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Gene therapy and its role in the medical field have evolved drastically in recent decades. Studies aim to define DNA-based medicine as well as encourage innovation and the further development of novel approaches. Gene therapy has been established as an alternative approach to treat a variety of diseases. Its range of mechanistic applicability is wide; gene therapy has the capacity to address the symptoms of disease, the body’s ability to fight disease, and in some cases has the ability to cure disease, making it a more attractive intervention than some traditional approaches to treatment (i.e., medicine and surgery). Such versatility also suggests gene therapy has the potential to address a greater number of indications than conventional treatments. Many DNA-based therapies have shown promise in clinical trials, and several have been approved for use in humans. Whereas current treatment regimens for chronic disease often require frequent dosing, DNA-based therapies can produce robust and durable expression of therapeutic genes with fewer treatments. This benefit encourages the application of DNA-based gene therapy to manage chronic diseases, an area where improving efficiency of current treatments is urgent. Here, we provide an overview of two DNA-based gene therapies as well as their delivery methods: adeno associated virus (AAV)-based gene therapy and plasmid DNA (pDNA)-based gene therapy. We will focus on how these therapies have already been utilized to improve treatment of chronic disease, as well as how current literature supports the expansion of these therapies to treat additional chronic indications in the future.

Electroporation (EP) stands out as a promising non-viral plasmid delivery strategy, although achieving optimal transfection efficiency in vivo remains a challenge. A noteworthy advancement in the field of in vivo EP is the application of hyaluronidase, an enzyme with the capacity to degrade hyaluronic acid in the extracellular matrix, which thereby enhances DNA transfer efficiency by 2- to 3-fold. This paper focuses on elucidating the mechanism of hyaluronidase’s impact on transfection efficiency. We demonstrate that hyaluronidase promotes a more uniform distribution of plasmid DNA (pDNA) within skeletal muscle. Additionally, our study investigates the effect of the timing of hyaluronidase pretreatment on EP efficiency by including time intervals of 0, 5, and 30 min between hyaluronidase treatment and the application of pulses. Serum levels of the pDNA-encoded transgene reveal a minimal influence of the hyaluronidase pretreatment time on the final serum protein levels following delivery in both mice and rabbit models. Leveraging bioimpedance measurements, we capture morphological changes in muscle induced by hyaluronidase treatment, which result in a varied pDNA distribution. Subsequently, these findings are employed to optimize EP electrical parameters following hyaluronidase treatment in animal models. This paper offers novel insights into the potential of hyaluronidase in enhancing the effectiveness of in vivo EP, as well as guides optimized electroporation strategies following hyaluronidase use.

A series of coordination polymers (CPs), some of them featuring an unusual architecture, have been constructed by treatment of RSCH2C≡CCH2SR (R = C6H11L1, t-Bu L2) with CuX (X = Cl, Br, I) and CuX2. The outcome of the reaction of L1 with CuI depends on the metal-to-ligand ratio. Treatment of CuI with L1 in a 2 : 1 ratio affords the luminescent 2D CP [Cu4I4(μ-L1)2]n (CP1), whose grid-shaped network is built upon Cu4(μ3-I)4 cubane-like clusters as secondary building units (SBUs), interconnected via bridging L1 ligands. The use of a 1 : 1 ratio gives a material, whose particularity is the coexistence of two topological isomers within the unit cell. The first one, [{Cu(μ2-I)2Cu}(μ-L1)2]n (CP2), consists of 1D ribbons. The second isomer having a 0D topology, [{Cu(μ2-I)2Cu}(μ-L1)2] D1, is built upon discrete molecular complexes, whose dinuclear [Cu(μ2-I)2Cu] rhomboid-shaped core is spanned by two bridging L1 ligands. Mixing CuBr with L1 in MeCN solution leads to an isostructural material incorporating both 0D [{Cu(μ2-Br)2Cu}(μ-L1)2] complex D2 along with the 1D isomer [{Cu(μ2-Br)2Cu}(μ-L1)2]n (CP3). However, only the 1D CP [{Cu(μ2-Cl)2Cu}(μ-L1)2]n (CP4) results from complexation of L1 with CuCl. A stoichiometry-dependence is also noticed upon treatment of CuI with L2. Conducting the reaction in a 2 : 1 ratio yields the luminescent 2D CP [Cu4I4(μ-L2)2]n (CP5), whereas mixing equimolar amounts of the reactants produces 2D CP [{Cu(μ2-I)2Cu}(μ-L2)2]n (CP6). Structurally similar 2D CPs [{Cu(μ2-X)2Cu}(μ-L2)2]n (CP8 and CP9) result from complexation of L2 on CuBr or CuCl, respectively. Treatment of L2 with an excess of CuBr or CuBr2 in refluxing acetonitrile led to the transfer of Br to the acetylenic triple bond, generating an olefinic halogenated dithioether ligand Bu L3 that coordinates to CuBr to generate a 1D network [{Cu(μ2-Br)2Cu}(CH3CN)(μ-L3)]n (CP9). Using different conditions (propionitrile at 293 K), the reaction of L2 and excess CuBr led to the formation of a 2D network [{Cu(μ2-Br)2Cu}(μ-L2)(μ-L3)]n (CP10) incorporating both L2 and L3 in an alternating manner as assembling ligands. An isostructural chloro-analogue 2D [{Cu(μ2-Cl)2Cu}(μ-L2)(μ-L4)]n (CP11) was obtained using CuCl or CuCl2. The crystallographic work is completed by thermal analyses and investigation of the luminescence properties of CP1 and CP5 at 77 and 298 K. [ABSTRACT FROM AUTHOR]

