Miracle-dz/UniFAR-FTUs huggingface dataset:
New genes involved in Angelman syndrome-like: Expanding the genetic spectrum

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis. New AS-like genes do not interact directly with UBE3A gene product but are involved in synapsis and neuron system development.
Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence Summary NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.
Apolipoprotein E isoform-specific phase transitions in the retinal pigment epithelium drive disease phenotypes in age-related macular degeneration

The retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer’s disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis.
A Novel High-Content Phenotypic Screen To Identify Inhibitors of Mitochondrial DNA Maintenance in Trypanosomes

Kinetoplastid parasites cause diverse neglected diseases in humans and livestock, with an urgent need for new treatments. The survival of kinetoplastids depends on their uniquely structured mitochondrial genome (kDNA), the eponymous kinetoplast. ABSTRACT Kinetoplastid parasites cause diverse neglected diseases in humans and livestock, with an urgent need for new treatments. The survival of kinetoplastids depends on their uniquely structured mitochondrial genome (kDNA), the eponymous kinetoplast. Here, we report the development of a high-content screen for pharmacologically induced kDNA loss, based on specific staining of parasites and automated image analysis. As proof of concept, we screened a diverse set of ∼14,000 small molecules and exemplify a validated hit as a novel kDNA-targeting compound.
Trans-synaptic assemblies link synaptic vesicles and neuroreceptors

Tripartite trans-synaptic assemblies directly link pre- and postsynaptic complexes crucial for synaptic transmission. Synaptic transmission is characterized by fast, tightly coupled processes and complex signaling pathways that require a precise protein organization, such as the previously reported nanodomain colocalization of pre- and postsynaptic proteins. Here, we used cryo–electron tomography to visualize synaptic complexes together with their native environment comprising interacting proteins and lipids on a 2- to 4-nm scale. Using template-free detection and classification, we showed that tripartite trans-synaptic assemblies (subcolumns) link synaptic vesicles to postsynaptic receptors and established that a particular displacement between directly interacting complexes characterizes subcolumns. Furthermore, we obtained de novo average structures of ionotropic glutamate receptors in their physiological composition, embedded in plasma membrane. These data support the hypothesis that synaptic function is carried by precisely organized trans-synaptic units. It provides a framework for further exploration of synaptic and other large molecular assemblies that link different cells or cellular regions and may require weak or transient interactions to exert their function.
Migration phenology and winter habitat quality are related to circulating androgen in a long‐distance migratory bird

In migratory birds, the timing of departure from wintering grounds is often dependant on the quality of habitat on an individual’s territory and may influence individual fitness, resulting in an interaction of life history stages across large geographical distances. American redstart Setophaga ruticilla males who overwinter in high quality habitats arrive early to breed and subsequently produce more offspring than late arrivers. Since many migratory species overlap vernal migration with the physiological transition to breeding, we examined if breeding preparation plays a role in this seasonal interaction. We tested the hypothesis that early arriving male redstarts from high quality winter habitats are in superior breeding condition by simultaneously measuring winter habitat quality (stable-carbon isotopes) and breeding preparation (circulating androgen, cloacal protuberance (CP) diameter) upon arrival at breeding grounds. Compared with late arrivers, early arriving males were from higher quality winter habitats and had higher androgen, but smaller CPs. Males arriving with higher androgen were in more advanced physiological migratory condition, as measured by haematocrit. Early arrivers were more likely to successfully breed, but there was no significant relationship between androgen upon arrival and breeding success. One possible explanation for these relationships is that androgen measured during arrival is most relevant in a migratory context, such that birds with high androgen may benefit from effects on migratory condition, positively influencing fitness through earlier arrival.
Automatic Integration of Gender Information during Phrase Processing: ERP Evidence

