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

Self-assembly of model short triblock amphiphiles in dilute solution

In this work, a molecular theory is used to study the self-assembly of short diblock and triblock amphiphiles, with head-tail and head-linker-tail structures, respectively. The theory was used to systematically explore the effects of the molecular architecture and the affinity of the solvent for the linker and tail blocks on the relative stability of the different nanostructures formed by the amphiphiles in dilute solution, which include spherical micelles, cylindrical fibers and planar lamellas. Moreover, the theory predicts that each of these nanostructures can adopt two different types of internal organization: (i) normal nanostructures with a core composed of tail segments and a corona composed of head segments, and (ii) nanostructures with a core formed by linker segments and a corona formed by tail and head segments. The theory predicts the occurrence of a transition from micelle to fiber to lamella when increasing the length of the tail or the linker blocks, which is in qualitative agreement with the geometric packing theory and with experiments in the literature. The theory also predicts a transition from micelle to fiber to lamella as the affinity of the solvent for the tail or linker block is decreased. This result is also in qualitative agreement with experiments in the literature but cannot be explained in terms of the geometric packing theory. The molecular theory provides an explanation for this result in terms of the competition between solvophobic attractions among segments in the core and steric repulsions between segments in the corona for the different types of self-assembled nanostructures.Fil: Zaldivar, Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaFil: Samad, M. B.. University of Nebraska; Estados UnidosFil: Conda Sheridan, Martin. University of Nebraska; Estados UnidosFil: Tagliazucchi, Mario Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentin

Characterization of yeasts isolated from parmigiano reggiano cheese natural whey starter: From spoilage agents to potential cell factories for whey valorization

Whey is the main byproduct of the dairy industry and contains sugars (lactose) and proteins (especially serum proteins and, at lesser extent, residual caseins), which can be valorized by the fermentative action of yeasts. In the present study, we characterized the spoilage yeast population inhabiting natural whey starter (NWS), the undefined starter culture of thermophilic lactic acid bacteria used in Parmigiano Reggiano (PR) cheesemaking, and evaluated thermotolerance, mating type, and the aptitude to produce ethanol and bioactive peptides from whey lactose and proteins, respectively, in a selected pool of strains. PCR-RFLP assay of ribosomal ITS regions and phylogenetic analysis of 26S rDNA D1/D2 domains showed that PR NWS yeast population consists of the well-documented Kluyveromyces marxianus, as well as of other species (Saccharomyces cerevisiae, Wickerhamiella pararugosa, and Torulaspora delbrueckii), with multiple biotypes scored within each species as demonstrated by (GTG)5-based MSP-PCR. Haploid and diploid K. marxianus strains were identified through MAT genotyping, while thermotolerance assay allowed the selection of strains suitable to grow up to 48◦C. In whey fermentation trials, one thermotolerant strain was suitable to release ethanol with a fermentation efficiency of 86.5%, while another candidate was able to produce the highest amounts of both ethanol and bioactive peptides with potentially anti-hypertensive function. The present work demonstrated that PR NWS is a reservoir of ethanol and bioactive peptides producer yeasts, which can be exploited to valorize whey, in agreement with the principles of circularity and sustainability

Lessons from being challenged by COVID-19

We present results of different approaches to model the evolution of the COVID-19 epidemic in Argentina, with a special focus onthe megacity conformed by the city of Buenos Aires and its metropolitan area, including a total of 41 districts with over 13 millioninhabitants. We first highlight the relevance of interpreting the early stage of the epidemic in light of incoming infectious travelersfrom abroad. Next, we critically evaluate certain proposed solutions to contain the epidemic based on instantaneous modificationsof the reproductive number. Finally, we build increasingly complex and realistic models, ranging from simple homogeneous modelsused to estimate local reproduction numbers, to fully coupled inhomogeneous (deterministic or stochastic) models incorporatingmobility estimates from cell phone location data. The models are capable of producing forecasts highly consistent with the officialnumber of cases with minimal parameter fitting and fine-tuning.  We discuss the strengths and limitations of the proposed models,focusing on the validity of different necessary first approximations, and caution future modeling efforts to exercise great care in theinterpretation of long-term forecasts, and in the adoption of non-pharmaceutical interventions backed by numerical simulations.Fil: Tagliazucchi, Enzo Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Balenzuela, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Travizano, M.. Grandata Labs; Estados UnidosFil: Mindlin, Bernardo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Mininni, Pablo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentin

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

Cultivable microbial diversity, peptide profiles, and bio-functional properties in Parmigiano Reggiano cheese

Introduction: Lactic acid bacteria (LAB) communities shape the sensorial and functional properties of artisanal hard-cooked and long-ripened cheeses made with raw bovine milk like Parmigiano Reggiano (PR) cheese. While patterns of microbial evolution have been well studied in PR cheese, there is a lack of information about how this microbial diversity affects the metabolic and functional properties of PR cheese. Methods: To fill this information gap, we characterized the cultivable fraction of natural whey starter (NWS) and PR cheeses at different ripening times, both at the species and strain level, and investigated the possible correlation between microbial composition and the evolution of peptide profiles over cheese ripening. Results and discussion: The results showed that NWS was a complex community of several biotypes belonging to a few species, namely, Streptococcus thermophilus, Lactobacillus helveticus, and Lactobacillus delbrueckii subsp. lactis. A new species-specific PCR assay was successful in discriminating the cheese-associated species Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Lacticaseibacillus zeae. Based on the resolved patterns of species and biotype distribution, Lcb. paracasei and Lcb. zeae were most frequently isolated after 24 and 30 months of ripening, while the number of biotypes was inversely related to the ripening time. Peptidomics analysis revealed more than 520 peptides in cheese samples. To the best of our knowledge, this is the most comprehensive survey of peptides in PR cheese. Most of them were from β-caseins, which represent the best substrate for LAB cell-envelope proteases. The abundance of peptides from β-casein 38–88 region continuously increased during ripening. Remarkably, this region contains precursors for the anti-hypertensive lactotripeptides VPP and IPP, as well as for β-casomorphins. We found that the ripening time strongly affects bioactive peptide profiles and that the occurrence of Lcb. zeae species is positively linked to the incidence of eight anti-hypertensive peptides. This result highlighted how the presence of specific LAB species is likely a pivotal factor in determining PR functional properties

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

Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC