Functional Approach Research Articles

Resting-State Functional MRI Approaches to Parkinsonisms and Related Dementia.

In this review, we attempt to summarize the most updated studies that applied resting-state functional magnetic resonance imaging (rs-fMRI) in the field of Parkinsonisms and related dementia. Over the past decades, increasing interest has emerged on investigating the presence and pathophysiology of cognitive symptoms in Parkinsonisms and their possible role as predictive biomarkers of neurodegenerative brain processes. In recent years, evidence has been provided, applying mainly three methodological approaches (i.e. seed-based, network-based and graph-analysis) on rs-fMRI data, with promising results. Neural correlates of cognitive impairment and dementia have been detected in patients with Parkinsonisms along the diseases course. Interestingly, early functional connectivity signatures were proposed to track and predict future progression of neurodegenerative processes. However, longitudinal studies are still sparce and further investigations are needed to overcome this knowledge gap.

Recent Toolboxes for Chemoselective Dual Modifications of Proteins.

Site-selective chemical modifications of proteins have emerged as a potent technology in chemical biology, materials science, and medicine, facilitating precise manipulation of proteins with tailored functionalities for basic biology research and developing innovative therapeutics. Compared to traditional recombinant expression methods, one of the prominent advantages of chemical protein modification lies in its capacity to decorate proteins with a wide range of functional moieties, including non-genetically encoded ones, enabling the generation of novel protein conjugates with enhanced or previously unexplored properties. Among these, approaches for dual or multiple protein modifications are increasingly garnering attention, as it has been found that single modifications of proteins are inadequate to meet current demands. Therefore, in light of the rapid developments in this field, this review provides a timely and comprehensive overview of the latest advancements in chemical and biological approaches for protein dual functionalization. It further discusses their advantages, limitations, and potential future directions in this relatively nascent area.

Nonequilibrium Green's function approach to low-energy fission dynamics: Fluctuations in fission reactions

Nonequilibrium Green's function approach to low-energy fission dynamics: Fluctuations in fission reactions

QCD equation of state and thermodynamic observables from computationally minimal Dyson-Schwinger equations

We study the QCD equation of state and other thermodynamic observables including the isentropic trajectories and the speed of sound. These observables are of eminent importance for the understanding of experimental results in heavy ion collisions and also provide a QCD input for studies of the timeline of heavy-ion-collisions with hydrodynamical simulations. They can be derived from the quark propagator whose gap equation is solved within a minimal approximation to the Dyson-Schwinger equations (DSEs) of QCD at finite temperature and density. This minimal approximation aims at a combination of computational efficiency and simplification of the truncation scheme while maintaining quantitative precision. This minimal DSE scheme is confronted and benchmarked with results for correlation functions and observables from lattice QCD at vanishing density and quantitative functional approaches at finite density. Published by the American Physical Society 2024

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

Consecutive k-out-of-n:W system signature reliability appraisal via structure–function approach and u-function approach

Consecutive k-out-of-n:W system signature reliability appraisal via structure–function approach and u-function approach

Dynamics of a two-level atom in the presence of a medium-assisted thermal field

In this paper, the time evolution of a two-level atom in the presence of a medium-assisted thermal field is explored through which the formula for the decay rate of an excited atom is generalized in two aspects. The obtained formula applies to a thermal electromagnetic field as well as to the presence of an arbitrary arrangement of magnetoelectric media. In order to be general with respect to the material environment, the Green’s function approach is used. It is shown that the non-zero temperature contributes to the decay rate via an additive term that is equal to the zero-temperature result multiplied by two times the photon number at the atomic transition frequency.

