Piezoelectric Transducers: Complete Electromechanical Model with Parameter Extraction.

This paper presents a complete electromechanical (EM) model of piezoelectric transducers (PTs) independent of high or low coupling assumptions, vibration conditions, and geometry. The PT's spring stiffness is modeled as part of the domain coupling transformer, and the piezoelectric EM coupling coefficient is modeled explicitly as a split inductor transformer. This separates the coupling coefficient from the coefficient used for conversion between mechanical and electrical domains, providing a more insightful understanding of the energy transfers occurring within a PT and allowing for analysis not previously possible. This also illustrates the role the PT's spring plays in EM energy conversion. The model is analyzed and discussed from a circuits and energy harvesting perspective. Coupling between domains and how loading affects coupled energy are examined. Moreover, simple methods for experimentally extracting model parameters, including the coupling coefficient, are provided to empower engineers to quickly and easily integrate PTs in SPICE simulations for the rapid and improved development of PT interface circuits. The model and parameter extractions are validated by comparing them to the measured response of a physical cantilever-style PT excited by regular and irregular vibrations. In most cases, less than a 5-10% error between measured and simulated responses is observed.

Peptide-based drug discovery through artificial intelligence: towards an autonomous design of therapeutic peptides.

With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling capabilities. Despite their advantages, therapeutic peptides face challenges such as short half-life, limited oral bioavailability and susceptibility to plasma degradation. The rise of computational tools and artificial intelligence (AI) in peptide research has spurred the development of advanced methodologies and databases that are pivotal in the exploration of these complex macromolecules. This perspective delves into integrating AI in peptide development, encompassing classifier methods, predictive systems and the avant-garde design facilitated by deep-generative models like generative adversarial networks and variational autoencoders. There are still challenges, such as the need for processing optimization and careful validation of predictive models. This work outlines traditional strategies for machine learning model construction and training techniques and proposes a comprehensive AI-assisted peptide design and validation pipeline. The evolving landscape of peptide design using AI is emphasized, showcasing the practicality of these methods in expediting the development and discovery of novel peptides within the context of peptide-based drug discovery.

Regional Brain Perfusion Is Associated with Endothelial Dysfunction Markers in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is an important independent risk factor for cardiovascular disease. Cumulative data suggest that depressive patients exhibit derangement in regional cerebral blood flow (rCBF), although underlying mechanisms remain mostly unknown. Endothelial dysfunction (ED), defined as different forms of abnormal endothelial activity, plays a key role in the pathogenesis of vascular disease. ED is associated with several clinical conditions characterized by high cardiovascular risk. Diverse ED markers have been found in mood disorders. PURPOSE: To evaluate the association between rCBF and peripheral ED markers in MDD patients, at baseline and after selective serotonin receptor inhibitors (SSRIs) therapy. PATIENTS AND METHODS: Twenty-seven untreated unipolar MDD patients in their first episode were evaluated with the Hamilton Depression Rating Scale (HAM-D) and brain perfusion SPECT at baseline and after 2 months of SSRIs. Statistical Parametric Mapping (SPM) was employed to evaluate rCBF; circulating endothelial cells (CECs), plasma soluble intercellular adhesion molecule (sICAM), and high-sensitivity C-reactive protein (hsCRP) were used as independent covariates. RESULTS: Baseline CECs and sICAM were increased in MDD patients compared with matching controls (p = 0.0001) and hsCRP (p = 0.03). HAM-D scores (21 items) and CECs diminished after SSRI therapy in MDD patients (p < 0.0001). There was a significant rCBF decrease, mainly in deep central structures. HAM-D change was associated with rCBF decrease at the left amygdala, right striatum levels, and Brodmann area 25. CEC change was associated with rCBF at deep brain level and sICAM with large rCBF areas at the left caudate and tectum; hsCRP was associated, to a lesser extent, with the left dorsal striatum and mesencephalic tectum. CONCLUSION: ED markers in patients with MDD are associated with significant changes in rCBF which are features of depression. These findings suggest that systemic damage/activation of the endothelium may contribute to the abnormal rCBF observed in MDD patients.

A diacidic motif determines unconventional secretion of wild-type and ALS-linked mutant SOD1.

The nutrient starvation-specific unconventional secretion of Acb1 in Saccharomyces cerevisiae requires ESCRT-I, -II, and -III and Grh1. In this study, we report that another signal sequence lacking cytoplasmic protein, superoxide dismutase 1 (SOD1), and its mutant form linked to amyotrophic lateral sclerosis (ALS), is also secreted by yeast upon nutrient starvation in a Grh1- and ESCRT-I-, -II-, and -III-dependent process. Our analyses reveal that a conserved diacidic motif (Asp-Glu) in these proteins is necessary for their export. Importantly, secretion of wild-type human SOD1 and the ALS-linked mutant in human cells also require the diacidic residues. Altogether, these findings reveal information encoded within the cytoplasmic proteins required for their unconventional secretion and provide a means to unravel the significance of the cytoplasmic versus the secreted form of mutant SOD1 in the pathology of ALS. We also propose how cells, based on a signal-induced change in cytoplasmic physiology, select a small pool of a subset of cytoplasmic proteins for unconventional secretion.

Spatial control of lipid droplet proteins by the ERAD ubiquitin ligase Doa10.

