Characterization of the Mitochondrial Proteome in the Ctenophore Mnemiopsis leidyi Using MitoPredictor.

Mitochondrial proteomes have been experimentally characterized for only a handful of animal species. However, the increasing availability of genomic and transcriptomic data allows one to infer mitochondrial proteins using computational tools. MitoPredictor is a novel random forest classifier, which utilizes orthology search, mitochondrial targeting signal (MTS) identification, and protein domain content to infer mitochondrial proteins in animals. MitoPredictor's output also includes an easy-to-use R Shiny applet for the visualization and analysis of the results. In this article, we provide a guide for predicting and analyzing the mitochondrial proteome of the ctenophore Mnemiopsis leidyi using MitoPredictor.

Hominin population bottleneck coincided with migration from Africa during the Early Pleistocene ice age transition.

Two recently published analyses make cases for severe bottlenecking of human populations occurring in the late Early Pleistocene, one case at about 0.9 Mya based on a genomic analysis of modern human populations and the low number of hominin sites of this age in Africa and the other at about 1.1 Mya based on an age inventory of sites of hominin presence in Eurasia. Both models point to climate change as the bottleneck trigger, albeit manifested at very different times, and have implications for human migrations as a mechanism to elude extinction at bottlenecking. Here, we assess the climatic and chronologic components of these models and suggest that the several hundred-thousand-year difference is largely an artifact of biases in the chronostratigraphic record of Eurasian hominin sites. We suggest that the best available data are consistent with the Galerian hypothesis expanded from Europe to Eurasia as a major migration pulse of fauna including hominins in the late Early Pleistocene as a consequence of the opening of land routes from Africa facilitated by a large sea level drop associated with the first major ice age of the Pleistocene and concurrent with widespread aridity across Africa that occurred during marine isotope stage 22 at ~0.9 Mya. This timing agrees with the independently dated bottleneck from genomic analysis of modern human populations and allows speculations about the relative roles of climate forcing on the survival of hominins.

A Comparative Analysis of Three Antioxidants in Addition to Scaling and Root Planing in Stage Three Grade B Periodontitis.

INTRODUCTION: The main feature of periodontitis is the development of periodontal pockets as a secondary consequence, which is mainly caused by an excessive immune response to the dental biofilm. The prime factor in the pathogenesis of periodontitis is an increase in oxidative stress. Numerous clinical studies have demonstrated that antioxidant supplementation can reduce endogenous antioxidant depletion and the oxidative damage that goes along with it. Hence, antioxidant therapy in the treatment of periodontal disease may prove to be a promising tool. OBJECTIVE: The objective of the study is to compare the efficiency of three different antioxidants as oral supplements. MATERIALS AND METHODS: Eighty patients with chronic periodontitis were randomly split into four groups. The control group received scaling and root planning (SRP), and the test group received oral supplements for 30 days with SRP. Pocket depth (PD), clinical attachment level (CAL), oral hygiene index-simplified (OHI-S), and sulcus bleeding index (SBI) were evaluated at baseline and 30 days. The analysis of the data was done with ANOVA, Kruskal-Wallis, and post hoc tests. The significance level was set at p<0.05 and p<0.001. RESULTS: All groups resulted in a statistically significant reduction in all parameters from baseline to one month. The treatment groups revealed a statistically significant reduction in PD and CAL (p<0.00) but no reduction in OHI-S and SBI (p>0.05) scores. A highly statistically significant reduction was observed in PD with green coffee bean extract when compared with other groups. CONCLUSION: Green coffee bean extract oral supplements may prove to be a promising appendage in therapeutic and prophylactic fashion, along with SRP, in the treatment of stage III grade B periodontitis patients.

Phylomitogenomics bolsters the high-level classification of Demospongiae (phylum Porifera).

