The INSIDEOUT framework provides precise signatures of the balance of intrinsic and extrinsic dynamics in brain states

Finding precise signatures of different brain states is a central, unsolved question in neuroscience. We reformulated the problem to quantify the 'inside out' balance of intrinsic and extrinsic brain dynamics in brain states. The difference in brain state can be described as differences in the detailed causal interactions found in the underlying intrinsic brain dynamics. We used a thermodynamics framework to quantify the breaking of the detailed balance captured by the level of asymmetry in temporal processing, i.e. the arrow of time. Specifically, the temporal asymmetry was computed by the time-shifted correlation matrices for the forward and reversed time series, reflecting the level of non-reversibility/non-equilibrium. We found precise, distinguishing signatures in terms of the reversibility and hierarchy of large-scale dynamics in three radically different brain states (awake, deep sleep and anaesthesia) in electrocorticography data from non-human primates. Significantly lower levels of reversibility were found in deep sleep and anaesthesia compared to wakefulness. Non-wakeful states also showed a flatter hierarchy, reflecting the diversity of the reversibility across the brain. Overall, this provides signatures of the breaking of detailed balance in different brain states, perhaps reflecting levels of conscious awareness

Strength-dependent perturbation of whole-brain model working in different regimes reveals the role of fluctuations in brain dynamics

Despite decades of research, there is still a lack of understanding of the role and generating mechanisms of the ubiquitous fluctuations and oscillations found in recordings of brain dynamics. Here, we used whole-brain computational models capable of presenting different dynamical regimes to reproduce empirical data's turbulence level. We showed that the model's fluctuations regime fitted to turbulence more faithfully reproduces the empirical functional connectivity compared to oscillatory and noise regimes. By applying global and local strength-dependent perturbations and subsequently measuring the responsiveness of the model, we revealed each regime's computational capacity demonstrating that brain dynamics is shifted towards fluctuations to provide much-needed flexibility. Importantly, fluctuation regime stimulation in a brain region within a given resting state network modulates that network, aligned with previous empirical and computational studies. Furthermore, this framework generates specific, testable empirical predictions for human stimulation studies using strength-dependent rather than constant perturbation. Overall, the whole-brain models fitted to the level of empirical turbulence together with functional connectivity unveil that the fluctuation regime best captures empirical data, and the strength-dependent perturbative framework demonstrates how this regime provides maximal flexibility to the human brain

Data-driven discovery of canonical large-scale brain dynamics

Human behavior and cognitive function correlate with complex patterns of spatio-temporal brain dynamics, which can be simulated using computational models with different degrees of biophysical realism. We used a data-driven optimization algorithm to determine and classify the types of local dynamics that enable the reproduction of different observables derived from functional magnetic resonance recordings. The phase space analysis of the resulting equations revealed a predominance of stable spiral attractors, which optimized the similarity to the empirical data in terms of the synchronization, metastability, and functional connectivity dynamics. For stable limit cycles, departures from harmonic oscillations improved the fit in terms of functional connectivity dynamics. Eigenvalue analyses showed that proximity to a bifurcation improved the accuracy of the simulation for wakefulness, while deep sleep was associated with increased stability. Our results provide testable predictions that constrain the landscape of suitable biophysical models, while supporting noise-driven dynamics close to a bifurcation as a canonical mechanism underlying the complex fluctuations that characterize endogenous brain activity

The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

Human pluripotent stem cells (hPSCs) have the capacity to give rise to all differentiated cells of the adult. TGF-beta is used routinely for expansion of conventional hPSCs as flat epithelial colonies expressing the transcription factors POU5F1/OCT4, NANOG, SOX2. Here we report a global analysis of the transcriptional programme controlled by TGF-beta followed by an unbiased gain-of-function screening in multiple hPSC lines to identify factors mediating TGF-beta activity. We identify a quartet of transcriptional regulators promoting hPSC self-renewal including ZNF398, a human-specific mediator of pluripotency and epithelial character in hPSCs. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300, enabling transcription of TGF-beta targets. In the context of somatic cell reprogramming, inhibition of ZNF398 abolishes activation of pluripotency and epithelial genes and colony formation. Our findings have clear implications for the generation of bona fide hPSCs for regenerative medicine