Both linguistic (e.g., words, syntax) and extralinguistic (e.g., voice quality) information needs to be considered by interlocutors during linguistic communication. The effects of extralinguistic information on neural sentence processing are particularly poorly understood. Here, we used EEG and passive non-attend design with visual distraction in order to investigate how extralinguistic information affects brain activity during syntactic processing. We collected ERPs while participants listened to Russian pronoun-verb phrases recorded in either male or female voice. We manipulated congruency between the grammatical gender signaled by the verb’s ending and the speaker’s apparent gender. We registered both early and late phrase processing signatures in the incongruent conditions including ELAN (peaking at ∼150 ms) and N400. Our data suggest a high degree of automaticity in integrating extralinguistic information during syntactic processing indicating existence of a rapid automatic syntactic integration mechanism sensitive to both linguistic and extralinguistic information.
Molecular signatures of cognition and affect

Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here we directly bridge the microscale and macroscale by mapping gene expression patterns to functional activation patterns across the cortical sheet. Applying unsupervised learning to the Allen Human Brain Atlas and Neurosynth databases, we identify a ventromedial-dorsolateral gradient of gene assemblies that separate affective and cognitive domains. This topographic molecular-psychological signature reflects the hierarchical organization of the neocortex, including systematic variations in cell type, myeloarchitecture, laminar differentiation, and intrinsic network affiliation. In addition, this molecular-psychological signature is related to individual differences in cognitive performance, strengthens over neurodevelopment, and can be replicated in two independent repositories. Collectively, our results reveal spatially covarying transcriptomic and cognitive architectures, highlighting the influence that molecular mechanisms exert on psychological processes.
Inhibition of p-glycoprotein does not increase the efficacy of proteasome inhibitors in multiple myeloma cells

The aim of this study is to determine whether manipulation of the drug transporter P-glycoprotein improves the efficacy of proteasome inhibitors in multiple myeloma cells. P-glycoprotein is a well-known drug transporter that is associated with chemotherapy resistance in a number of cancers but its role in modulating the efficacy of proteasome inhibitors in multiple myeloma is not well understood. Research has shown that the second generation proteasome inhibitor carfilzomib is a substrate of P-glycoprotein and as such its efficacy may correlate with P-glycoprotein activity. In contrast to carfilzomib, research concerning the first-in-class proteasome inhibitor bortezomib is inconsistent with some reports suggesting that inhibition of P-glycoprotein increases bortezomib cytotoxicity in multiple myeloma cells whereas others have shown no effect. Through the mining of publicly available gene expression microarrays of patient bone marrow, we show that P-glycoprotein gene expression increases with the disease stages leading to multiple myeloma. However, RNA-seq on LP-1 cells treated with bortezomib or carfilzomib demonstrated minimal basal P-glycoprotein expression which did not increase with treatment. Moreover, only one (KMS-18) of nine multiple myeloma cell lines expressed P-glycoprotein, including RPMI-8226 cells that are resistant to bortezomib or carfilzomib. We hypothesised that by inhibiting P-glycoprotein, multiple myeloma cell sensitivity to proteasome inhibitors would increase, thus providing a potential approach to improving responses and reversing resistance to these agents. However, the sensitivity of multiple myeloma cells lines to proteasome inhibition was not enhanced by inhibition of P-glycoprotein with the specific inhibitor tariquidar. In addition, targeting glucosylceramide synthase with eliglustat did not inhibit P-glycoprotein activity and also did not improve proteasome inhibitor efficacy except at a high concentration. We conclude that P-glycoprotein is poorly expressed in multiple myeloma cells, its inhibition does not enhance the efficacy of proteasome inhibitors, and it is unlikely to be a useful avenue for further translational research.
Dopamine axons to dorsal striatum encode contralateral stimuli and actions