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The thioether-functionalized 2-azabutadiene (iPrS)2C=C(H)-N=CPh2 L ligates to CdI2 and HgI2 to form the chelate compounds [CdI2{(iPrS)2C=C(H)-N=CPh2] (1) and [HgI2(iPrS)2C=C(H)-N=CPh2] (2). Their crystal structures were solved via X-ray diffraction. Both crystallize in the non-centrosymmetric space groups: monoclinic P21 (1) and orthorhombic P212121 (2), respectively. The closed-shell d10 metal centers are four-coordinated (two iodides and S and N coordinating atoms from the ligand L) in both complexes. The geometrical indexes τ indicate that a highly distorted trigonal pyramidal is adopted for 1 and a seesaw geometry for 2. The comparative nature of metal–ligand bonds is discussed on the basis of metric parameters and of QT-AIM (quantum theory of atoms in molecules) calculations. L was also treated with CuI to obtain the dinuclear species [LCu(μ2-I2)CuL] (3), in which the two Cu(I) centers are linked by a short metal–metal bond. The geometric and electronic properties of 3 are compared with those of 1 and 2. [ABSTRACT FROM AUTHOR]

Citrus reticulata L leaves are one of the main post-harvest byproduct, containing bioactive compounds, that are usually undervalued. This work describes the development of a biorefinery process based on the application of supercritical CO 2 (SC-CO 2 ) followed by ultrasonic-assisted extraction (UAE) combined with Natural Deep Eutectic Solvents (NaDES) to extract bioactive terpenoids and phenolic compounds from these leaves. Extraction temperature and pressure of SC-CO 2 were optimized, obtaining the highest bioactive terpenoids content using 200 bar at 60 °C. A Box-Behnken experimental design showed that 57% of water in NaDES composed of Choline Chloride and Glycerol (1:2) as extraction solvent at 25 °C for 50 min were the optimal UAE-NaDES extraction conditions to obtain the highest bioactive phenolic content from the residue of the optimal SC-CO 2 extraction. The optimum extract presented the highest bioactivity and polyphenol content determined by LC-DAD-MS compared with extracts obtained using only water or NaDES as solvent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The demand for COVID-19 vaccines has diminished as the pandemic lingers. Understanding vaccine hesitancy among essential workers is important in reducing the impact of future pandemics by providing effective immunization programs delivered expeditiously., Method: Two surveys exploring COVID-19 vaccine acceptance in 2021 and 2022 were conducted in cohorts of health care providers (HCP) and education workers participating in prospective studies of COVID-19 illnesses and vaccine uptake. Demographic factors and opinions about vaccines (monovalent and bivalent) and public health measures were collected in these self-reported surveys. Modified multivariable Poisson regression was used to determine factors associated with hesitancy., Results: In 2021, 3 % of 2061 HCP and 6 % of 3417 education workers reported hesitancy (p < 0.001). In December 2022, 21 % of 868 HCP and 24 % of 1457 education workers reported being hesitant to receive a bivalent vaccine (p = 0.09). Hesitance to be vaccinated with the monovalent vaccines was associated with earlier date of survey completion, later receipt of first COVID-19 vaccine dose, no influenza vaccination, and less worry about becoming ill with COVID-19. Factors associated with hesitance to be vaccinated with a bivalent vaccine that were common to both cohorts were receipt of two or fewer previous COVID-19 doses and lower certainty that the vaccines were safe and effective., Conclusion: Education workers were somewhat more likely than HCP to report being hesitant to receive COVID-19 vaccines but reasons for hesitancy were similar. Hesitancy was associated with non-receipt of previous vaccines (i.e., previous behaviour), less concern about being infected with SARS-CoV-2, and concerns about the safety and effectiveness of vaccines for both cohorts. Maintaining inter-pandemic trust in vaccines, ensuring rapid data generation during pandemics regarding vaccine safety and effectiveness, and effective and transparent communication about these data are all needed to support pandemic vaccination programs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brenda L Coleman reports financial support was provided by Canadian Institutes of Health Research. Allison McGeer reports financial support was provided by Canadian Institutes of Health Research. Allison McGeer reports financial support was provided by Physicians' Services Inc. Foundation. Dawn Bowdish reports financial support was provided by Weston Family Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cyanobacteria blooms in fishponds, driven by climate change and anthropogenic activities, have