Class Demospongiae is the largest in the phylum Porifera (Sponges) and encompasses nearly 8,000 accepted species in three subclasses: Keratosa, Verongimorpha, and Heteroscleromorpha. Subclass Heteroscleromorpha contains ∼90% of demosponge species and is subdivided into 17 orders. The higher level classification of demosponges underwent major revision as the result of nearly three decades of molecular studies. However, because most of the previous molecular work only utilized partial data from a small number of nuclear and mitochondrial (mt) genes, this classification scheme needs to be tested by larger datasets. Here we compiled a mt dataset for 136 demosponge species-including 64 complete or nearly complete and six partial mt-genome sequences determined or assembled for this study-and used it to test phylogenetic relationships among Demospongiae in general and Heteroscleromorpha in particular. We also investigated the phylogenetic position of Myceliospongia araneosa, a highly unusual demosponge without spicules and spongin fibers, currently classified as Demospongiae incertae sedis, for which molecular data were not available. Our results support the previously inferred sister-group relationship between Heteroscleromorpha and Keratosa + Verongimorpha and suggest five main clades within Heteroscleromorpha: Clade C0 composed of order Haplosclerida; Clade C1 composed of Scopalinida, Sphaerocladina, and Spongillida; Clade C2 composed of Axinellida, Biemnida, Bubarida; Clade C3 composed of Tetractinellida; and Clade C4 composed of Agelasida, Clionaida, Desmacellida, Merliida, Suberitida, Poecilosclerida, Polymastiida, and Tethyida. The inferred relationships among these clades were (C0(C1(C2(C3+C4)))). Analysis of molecular data from M. araneosa placed it in the C3 clade as a sister taxon to the highly skeletonized tetractinellids Microscleroderma sp. and Leiodermatium sp. Molecular clock analysis dated divergences among the major clades in Heteroscleromorpha from the Cambrian to the Early Silurian, the origins of most heteroscleromorph orders in the middle Paleozoic, and the most basal splits within these orders around the Paleozoic to Mesozoic transition. Overall, the results of this study are mostly congruent with the accepted classification of Heteroscleromorpha, but add temporal perspective and new resolution to phylogenetic relationships within this subclass.

Bispecific Complement Engagers for Targeted Complement Activation.

Activation of the complement system represents an important effector mechanism of endogenous and therapeutic Abs. However, efficient complement activation is restricted to a subset of Abs due to the requirement of multivalent interactions between the Ab Fc regions and the C1 complex. In the present study, we demonstrate that Fc-independent recruitment of C1 by modular bispecific single-domain Abs that simultaneously bind C1q and a surface Ag can potently activate the complement system. Using Ags from hematological and solid tumors, we show that these bispecific Abs are cytotoxic to human tumor cell lines that express the Ag and that the modular design allows a functional exchange of the targeting moiety. Direct comparison with clinically approved Abs demonstrates a superior ability of the bispecific Abs to induce complement-dependent cytotoxicity. The efficacy of the bispecific Abs to activate complement strongly depends on the epitope of the C1q binding Ab, demonstrating that the spatial orientation of the C1 complex upon Ag engagement is a critical factor for efficient complement activation. Collectively, our data provide insight into the mechanism of complement activation and provide a new platform for the development of immunotherapies.

Tuning Oxide Properties by Oxygen Vacancy Control During Growth and Annealing.

Electrical, optical, and magnetic properties of oxide materials can often be controlled by varying the oxygen content. Here we outline two approaches for varying the oxygen content and provide concrete examples for tuning the electrical properties of SrTiO3-based heterostructures. In the first approach, the oxygen content is controlled by varying the deposition parameters during a pulsed laser deposition. In the second approach, the oxygen content is tuned by subjecting the samples to annealing in oxygen at elevated temperatures after the film growth. The approaches can be used for a wide range of oxides and nonoxide materials where the properties are sensitive to a change in the oxidation state. The approaches differ significantly from electrostatic gating, which is often used to change the electronic properties of confined electronic systems such as those observed in SrTiO3-based heterostructures. By controlling the oxygen vacancy concentration, we are able to control the carrier density over many orders of magnitude, even in nonconfined electronic systems. Moreover, properties can be controlled, which are not sensitive to the density of itinerant electrons.

