Browse Articles

Enhancing in search of Milankovitch cycles from stratigraphic record using convex optimization algorithm

AbstractAccurately identifying Milankovitch cycles has been a significant challenge in cyclostratigraphic studies, as it is essential for improving geochronology. This manuscript focuses on developing a method that distinguishes Milankovitch cycles from sedimentary noise to enhance stratigraphic precision. Despite their often-conspicuous magnitude, these periodicities frequently intertwine with noise, posing a challenge for conventional spectral analysis. Therefore, to address this issue, we have developed an algorithm that enhances the resolution of the Milankovitch signal by employing convex optimization in spectral analysis. To evaluate the effectiveness of this new algorithm, we applied it to four distinct types of local stratigraphy where the Milankovitch signal has been confirmed. These include the stratigraphic sections in the middle Miocene molluscan beds of Java and the Mahakam Delta, Pleistocene sediments of Hominin Flores, and the Towuti Lake in Sulawesi Island, Indonesia. Our findings demonstrate the preservation of all targeted signals, with a confidence level surpassing 99%. By setting the significance level to 1%, we can reject the null hypothesis, which assumes noise or the absence of a Milankovitch signal in the stratigraphic data being tested. The absence of deviations from the identified periodicities further strengthens the Milankovitch signal, underscoring the robustness of our algorithm. However, we acknowledge that achieving optimal results still hinges on the accurate selection of the initial parameters z and λ.

Oppositional and competitive instigation of hippocampal synaptic plasticity by the VTA and locus coeruleus

The novelty, saliency, and valency of ongoing experiences potently influence the firing rate of the ventral tegmental area (VTA) and the locus coeruleus (LC). Associative experience, in turn, is recorded into memory by means of hippocampal synaptic plasticity that is regulated by noradrenaline sourced from the LC, and dopamine, sourced from both the VTA and LC. Two persistent forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD) support the encoding of different kinds of spatial experience. To what extent the VTA and the LC influence the direction of change of synaptic plasticity and therefore the content of stored experience is not clear. Here, we report that test-pulse activation of Schaffer-collateral–CA1 synapses of freely behaving male rats, in conjunction with VTA stimulation, results in LTP (>24 h), whereas concomitant hippocampal afferent and LC stimulation results in LTD (>24 h). Effects are frequency-dependent (1 to 50 Hz) and competitive: high-frequency (25 Hz), but not low-frequency (5 Hz) optogenetic activation of tyrosine hydroxylase-positive (TH+) neurons in the VTA, results in D1/D5R-dependent LTP, whereas 5 Hz (but not 1, or 25 Hz) activation of TH+ neurons in the LC results in hippocampal LTD that is both D1/D5 and β-AR-dependent. These results suggest that the VTA and LC do not work in synergy, but rather function in a competing fashion to drive different forms of information encoding through synaptic plasticity. Our findings indicate that information transmitted by the VTA and LC is likely to play a decisive role in the shaping of hippocampal information storage and the nature of learned experience.

Association of Body Mass Index trajectory with thyroid nodules during young adulthood in China

Electron transfer in polysaccharide monooxygenase catalysis

Polysaccharide monooxygenase (PMO) catalysis involves the chemically difficult hydroxylation of unactivated C–H bonds in carbohydrates. The reaction requires reducing equivalents and will utilize either oxygen or hydrogen peroxide as a cosubstrate. Two key mechanistic questions are addressed here: 1) How does the enzyme regulate the timely and tightly controlled electron delivery to the mononuclear copper active site, especially when bound substrate occludes the active site? and 2) How does this electron delivery differ when utilizing oxygen or hydrogen peroxide as a cosubstrate? Using a computational approach, potential paths of electron transfer (ET) to the active site copper ion were identified in a representative AA9 family PMO from Myceliophthora thermophila ( Mt PMO9E). When Y62, a buried residue 12 Å from the active site, is mutated to F, lower activity is observed with O 2 . However, a WT-level activity is observed with H 2 O 2 as a cosubstrate indicating an important role in ET for O 2 activation. To better understand the structural effects of mutations to Y62 and axial copper ligand Y168, crystal structures were solved of the wild type Mt PMO9E and the variants Y62W, Y62F, and Y168F. A bioinformatic analysis revealed that position 62 is conserved as either Y or W in the AA9 family. The Mt PMO9E Y62W variant has restored activity with O 2 . Overall, the use of redox-active residues to supply electrons for the reaction with O 2 appears to be widespread in the AA9 family. Furthermore, the results provide a molecular framework to understand catalysis with O 2 versus H 2 O 2 .