become a critical concern for aquatic ecosystems worldwide. The diversity in fishpond sizes and fish densities further complicates their monitoring. This study addresses the challenge of accurately predicting cyanobacteria concentrations in turbid waters via remote sensing, hindered by optical complexities and diminished light signals. A comprehensive dataset of 740 sampling points was compiled, encompassing water quality metrics (cyanobacteria levels, total chlorophyll, turbidity, total cell count) and spectral data obtained through AlgaeTorch, alongside Sentinel-2 reflectance data from three Třeboň fishponds (UNESCO Man and Biosphere Reserve) in the Czech Republic over 2022-2023. Partial Least Squares Regression (PLSR) and three machine learning algorithms, Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost), were developed based on seasonal and annual data volumes. The SVM algorithm demonstrated commendable performance on the one-year data validation dataset from the Svět fishpond for the prediction of cyanobacteria, reflected by the key performance indicators: R 2  = 0.88, RMSE = 15.07 μg Chl-a/L, and RPD = 2.82. Meanwhile, SVM displayed steady results in the unified one-year validation dataset from Naděje, Svět, and Vizír fishponds, with metrics showing R 2  = 0.56, RMSE = 39.03 μg Chl-a/L, RPD = 1.50. Thus, Sentinel data proved viable for seasonal cyanobacteria monitoring across different fishponds. Overall, this study presents a novel approach for enhancing the precision of cyanobacteria predictions and long-term ecological monitoring in fishponds, contributing significantly to the water quality management strategies in the Třeboň region., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aims to investigate the impact of the π → π* excitation localised in one monomer on the equilibrium geometry and oscillations of the AA dimer. Several low-frequency vibrations appear in pairs in the LIF spectrum because oscillations involving intermolecular hydrogen bonds are coupled, generating approximately symmetric and antisymmetric combinations (especially the COOH rocking modes, LIF: 295 and 301 cm -1 ). Furthermore, quantitative evaluation based on the TDDFT(B3LYP) results indicates that a dozen among 90 intramolecular oscillations are strongly coupled. In contrast, most vibrations are decoupled or weakly coupled, since they involve remote parts of the monomers. This makes several single vibrations active in the LIF spectrum (including the bending mode of the NH···O intramolecular hydrogen bond associated the strongest vibronic band 442 cm -1 ), while the other in each pair remains inactive. The reason for decoupling of oscillations and symmetry breaking is that the π → π* electronic excitation is entirely localised within one of the monomers, which makes them no longer equivalent in terms of geometry and dynamics. Additionally, the excitation of one monomer induces strengthening and shortening by 6 pm of only one intermolecular hydrogen bond linking the carboxylic groups of both molecules. This causes the 1.7° in-plane distortion of the dimer and lowering of its symmetry to C s group (from C 2 h for the S 0 state). The distortion induces the activity of two low-frequency in-plane intermolecular vibrations, i.e. the geared oscillation (LIF: 58 cm -1 ) and the shearing motion (99 cm -1 ) of the monomers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Active inference is a state-of-the-art framework for modeling the brain that explains a wide range of mechanisms. Recently, two versions of branching time active inference (BTAI) have been developed to handle the exponential (space and time) complexity class that occurs when computing the prior over all possible policies up to the time horizon. However, those two versions of BTAI still suffer from an exponential complexity class with regard to the number of observed and latent variables being modeled. We resolve this limitation by allowing each observation to have its own likelihood mapping and each latent variable to have its own transition mapping. The implicit mean field approximation was tested in terms of its efficiency and computational cost using a dSprites environment in which the metadata of the dSprites data set was used as input to the model. In this setting, earlier implementations of branching time active inference (namely, BTAIVMP and BTAIBF) underperformed in relation to the mean field approximation (BTAI3MF) in terms of performance and computational efficiency. Specifically, BTAIVMP was able to solve 96.9% of the task in 5.1 seconds, and BTAIBF was able to solve 98.6% of the task in 17.5 seconds. Our new approach outperformed both of its predecessors by solving the task completely (100%) in only 2.559 seconds., (© 2024 Massachusetts Institute of Technology.)