Epicardial Adipose Tissue in Myocardial Disease: From Physiology to Heart Failure Phenotypes.

Epicardial adipose tissue (EAT) is increasingly being recognized as a determinant of myocardial biology. The EAT-heart crosstalk suggests causal links between dysfunctional EAT and cardiomyocyte impairment. Obesity promotes EAT dysfunction and shifts in secreted adipokines which adversely affect cardiac metabolism, induce cardiomyocyte inflammation, redox imbalance and myocardial fibrosis. Thus, EAT determines cardiac phenotype via effects on cardiac energetics, contractility, diastolic function, and atrial conduction. Vice-versa the EAT is altered in heart failure (HF), and such phenotypic changes can be detected by noninvasive imaging or incorporated in Artificial Intelligence-enhanced tools to aid the diagnosis, subtyping or risk prognostication of HF. In the present article, we summarize the links between EAT and the heart, explaining how the study of epicardial adiposity can improve the understanding of cardiac disease, serve as a source of diagnostic and prognostic biomarkers, and as a potential therapeutic target in HF to improve clinical outcomes.

Tissue and Serum Biomarkers in Degenerative Aortic Stenosis-Insights into Pathogenesis, Prevention and Therapy.

BACKGROUND AND AIM: Degenerative Aortic Stenosis (DAS) is a common disease that causes substantial morbidity and mortality worldwide, especially in the older population. Our aim was to further investigate novel serum and tissue biomarkers to elucidate biological processes involved in this entity. MATERIAL AND METHODS: We evaluated the expression of six biomarkers significantly involved in cardiovascular pathology, i.e., irisin, periostin, osteoglycin, interleukin 18, high mobility group box 1 and proprotein convertase subtilisin/kexin type 9 in the serum at the protein level, and in the tissue at both the protein and mRNA levels of patients with AS (N = 60). Five normal valves obtained after transplantation from hearts of patients with idiopathic dilated cardiomyopathy were also studied. Serum measurements were also performed in 22 individuals without valvular disease who served as controls (C). RESULTS: Higher levels of all factors were found in DAS patients' serum than in normal C. IHC and PCR mRNA tissue analysis showed the presence of all biomarkers in the aortic valve cusps with DAS, but no trace of PCR mRNA was found in the five transplantation valves. Moreover, periostin serum levels correlated significantly with IHC and mRNA tissue levels in AS patients. CONCLUSION: We showed that six widely prevalent biomarkers affecting the atherosclerotic process were also involved in DAS, suggesting a strong osteogenic and pro-inflammatory profile, indicating that aortic valve calcification is a multifactorial biological process.

Neuroendocrine System Adaptation during Consecutive Extrinsic Stimuli: A Pilot Dynamic Study.

This pilot repeated measures study aims to evaluate the dynamics of the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and/or their interplay with low-level inflammation in healthy schoolchildren during consecutive extrinsic stimuli. Twenty healthy schoolchildren and adolescents aged 11-14 years (12.5 ± 1.5) were consecutively exposed to an oral task (#2) and an arithmetic task (#3) (Trier Social Stress Test for Children (TSST-C)), lasting 5 min each, and a three-minute cellular phone call (#4). Salivary cortisol (SC) was sampled at baseline (#1) and immediately after each exposure (#2, 3, and 4). Baseline serum high-sensitivity C-reactive protein (hsCRP) and cortisol levels were also assessed. ANS dynamics and complexity were measured using Sample Entropy (SampEn) at each experimental time period (#1-4). Baseline serum hCRP and cortisol correlated negatively to each other, while the ANS and HPA axis acute reactions to the three consecutive stimuli differed over time. The ANS adaptation to these stimuli included complexity modulation, which was not dependent on baseline hsCRP or cortisol, and weakened during the third stimulation. However, baseline hsCRP and cortisol had a weakening and an increasing effect on the HPA axis over time, respectively. We conclude that low-level inflammation and baseline morning cortisol level have no effect on ANS dynamics but influence the HPA axis response to consecutive external stimuli.