Lightweight detection model for safe wear at worksites using GPD-YOLOv8 algorithm

Unlocking the catalytic precision of ligand-controlled enzymatic halogenation

A single-component flavin-dependent halogenase, AetF, has emerged as an attractive biocatalyst for catalyzing halogenation. However, its flavin chemistry remains unexplored and cannot be predicted due to its uniqueness in sequence and structure compared to other flavin-dependent monooxygenases. Here, we investigated the flavin reactions of AetF using transient kinetics. Our data revealed that NADP + binding is required for formation of C4a-hydroperoxy flavin adenine dinucleotide (FAD) (FAD C4aOOH ), a key flavin-oxygen adduct required for generating a halogenating species. In the presence of NaBr without L-tryptophan, the flavin oxygen adduct intermediates [possibly FAD C4aOOH and C4a-hydroxy FAD (FAD C4aOH )] are highly stabilized (>4,000 s) before returning to the oxidized FAD state. In the presence of L-tryptophan, the rate of FAD C4aOH dehydration to form oxidized FAD increased by ~825-fold. These data suggest that the presence of all substrates is required for speeding up AetF’s catalytic cycle. Our findings underscore the adeptness of AetF in managing its reactivity through ligand control. Structural and tunnel analyses revealed that the binding of NADP + and L-tryptophan induces changes in protein tunnels which may potentially link to the ligand-controlled mechanisms. Leveraging these catalytic insights, we employed light-induced flavin reduction and NADP + stimulation to enable AetF halogenation of various compounds. Our findings demonstrate the mechanisms of precise control over flavin chemistry by AetF. These mechanistic insights may be useful for the biocatalytic development of single-component flavin-dependent halogenases.

Restoration effect of chemically modified microRNA-143-3p on acute myocardial infarction in animal models

Income inequality and the erosion of democracy in the twenty-first century

Among the most pressing problems societies face today are economic inequality and the erosion of democratic norms and institutions. In fact the two problems—inequality and democratic erosion—are linked. In a large cross-national statistical study of risk factors for democratic erosion, we establish that economic inequality is one of the strongest predictors of where and when democracy erodes. Even wealthy and longstanding democracies are vulnerable if they are highly unequal (though national wealth might provide some resiliency). The association between inequality and risk of democratic backsliding is robust, and holds under different measures and structures of both income inequality and wealth inequality. The association is unlikely to be a case of reverse causation. For concerned citizens seeking to understand why so many democracies are eroding and how to stop this process, our study indicates that policies for ameliorating inequality are a promising path forward.

Optoelectronic device library containing multiple Verilog-A models

A hybrid meta on-top functional for multiconfiguration pair-density functional theory

Multiconfiguration pair-density functional theory (MC-PDFT) was proposed a decade ago, but it is still in the early stage of density functional development. MC-PDFT uses functionals that are called on-top functionals; they depend on the density and the on-top pair density. Most MC-PDFT calculations to date have been unoptimized translations of generalized gradient approximations (GGAs) of Kohn–Sham density functional theory (KS-DFT). A hybrid MC-PDFT has also been developed, in which one includes a fraction of the complete active space self-consistent-field wave function energy in the total energy. Meta-GGA functionals, which use kinetic-energy densities in addition to GGA ingredients, have shown higher accuracy than GGAs in KS-DFT, yet the translation of meta-GGAs has not been previously proposed for MC-PDFT. In this paper, we propose a way to include kinetic energy density in a hybrid on-top functional for MC-PDFT, and we optimize the parameters of the resulting functional by training with a database developed as part of the present work that contains a wide variety of systems with diverse characters. The resulting hybrid meta functional is called the MC23 functional. We find that MC23 has improved performance as compared to KS-DFT functionals for both strongly and weakly correlated systems. We recommend MC23 for future MC-PDFT calculations.