Active inference is a theory of perception, learning, and decision making that can be applied to neuroscience, robotics, psychology, and machine learning. Recently, intensive research has been taking place to scale up this framework using Monte Carlo tree search and deep learning. The goal of this activity is to solve more complicated tasks using deep active inference. First, we review the existing literature and then progressively build a deep active inference agent as follows: we (1) implement a variational autoencoder (VAE), (2) implement a deep hidden Markov model (HMM), and (3) implement a deep critical hidden Markov model (CHMM). For the CHMM, we implemented two versions, one minimizing expected free energy, CHMM[EFE] and one maximizing rewards, CHMM[reward]. Then we experimented with three different action selection strategies: the ε-greedy algorithm as well as softmax and best action selection. According to our experiments, the models able to solve the dSprites environment are the ones that maximize rewards. On further inspection, we found that the CHMM minimizing expected free energy almost always picks the same action, which makes it unable to solve the dSprites environment. In contrast, the CHMM maximizing reward keeps on selecting all the actions, enabling it to successfully solve the task. The only difference between those two CHMMs is the epistemic value, which aims to make the outputs of the transition and encoder networks as close as possible. Thus, the CHMM minimizing expected free energy repeatedly picks a single action and becomes an expert at predicting the future when selecting this action. This effectively makes the KL divergence between the output of the transition and encoder networks small. Additionally, when selecting the action down the average reward is zero, while for all the other actions, the expected reward will be negative. Therefore, if the CHMM has to stick to a single action to keep the KL divergence small, then the action down is the most rewarding. We also show in simulation that the epistemic value used in deep active inference can behave degenerately and in certain circumstances effectively lose, rather than gain, information. As the agent minimizing EFE is not able to explore its environment, the appropriate formulation of the epistemic value in deep active inference remains an open question., (© 2024 Massachusetts Institute of Technology.)

Biodegradable plastics play a vital role in addressing global plastics disposal challenges. Poly-3-hydroxybutyrate (P3HB) is a biodegradable bacterial intracellular storage polymer with substantial usage potential in agriculture. Poly-3-hydroxybutyrate and its degradation products are non-toxic; however, previous studies suggest that P3HB biodegradation negatively affects plant growth because the microorganisms compete with plants for nutrients. One possible solution to this issue could be inoculating soil with a consortium of plant growth-promoting and N-fixing microorganisms. To test this hypothesis, we conducted a pot experiment using lettuce (Lactuca sativa L. var. capitata L.) grown in soil amended with two doses (1 % and 5 % w/w) of P3HB and microbial inoculant (MI). We tested five experimental variations: P3HB 1 %, P3HB 1 % + MI, P3HB 5 %, P3HB 5 % + MI, and MI, to assess the impact of added microorganisms on plant growth and P3HB biodegradation. The efficient P3HB degradation, which was directly dependent on the amount of bioplastics added, was coupled with the preferential utilization of P3HB as a carbon (C) source. Due to the increased demand for nutrients in P3HB-amended soil by microbial degraders, respiration and enzyme activities were enhanced. This indicated an increased mineralisation of C as well as nitrogen (N), sulphur (S), and phosphorus (P). Microbial inoculation introduced specific bacterial taxa that further improved degradation efficiency and nutrient turnover (N, S, and P) in P3HB-amended soil. Notably, soil acidification related to P3HB was not the primary factor affecting plant growth inhibition. However, despite plant growth-promoting rhizobacteria and N 2 -fixing microorganisms originating from MI, plant biomass yield remained limited, suggesting that these microorganisms were not entirely successful in mitigating the growth inhibition caused by P3HB., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Percutaneous coronary intervention (PCI) with drug-coated balloons (DCB) or drug-eluting stents (DES) are well-established treatments for in-stent restenosis, however little is known about the impact of vessel size on the outcomes. The study aimed to evaluate the efficacy and safety profile of DCB versus DES in DES in-stent restenosis depending on the vessel size., Methods: Consecutive patients with DES in-stent restenosis who underwent PCI between January 2010 and February 2018 entered the registry with a long-term follow-up. Patients who received DCB at the index procedure were compared with those who received DES in three subgroups depending on the vessel size (≤2.5 mm; 2.5-3.5 mm; >3.5 mm). Data were analyzed using propensity score matching and Kaplan-Meier estimator plots., Results: Among 1,374 patients with DES in-stent restenosis, 615 were treated with DES and 759 with DCB. After propensity score matching, we analyzed 752 patients in the DES and DCB groups at a long-term follow-up. The risk of DOCE did not differ significantly between the DES and DCB groups, both in the overall population (HR 0.85; 95%CI [0.58; 1.26], log-rank p = 0.41) and when divided into small (HR 0.84; 95%CI [0.36; 1.95], log-rank p = 0.70), medium-sized (HR 0.90; 95%CI [0.49; 1.65], log-rank p = 0.73), and large-sized (HR 0.81; 95%CI [0.42; 1.53], log-rank p = 0.50) coronary arteries. The incidence of all-cause death was significantly higher in the overall DES population (HR 4.03; 95%CI [2.40; 6.79], log-rank p < 0.001) and subgroup of small (HR 5.54; 95%CI [1.80; 17.02], log-rank p = 0.003), medium-sized (HR 4.37; 95%CI [1.92; 9.94], log-rank p = 0.009) and large-sized coronary arteries (HR 3.26; 95%CI [1.35; 7.86], log-rank p = 0.02)., Conclusions: DES and DCB strategies are comparable methods of treating ISR regardless of the diameter of the treated vessel in a long-term follow-up., (© 2024 Wiley Periodicals LLC.)

