A Thermoresponsive injectable drug delivery system of chitosan/ß-glycerophosphate with gellan gum/alginate microparticles.

The development of new Drug Delivery Systems (DDS) by incorporating microparticles within hydrogels can prolong the release rate of drugs and/or other bioactive agents. In this study, we combined gellan gum/alginate microparticles within a thermoresponsive chitosan (Ch) hydrogel with ß-Glycerophosphate (ß-GP), designing the system to be in the sol state at 21 °C and in the gel state at 37 °C to enable the injectability of the system. The system was in the sol state between 10 °C and 21 °C. Higher concentrations of ß-GP (0, 2, 3, 4, 5 w/v%) and microparticles (0, 2 and 5 w/v%) allowed a faster sol-gel transition with higher mechanical strength at 37 °C. However, the sol-gel transition was not instantaneous. The release profile of methylene blue (MB) from the microparticles was significantly affected by their incorporation in Ch/ß-GP hydrogels, only allowing the release of 60-70 % of MB for 6 days, while the microparticles alone released all the MB in 48 h. The proposed system did not present cytotoxicity to VERO cell lines as a preliminary assay, with the Ch/ß-GP/GG:Alg having >90 % of cellular viability. The proposed Ch/ß-GP system proved to have a delaying effect on drug release and biocompatible properties, being a promising future DDS.

Cryoprotective Polysaccharides with Ordered Gel Structures Induce Ice Growth Anticipation and Survival Enhancement during Cell Cryopreservation.

This work cross-correlated rheological, thermodynamic, and conformational features of several natural polysaccharides to their cryoprotective performance. The basis of cryoprotection of FucoPol, pectin, and agar revealed a causal combination of (i) an emerging sol-gel transition (p = 0.014) at near-hypothermia (4 °C), (ii) noncolligative attenuated supercooling of the kinetic freezing point of water (p = 0.026) supporting ice growth anticipation, and (iii) increased conformational order (p < 0.0001), where helix-/sheet-like features boost cryoprotection. FucoPol, of highest cryoprotective performance, revealed a predominantly helical structure (α/ß = 1.5) capable of forming a gel state at 4 °C and the highest degree of supercooling attenuation (TH = 6.2 °C). Ice growth anticipation with gel-like polysaccharides suggests that the gel matrix neutralizes elastic deformations and lethal cell volumetric fluctuations during freezing, thus preventing the loss of homeostasis and increasing post-thaw viability. Ultimately, structured gels capable of attenuated supercooling enable cryoprotective action at the polymer-cell interface, in addition to polymer-ice interactions. This rationale potentiates implementing alternative, biobased, noncytotoxic polymers in cryobiology.

Pyrazoles have a multifaceted anti-inflammatory effect targeting prostaglandin E2, cyclooxygenases and leukocytes' oxidative burst.

Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

GNB1 and obesity: Evidence for a correlation between haploinsufficiency and syndromic obesity.

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.

Exploring the Impact of Copper Oxide Substitution on Structure, Morphology, Bioactivity, and Electrical Properties of 45S5 Bioglass®.

In recent decades, the requirements for implantable medical devices have increased, but the risks of implant rejection still exist. These issues are primarily associated with poor osseointegration, leading to biofilm formation on the implant surface. This study focuses on addressing these issues by developing a biomaterial for implant coatings. 45S5 bioglass® has been widely used in tissue engineering due to its ability to form a hydroxyapatite layer, ensuring a strong bond between the hard tissue and the bioglass. In this context, 45S5 bioglasses®, modified by the incorporation of different amounts of copper oxide, from 0 to 8 mol%, were synthesized by the melt-quenching technique. The incorporation of Cu ions did not show a significant change in the glass structure. Since the bioglass exhibited the capacity for being polarized, thereby promoting the osseointegration effectiveness, the electrical properties of the prepared samples were studied using the impedance spectroscopy method, in the frequency range of 102-106 Hz and temperature range of 200-400 K. The effects of CuO on charge transport mobility were investigated. Additionally, the bioactivity of the modified bioglasses was evaluated through immersion tests in simulated body fluid. The results revealed the initiation of a Ca-P-rich layer formation on the surface within 24 h, indicating the potential of the bioglasses to enhance the bone regeneration process.

Bioactive Hydroxyapatite Aerogels with Piezoelectric Particles.