Midbrain dopamine neurons play key roles in decision-making by regulating reward valuation and actions. These roles are thought to depend on dopamine neurons innervating striatum. In addition to actions and rewards, however, efficient decisions often involve consideration of uncertain sensory signals. The functions of striatal dopamine during sensory decisions remains unknown. We trained mice in a task that probed decisions based on sensory evidence and reward value, and recorded the activity of striatal dopamine axons. Dopamine axons in ventral striatum (VS) responded to bilateral stimuli and trial outcomes, encoding prediction errors that scaled with decision confidence and reward value. By contrast, dopamine axons in dorsal striatum (DS) responded to contralateral stimuli and contralateral actions. Thus, during sensory decisions, striatal dopamine signals are anatomically organized. VS dopamine resembles prediction errors suitable for reward maximization under sensory uncertainty whereas DS dopamine encodes specific combinations of stimuli and actions in a lateralized fashion.
Positivity effect in aging: evidence for the primacy of positive responses to emotional ambiguity

Older compared to younger adults show greater amygdala activity to positive emotions, and are more likely to interpret emotionally ambiguous stimuli (e.g., surprised faces) as positive. While some evidence suggests this positivity effect results from a relatively slow, top-down mechanism, others suggest it emerges from early, bottom-up processing. The amygdala is a key node in rapid, bottom-up processing and patterns of amygdala activity over time (e.g., habituation) can shed light on the mechanisms underlying the positivity effect. Younger and older adults passively viewed neutral and surprised faces in an MRI. Only in older adults, we found that amygdala habituation was associated with the tendency to interpret surprised faces as positive or negative (valence bias), where a more positive bias was associated with greater habituation. Interestingly, although a positive bias in younger adults was associated with slower reaction times, consistent with an initial negativity hypothesis in younger adults, older adults showed faster ratings of positivity. Together, we propose that there may be a switch to a primacy of positivity in aging.
Biodiversity and niche partitioning in an anaerobic benzene degrading culture

A key question in microbial ecology is what the driving forces behind the persistence of large biodiversity in natural environments are. We studied a microbial community with more than 100 different types of species which evolved in a 15-years old bioreactor with benzene as the main carbon and free energy source and nitrate as the electron acceptor. We demonstrate that only a few community members are able to degrade benzene, and that most of the others feed on the metabolic left-overs or on the contents of dead cells making up a food web with different trophic levels. As a result of niche partitioning, a high species richness is maintained and the complexity of a natural community is stabilized in a relatively simple environment. This view highlights the importance of species interactions and interdependencies, which drive microbial community structure and function. These mechanisms may well be conserved across ecosystems.
Transcriptional signatures of synaptic vesicle genes define myotonic dystrophy type I neurodegeneration

Despite significant research, the biological mechanisms underlying the brain degeneration in Myotonic Dystrophy Type I (DM1) remain largely unknown. Here we have assessed brain degeneration by measuring the volume loss (VL) and cognitive deficits (CD) in two cohorts of DM1 patients, and associating them to the large-scale brain transcriptome maps provided by the Allen Human Brain Atlas (AHBA). From a list of preselected hypothesis-driven genes, three of them appear to play a major role in degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Moreover, a purely data-driven strategy identified gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. Therefore, by combining large-scale transcriptome interactions with brain imaging and cognitive function, we provide a new more comprehensive understanding of DM1 that might help define future therapeutic strategies and research into this condition.
Visual Search P300 Source Analysis Based On ERP-fMRI Integration

Attention control can be achieved in two ways, stimulus-driven bottom-up attention and goal-driven top-down attention. Different visual search tasks involve different attention control. The pop-out task requires more bottom-up attention, whereas the search task involves more top-down attention. P300 which is the positive potential generated by the brain in the latency of 300-600 ms after the stimulus, reflects the processing of cognitive process and is an important component in visual attention. The P300 source is not consistent in the previous researches, our aim therefore, is to study the source location of P300 component based on visual search attention process. Here we use pop-out and search paradigm to get the ERP data of 13 subjects and the fMRI data of 25 subjects, and analyze the source location of P300 using the ERP-fMRI integration technology with high temporal resolution and high spatial resolution. The target differs from the distractor in color and orientation in the pop-out task, whereas the target and the distractor have different orientation and the same color in the search task. ERP results indicate that pop-out induces larger P300 concentrated in the parietal lobe, whereas search induced P300 is more distributed in the frontal lobe. Further ERP and fMRI integration analyses reveal that the left angular gyrus, right postcentral gyrus of parietal lobe and the left superior frontal gyrus (medial orbital) are the source of P300. Our study suggests the contribution of the frontal and parietal lobes to the P300 component.
Upper body and ankle strategies compensate for reduced lateral stability at very slow walking speeds