Two-dimensional materials composed of elements from the 15th group of the periodic table remain largely unexplored. The primary challenge in advancing this research is the lack of large-scale layers that would facilitate extensive studies using laterally averaging techniques and enable functionalization for the fabrication of novel electronic, optoelectronic, and spintronic devices. In this report, we present a method for synthesizing large-scale antimonene layers, on the order of cm 2 . By employing molecular beam epitaxy, we successfully grow a monolayer film of α-phase antimonene on a W(110) surface passivated with a single-atom-thick layer of Sb atoms. The formation of α phase antimonene is confirmed through scanning tunneling microscopy and low-energy electron diffraction measurements. The isolated nature of the α-phase is further evidenced in the electronic structure, with linearly dispersed bands observed through angle-resolved photoelectron spectroscopy and supported by ab initio calculations.

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The one-step carbonization of low cost and abundant chitosan biopolymer in the presence of salt eutectics ZnCl 2 /NaCl results in nitrogen-doped carbon nanostructures (8.5 wt.% total nitrogen content). NaCl yields the spacious 3D structure, which allows external oxygen to easily reach the active sites for the oxygen reduction reaction (ORR) distinguished by their high onset potential and the maximum turnover frequency of 0.132 e site⁻ 1  s⁻ 1 . Data show that the presence of NaCl during the synthesis exhibits the formation of pores having large specific volumes and surface (specific surface area of 1217 m 2  g -1 ), and holds advantage by their pores characteristics such as their micro-size part, which provides a platform for mass transport distribution in three-dimensional N-doped catalysts for ORR. It holds benefit over sample pre-treated with LiCl in terms of the micropores specific volume and area, seen as their percentage rate, measured in the BET. Therefore, the average concentration of the active site on the surface is larger., (© 2024. The Author(s).)

Recent studies have shown that spontaneous pre-stimulus fluctuations in brain activity affect higher-order cognitive processes, including risky decision-making, cognitive flexibility, and aesthetic judgments. However, there is currently no direct evidence to suggest that pre-choice activity influences value-based decisions that require self-control. We examined the impact of fluctuations in pre-choice activity in key regions of the reward system on self-control in food choice. In the functional magnetic resonance imaging (fMRI) scanner, 49 participants made 120 food choices that required self-control in high and low working memory load conditions. The task was designed to ensure that participants were cognitively engaged and not thinking about upcoming choices. We defined self-control success as choosing a food item that was healthier over one that was tastier. The brain regions of interest (ROIs) were the ventral tegmental area (VTA), putamen, nucleus accumbens (NAc), and caudate nucleus. For each participant and condition, we calculated the mean activity in the 3-s interval preceding the presentation of food stimuli in successful and failed self-control trials. These activities were then used as predictors of self-control success in a fixed-effects logistic regression model. The results indicate that increased pre-choice VTA activity was linked to a higher probability of self-control success in a subsequent food-choice task within the low-load condition, but not in the high-load condition. We posit that pre-choice fluctuations in VTA activity change the reference point for immediate (taste) reward evaluation, which may explain our finding. This suggests that the neural context of decisions may be a key factor influencing human behavior., (© 2024. The Author(s).)