Open-cell foams based on hydroxyapatite (HAp) can mimic the extracellular matrix (ECM) to better replace damaged hard tissues and assist in their regeneration processes. Aerogels of HAp nanowires (NW) with barium titanate (BT) particles were produced and characterized regarding their physical and chemical properties, bioactivity, and in vitro cytotoxicity. Considering the role of piezoelectricity (mainly due to collagen) and surface charges in bone remodeling, all BT particles, of size 280 nm and 2 and 3 µm, contained BaTiO3 in their piezoelectric tetragonal phase. The synthesized nanowires were verified to be AB-type carbonated hydroxyapatite. The aerogels showed high porosity and relatively homogeneous distribution of the BT particles. Barium titanate proved to be non-cytotoxic while all the aerogels produced were cytotoxic for an extract concentration of 1 mg/mL but became non-cytotoxic at concentrations of 0.5 mg/mL and below. It is possible that these results were affected by the higher surface area and quicker dissolution rate of the aerogels. In the bioactivity assays, SEM/EDS, it was not easy to differentiate between the apatite deposition and the surface of the HAp wires. However, a quantitative EDS analysis shows a possible CaP deposition/dissolution cycle taking place.

Multi-datasets to monitor and assess meteorological and hydrological droughts in a typical basin of the Brazilian semiarid region.

This study analyzed the meteorological and hydrological droughts in a typical basin of the Brazilian semiarid region from 1994 to 2016. In recent decades, this region has faced prolonged and severe droughts, leading to marked reductions in agricultural productivity and significant challenges to food security and water availability. The datasets employed included a digital elevation model, land use and cover data, soil characteristics, climatic data (temperature, wind speed, solar radiation, humidity, and precipitation), runoff data, images from the MODIS/TERRA and AQUA sensors (MOD09A1 and MODY09A1 products), and soil water content. A variety of methods and products were used to study these droughts: the meteorological drought was analyzed using the Standardized Precipitation Index (SPI) derived from observed precipitation data, while the hydrological drought was assessed using the Standardized Soil Index (SSI), the Nonparametric Multivariate Standardized Drought Index (NMSDI), and the Parametric Multivariate Standardized Drought Index (PMSDI). These indices were determined using water balance components, including streamflow and soil water content, from the Soil Water Assessment Tool (SWAT) model, and evapotranspiration data from the Surface Energy Balance Algorithm for Land (SEBAL). The findings indicate that the methodology effectively identified variations in water dynamics and drought periods in a headwater basin within Brazil's semiarid region, suggesting potential applicability in other semiarid areas. This study provides essential insights for water resource management and resilience building in the face of adverse climatic events, offering a valuable guide for decision-making processes.

Resistant anemia in a kidney transplant recipient: Pure red cell aplasia due to parvovirus B19 infection.

Anemia in kidney transplant recipients can stem from a diverse array of etiologies, including dietary deficiencies, inflammatory processes, allograft dysfunction, as well as viral and bacterial infections. We present a case of refractory anemia in a 49-year-old male patient occurring within the initial month following a kidney transplant, which persisted despite numerous transfusions, posing a formidable challenge. The patient was maintained on the standard immunosuppressant regimen-Tacrolimus, Mycophenolate, and Prednisolone. Diagnostic evaluations eliminated well-established causes such as dietary deficiencies, gastrointestinal losses, and prevalent infections. Subsequently, after viral PCR testing, a diagnosis of Pure Red Cell Aplasia (PRCA) due to infection with parvovirus B19 was made. Although the patient had a reduction in the immunosuppression drugs and received a course of Intravenous Immunoglobulins (IVIG) on two separate occasions spanning two months, the anemia relapsed. Subsequently, after an additional dose of IVIG with further modification and reduction of the immunosuppressant regimen, including stopping the mycophenolate and switching tacrolimus with cyclosporine, the patient ultimately achieved successful resolution of his symptoms and a significant decrease in viral load. Our case highlights the significance of unconventional etiologies when confronted with anemia in the setting of kidney transplantation. Furthermore, it also provides further insights into therapeutic avenues for addressing PRCA in kidney transplant recipients.

Plant Monoterpenes and Essential Oils as Potential Anti-Ageing Agents: Insights from Preclinical Data.

Ageing is a natural process characterized by a time-dependent decline of physiological integrity that compromises functionality and inevitably leads to death. This decline is also quite relevant in major human pathologies, being a primary risk factor in neurodegenerative diseases, metabolic disorders, cardiovascular diseases and musculoskeletal disorders. Bearing this in mind, it is not surprising that research aiming at improving human health during this process has burst in the last decades. Importantly, major hallmarks of the ageing process and phenotype have been identified, this knowledge being quite relevant for future studies towards the identification of putative pharmaceutical targets, enabling the development of preventive/therapeutic strategies to improve health and longevity. In this context, aromatic plants have emerged as a source of potential bioactive volatile molecules, mainly monoterpenes, with many studies referring to their anti-ageing potential. Nevertheless, an integrated review on the current knowledge is lacking, with several research approaches studying isolated ageing hallmarks or referring to an overall anti-ageing effect, without depicting possible mechanisms of action. Herein, we aim to provide an updated systematization of the bioactive potential of volatile monoterpenes on recently proposed ageing hallmarks, and highlight the main mechanisms of action already identified, as well as possible chemical entity-activity relations. By gathering and categorizing the available scattered information, we also aim to identify important research gaps that could help pave the way for future research in the field.