Peak exercise myocardial deformation indices during cardiopulmonary exercise testing are associated with exercise capacity and ventilatory efficiency in patients with dilated cardiomyopathy.

OBJECTIVE: Little is known about the exercise-induced changes in the multidimensional mechanical properties of the heart. We aimed to evaluate the myocardial deformation indices (MDI) at rest and their response at peak exercise during the same cardiopulmonary exercise testing (CPET) session, investigating their relationship to exercise capacity and ventilatory sufficiency in dilated cardiomyopathy (DCM) patients. METHODS: We evaluated left ventricular (LV) function using speckle tracking imaging (STI) at rest and peak exercise during the same CPET session in 57 idiopathic DCM patients in New York Heart Association (NYHA) I-II class [54 ± 12 years, 42 males, ejection fraction (EF) 33 ± 9%]. We measured global longitudinal strain (GLS), longitudinal strain rate at systole (LSRS) and diastole (LSRD), and circumferential strain rate (CircS). RESULTS: Resting GLS, LSRS, and LSRD were impaired compared with the predicted values but were improved at peak exercise (p < 0.001). All MDI at rest and/or at peak exercise were related to several CPET-derived parameters, including peak VO2, load, O2 pulse, and VE/VCO2 slope. Peak exercise LSRS > -1.10 sec-1 (AUC = 0.80, p < 0.001) and GLS > -13% (AUC = 0.81, p = 0.002) predicted impaired exercise capacity (peak VO2 < 20 ml/min/kg) and ventilatory inefficiency (VE/VCO2 slope>34). In multiple regression analysis, peak exercise LSRS and GLS were independently related to the peak VO2 (Beta = -0.39, p = 0.003) and VE/VCO2 slope (Beta = 0.35, p = 0.02), respectively. CONCLUSIONS: Peak exercise LSRS and GLS in NYHA I-II DCM patients subjected to CPET were associated with aerobic exercise capacity and ventilatory efficiency. Consequently, LSRS and GLS at peak exercise, through their association with CPET-derived CV risk indices, may underline the severity of heart failure and predict future CV events in this DCM population.

Atomically engineered interfaces yield extraordinary electrostriction.

Electrostriction is a property of dielectric materials whereby an applied electric field induces a mechanical deformation proportional to the square of that field. The magnitude of the effect is usually minuscule (<10-19 m2 V-2 for simple oxides). However, symmetry-breaking phenomena at the interfaces can offer an efficient strategy for the design of new properties1,2. Here we report an engineered electrostrictive effect via the epitaxial deposition of alternating layers of Gd2O3-doped CeO2 and Er2O3-stabilized δ-Bi2O3 with atomically controlled interfaces on NdGaO3 substrates. The value of the electrostriction coefficient achieved is 2.38 × 10-14 m2 V-2, exceeding the best known relaxor ferroelectrics by three orders of magnitude. Our theoretical calculations indicate that this greatly enhanced electrostriction arises from coherent strain imparted by interfacial lattice discontinuity. These artificial heterostructures open a new avenue for the design and manipulation of electrostrictive materials and devices for nano/micro actuation and cutting-edge sensors.

Stacking and Twisting of Freestanding Complex Oxide Thin Films.

The integration of dissimilar materials in heterostructures has long been a cornerstone of modern materials science-seminal examples are 2D materials and van der Waals heterostructures. Recently, new methods have been developed that enable the realization of ultrathin freestanding oxide films approaching the 2D limit. Oxides offer new degrees of freedom, due to the strong electronic interactions, especially the 3d orbital electrons, which give rise to rich exotic phases. Inspired by this progress, a new platform for assembling freestanding oxide thin films with different materials and orientations into artificial stacks with heterointerfaces is developed. It is shown that the oxide stacks can be tailored by controlling the stacking sequences, as well as the twist angle between the constituent layers with atomically sharp interfaces, leading to distinct moiré patterns in the transmission electron microscopy images of the full stacks. Stacking and twisting is recognized as a key degree of structural freedom in 2D materials but, until now, has never been realized for oxide materials. This approach opens unexplored avenues for fabricating artificial 3D oxide stacking heterostructures with freestanding membranes across a broad range of complex oxide crystal structures with functionalities not available in conventional 2D materials.