Multi-omics analysis of green lineage osmotic stress pathways unveils crucial roles of different cellular compartments

Maintenance of water homeostasis is a fundamental cellular process required by all living organisms. Here, we use the single-celled green alga Chlamydomonas reinhardtii to establish a foundational understanding of osmotic-stress signaling pathways through transcriptomics, phosphoproteomics, and functional genomics approaches. Comparison of pathways identified through these analyses with yeast and Arabidopsis allows us to infer their evolutionary conservation and divergence across these lineages. 76 genes, acting across diverse cellular compartments, were found to be important for osmotic-stress tolerance in Chlamydomonas through their functions in cytoskeletal organization, potassium transport, vesicle trafficking, mitogen-activated protein kinase and chloroplast signaling. We show that homologs for five of these genes have conserved functions in stress tolerance in Arabidopsis and reveal a novel PROFILIN-dependent stage of acclimation affecting the actin cytoskeleton that ensures tissue integrity upon osmotic stress. This study highlights the conservation of the stress response in algae and land plants, and establishes Chlamydomonas as a unicellular plant model system to dissect the osmotic stress signaling pathway.

An EGF technique to infer the source parameters of a circular crack growing at a variable rupture velocity

Circular crack models with a constant rupture velocity struggle to effectively model both the amplitude and duration of first P-wave pulses generated by small magnitude seismic events. Assuming a constant rupture velocity is unphysical, necessitating a deceleration phase in the rupture velocity to uphold the causality of the healing process. Moreover, a comprehensive failure model might encompass an initial nucleation phase, typically characterized by an increase of the initial rupture velocity. Studies have demonstrated that quasi-dynamic circular crack models featuring variable rupture velocities can accurately model the shape of the observed first P-wave pulse. Based on these principles, an Empirical Green’s function (EGF) approach was previously formulated to estimate the source parameters of small magnitude earthquakes, called MAIN. In addition to determine the source radius and stress drop, this method also enables the inference of the temporal evolution of rupture velocity. However, this method encounters difficulties when the noise-to-signal ratio in the recordings of smaller earthquakes used as EGF exceeds 5%, a common situation when employing regional-scale recordings of small-magnitude earthquakes as EGF. Through synthetic tests, we demonstrated that, in such instances, the problem of this technique is that the alignment between the onset of P waves of EGF and MAIN is not rightly recovered after the initial inversion step. Consequently, a novel inversion method has been developed to address this issue, enabling the identification of the optimal alignment of P-wave arrivals in EGF and MAIN across all stations. A Bayesian statistical approach is proposed to meticulously investigate the solutions of model parameters and their correlations. Using the new technique on a small magnitude earthquake (ML = 3.3) occurred in Central Italy enabled us to identify the most likely rupture models and examine the issue of correlation among model parameters. Application of Occam’s Razor Principle suggests that, for the investigated event, a circular crack model should be favored over a heterogeneous rupture model.

Dual-task training is as effective as functional training on the functional fitness of older women: a randomized clinical trial

BackgroundThe interest in approaches that improve older individuals’ functional fitness and autonomy is increasing. However, the effects of dual-task training on older women’s functional fitness and the comparison with the functional training approach are unclear. Therefore, we compared dual-task and functional training on the functional fitness of older women and the effects of three months of detraining.MethodsSixty-one women performed 16 weeks of dual-task training or functional training. The functional fitness was measured pre-, post-training, and post-detraining, based on the ability to put on and take off a t-shirt, evaluating the mobility of the upper limb, standing-up from the prone position measuring the global functionality, five times sit-to-stand test to assess the lower limbs muscle power, timed up and go to measure the dynamic balance and agility, gallon-jug shelf-transfer to evaluate the global functionality emphasizing the upper limbs and 10 m walk test to analyze the gait ability.ResultsDual-task training and functional training generally provided significant small to moderate magnitude performance increases in the put on and take off a t-shirt (dual-task training: d = 0.35 / functional training: d = 0.49), five times sit-to-stand test (dual-task training: d = 0.41 / functional training: d = 0.77), timed up and go (dual-task training: d = 0.34 / functional training: d = 0.78), and gallon-jug shelf-transfer (dual-task training: d = 0.76 / functional training: d = 0.82). Only the functional training improved the 10 m walk test (d = 0.32; p = 0.013), and both groups did not change the standing-up from the prone position performance. After the detraining period, both groups kept the adaptations for the gallon-jug shelf-transfer and five times sit-to-stand test. At the same time, only the dual-task training maintained the adaptations for the put on and take off a t-shirt and the functional training for the timed up and go.ConclusionSixteen weeks of dual-task and functional training are similarly effective in improving older women’s functional fitness, maintaining their benefits even after three months of detraining.Trial registrationRBR-10ny848z (https://ensaiosclinicos.gov.br/rg/RBR-10ny848z).