Electrospun Polycaprolactone Membranes Expanded with Chitosan Granules for Cell Infiltration.

The small pore size of electrospun membranes prevents their use as three-dimensional scaffolds. In this work, we produced polycaprolactone (PCL) electrospun fibrous membranes with expanded pores by incorporating chitosan (CS) granules into the PCL solution. Scanning electron microscopy images confirmed the presence of the CS granules embedded in the PCL fibers, creating an open structure. Tensile testing results showed that the addition of CS decreased both Young's modulus and the yield stress, but co-electrospun membranes (PCL fibers blended with CS-containing PCL fibers) exhibited higher values compared to single electrospun membranes (CS-containing PCL fibers). Human fibroblasts adhered to and proliferated on all scaffolds. Nuclear staining revealed that cells populated the entire scaffold when CS granules were present, while in PCL membranes, cells were mostly limited to the surface due to the small pore size. Overall, our findings demonstrate that electrospun membranes containing CS granules have sufficiently large pores to facilitate fibroblast infiltration without compromising the mechanical stability of the structure.

Stress Inoculation in Police Officers Using Virtual Reality: A Controlled Study.

Policing is a highly demanding and stressful profession. Virtual reality (VR) has emerged as a promising tool for enhancing stress management programs, including for police officers. The use of VR in combination with biosensors enables measurement of psychophysiological responses such as peripheral temperature (PT) and skin conductance level (SCL). This study investigated the psychophysiological responses of police officers exposed to a VR scenario simulating a car accident. The study included a total of 63 police officers from the Public Security Police. Participants were divided into three groups based on their police divisions: the Investigation Brigade of Traffic Accidents, the Traffic Surveillance Squad (TSS), and a control group from the Lisbon Metropolitan Command. The results indicated that the VR environment effectively induced psychophysiological arousal, particularly in less experienced officers (TSS), that is, there were significant group differences in mean SCL and PT, showing this group with higher SCL and lower PT during the VR exposure. These results support the potential of VR as a stress inoculation strategy for training police officers and highlight the complex nature of stress responses that are influenced by individual factors and psychopathology.

A Late Pleistocene hominin footprint site on the North African coast of Morocco.

Footprints represent a relevant vestige providing direct information on the biology, locomotion, and behaviour of the individuals who left them. However, the spatiotemporal distribution of hominin footprints is heterogeneous, particularly in North Africa, where no footprint sites were known before the Holocene. This region is important in the evolution of hominins. It notably includes the earliest currently known Homo sapiens (Jebel Irhoud) and the oldest and richest African Middle Stone Age hominin sites. In this fragmented ichnological record, we report the discovery of 85 human footprints on a Late Pleistocene now indurated beach surface of about 2800 m2 at Larache (Northwest coast of Morocco). The wide range of sizes of the footprints suggests that several individuals from different age groups made the tracks while moving landward and seaward across a semi-dissipative bar-trough sandy beach foreshore. A geological investigation and an optically stimulated luminescence dating of a rock sample extracted from the tracksite places this hominin footprint surface at 90.3 ± 7.6 ka (MIS 5, Late Pleistocene). The Larache footprints are, therefore, the oldest attributed to Homo sapiens in Northern Africa and the Southern Mediterranean.

Influence of the Addition of Zinc, Strontium, or Magnesium Oxides to the Bioglass 45S5 Network on Electrical Behavior.

45S5 Bioglass has been widely used in regenerative medicine due to its ability to dissolve when inserted into the body. Its typically amorphous structure allows for an ideal dissolution rate for the formation of the hydroxyapatite layer, which is important for the development of new bone. This bioactive capacity can also be controlled by adding other oxides (e.g., SrO, ZnO, and MgO) to the 45S5 Bioglass network or by storing electrical charge. Ions such as zinc, magnesium, and strontium allow for specific biological responses to be added, such as antibacterial action and the ability to increase the rate of osteoblast proliferation. The charge storage capacity allows for a higher rate of bioactivity to be achieved, allowing for faster attachment to the host bone, decreasing the patient's recovery time. Therefore, it is necessary to understand the variation in the structure of the bioglass with regard to the amount of non-bridging oxygens (NBOs), which is important for the bioactivity rate not to be compromised, and also its influence on the electrical behavior relevant to its potential as electrical charge storage. Thus, several bioactive glass compositions were synthesized based on the 45S5 Bioglass formulation with the addition of various concentrations (0.25, 0.5, 1, and 2, mol%) of zinc, strontium, or magnesium oxides. The influence of the insertion of these oxides on the network was evaluated by studying the amount of NBOs using Raman spectroscopy and their implication on the electrical behavior. Electrical characterization was performed in ac (alternating current) and dc (direct current) regimes.

