Miracle-dz/UniFAR-FTUs huggingface dataset:
The Influence of Music on the Behaviour of Persons with Autism Spectrum Disorder (ASD) and Low Cognitive Functioning: A Systematic Observational Study

ABSTRACT Abstract: Persons with Autism Spectrum Disorder (ASD) and low cognitive functioning tend to demonstrate regulatory responses to auditory sensations, leading to disturbed behaviours such as self-stimulation, stereotypical movements, even aggression and self-harm. The aim of this study was to investigate whether listening to specific sounds and music reduced these behaviours. A systematic observational study of 16 participants was carried out with parental consent. A range of music types and sounds were played to participants including dissonant music (contemporary classical with dissonant chords), consonant music (classical romantic with consonant chords) and ambient sounds. Intermittent periods of silence between tracks were introduced to check for any potential influence of previous listening. It was noted that disturbed behaviour was least evident during periods of ‘silence’ (without additional auditory input), compared to any of the other conditions. Silence was therefore used as a baseline before listening to any sounds. Consonant music appeared to decrease disturbed behaviours compared with the other types of music and proved more effective than silence. These findings suggest that using specific types of music might help decrease some disturbed behaviour.
IL-27 skews TNF-alpha-induced inflammatory microenvironment in keratinocytes

Inflammaging has received considerable attention because aging is characterized by low-grade, chronic and asymptomatic inflammation, concomitant with increased blood levels of senescence-associated secretory phenotype (SASP) factors, including IL-1, IL-6, IL-8, IL-18 and tumor necrosis factor-alpha (TNF-alpha). On the other hand, IL-27 is not categorized as SASP factors though it is known that IL-27 has pleiotropic roles in inflammation. Here, we evaluated the interaction between TNF-alpha and IL-27 in the context of low-grade inflammation by using in HaCaT cells. TNF-alpha induced significant upregulation of IL-6 and IL-8 through the experimental concentrations (~10 ng/ml) of TNF-alpha, while the mRNA expression levels of IL-1RA, IL-10 and IL-18BP were unchanged. After confirming the expression of IL-27 receptor in HaCaT cells, we examined the effects of IL-27 alone on the cytokine expression. IL-27 alone significantly enhanced mRNA expression levels of IL-10 and IL-18BP by 1.61-fold and 1.46-fold, respectively, and also enhanced mRNA expression levels of IL-6 by 2.32-fold. In the presence of 100 ng/ml IL-27, the expression levels of anti-inflammatory cytokines, IL-1RA, IL-10 and IL-18BP, were significantly upregulated with the treatment of a physiological concentration (1 ng/ml) TNF-alpha. Taken together, a high concentration of IL-27 exhibits anti-inflammatory effects in the presence of a low concentration of TNF-alpha when keratinocytes are the recipient of IL-27 signaling, suggesting the anti-inflammatory roles of IL-27 in inflammaging may be regulated by TNF-alpha concentration.
Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin

Background Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. Methods Whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brainwide in situ hybridization data. Results Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe, lateral habenula, and insular cortex for psilocybin and retrosplenial cortex for ketamine. Correlation of psilocybin’s effects with gene expression highlighted potential roles of 5-HT2A and GluN2B subunit of NMDA receptors. Conclusions The systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a valuable resource that highlights previously underappreciated regions for future investigations. By identifying regions with similar and disparate effects, the results provide insights into how psilocybin and ketamine may produce their rapid-acting and long-lasting therapeutic effects.
Inducible depletion of Scleraxis-lineage cells during tendon healing impairs multi-scale restoration of tendon structure

Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTR) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTR were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.
Durable protection against SARS-CoV-2 Omicron induced by an adjuvanted subunit vaccine

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity, and the emergence of SARS-CoV-2 variants such as Omicron represents a major global health challenge. Here we present data from a study in non-human primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine, consisting of RBD (receptor binding domain) on the I53-50 nanoparticle, adjuvanted with AS03, currently in Phase 3 clinical trial (NCT05007951). Vaccination induced robust neutralizing antibody (nAb) titers that were maintained at high levels for at least one year after two doses (Pseudovirus nAb GMT: 2207, Live-virus nAb GMT: 1964) against the ancestral strain, but not against Omicron. However, a booster dose at 6-12 months with RBD-Wu or RBD-β (RBD from the Beta variant) displayed on I53-50 elicited equivalent and remarkably high neutralizing titers against the ancestral as well as the Omicron variant. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Importantly, vaccination resulted in protection against Omicron infection in the lung (no detectable virus in any animal) and profound suppression of viral burden in the nares (median peak viral load of 7567 as opposed to 1.3×107 copies in unvaccinated animals) at 6 weeks post final booster. Even at 6 months post vaccination, there was significant protection in the lung (with 7 out of 11 animals showing no viral load, 3 out of 11 animals showing ~20-fold lower viral load than unvaccinated controls) and rapid control of virus in the nares. These results highlight the durable cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine platform.
Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination

Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.
Beyond inappropriate fire regimes: a synthesis of fire-driven declines of threatened mammals in Australia