At the typical walking speeds of healthy humans, step placement seems to be the primary strategy to maintain gait stability, with ankle torques and upper body momentum providing additional compensation. The average walking speeds of populations with an increased risk of falling, however, are much slower and may require differing control strategies. The purpose of this study was to analyze mediolateral gait stability and the contributions of the different control strategies at very slow walking speeds. We analyzed an open dataset including kinematics and kinetics from eight healthy subjects walking at speeds from 0.1 to 0.6 m/s as well as a self-selected speed. As gait speed slowed, we found that the margin of stability decreased linearly. Increased lateral excursions of the extrapolated centre of mass, caused by increased lateral excursions of the trunk, were not compensated for by an equivalent increase in the lateral centre of pressure, leading to decreased margin of stability. Additionally, both the ankle eversion torque and hip abduction torque at the minimum margin of stability event increased at the same rate as gait speed slowed. These results suggest that the contributions of both the ankle and the upper body to stability are more crucial than stepping at slow speeds, which have important implications for populations with slow gait and limited motor function.
Near-infrared spectroscopy outperforms genomics for predicting sugarcane feedstock quality traits

The main objectives of this study were to evaluate the prediction performance of genomic and near-infrared spectroscopy (NIR) data and whether the integration of genomic and NIR predictor variables can increase the prediction accuracy of two feedstock quality traits (fiber and sucrose content) in a sugarcane population (Saccharum spp.). The following three modeling strategies were compared: M1 (genome-based prediction), M2 (NIR-based prediction), and M3 (integration of genomics s and NIR wavenumbers). Data were collected from a commercial population comprised of three hundred and eighty-five individuals, genotyped for single nucleotide polymorphisms (SNPs) and screened using NIR spectroscopy. We compared partial least squares (PLS) and BayesB regression methods to estimate marker and wavenumber effects. In order to assess model performance, we employed random sub-sampling cross-validation to calculate the mean Pearson correlation coefficient between observed and predicted genotypic values. Our results showed that models fitted using BayesB were most predictive than PLS models. We found that NIR (M2) provided the highest prediction accuracy, whereas genomics (M1) presented the lowest predictive ability, regardless of the measured traits and regression methods used. The integration of predictors derived from NIR spectroscopy and genomics into a single model (M3) did not significantly improve the prediction accuracy for the two traits evaluated. These findings suggest that NIR-based prediction can be an effective strategy for predicting the genotypic value of sugarcane clones.
Novel features of centriole polarity and cartwheel stacking revealed by cryo-tomography

Centrioles are polarized microtubule-based organelles that seed the formation of cilia, and which assemble from a cartwheel containing stacked ring oligomers of SAS-6 proteins. A cryo-tomography map of centrioles from the termite flagellate Trichonympha spp. was obtained previously, but higher resolution analysis is likely to reveal novel features. Using sub-tomogram averaging (STA) in T. spp. and Trichonympha agilis, we delineate the architecture of centriolar microtubules, pinhead and A-C-linker. Moreover, we report ∼25 Å resolution maps of the central cartwheel, revealing notably polarized cartwheel inner densities (CID). Furthermore, STA of centrioles from the distant flagellate Teranympha mirabilis uncovers similar cartwheel architecture and a distinct filamentous CID. Fitting the CrSAS-6 crystal structure into the flagellate maps and analyzing cartwheels generated in vitro indicates that SAS-6 rings can directly stack onto one another in two alternating configurations: with a slight rotational offset and in register. Overall, improved STA maps in three flagellates enabled us to unravel novel architectural features, including of centriole polarity and cartwheel stacking, thus setting the stage for an accelerated elucidation of underlying assembly mechanisms.