosmicusclade attached as suspended aggregates to the surface and henceforth showed fastest establishment of biofilm. Transcription profiles were significantly different between planktonic and biofilm growth in all strains and revealed individual reactions, often fulfilling shared functions. In particular the strong expression of different types of multicopper oxidases was observed in all strains indicating modifications of their cell coats. S-layer carrying AOA each additionally expressed a set of adhesion proteins supporting attachment. Detoxification of nitrous compounds, copper acquisition as well as the expression of transcription factor B were also shared reactions among biofilm producing strains. However, the majority of differentially expressed protein families was distinct among the three strains illustrating that individual solutions have evolved for the shared growth mode of biofilm formation in AOA, probably driven by the different ecological niches.
Delta phase-dependent modulation of temporal predictions by parietal transcranial alternating current stimulation
Authors: Burke Rebecca , Maÿe Alexander , Misselhorn Jonas , Fiene Marina , Engelhardt Felix J. , Schneider Till R. , Engel Andreas K.
Published: November 2024

Background

Previous research has shown that temporal prediction processes are associated with phase resets of low-frequency delta oscillations in a network of parietal, sensory and frontal areas during non-rhythmic sensory stimulation. Transcranial alternating current stimulation (tACS) modulates perceptually relevant brain oscillations in a frequency and phase-specific manner, allowing the assessment of their functional qualities in certain cognitive functions like temporal prediction.

Objective

We addressed the relation between oscillatory activity and temporal prediction by using tACS to manipulate brain activity in a sinusoidal manner. This enables the investigation of the relevance of low-frequency oscillations’ phase for temporal prediction.

Methods

Delta tACS was applied over the left and right parietal cortex in two separate unimodal and crossmodal experiments. Participants judged either the visual or the tactile reappearance of a uniformly moving visual stimulus, which shortly disappeared behind and occluder. Using an intermittent electrical stimulation protocol, tACS was applied with six different phase shifts relative to sensory stimulation in both experiments while participants performed a temporal prediction task. Additionally, a computational model was developed and analysed to elucidate oscillation-based functional principles for the generation of temporal predictions.

Results

Only in the unimodal experiment, the application of delta tACS resulted in a phase-dependent modulation of temporal prediction performance. By considering the effect of sustained tACS in the computational model, we demonstrate that the entrained dynamics can phase-specifically modulate temporal prediction accuracy.

Conclusion

Our findings suggest that phase-specific neuromodulation through delta tACS can influence temporal prediction accuracy in a unimodal context. This provides support to the notion that low-frequency delta oscillations are of causal relevance for temporal prediction.
A human cytomegalovirus prefusion-like glycoprotein B subunit vaccine elicits similar humoral immunity to that of postfusion gB in mice
Authors: Karthigeyan Krithika P. , Connors Megan , Binuya Christian R. , Gross Mackensie , Fuller Adelaide S. , Crooks Chelsea M. , Wang Hsuan-Yuan , Sponholtz Madeline R. , Byrne Patrick O. , Herbek Savannah , Andy Caroline , Gerber Linda M. , Campbell John D. , Williams Caitlin A. , Miller Itzayana , Yu Dong , Bottomley Matthew J. , McLellan Jason S. , Permar Sallie R.
Published: November 2024

Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects. Despite the global disease burden, there is no FDA-approved HCMV vaccine. The most efficacious HCMV vaccine candidates to date have used glycoprotein B (gB), a class III viral fusion protein, in its postfusion form. While some viral fusion proteins have been shown to elicit stronger neutralizing responses in their prefusion conformation, HCMV prefusion-like and postfusion gB were recently shown to elicit antibodies with similar fibroblast neutralization titers in mice. We aimed to define and compare the specificity and functionality of plasma IgG elicited by distinct prefusion-like and postfusion gB constructs. Prefusion-like and postfusion gB elicited comparable IgG responses that predominantly mapped to AD-5 antigenic domain known to elicit neutralizing antibodies. Interestingly, postfusion gB elicited significantly higher plasma IgG binding to cell-associated gB and antibody dependent cellular phagocytosis than that of prefusion-like gB. The vaccines elicited comparable neutralization titers of heterologous HCMV strain AD169r in fibroblasts, yet neither elicited neutralizing titers against the vaccine-matched strain Towne in fibroblasts. Our data indicate that gB in this prefusion-like conformation elicits similar specificity and functional humoral immunity to that of postfusion gB, unlike certain class I viral fusion proteins which have been used as vaccine antigens. These findings deepen our understanding of the immune response elicited by class III fusion proteins and may inform further design and testing of conformationally-dependent herpesvirus glycoprotein vaccine candidates.
CATSPERε extracellular domains are essential for sperm calcium channel assembly and activity modulation
Authors: Hwang Jae Yeon , Wang Huafeng , Clouser Gillian , Oh Jong-Nam , Finnegan Sarah F. , Skakkebaek Niels E. , Chung Jean-Ju
Published: November 2024

The sperm flagellar-specific CatSper Ca2+channel is a multiprotein complex critical for successful fertilization. The four ancillary subunits, CATSPERβ, γ, δ, and ε, form a unique canopy structure over the pore-forming channel. However, how the canopy is formed and what it does in the assembled channel complex remains unknown. Here, we report that extracellular domains (ECDs) of CATSPERε are essential for canopy and holo-complex assembly and modulate channel activity during sperm capacitation. CATSPERε-deficient males are sterile due to the absence of the entire channel and defective sperm hyperactivation. Expressing ECDs-truncated CATSPERε during spermatogenesis does not rescue the knockout because it fails to incorporate into the native complex. In contrast, addition of a CATSPERε ECD fragment during sperm capacitation significantly reduces channel activity. These findings provide insight into the underlying molecular and developmental mechanisms of CatSper assembly and how the channel can be modulated in physiological settings and by therapeutic intervention.

Teaser

CATSPERε extracellular domains are essential for CatSper canopy and holo-complex assembly and regulate channel activity during sperm capacitation.
Topoisomerase 3α (TOP3A) Dependent Alternative Lengthening of Telomeres (ALT)
Authors: Khandagale Prashant , Sun Yilun , Saha Sourav , Saha Liton Kumar , Pommier Yves
Published: November 2024

Alternative Lengthening of Telomeres (ALT) is a homologous recombination-dependent telomere elongation mechanism utilized by at least 10-15% of all cancers. Here we identified that the DNA topoisomerase, TOP3A is enriched at the telomeres of ALT cells but not at the telomeres of telomerase-positive (Tel) cancer cells. We demonstrate that TOP3A stabilizes the shelterin protein TERF2 in ALT cancer cell lines but not in Tel cells and that long non-coding telomere transcribed RNA (TERRA) enrichment at telomeres depends upon TOP3A. TOP3A also promotes the generation of single-stranded telomeric C-strand (ssTeloC) DNA, which is a recently discovered marker for ALT. Additionally, we found that inducing TOP3A-DNA-protein crosslinks in ALT cells suppresses TERRA enrichment as well as destabilizes TERF2. Taken together these observations uncover the unexplored functions of TOP3A at ALT telomeres and suggest the potential of developing an ALT-specific cancer therapeutic strategy targeting TOP3A.