Library user digital profiling: The structural and functional approach. (Part I)

This is the first of two articles on the problem. The theoretical significance of the article lies in the demonstration of the potential of library user digital profiles (DP). The author examines the following problem components: a) user DP structure with specifying the layers – subject, object, domain, communications, and b) layer function – identification, clusterization, filtration, and collaboration. For each layer, the dominant factors are identified that enable to model, structure and use DPs for proactive meeting of library users’ information demands. The practical value of the study lies in the DP development and application for services personalization: proactive building awareness of new acquisitions, digital user support and curation, support of research projects; reconciling library collection and the demands of core user groups (collection structure enhancement, changing of the policy of acquisitions, cataloguing, and library services promotion); need-demand interdependence through using DP information, which makes acquisitions and services more efficient; and accommodation of library activities with local community’s plans and expectations.

Joint Component Estimation for Electricity Price Forecasting Using Functional Models

This work considers the issue of modeling and forecasting electricity prices within the functional time series approach. As this is often performed by estimating and predicting the different components of the price dynamics, we study whether jointly modeling the components, able to account for their inter-relations, could improve prediction with respect to a separate instance of modeling. To investigate this issue, we consider and compare the predictive performance of four different predictors. The first two, namely Smoothing Splines-Seasonal Autoregressive (SS-SAR) and Smoothing Splines-Functional Autoregressive (SS-FAR) are based on separate modeling while the third one is derived from a single-step procedure that jointly estimates all the components by suitably including exogenous variables. It is called Functional Autoregressive with eXogenous variables (FARX) model. The fourth one is a combination of the SS-FAR and FARX predictors. The predictive performances of the models are tested using electricity price data from the northern zone of the Italian electricity market (IPEX), both in terms of forecasting error indicators (MAE, MAPE and RMSE) and by means of the Diebold and Mariano test. The results point out that jointly estimating the components leads to significantly more accurate predictions than using a separate instance of modeling. In particular, the MAE, MAPE, and RMSE values for the best predictor, based on the FARX(3,0,4) model, are 4.25, 9.28, and 5.38, respectively. The percentage error reduction is about 20% with respect to SS-SAR(3,1) and about 10% with respect to SS-FAR(5). Finally, this study suggests that the forecasting errors are generally higher on Sunday and Monday, from hours 3 to 6 in the morning and 14 to 15 in the afternoon, and in June and December. On the other hand, prices are relatively lower on Wednesday, Thursday, and Friday, from hour 20 to 1 a.m., and in January and February.

A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment.

Vitamin A/Retinoic Acid (Vit A/RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (i.e scRNAseq and snATACseq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP1 and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, in vivo analysis of control and conditionally YAP1 KO mouse embryos (Sox2-cre) revealed that the expression of atrial lineage genes, such as NR2F2, is compromised by YAP1 deletion in the CPCs of the second heart field. Accordingly, we found that YAP1 is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.

MoSey1 regulates the unfolded protein response, appressorium development, and pathogenicity of Magnaporthe oryzae

Endoplasmic reticulum (ER) is an enclosed three-dimensional eukaryotic membrane network composed of flattened sacs. Fusion of homologous membranes to the ER membrane is essential for the maintenance of this network structure. In yeast, ER membrane fusion is mediated by Sey1p, whose paralogues function distinctly in different species. In this study, we investigated the biological functions of MoSEY1 in the devastating rice blast fungus Magnaporthe oryzae by functional genomic approach. Compared to wild type, deletion of MoSEY1 considerably decreased the growth and conidia production of M. oryzae. Additionally, the absence of MoSEY1 delayed appressorium formation and invasive hyphae growth. The appressorium function was also impaired in ΔMosey1 mutant. Subcellular localization analysis revealed that MoSey1 is localized at the ER. The ΔMosey1 mutant showed augmented sensitivity to ER stress. Additionally, we found that MoSey1 regulated the unfolded protein response, autophagy, and protein secretion in M. oryzae. In conclusion, our study unveiled the involvement of MoSey1 in the development, pathogenesis, and ER functions in M. oryzae.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Optimal energy storage configuration to support 100 % renewable energy for Indonesia