Prolonged RT-PCR test positivity in hemodialysis patients with COVID-19

Background: The weakened immune system of patients on hemodialysis (HD) may prolong SARS-CoV-2 infection compared to the general population. Current international guidelines recommend ending isolation in conjunction with serial testing in moderately and severely immunocompromised subjects. This study aimed to estimate SARS-CoV-2 infectivity by measuring RT-PCR test positivity in HD patients. A comparison between RT-PCR test and cycle threshold (Ct) value has been performed as a secondary endpoint. Methods: A single-center retrospective study was conducted at the University of Modena (Italy) from March 2020 to October 2022. Only patients on chronic HD therapy with COVID-19 were enrolled in the study. In our HD Center, two negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) results were used to end quarantine in this population. SARS-CoV-2 RT-PCR test positivity duration measured the time elapsed from a positive RT-PCR to a second negative test. Ct cut-off of 35 cycles was used to definite “high Ct value,” a condition characterized by a large number of cycles of PCR amplification to register a positive RT-PCR test. Results: During the observational period, 159 cases of SARS-CoV-2 infections were diagnosed in 151 patients. Median age was 70.1 (54.3–81.6) years and males accounted for 59.6% of the COVID-19 population. Median duration of SARS-CoV-2 RT-PCR test positivity on the nasal mucosa accounted for 30 (IQR, 21–40.5) days. Unvaccinated patients experienced significantly longer RT-PCR test positivity compared to vaccinated patients (42 [IQR,31–56] vs. 28 [IQR,20–35.7] days; p = < 0.001). The use of high Ct value, a laboratory surrogate of SARS-CoV-2 replication, anticipated a negative RT-PCR test of 9 (IQR, 6–12) days. Multivariate linear regression analysis showed that increased age (β coefficient 0.31; confidence interval [CI] 95%, 0.14—0.43; p = < 0.001) and the lack of anti-SARS-CoV-2 vaccination (β 0.49 CI95%, 11.9–22.5; p = < 0.001) were predictors of a prolonged RT-PCR positivity. Conclusions: Patients with COVID-19 on HD had prolonged RT-PCR test positivity. The adoption of “high Ct value” criteria led to a significant reduction in the duration of RT-PCR test positivity compared to the use of the classical nucleic acid amplification test. In our study, the lack of SARS-CoV-2 vaccination and older age were independently associated with a longer RT-PCR positivity

OeBAS and CYP716C67 catalyze the biosynthesis of health-beneficial triterpenoids in olive (Olea europaea) fruits

center dot The bioactive properties of olive (Olea europaea) fruits and olive oil are largely attributed to terpenoid compounds, including diverse triterpenoids such as oleanolic, maslinic and ursolic acids, erythrodiol, and uvaol. They have applications in the agri-food, cosmetics, and pharmaceutical industries. Some key steps involved in the biosynthesis of these compounds are still unknown.center dot Genome mining, biochemical analysis, and trait association studies have been used to identify major gene candidates controlling triterpenoid content of olive fruits.center dot Here, we identify and functionally characterize an oxidosqualene cyclase (OeBAS) required for the production of the major triterpene scaffold beta-amyrin, the precursor of erythrodiol, oleanolic and maslinic acids, and a cytochrome P450 (CYP716C67) that mediates 2 alpha oxidation of the oleanane- and ursane-type triterpene scaffolds to produce maslinic and corosolic acids, respectively. To confirm the enzymatic functions of the entire pathway, we have reconstituted the olive biosynthetic pathway for oleanane- and ursane-type triterpenoids in the heterologous host, Nicotiana benthamiana. Finally, we have identified genetic markers associated with oleanolic and maslinic acid fruit content on the chromosomes carrying the OeBAS and CYP716C67 genes.center dot Our results shed light on the biosynthesis of olive triterpenoids and provide new gene targets for germplasm screening and breeding for high triterpenoid content

Effects of classic psychedelic drugs on turbulent signatures in brain dynamics

Psychedelic drugs show promise as safe and effective treatments for neuropsychiatric disorders, yet their mechanisms of action are not fully understood. A fundamental hypothesis is that psychedelics work by dose-dependently changing the functional hierarchy of brain dynamics, but it is unclear whether different psychedelics act similarly. Here, we investigated the changes in the brain’s functional hierarchy associated with two different psychedelics (LSD and psilocybin). Using a novel turbulence framework, we were able to determine the vorticity, that is, the local level of synchronization, that allowed us to extend the standard global time-based measure of metastability to become a local-based measure of both space and time. This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network. Overall, our findings directly support a prior hypothesis that psychedelics modulate (i.e., “compress”) the functional hierarchy and provide a quantification of these changes for two different psychedelics. Implications for therapeutic applications of psychedelics are discussed