Treatment of Limbal Stem Cell Deficiency (LSCD), based on autologous transplantation of the patient's stem cells, is one of the few medical stem cell therapies approved by the European Medicines Agency (EMA). It relies on isolating and culturing in vivo Limbal Epithelial Stem Cells (LESC) and then populating them on the fibrin substrate, creating a scaffold for corneal epithelial regeneration. Such a solution is then implanted into the patient's eye. The epithelial cell culture process is specific, and its results strongly depend on the initial cell seeding density. Achieving control of the density and repeatability of the process is a desirable aim and can contribute to the success of the therapy. The study aimed to test bioprinting as a potential technique to increase the control over LESCs seeding on a scaffold and improve process reproducibility. Cells were applied to 0.5 mm thick, flat, transparent fibrin substrates using extrusion bioprinting; the control was the traditional manual application of cells using a pipette. The use of 3D printer enabled uniform coverage of the scaffold surface, and LESCs density in printed lines was close to the targeted value. Moreover, printed cells had higher cell viability than those seeded traditionally (91.1 ± 8.2% vs 82.6 ± 12.8%). The growth rate of the epithelium was higher in bioprinted samples. In both methods, the epithelium had favorable phenotypic features (p63 + and CK14 +). 3D printing constitutes a promising approach in LSCD therapy. It provides favorable conditions for LESCs growth and process reproducibility. Its application may lead to reduced cell requirements, thereby to using fewer cells on lower passages, which will contribute to preserving LESCs proliferative potential., (© 2024. The Author(s).)

Background: Modern trends in reconstructive surgery involve the use of free perforator flaps to reduce the donor site morbidity. The course of perforator vessels has a great anatomic variability and demands a careful knowledge of the anatomical relationships and the variability of the course of the perforators. The numerous modifications of perforator nomenclature were proposed by many authors and brought confusion rather than a simplification. In our study we focused on a hypothesis, that septocutaneous perforator passes from the given source vessel to the deep fascia adherent to, but not to within the septum itself., Methods: 69 septocutaneous perforators from three different limb donor sites (Lateral Arm Flap, Anterolateral Thigh Flap, Radial Forearm Free Flap) were collected from gross pathology specimens of 14 fresh cadavers. The gross picture and the cross sections with the histological cross sections on different levels were examined to determine the position of vessel to the septal tissue., Results: Of the observed 69 septal perforators, 61 (88,5%) perforators were adherent to but not within the septum. Remaining eight (12,5%) perforators passed through the septum. All these eight perforators were found in multiple different cross section levels. (two of 19 in Lateral Arm Flap, three of 27 in Anterolateral Thigh Flap, three of 23 in Radial Forearm Free Flap)., Conclusion: Although macroscopically identical septocutaneous vessels, microscopically we observe two types of vessels - with paraseptal and intraseptal pathways. The majority are merely adherent to the septum having a paraseptal pathway. A minority are within the septum, and are "true" septocutaneous perforators. It is advisable to dissect with a piece of the septum in order to avoid damage any injury of perforator., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: We report our single-center experience of mid-term to long-term retrieval and reimplantation of a tines-based leadless pacemaker (Micra transcatheter pacing system; TPS)., Backgrounds: The TPS is a clinically effective alternative to transvenous single-chamber ventricular pacemakers. Whereas it is currently recommended to abandon the TPS at the end of device life, catheter-based retrieval may be favorable in specific scenarios., Methods: We report on nine consecutive patients with the implanted TPS who subsequently underwent transcatheter retrieval attempts. The retrieval system consists of the original TPS delivery catheter and an off-the-shelf single-loop 7 mm snare. The procedure was guided by fluoroscopy and intracardiac echocardiography., Results: After an implantation duration of 3.1 ± 2.8 years (range 0.4-9.0), the overall retrieval success rate was 88.9% (8 of 9 patients). The mean procedure time was 89 ± 16 minutes, and fluoroscopy time was 18.0 ± 6.6 min. No procedure-related adverse device events occurred. In the one unsuccessful retrieval, intracardiac echocardiography revealed that the TPS was partially embedded in the ventricular tissue surrounding the leadless pacemaker body in the right ventricle. After retrieval, three patients were reimplanted with a new TPS device. All implantations were successful without complications., Conclusions: A series of transvenous late retrievals of implanted TPS devices demonstrated safety and feasibility, followed by elective replacement with a new leadless pacing device or conventional transvenous pacing system. This provides a viable end-of-life management alternative to simple abandonment of this leadless pacemaker., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