Importance of EQA/PT for the detection of genetic variants in comprehensive cancer genome testing

Synapse-specific catecholaminergic modulation of neuronal glutamate release

Norepinephrine in vertebrates and its invertebrate analog, octopamine, regulate the activity of neural circuits. We find that, when hungry, Drosophila larvae switch activity in type II octopaminergic motor neurons (MNs) to high-frequency bursts, which coincide with locomotion-driving bursts in type I glutamatergic MNs that converge on the same muscles. Optical quantal analysis across hundreds of synapses simultaneously reveals that octopamine potentiates glutamate release by tonic type Ib MNs, but not phasic type Is MNs, and occurs via the G q -coupled octopamine receptor (OAMB). OAMB is more abundant in type Ib terminals and acts through diacylglycerol and its target Unc13A, a key component of the glutamate release machinery. Potentiation varies significantly—by up to 1,000%—across synapses of a single Ib axon, with synaptic Unc13A levels determining both release probability and potentiation. We propose that a dual molecular mechanism—an upstream neuromodulator receptor and a downstream transmitter release controller—fine-tunes catecholaminergic modulation so that strong tonic synapses exhibit large potentiation, while weaker tonic and all phasic synapses maintain consistency, yielding a sophisticated regulation of locomotor behavior.

Comprehensive analysis of inhibin-β A as a potential biomarker for gastrointestinal tract cancers through bioinformatics approaches

Tetrameric PilZ protein stabilizes stator ring in complex flagellar motor and is required for motility in <i>Campylobacter jejuni</i>

Rotation of the bacterial flagellum, the first identified biological rotary machine, is driven by its stator units. Knowledge gained about the function of stator units has increasingly led to studies of rotary complexes in different cellular pathways. Here, we report that a tetrameric PilZ family protein, FlgX, is a structural component underneath the stator units in the flagellar motor of Campylobacter jejuni . FlgX forms a stable tetramer that does not bind cyclic di-GMP (c-di-GMP), unlike other canonical PilZ domain–containing proteins. Cryoelectron tomography and subtomogram averaging of flagellar motors in situ provide evidence that FlgX interacts with each stator unit and plays a critical role in stator ring assembly and stability. Furthermore, FlgX is conserved and was most likely present in the common ancestor of the phylum Campylobacterota . Overall, FlgX represents a divergence in function for PilZ superfamily proteins as well as a player in the key stator–rotor interaction of complex flagellar motors.

Segmentation of the iliac crest from CT-data for virtual surgical planning of facial reconstruction surgery using deep learning

AbstractBackground and objectives: For the planning of surgical procedures involving the bony reconstruction of the mandible, the autologous iliac crest graft, along with the fibula graft, has become established as a preferred donor region. While computer-assisted planning methods are increasingly gaining importance, the necessary preparation of geometric data based on CT imaging remains largely a manual process. The aim of this work was to develop and test a method for the automated segmentation of the iliac crest for subsequent reconstruction planning. Methods: A total of 1,398 datasets with manual segmentations were obtained as ground truth, with a subset of 400 datasets used for training and validation of the Neural Networks and another subset of 177 datasets used solely for testing. A deep Convolutional Neural Network implemented in a 3D U-Net architecture using Tensorflow was employed to provide a pipeline for automatic segmentation. Transfer learning was applied for model training optimization. Evaluation metrics included the Dice Similarity Coefficient, Symmetrical Average Surface Distance, and a modified 95% Hausdorff Distance focusing on regions relevant for transplantation. Results: The automated segmentation achieved high accuracy, with qualitative and quantitative assessments demonstrating predictions closely aligned with ground truths. Quantitative evaluation of the correspondence yielded values for geometric agreement in the transplant-relevant area of 92% +/- 7% (Dice coefficient) and average surface deviations of 0.605 +/- 0.41 mm. In all cases, the bones were identified as contiguous objects in the correct spatial orientation. The geometries of the iliac crests were consistently and completely recognized on both sides without any gaps. Conclusions: The method was successfully used to extract the individual geometries of the iliac crest from CT data. Thus, it has the potential to serve as an essential starting point in a digitized planning process and to provide data for subsequent surgical planning. The complete automation of this step allows for efficient and reliable preparation of anatomical data for reconstructive surgeries.