Chemical Characterization, Phenolic Compounds Quantification, and Assessment of Antioxidant and Anti-Acetylcholinesterase Activities of Byrsonima sericea DC fruits.

Byrsonima sericea is a species native to Brazil that is widely used in traditional medicine. The seed ethanol extract (SEE) had the highest content of total phenols (179.35 mg GAE g-1 extract) and flavonoids (10.42 mg QE g-1 extract) and was the most active in relation to antioxidant activity (DPPH: IC50 =4.25 µg mL-1 and ABTS: IC50 =4.82 µg mL-1 ). The peel/pulp ethanol extract (PEE) had the best anticholinesterase activity (IC50 =6.02 µg mL-1 ). Chromatographic investigation identified gallic acid, isoquercitrin, quercetin and amentoflavone in SEE, and gallic acid, isoquercitrin, quercetin and rutin in PEE. Six fatty acid methyl esters and seven triterpenes were identified, highlighting oleic acid in the seed hexane extract (61.85 %) and in the peel/pulp hexane extract (52.61 %), and betulin in the peel/pulp hexane extract (5.25 %). The substances and biological activities identified in B. sericea characterize this fruit as a functional food for future studies.

Elevated fucose content enhances the cryoprotective performance of anionic polysaccharides.

Biological cryopreservation often involves using a cryoprotective agent (CPA) to mitigate lethal physical stressors cells endure during freezing and thawing, but effective CPA concentrations are cytotoxic. Hence, natural polysaccharides have been studied as biocompatible alternatives. Here, a subset of 26 natural polysaccharides of various chemical composition was probed for their potential in enhancing the metabolic post-thaw viability (PTV) of cryopreserved Vero cells. The best performing cryoprotective polysaccharides contained significant fucose amounts, resulting in average PTV 2.8-fold (up to 3.1-fold) compared to 0.8-fold and 2.2-fold for all non-cryoprotective and cryoprotective polysaccharides, respectively, outperforming the optimized commercial CryoStor™ CS5 formulation (2.6-fold). Stoichiometrically, a balance between fucose (18-35.7 mol%), uronic acids (UA) (13.5-26 mol%) and high molecular weight (MW > 1 MDa) generated optimal PTV. Principal component analysis (PCA) revealed that fucose enhances cell survival by a charge-independent, MW-scaling mechanism (PC1), drastically different from the charge-dominated ice growth disruption of UA (PC2). Its neutral nature and unique properties distinguishable from other neutral monomers suggest fucose may play a passive role in conformational adaptability of polysaccharide to ice growth inhibition, or an active role in cell membrane stabilization through binding. Ultimately, fucose-rich anionic polysaccharides may indulge in polymer-ice and polymer-cell interactions that actively disrupt ice and minimize lethal volumetric fluctuations due to a balanced hydrophobic-hydrophilic character. Our research showed the critical role neutral fucose plays in enhancing cellular cryopreservation outcomes, disputing previous assumptions of polyanionicity being the sole governing predictor of cryoprotection.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Student survey after ten years of continuous blended teaching of echocardiography.

OBJECTIVE: To analyse the impact of 10 years of blended echocardiography teaching. METHODS AND RESULTS: A questionnaire was emailed to all medical doctors who graduated from the blended learning diploma in echocardiography developed by the University of Chile and taught by a team from Chile and Spain. One hundred and forty of the 210 students who graduated from the program between 2011 and 2020 completed the questionnaire: 53.57% were anaesthesiologists, and 26.42% were intensivists. More than 85% of respondents indicated that the online teaching met their expectations, and 70.2% indicated that the hands-on practice fulfilled the stated objectives. In a retrospective analysis using self-reported data, graduates reported that their use of transthoracic and transoesophageal echocardiography has increased from 24.29% to 40.71% and from 13.57% to 27.86%, repectively, after the programme compared to before the programme. They used echocardiography mainly in the perioperative period (56.7%) and during intensive care (32.3%), while only 11% of respondents used it in emergency care units. Nearly all (92.4%) respondents reported that the skills learned was very useful in their professional practice. CONCLUSIONS: Ten years after its launch, the blended learning diploma in echocardiography was well rated by graduate specialists, and is associated with a significant increase in the use of echocardiography in the perioperative period and during intensive care. The main challenges are to establish a longer period of practice and achieve greater implantation in emergency medicine.