Planetary chaos and inverted climate phasing in the Late Triassic of Greenland.

Sedimentological records provide the only accessible archive for unraveling Earth's orbital variations in the remote geological past. These variations modulate Earth's climate system and provide essential constraints on gravitational parameters used in solar system modeling. However, geologic documentation of midlatitude response to orbital climate forcing remains poorly resolved compared to that of the low-latitude tropics, especially before 50 Mya, the limit of reliable extrapolation from the present. Here, we compare the climate response to orbital variations in a Late Triassic midlatitude temperate setting in Jameson Land, East Greenland (∼43°N paleolatitude) and the tropical low paleolatitude setting of the Newark Basin, with independent time horizons provided by common magnetostratigraphic boundaries whose timing has been corroborated by uranium-lead (U-Pb) zircon dating in correlative strata on the Colorado Plateau. An integrated cyclostratigraphic and magnetostratigraphic age model revealed long-term climate cycles with periods of 850,000 and 1,700,000 y ascribed to the Mars­Earth grand orbital cycles. This indicates a 2:1 resonance between modulation of orbital obliquity and eccentricity variations more than 200 Mya and whose periodicities are inconsistent with astronomical solutions and indicate chaotic diffusion of the solar system. Our findings also demonstrate antiphasing in climate response between low and midlatitudes that has implications for precise global correlation of geological records.

Hypertension Predisposition and Thermoregulation Delays in Adolescents with Polycystic Ovary Syndrome: A Pilot Study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder in which clinical, sonographic, and endophenotypic features have been underinvestigated or inconclusive, especially in the early stages of the disease (adolescence/young adulthood). OBJECTIVE: This prospective pilot study focused on the differences of multiple physiological functions between Greek adolescent/young adult females suffering from PCOS and age- and body mass index (BMI)- matched healthy controls. STUDY DESIGN: Nineteen PCOS patients and eighteen healthy controls (aged 13 to 23 years) were studied for: (i) biochemical and hormonal dysfunction by measuring circulating glucose, insulin, and androgen levels; (ii) arterial stiffness with pulse wave analysis (PWA) by Sphygmocord; (iii) intima-media thickness (IMT) by ultrasound; (iv) heart rate variability (HRV) by Task Force Monitor; and (v) QT, QRS, QT, P, QRSD by electrocardiogram (ECG). Statistical analysis included Hedge's g correction for small samples bias, and the results are shown using the Hedge's g effect size and 95% CI, in line with precision medicine prerequisites. RESULTS: Significant differences in pulse wave velocity (PWV) (g = 0.964 [0.296, 1.632]), subendocardial viability ratio (SEVR) carotid (g = -0.679 [-1.329, -0.030]), pulse pressure (PP) carotid (g = 0.942 [0.275, 1.608]), systolic pressure (SP) carotid (g = 0.785 [0.129, 1.440]), free-testosterone (g = 0.677 [0.042, 0.312]), and Delta4-androstenedione (g = 0.735 [0.097, 0.373]) were observed between PCOS patients and controls. No differences were detected in the remaining endocrine and PWA or ECG biomarkers. CONCLUSIONS: Our multidisciplinary approach showed early onset of vascular dysfunction, predisposition to hypertension, thermoregulation delays, and metabolic syndrome changes in adolescent/young adult PCOS.

Structure and function of a family of tick-derived complement inhibitors targeting properdin.