Deep conservation complemented by novelty and innovation in the insect eye ground plan

A spectacular diversity of forms and features allow species to thrive in different environments, yet some structures remain relatively unchanged. Insect compound eyes are easily recognizable despite dramatic differences in visual abilities across species. It is unknown whether distant insect species use similar or different mechanisms to pattern their eyes or what types of genetic changes produce diversity of form and function. We find that flies, mosquitos, butterflies, moths, beetles, wasps, honeybees, and crickets use homologous developmental programs to pattern their retinas. Transcription factor expression can be used to establish homology of different photoreceptor (PR) types across the insects: Prospero (Pros) for R7, Spalt (Sal) for R7+R8, and Defective proventriculus (Dve) for R1-6. Using gene knockout (CRISPR/Cas9) in houseflies, butterflies, and crickets and gene knockdown (RNAi) in beetles, we found that like Drosophila , EGFR and Sevenless (Sev) signaling pathways are required to recruit motion and color vision PRs, though Drosophila have a decreased reliance on Sev signaling relative to other insects. Despite morphological and physiological variation across species, retina development passes through a highly conserved phylotypic stage when the unit eyes (ommatidia) are first patterned. This patterning process likely represents an “insect eye ground plan” that is established by an ancient developmental program. We identify three types of developmental patterning modifications (ground plan modification, nonstochastic patterns, and specialized regions) that allow for the diversification of insect eyes. We suggest that developmental divergence after the ground plan is established is responsible for the exceptional diversity observed across insect visual systems.

Early postoperative bevacizumab for preventing neovascular glaucoma in phacovitrectomy for proliferative diabetic retinopathy

Learning the language of antibody hypervariability

Protein language models (PLMs) have demonstrated impressive success in modeling proteins. However, general-purpose “foundational” PLMs have limited performance in modeling antibodies due to the latter’s hypervariable regions, which do not conform to the evolutionary conservation principles that such models rely on. In this study, we propose a transfer learning framework called Antibody Mutagenesis-Augmented Processing (AbMAP), which fine-tunes foundational models for antibody-sequence inputs by supervising on antibody structure and binding specificity examples. Our learned feature representations accurately predict mutational effects on antigen binding, paratope identification, and other key antibody properties. We experimentally validate AbMAP for antibody optimization by applying it to refine a set of antibodies that bind to a SARS-CoV-2 peptide, and obtain an 82% hit-rate and up to 22-fold increase in binding affinity. AbMAP also unlocks large-scale analyses of immune repertoires, revealing that B-cell receptor repertoires of individuals, while remarkably different in sequence, converge toward similar structural and functional coverage. Importantly, AbMAP’s transfer learning approach can be readily adapted to advances in foundational PLMs. We anticipate AbMAP will accelerate the efficient design and modeling of antibodies, expedite the discovery of antibody-based therapeutics, and deepen our understanding of humoral immunity.

Muon spectroscopy of a 12-phosphatetraphene with extremely efficient radical trapping properties

A minimal vertex model explains how the amnioserosa avoids fluidization during <i>Drosophila</i> dorsal closure

Dorsal closure is a process that occurs during embryogenesis of Drosophila melanogaster . During dorsal closure, the amnioserosa (AS), a one-cell thick epithelial tissue that fills the dorsal opening, shrinks as the lateral epidermis sheets converge and eventually merge. During this process, both shape index and aspect ratio of amnioserosa cells increase markedly. The standard 2-dimensional vertex model, which successfully describes tissue sheet mechanics in multiple contexts, would in this case predict that the tissue should fluidize via cell neighbor changes. Surprisingly, however, the amnioserosa remains an elastic solid with no such events. We here present a minimal extension to the vertex model that explains how the amnioserosa can achieve this unexpected behavior. We show that continuous shrinkage of the preferred cell perimeter and cell perimeter polydispersity lead to the retention of the solid state of the amnioserosa. Our model accurately captures measured cell shape and orientation changes and predicts nonmonotonic junction tension that we confirm with laser ablation experiments.