OXA-244-producing Escherichia coli (OXA-244-Ec) has disseminated in Europe, mostly in the community. In Poland it has spread since 2017, especially in 2023, but in contrast to other countries, all isolates have been identified in hospitals so far. The isolates (n = 101) represented one large and two limited outbreaks in different regions, and multiple epidemiologically and genetically non-related organisms. The OXA-244-Ec population consisted of 14 STs, with ST38 dominating. The ST38 isolates belonged to two major lineages, Clusters A and B, responsible for two of the hospital outbreaks. Enhanced concern and vigilance are necessary in the OXA-244-Ec surveillance., (© 2024. The Author(s).)

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL., Methods: Eligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR., Results: Of 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade ≥2, 22.7%]) versus 1,000 mg (87.5%; grade ≥2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections)., Conclusion: Fixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.

The honey bee, Apis mellifera L., is one of the main pollinators worldwide. In a temperate climate, seasonality affects the life span, behavior, physiology, and immunity of honey bees. In consequence, it impacts their interaction with pathogens and parasites. In this study, we used Bayesian statistics and modeling to examine the immune response dynamics of summer and winter honey bee workers after injection with the heat-killed bacteria Serratia marcescens, an opportunistic honey bee pathogen. We investigated the humoral and cellular immune response at the transcriptional and functional levels using qPCR of selected immune genes, antimicrobial activity assay, and flow cytometric analysis of hemocyte concentration. Our data demonstrate increased antimicrobial activity at transcriptional and functional levels in summer and winter workers after injection, with a stronger immune response in winter bees. On the other hand, an increase in hemocyte concentration was observed only in the summer bee population. Our results indicate that the summer population mounts a cellular response when challenged with heat-killed S. marcescens, while winter honey bees predominantly rely on humoral immune reactions. We created a model describing the honey bee immune response dynamics to bacteria-derived components by applying Bayesian statistics to our data. This model can be employed in further research and facilitate the investigating of the honey bee immune system and its response to pathogens., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Hurychová et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC-MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4-28 months and adults aged 19-65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable., (© 2024. The Author(s).)