The endoplasmic reticulum (ER) plays a central role in the biogenesis of most membrane proteins. Among these are proteins localized to the surface of lipid droplets (LDs), fat storage organelles delimited by a phospholipid monolayer. The LD monolayer is often continuous with the membrane of the ER allowing certain membrane proteins to diffuse between the two organelles. In these connected organelles, how some proteins concentrate specifically at the surface of LDs is not known. Here, we show that the ERAD ubiquitin ligase Doa10 controls the levels of some LD proteins. Their degradation is dependent on the localization to the ER and appears independent of the folding state. Moreover, we show that by degrading the ER pool of these LD proteins, ERAD contributes to restrict their localization to LDs. The signals for LD targeting and Doa10-mediated degradation overlap, indicating that these are competing events. This spatial control of protein localization is a novel function of ERAD that might contribute to generate functional diversity in a continuous membrane system.

The seipin complex Fld1/Ldb16 stabilizes ER-lipid droplet contact sites.

Lipid droplets (LDs) are storage organelles consisting of a neutral lipid core surrounded by a phospholipid monolayer and a set of LD-specific proteins. Most LD components are synthesized in the endoplasmic reticulum (ER), an organelle that is often physically connected with LDs. How LD identity is established while maintaining biochemical and physical connections with the ER is not known. Here, we show that the yeast seipin Fld1, in complex with the ER membrane protein Ldb16, prevents equilibration of ER and LD surface components by stabilizing the contact sites between the two organelles. In the absence of the Fld1/Ldb16 complex, assembly of LDs results in phospholipid packing defects leading to aberrant distribution of lipid-binding proteins and abnormal LDs. We propose that the Fld1/Ldb16 complex facilitates the establishment of LD identity by acting as a diffusion barrier at the ER-LD contact sites.

Neutral lipid metabolism influences phospholipid synthesis and deacylation in Saccharomyces cerevisiae.

Establishment and maintenance of equilibrium in the fatty acid (FA) composition of phospholipids (PL) requires both regulation of the substrate available for PL synthesis (the acyl-CoA pool) and extensive PL turnover and acyl editing. In the present study, we utilize acyl-CoA synthetase (ACS) deficient cells, unable to recycle FA derived from lipid deacylation, to evaluate the role of several enzymatic activities in FA trafficking and PL homeostasis in Saccharomyces cerevisiae. The data presented show that phospholipases B are not contributing to constitutive PL deacylation and are therefore unlikely to be involved in PL remodeling. In contrast, the enzymes of neutral lipid (NL) synthesis and mobilization are central mediators of FA trafficking. The phospholipid:DAG acyltransferase (PDAT) Lro1p has a substantial effect on FA release and on PL equilibrium, emerging as an important mediator in PL remodeling. The acyl-CoA dependent biosynthetic activities of NL metabolism are also involved in PL homeostasis through active modulation of the substrate available for PL synthesis. In addition TAG mobilization makes an important contribution, especially in cells from stationary phase, to FA availability. Beyond its well-established role in the formation of a storage pool, NL metabolism could play a crucial role as a mechanism to uncouple the pools of PL and acyl-CoAs from each other and thereby to allow independent regulation of each one.

A 2- µ m BiCMOS Rectifier-Free AC-DC Piezoelectric Energy Harvester-Charger IC.

A fundamental problem that miniaturized systems, such as biomedical implants, face is limited space for storing energy, which translates to short operational life. Harvesting energy from the surrounding environment, which is virtually a boundless source at these scales, can overcome this restriction, if losses in the system are sufficiently low. To that end, the 2-µm bi-complementary metal-oxide semiconductor switched-inductor piezoelectric harvester prototype evaluated and presented in this paper eliminates the restrictions associated with a rectifier to produce and channel 30 µW from a periodic 72- µW piezoelectric source into a battery directly. In doing so, the circuit also increases the system's electrical damping force to draw more power and energy from the transducer, effectively increasing its mechanical-electrical efficiency by up to 78%. The system also harnesses up to 659 nJ from nonperiodic mechanical vibrations, which are more prevalent in the environment, with 6.1±1.5% to 8.8±6.9% of end-to-end mechanical-electrical efficiency.

Mutants of Saccharomyces cerevisiae deficient in acyl-CoA synthetases secrete fatty acids due to interrupted fatty acid recycling.

In the present study, acyl-CoA synthetase mutants of Saccharomyces cerevisiae were employed to investigate the impact of this activity on certain pools of fatty acids. We identified a genotype responsible for the secretion of free fatty acids into the culture medium. The combined deletion of Faa1p and Faa4p encoding two out of five acyl-CoA synthetases was necessary and sufficient to establish mutant cells that secreted fatty acids in a growth-phase dependent manner. The mutants accomplished fatty acid export during exponential growth-phase followed by fatty acid re-import into the cells during the stationary phase. The data presented suggest that the secretion is driven by an active component. The fatty acid re-import resulted in a severely altered ultrastructure of the mutant cells. Additional strains deficient of any cellular acyl-CoA synthetase activity revealed an almost identical phenotype, thereby proving transfer of fatty acids across the plasma membrane independent of their activation with CoA. Further experiments identified membrane lipids as the origin of the observed free fatty acids. Therefore, we propose the recycling of endogenous fatty acids generated in the course of lipid remodelling as a major task of both acyl-CoA synthetases Faa1p and Faa4p.

Desfribilador automatico implantado y marcapaso epicardico en el manejo de taquicardia ventricular polimorfa pausa-dependiente / Cardio-desfibrillator implanted into the endocardium and epicardial pacemaker in the treatment of a patient with pause-dependent polymorphic

Se presenta el primer caso de la utilización de un cardiodesfíbrilador implantado por vía endocárdica y marcapaso epicárdico en el manejo de un paciente con taquicardia ventricular polimorfa pausa-dependiente. Se revisa la literatura en cuanto a la interacción de los dos dispositivos, encontrándose que con adecuada programación y localización de los electrodos, se disminuye la posibilidad de interferencia en el funcionamiento de cada uno de ellos