Fire can promote biodiversity but changing patterns of fire threaten species worldwide. While scientific literature often describes ‘inappropriate fire regimes’ as a significant threat to biodiversity, less attention has been paid to the characteristics that make a fire regime inappropriate. We go beyond this generic description and synthesize how inappropriate fire regimes contribute to declines of animal populations, using threatened mammals as a case study. We developed a demographic framework for classifying mechanisms by which fire regimes cause population decline, and applied the framework in a systematic review to identify fire characteristics and interacting threats associated with population declines in Australian threatened land mammals (n=99). Inappropriate fire regimes threaten 88% of Australian threatened land mammals. Our review indicates that intense, large, and frequent fires are the primary cause of fire-related population declines, particularly through their influence on survival rates. However, several species are threatened by a lack of fire and there is considerable uncertainty in the evidence base for fire-related declines. Climate change and predation are documented or predicted to interact with fire to exacerbate mammalian declines. This demographic framework will help target conservation actions globally and would be enhanced by empirical studies of animal survival, dispersal, and reproduction.
Dynamic control of metabolic zonation and liver repair by endothelial cell Wnt2 and Wnt9b revealed by single cell spatial transcriptomics using Molecular Cartography

The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Conditional EC-elimination of Wnt2 and Wnt9b led to perturbation of LZ with not only loss of β-catenin targets in zone 3, but also re-appearance of zone 1 genes in zone 3, unraveling dynamicity as revealed by single-cell spatial transcriptomics using Molecular Cartography. Defective LR observed in the knockouts phenocopied other models of defective hepatic Wnt signaling. Administration of a tetravalent antibody to activate Wnt signaling rescued LZ and LR in the knockouts. Molecular Cartography on the livers of the agonist-treated animal revealed changes in LZ. Administration of the agonist also promoted LR in acetaminophen overdose acute liver failure (ALF) fulfilling an unmet clinical need. Overall, we report an unequivocal role of EC-Wnt2 and Wnt9b in LZ and LR and show the role of Wnt activators as regenerative therapy for ALF.
A naturally arising broad and potent CD4-binding site antibody with low somatic mutation

The induction of broadly neutralizing antibodies (bNAbs) is a potential strategy for a vaccine against HIV-1. However, most bNAbs exhibit features such as unusually high somatic hypermutation, including insertions and deletions, which make their induction challenging. VRC01-class bNAbs exhibit extraordinary breadth and potency, but also rank among the most highly somatically-mutated bNAbs. Here we describe a VRC01-class antibody isolated from a viremic controller, BG24, that has less than half the mutations of most other relatives of its class, while achieving comparable breadth and potency. A 3.8 Å X-ray crystal structure of a BG24-BG505 Env trimer complex revealed conserved contacts at the gp120 interface characteristic of the VRC01-class Abs, despite lacking common CDR3 sequence motifs. The existence of moderately-mutated CD4-binding site (CD4bs) bNAbs such as BG24 provides a simpler blueprint for CD4bs antibody induction by a vaccine, raising the prospect that such an induction might be feasible with a germline-targeting approach. Teaser An anti-HIV-1 antibody with comparable neutralization breadth and potency to similarly-classed antibodies, with half as many mutations.
Pore-forming protein βγ-CAT promptly responses to fasting with capacity to deliver macromolecular nutrients

During animal fasting, the nutrient supply and metabolism switch from carbohydrates to a new reliance on the catabolism of energy-dense lipid stores. Assembled under tight regulation, βγ-CAT is a pore-forming protein and trefoil factor complex identified in toad Bombina maxima. Here, we determined that this protein complex is a constitutive component in toad blood, that actively responds to the animal fasting. The protein complex was able to promote cellular albumin and albumin-bound fatty acid uptake in a variety of epithelial and endothelial cells, and the effects were attenuated by a macropinocytosis inhibitor. Endothelial cell-derived exosomes containing largely enriched albumin and fatty acids, called nutrisomes, were released in the presence of βγ-CAT. These specific nutrient vesicles were readily taken by starved muscle cells to support their survival. The results uncovered that pore-forming protein βγ-CAT is a fasting responsive element able to drive cell vesicular import and export of macromolecular nutrients.
SciCV, the Swiss National Science Foundation’s new CV format