Background: Faecal microbiota transplantation (FMT) is a developing therapy for disorders related to gut dysbiosis. Despite its growing application, standardised protocols for FMT filtrate preparation and quality assessment remain undeveloped. The viability of bacteria in the filtrate is crucial for FMT's efficacy and for validating protocol execution. We compared two methods-in vitro cultivation and membrane integrity assessment-for their accuracy, reproducibility and clinical applicability in measuring bacterial viability in frozen FMT stool filtrate., Methods: Bacterial viability in stool filtrate was evaluated using (i) membrane integrity through fluorescent DNA staining with SYTO9 and propidium iodide, followed by flow cytometry and (ii) culturable bacteria counts (colony-forming units, CFU) under aerobic or anaerobic conditions., Results: Using different types of samples (pure bacterial culture, stool of germ-free and conventionally bred mice, native and heat-treated human stool), we refined the bacterial DNA staining protocol integrated with flow cytometry for assessment of bacterial viability in frozen human stool samples. Both the membrane integrity-based and cultivation-based methods exhibited significant variability in bacterial viability across different FMT filtrates, without correlation. The cultivation-based method showed a mean coefficient of variance of 30.3%, ranging from 7.4% to 60.1%. Conversely, the membrane integrity approach yielded more reproducible results, with a mean coefficient of variance for viable cells of 6.4% ranging from 0.2% to 18.2%., Conclusion: Bacterial viability assessment in stool filtrate using the membrane integrity method offers robust and precise data, making it a suitable option for faecal material evaluation in FMT. In contrast, the cultivation-dependent methods produce inconsistent outcomes., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Aging workers of the termite Neocapritermes taracua can defend their colony by sacrificing themselves by body rupture, mixing the externally stored blue laccase BP76 with hydroquinones to produce a sticky liquid rich in toxic benzoquinones. Here, we describe the crystal structure of BP76 isolated from N. taracua in its native form. The structure reveals several stabilization strategies, including compact folding, glycosylation, and flexible loops with disulfide bridges and tight dimer interface. The remarkable stability of BP76 maintains its catalytic activity in solid state during the lifespan of N. taracua workers, providing old workers with an efficient defensive weapon to protect their colony., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Paralysis of the muscles controlling the hand dramatically limits the quality of life for individuals living with spinal cord injury (SCI). Here, with a non-invasive neural interface, we demonstrate that eight motor complete SCI individuals (C5-C6) are still able to task-modulate in real-time the activity of populations of spinal motor neurons with residual neural pathways. In all SCI participants tested, we identified groups of motor units under voluntary control that encoded various hand movements. The motor unit discharges were mapped into more than 10 degrees of freedom, ranging from grasping to individual hand-digit flexion and extension. We then mapped the neural dynamics into a real-time controlled virtual hand. The SCI participants were able to match the cue hand posture by proportionally controlling four degrees of freedom (opening and closing the hand and index flexion/extension). These results demonstrate that wearable muscle sensors provide access to spared motor neurons that are fully under voluntary control in complete cervical SCI individuals. This non-invasive neural interface allows the investigation of motor neuron changes after the injury and has the potential to promote movement restoration when integrated with assistive devices., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Upper ministernotomy for sutureless aortic prosthesis implantation provides an attractive opportunity compared to conventional access. Although in the last decade, the former has gained popularity, data comparing quality of life (QoL) following these procedures are scarce., Objectives: The purpose of this study was to assess the patient's QoL after aortic valve replacement (AVR) using a ministernotomy approach compared to a full sternotomy., Material and Methods: One hundred fifteen AVR patients were operated on using either minimally invasive access with sutureless valve implantation through an upper median ministernotomy (group I; n = 58) or through a full sternotomy (group II; n = 57) with either biological Edwards Perimount Magna™ (Edwards Lifescience, Irvine, USA) (n = 30) or mechanical On-X™ (Carbomedics, Austin, USA) (n = 27) aortic valve prostheses implantation by 1 experienced surgeon. At the end of the follow-up period, QoL was assessed using the EQ-5D-5L scale telephone survey., Results: In group I, there were significantly fewer problems with mobility, pain and usual activities than in group II (p < 0.05). Moreover, the visual analogue scale (VAS) and Health Index (HI) scores were more favorable for patients treated with ministernotomy. Additionally, group II participants provided comments beyond the survey questions, such as tiredness, dyspnea or pain. These kinds of remarks were not reported in group I. Ultimately, the EQ-5D-5L Index Score (IS) was consistent with the variables and more beneficial for group I subjects. Each group was compatible with the benefits for patients in group I., Conclusions: Cardiac surgical procedures for severe aortic stenosis through minimally invasive access are associated with improved QoL parameters.

To gain a more comprehensive understanding of the phenomenon of high-fluorescence anisotropy of the normal form emission of ESIPT-active compounds in protic solvents, excitation wavelength dependence of emission anisotropy was investigated for 3-hydroxyflavone (3HF) using steady-state spectroscopic technique and quantum chemical calculations. It was shown for the first time that the anisotropy of 3HF normal form emission is characterized by significant dependence on excitation energy. Experimental results indicate that the fluorescence anisotropy of 3HF in methanol (at 20 °C) changes abruptly from about 0.18 to about 0.10 with a decrease in excitation wavelength. This spectroscopic phenomenon can be explained by two factors: (1) breaking of intermolecular solute-solvent hydrogen bonds upon photoexcitation and (2) excitation of ESIPT-active fluorophores to the second singlet state (S 2 ). The results of quantum chemical calculations clearly indicate that specific hydrogen bonding solvation interactions can lead to the formation of 3HF-methanol complexes with larger molecular volumes than the volume of free 3HF molecule. High excitation energy can reform and break solute-solvent bonds, which leads to a decrease in molecular system volume. This results in a decrease in rotational correlation time and fluorescence anisotropy. As is known, the fluorescence lifetime of small-sized molecules is closely correlated with the conformational changes in the excited state, and in the case of ESIPT-active compounds, the lifetime of normal form emission is almost fully determined by the ultrafast ESIPT process. Therefore, although in general, fluorescence lifetime is considered independent of excitation energy, but because the timescale of ESIPT processes is of the same order as the timescale of internal conversion, in the case of ESIPT-active compounds, fluorescence lifetime changes caused by high-energy state excitation cannot be neglected. The emission anisotropy of the normal form of an ESIPT-active compound will decrease with an increase in fluorescence lifetime caused by an increase in excitation energy sufficient to excite molecules to higher electronic states. In this work, both hypotheses are discussed and verified using experimental data and quantum chemical calculations for 3HF in methanol.

Climate change is currently one of humanity's greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries., (© 2024. The Author(s).)