Changing Ecological Conditions in the Marine Environment Generate Different Microbial Food Web Structures in a Repeatable Manner

The mechanisms responsible for the development of various structural and functional features of the microbial food web (MFW) and their dynamics at spatial and temporal scales, which are important for predicting their responses to future environmental changes, are largely unknown. More than 3000 datasets of environmental and microbial variables collected over a decade on a seasonal and large spatial scale in the Adriatic Sea were analyzed. The sets of environmental variables were classified into four clusters (representing different environmental states) using Neural Gas analysis and the differences in MFW structure between the clusters were analyzed. Different variants of MFW evolve in the different clusters in terms of the abundance of MFW components, their ratios, growth and grazing rates, predator preference in prey selection, the strength of predator-prey interaction, and the relative importance of top-down and bottom-up control. However, these clusters are neither spatially nor temporally fixed; rather, the area studied represents a mosaic of different environmental conditions that alternate from one state to another on a time scale. In each of the environmental states, a distinct structure of MFW develops that shows consistent and repeatable changes that strictly follow the switching in environmental conditions from one state to another.

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.

Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes

The human SLC22A6/OAT1 plays an important role in the disposition of a broad range of endogenous substances and xenobiotics. This is particularly important from the pharmacological point of view since OAT1 is involved in drug elimination events. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about OAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called "charge-relay system" that works as molecular switches modulating the conformation. The principal element of the event points at interactions charged residues that appear crucial for the transporter dynamics and function. Besides, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein. MD simulations supported the pivotal role of phosphatidylethanolamine (PE) components on the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.

Voltage-Dependent Anion Selective Channel 3: Unraveling Structural and Functional Features of the Least Known Porin Isoform

Voltage-dependent anion-selective channels (VDAC) are pore-forming proteins located in the outer mitochondrial membrane. Three isoforms are encoded by separate genes in mammals (VDAC1-3). These proteins play a crucial role in the cell, forming the primary interface between mitochondrial and cellular metabolisms. Research on the role of VDACs in the cell is a rapidly growing field, but the function of VDAC3 remains elusive. The high-sequence similarity between isoforms suggests a similar pore-forming structure. Electrophysiological analyzes revealed that VDAC3 works as a channel; however, its gating and regulation remain debated. A comparison between VDAC3 and VDAC1-2 underlines the presence of a higher number of cysteines in both isoforms 2 and 3. Recent mass spectrometry data demonstrated that the redox state of VDAC3 cysteines is evolutionarily conserved. Accordingly, these residues were always detected as totally reduced or partially oxidized, thus susceptible to disulfide exchange. The deletion of selected cysteines significantly influences the function of the channel. Some cysteine mutants of VDAC3 exhibited distinct kinetic behavior, conductance values and voltage dependence, suggesting that channel activity can be modulated by cysteine reduction/oxidation. These properties point to VDAC3 as a possible marker of redox signaling in the mitochondrial intermembrane space. Here, we summarize our current knowledge about VDAC3 predicted structure, physiological role and regulation, and possible future directions in this research field.

Leptin participation in the processes of nervous impulse transmission and its influence on the formation of neuro-mental development of children

Review of publications on the functional features of leptin in the central nervous system in children. The participation of leptin mechanisms in the transmission of nerve impulses, the effect of leptin on cognitive functions in children. The article reveals the general mechanisms of maturation of the central nervous system in children, the participation of leptin and leptin receptors in the formation of cognitive abilities in children. Possible interrelationships of impairments in cognitive development and lipid metabolism including obesity are revealed.

The rumen liquid metatranscriptome of post-weaned dairy calves differed by pre-weaning ruminal administration of differentially-enriched, rumen-derived inocula

Background Targeted modification of the dairy calf ruminal microbiome has been attempted through rumen fluid inoculation to alter productive phenotypes later in life. However, sustainable effects of the early life interventions have not been well studied, particularly on the metabolically active rumen microbiota and its functions. This study investigated the sustained effects of adult-derived rumen fluid inoculations in pre-weaning dairy calves on the active ruminal microbiome of post-weaned dairy calves analyzed via RNA-sequencing. Results Two different adult-derived microbial inocula (bacterial- or protozoal-enriched rumen fluid; BE or PE, respectively) were administered in pre-weaned calves (3–6 weeks) followed by analyzing active rumen microbiome of post-weaned calves (9 weeks). The shared bacterial community at the genus level of 16S amplicon-seq and RNA-seq datasets was significantly different (P = 0.024), 21 out of 31 shared major bacterial genera differed in their relative abundance between the two analytic pipelines. No significant differences were found in any of the prokaryotic alpha- and beta-diversity measurements (P > 0.05), except the archaeota that differed for BE based on the Bray–Curtis dissimilarity matrix (P = 0.009). Even though the relative abundances of potentially transferred microbial and functional features from the inocula were minor, differentially abundant prokaryotic genera significantly correlated to various fermentation and animal measurements including butyrate proportion, body weight, and papillae length and counts. The overall microbial functions were affected quantitatively by BE and qualitatively by PE (P < 0.05), and this might be supported by the individual KEGG module and CAZymes profile differences. Exclusive networks between major active microbial (bacterial and archaeal genera) and functional features (KEGG modules) were determined which were differed by microbial inoculations. Conclusions This study demonstrated that actively transcribed microbial and functional features showed reliable connections with different fermentations and animal development responses through adult rumen fluid inoculations compared to our previous 16S amplicon sequencing results. Exclusive microbial and functional networks of the active rumen microbiome of dairy calves created by BE and PE might also be responsible for the different ruminal and animal characteristics. Further understanding of the other parts of the gastrointestinal tract (e.g., abomasum, omasum, and small intestine) using metatranscriptomics will be necessary to elucidate undetermined biological factors affected by microbial inoculations.

Beyond “Sex Prediction”: Estimating and Interpreting Multivariate Sex Differences and Similarities in the Brain

Previous studies have shown that machine-learning (ML) algorithms can “predict” sex based on brain anatomical/ functional features. The high classification accuracy achieved by ML algorithms is often interpreted as revealing large differences between the brains of males and females and as confirming the existence of “male/female brains”. However, classification and estimation are quite different concepts, and using classification metrics as surrogate estimates of between-group differences results in major statistical and interpretative distortions. The present study illustrates these distortions and provides a novel and detailed assessment of multivariate sex differences in gray matter volume (GMVOL) that does not rely on classification metrics. Moreover, modeling and clustering techniques and analyses of similarities (ANOSIM) were used to identify the brain areas that contribute the most to these multivariate differences, and to empirically assess whether they assemble into two sex-typical profiles. Results revealed that multivariate sex differences in GMVOL: 1) are “large” if not adjusted for total intracranial volume (TIV) variation, but “small” when controlling for this variable; 2) differ in size between individuals and also depends on the ML algorithm used for their calculation 3) do not stem from two sex-typical profiles, and so describing them in terms of “male/female brains” is misleading.

hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

Design of the University Mobile Educational Environment

The article addresses issues related to the description of the aspects of the instructional design of a mobile educational environment of a modern higher education institution. The authors give the definitions of the mobile educational environment, describe its functional features, and also consider the requirements for its instructional design and development. The article presents the clustering of digital services for the full implementation of a mobile educational environment (services for planning and supporting educational activities, services for organizing and supporting educational activities, communication and feedback services, general information services). The results of the experimental research to identify the attitude of students, teachers and administrative workers to the functional significance of mobile technologies and their application in the educational process are presented.