Background The Swiss National Science Foundation (SNSF) tested a new CV format called SciCV to encourage fair, DORA-compliant assessment of grant applicants. It was developed in close collaboration with the academic evaluation community and international experts, introduced through detailed change management and finally tested in its utility by an independent research team of the Center for Science and Technology Studies Leiden (CWTS). Methods We present the development of the SciCV pilot and its evaluation by the CWTS research group. The analysis comprised both quantitative and qualitative methods, with (i) surveys and semi-structured interviews with applicants and reviewers, (ii) text analysis of the narrative elements of SciCV, and (iii) participant observation in ten evaluation panel meetings. Results Narrative elements and the inclusion of the academic age were rated as most useful new CV elements, while the inclusion of two metrics, the h-index and the relative citation ratio, were received more critically. The omission of a full publication list had similar numbers of supporters and opponents among applicants and reviewers. Less experienced and junior applicants and reviewers rated the new format generally more positively than more senior applicants and reviewers. The text analysis of narrative elements yielded no significant gender specific differences. The participant observation revealed that the new elements in SciCV broadened the information base used in the evaluation of applicants but did not fundamentally alter traditional, publication-centred evaluation practices. Conclusion SciCV was a relevant and successful initiative for the SNSF, which showed that the implementation of a new, well-structured CV format is not only feasible but also something that many stakeholders welcome.The extensive experience and results obtained during the change process formed the basis for the development of SciCV 2.0 at the SNSF. It also offers a basis and guidance for other funding organisations planning similar initiatives.
Feature-Based Attention Multiplicatively Scales the fMRI-BOLD Contrast-Response Function

fMRI plays a key role in the study of attention. However, there remains a puzzling discrepancy between attention effects measured with fMRI and with electrophysiological methods. While electrophysiological studies find that attention increases sensory gain, amplifying stimulus-evoked neural responses by multiplicatively scaling the contrast-response function (CRF), fMRI appears to be insensitive to these multiplicative effects. Instead, fMRI studies typically find that attention produces an additive baseline shift in the BOLD signal. These findings suggest that attentional effects measured with fMRI reflect top-down inputs to visual cortex, rather than the modulation of sensory gain. If true, this drastically limits what fMRI can tell us about how attention improves sensory coding. Here, we examined whether fMRI is sensitive to multiplicative effects of attention using a feature-based attention paradigm designed to preclude any possible additive effects. We measured BOLD activity evoked by a probe stimulus in one visual hemifield while participants (6 male, 6 female) attended to the probe orientation (attended condition), or to an orthogonal orientation (unattended condition), in the other hemifield. To measure CRFs in visual areas V1-V3, we parametrically varied the contrast of the probe stimulus. In all three areas, feature-based attention increased contrast gain, improving sensitivity by shifting CRFs toward lower contrasts. In V2 and V3, we also found an increase in response gain, an increase in the responsivity of the CRF, that was greatest at inner eccentricities. These results provide clear evidence that the fMRI-BOLD signal is sensitive to multiplicative effects of attention. SIGNIFICANCE STATEMENT fMRI plays a central role in the study of attention because it allows researchers to precisely and noninvasively characterize the effects of attention throughout the brain. Electrophysiological studies have shown that attention increases sensory gain, amplifying stimulus-evoked neural responses. However, a growing body of work suggests that the BOLD signal that is measured with fMRI is not sensitive to these multiplicative effects of attention, calling into question what we can learn from fMRI about how attention improves sensory codes. Here, using a feature-based attention paradigm, we provide evidence that the BOLD signal can pick up multiplicative effects of attention.
Mapping the Cell-Membrane Proteome to the Cancer Hallmarks

The hallmarks of biological processes that underlie the development of cancer have been long recognized, yet, existing therapeutic treatments cannot prevent cancer from continuing to be one of the leading causes of death worldwide. This work was aimed at exploring the extent to which the cell-membrane proteins are implicated in triggering cancer hallmark processes. To achieve this goal, we created a database of human proteins associated broadly with ten cancer hallmarks, and mapped the cell-membrane proteome of the SKBR3/HER2+ breast cancer cell line to the hallmark categories. We show that the landscape of the cancer cell-membrane proteome points to unique opportunities that can be exploited to guide novel therapeutic interventions, including multi-agent, immuno-oncology and precision medicine applications. Significance Through heavy involvement in supporting cancer hallmark processes, the membrane proteome reveals an extensive catalogue of functionally diverse and networked proteins expected to inspire new cancer therapeutic perspectives.
Iron regulatory protein (IRP)–mediated iron homeostasis is critical for neutrophil development and differentiation in the bone marrow

Iron is mostly devoted to the hemoglobinization of erythrocytes for oxygen transport. Yet, emerging evidence points to a broader role for the metal in hematopoiesis, including the formation of the immune system. Iron availability in mammalian cells is controlled by iron-regulatory proteins (IRP)-1 and −2. We report that global disruption of both IRP1 and IRP2 in adult mice impairs neutrophil development and differentiation in the bone marrow, yielding immature neutrophils with abnormally high glycolytic and autophagic activity, resulting in neutropenia. IRPs promote neutrophil differentiation in a cell intrinsic manner by securing cellular iron supply together with transcriptional control of neutropoiesis to facilitate differentiation to fully mature neutrophils. Unlike neutrophils, monocyte count was not affected by IRP and iron deficiency, suggesting a lineage-specific effect of iron on myeloid output. This study unveils the previously unrecognized importance of IRPs and iron metabolism in the formation of a major branch of the innate immune system.
Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

Spinally-projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception. Our tracing experiments revealed that serotonergic neurons of the LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than medial hindbrain serotonergic neurons. Taking advantage of this difference, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and their impact on nociceptive sensitivity. The LPGi neurons that give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord appear to be ideally posed to contribute to widespread systemic pain control.