Activation of the serum-resident complement system begins a cascade that leads to activation of membrane-resident complement receptors on immune cells, thus coordinating serum and cellular immune responses. Whilst many molecules act to control inappropriate activation, Properdin is the only known positive regulator of the human complement system. By stabilising the alternative pathway C3 convertase it promotes complement self-amplification and persistent activation boosting the magnitude of the serum complement response by all triggers. In this work, we identify a family of tick-derived alternative pathway complement inhibitors, hereafter termed CirpA. Functional and structural characterisation reveals that members of the CirpA family directly bind to properdin, inhibiting its ability to promote complement activation, and leading to potent inhibition of the complement response in a species specific manner. We provide a full functional and structural characterisation of a properdin inhibitor, opening avenues for future therapeutic approaches.

Large dataset of octocoral mitochondrial genomes provides new insights into mt-mutS evolution and function.

All studied octocoral mitochondrial genomes (mt-genomes) contain a homologue of the Escherichia coli mutS gene, a member of a gene family encoding proteins involved in DNA mismatch repair, other types of DNA repair, meiotic recombination, and other functions. Although mutS homologues are found in all domains of life, as well as viruses, octocoral mt-mutS is the only such gene found in an organellar genome. While the function of mtMutS is not known, its domain architecture, conserved sequence, and presence of several characteristic residues suggest its involvement in mitochondrial DNA repair. This inference is supported by exceptionally low rates of mt-sequence evolution observed in octocorals. Previous studies of mt-mutS have been limited by the small number of octocoral mt-genomes available. We utilized sequence-capture data from the recent Quattrini et al. 2020 study [Nature Ecology & Evolution 4:1531-1538] to assemble complete mt-genomes for 94 species of octocorals. Combined with sequences publicly available in GenBank, this resulted in a dataset of 184 complete mt-genomes, which we used to re-analyze the conservation and evolution of mt-mutS. In our analysis, we discovered the first case of mt-mutS loss among octocorals in one of the two Pseudoanthomastus spp. assembled from Quattrini et al. data. This species displayed accelerated rate and changed patterns of nucleotide substitutions in mt-genome, which we argue provide additional evidence for the role of mtMutS in DNA repair. In addition, we found accelerated mt-sequence evolution in the presence of mt-mutS in several octocoral lineages. This accelerated evolution did not appear to be the result of relaxed selection pressure and did not entail changes in patterns of nucleotide substitutions. Overall, our results support previously reported patterns of conservation in mt-mutS and suggest that mtMutS is involved in DNA repair in octocoral mitochondria. They also indicate that the presence of mt-mutS contributes to, but does not fully explain, the low rates of sequence evolution in octocorals.

Multiple Losses of MSH1, Gain of mtMutS, and Other Changes in the MutS Family of DNA Repair Proteins in Animals.

MutS is a key component of the mismatch repair (MMR) pathway. Members of the MutS protein family are present in prokaryotes, eukaryotes, and viruses. Six MutS homologs (MSH1-6) have been identified in yeast, of which three function in nuclear MMR, while MSH1 functions in mitochondrial DNA repair. MSH proteins are believed to be well conserved in animals, except for MSH1-which is thought to be lost. Two intriguing exceptions to this general picture have been found, both in the class Anthozoa within the phylum Cnidaria. First, an ortholog of the yeast-MSH1 was reported in one hexacoral species. Second, a MutS homolog (mtMutS) has been found in the mitochondrial genome of all octocorals. To understand the origin and potential functional implications of these exceptions, we investigated the evolution of the MutS family both in Cnidaria and in animals in general. Our study confirmed the acquisition of octocoral mtMutS by horizontal gene transfer from a giant virus. Surprisingly, we identified MSH1 in all hexacorals and several sponges and placozoans. By contrast, MSH1 orthologs were lacking in other cnidarians, ctenophores, and bilaterian animals. Furthermore, while we identified MSH2 and MSH6 in nearly all animals, MSH4, MSH5, and, especially, MSH3 were missing in multiple species. Overall, our analysis revealed a dynamic evolution of the MutS family in animals, with multiple losses of MSH1, MSH3, some losses of MSH4 and MSH5, and a gain of the octocoral mtMutS. We propose that octocoral mtMutS functionally replaced MSH1 that was present in the common ancestor of Anthozoa.