This study presents a renewable energy (RE) optimization study to model the pathway to achieve 100 % carbon abatement, focussing on options for storage, using Indonesia's national electricity grid as a case study. Utilizing the PLEXOS energy simulation tool, the study covers the period 2021–2045. It employs an optimization of cost minimization function approach, encompassing investment, operation, maintenance, and unserved energy. The study integrates various components, including electricity supply and demand, transmission, renewable sources, and energy storage, while considering operational, build, and renewable energy target constraints. A range of scenarios are explored, varying in RE targets, battery capacities, and whether to include open-cycle gas turbines. The key novelty of this study is considering multiple versions of battery storage, with different options for the number of hours of storage. The findings indicate that higher RE targets lead to increased total installed nameplate capacity, with a significant portion from battery storage. In the early phases, batteries with 2-hour of capacity prioritized for short-term needs. As the focus shifts to more extended targets, batteries with a 4-hour capacity are recognized as more cost-effective and become the predominant choice. Over time, the least-cost strategy evolves to incorporate 10-hour capacity batteries to meet long-term energy storage requirements. To achieve a 100 % RE target by 2045, it is estimated that alongside every 100 MW of wind and solar capacity, there should be a corresponding 42 MW of energy storage. However, interpretations of these findings must consider the limited temporal resolution, uncertainties in demand and cost, and challenges related to grid inertia from energy storage, which may affect the stability and feasibility of the proposed solutions. This research offers crucial insights for energy policy and infrastructure development in renewable energy and storage system implementation.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Decentralized asymptotic tracking control for time‐varying interconnected nonlinear systems with prescribed performance

AbstractThis article studies decentralized adaptive asymptotic tracking control of time‐varying interconnected nonlinear systems. To address the obstacles caused by interactions and these unknown time‐varying parameters, a smooth function and a bound estimation approach are introduced. Additionally, by means of a class of funnel functions and barrier Lyapunov function approach, a prescribed performance control strategy is constructed, allowing tracking accuracy and the settling time to be predetermined in accordance with control requirements, without relying on initial conditions or design parameters. Particularly, reasoned proofs have been given to confirm that the presented control method not only guarantees the prescribed transient performance, but also achieves the asymptotic tracking without requiring knowledge of high‐order derivatives of the reference signal. Ultimately, the efficiency of our approach is verified by simulation results.

Potent and Selective Oxidatively Labile Ether‐Based Prodrugs through Late‐Stage Boronate Incorporation

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug‐activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal‐mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl‐linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin‐based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non‐cancerous cell lines. This late‐stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Quantifying myelin density in the feline auditory cortex.

The cerebral cortex comprises many distinct regions that differ in structure, function, and patterns of connectivity. Current approaches to parcellating these regions often take advantage of functional neuroimaging approaches that can identify regions involved in a particular process with reasonable spatial resolution. However, neuroanatomical biomarkers are also very useful in identifying distinct cortical regions either in addition to, or in place of functional measures. For example, differences in myelin density are thought to relate to functional differences between regions, are sensitive to individual patterns of experience, and have been shown to vary across functional hierarchies in a predictable manner. Accordingly, the current study provides quantitative stereological estimates of myelin density for each of the 13 regions that make up the feline auditory cortex. We demonstrate that significant differences can be observed between auditory cortical regions, with the highest myelin density observed in the regions that comprise the auditory core (i.e., the primary auditory cortex and anterior auditory field). Moreover, our myeloarchitectonic map suggests that myelin density varies in a hierarchical fashion that conforms to the traditional model of spatial organization in auditory cortex. Taken together, these results establish myelin as a useful biomarker for parcellating auditory cortical regions, and provide detailed estimates against which other, less invasive methods of quantifying cortical myelination may be compared.