Snake venom bioprospecting as an approach to finding potential anti-glioblastoma molecules.

Glioblastoma (GB) is the most common type of malignant tumor of the central nervous system, responsible for significant morbidity and with a 5-year overall relative survival of only 6.8%. Without advances in treatment in the last twenty years, the standard of care continues to be maximum safe resection, Temozolomide (TMZ), and radiotherapy. Many new trials are ongoing, and despite showing increased progression-free survival, these trials did not improve overall survival. They did not consider the adverse effects of these therapies. Therefore, an increasing number of bioprospecting studies have used snake venom molecules to search for new strategies to attack GB selectively without producing side effects. The present review aims to describe GB characteristics and current and new approaches for treatment considering their side effects. Besides, we focused on the antitumoral activity of snake venom proteins from the Viperidae family against GB, exploring the potential for drug design based on in vitro and in vivo studies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In January 2024, a systematic search was performed in the PubMed, EMBASE, and Web of Science databases from January 2000 to December 2023. Search terms were selected based on the population/exposure/outcome (PEO) framework and combined using Boolean operators ("AND", "OR"). The search strategy used these terms: glioblastoma, glioma, high-grade glioma, WHO IV glioma, brain cancer, snake venom, Viperidae, and bioprospection. We identified 10 in vivo and in vitro studies with whole and isolated proteins from Viperidae venom that could have antitumor activity against glioblastoma. Studies in bioprospecting exploring the advantage of snake venom proteins against GB deserve to be investigated due to their high specificity, small size, inherent bioactivity, and few side effects to cross the blood-brain barrier (BBB) to reach the tumor microenvironment.

Analysis of the swine movement network in Mexico: A perspective for disease prevention and control.

Pig farming in Mexico is critical to the economy and food supply. Mexico has achieved advancements in swine health and established an electronic database that records swine movements (Sistema Nacional de Avisos de Movilización, SNAM). In this study, we characterized swine movement patterns in México between 2017 and 2019 to identify specific areas and periods that require concentrated efforts for effective epidemiological surveillance and disease control. We employed a Social Network Analysis (SNA) methodology to comprehensively describe and analyze the intricate patterns of pig movement. In addition, we sought to integrate swine population density into the analysis. We used metrics to characterize the network structure and identify the most critical nodes in the movement network. Cohesion metrics were used to identify commercial communities characterized by a high level of interconnectivity in swine movements between groups of nodes. Of a cumulative count of 662,255 pig shipments, 95.9% were attributed to slaughterhouse shipments. We observed that 54% of all Mexican municipalities were part of the network; however, the density of the movement network was less than 0.14%. We identified four Swine Production Centers in Mexico with high interconnectivity in the movement network. We detected moderate positive correlations (ρ ≥0.4 and <0.6, p < 0.001) between node metrics and swine population indicators, whereas the number of commercial swine facilities showed weak correlations with the node metrics. We identified six large, geographically clustered commercial communities that aligned with the Swine Production Centers. This study provides a comprehensive overview of swine movement patterns in Mexico and their close association with swine production centers, which play a dual role as producers and traders within the swine industry of Mexico. Our research offers valuable insights for policymakers in developing disease prevention and control strategies.

Effect of viscosity of gelatin methacryloyl-based bioinks on bone cells.

The viscosity of gelatin methacryloyl (GelMA)-based bioinks generates shear stresses throughout the printing process that can affect cell integrity, reduce cell viability, cause morphological changes, and alter cell functionality. This study systematically investigated the impact of the viscosity of GelMA-gelatin bioinks on osteoblast-like cells in 2D and 3D culture conditions. Three bioinks with low, medium, and high viscosity prepared by supplementing a 5% GelMA solution with different concentrations of gelatin were evaluated. Cell responses were studied in a 2D environment after printing and incubation in non-cross-linked bioinks that caused the gelatin and GelMA to dissolve and release cells for attachment to tissue culture plates. The increased viscosity of the bioinks significantly affected cell area and aspect ratio. Cells printed using the bioink with medium viscosity exhibited greater metabolic activity and proliferation rate than those printed using the high viscosity bioink and even the unprinted control cells. Additionally, cells printed using the bioink with high viscosity demonstrated notably elevated expression levels of alkaline phosphatase and bone morphogenetic protein-2 genes. In the 3D condition, the printed cell-laden hydrogels were photo-cross-linked prior to incubation. The medium viscosity bioink supported greater cell proliferation compared to the high viscosity bioink. However, there were no significant differences in the expression of osteogenic markers between the medium and high viscosity bioinks. Therefore, the choice between medium and high viscosity bioinks should be based on the desired outcomes and objectives of the bone tissue engineering application. Furthermore, the bioprinting procedure with the medium viscosity bioink was used as an automated technique for efficiently seeding cells onto 3D printed porous titanium scaffolds for bone tissue engineering purposes.

3D Printing and Surface Engineering of Ti6Al4V Scaffolds for Enhanced Osseointegration in an In Vitro Study.

Ti6Al4V superalloy is recognized as a good candidate for bone implants owing to its biocompatibility, corrosion resistance, and high strength-to-weight ratio. While dense metal implants are associated with stress shielding issues due to the difference in densities, stiffness, and modulus of elasticity compared to bone tissues, the surface of the implant/scaffold should mimic the properties of the bone of interest to assure a good integration with a strong interface. In this study, we investigated the additive manufacturing of porous Ti6Al4V scaffolds and coating modification for enhanced osteoconduction using osteoblast cells. The results showed the successful fabrication of porous Ti6Al4V scaffolds with adequate strength. Additionally, the surface treatment with NaOH and Dopamine Hydrochloride (DOPA) promoted the formation of Dopamine Hydrochloride (DOPA) coating with an optimized coating process, providing an environment that supports higher cell viability and growth compared to the uncoated Ti6Al4V scaffolds, as demonstrated by the higher proliferation ratios observed from day 1 to day 29. These findings bring valuable insights into the surface modification of 3D-printed scaffolds for improved osteoconduction through the coating process in solutions.

Protein folding, cellular stress and cancer.

Proteins are acknowledged as the phenotypical manifestation of the genotype, because protein-coding genes carry the information for the strings of amino acids that constitute the proteins. It is widely accepted that protein function depends on the corresponding "native" structure or folding achieved within the cell, and that native protein folding corresponds to the lowest free energy minimum for a given protein. However, protein folding within the cell is a non-deterministic dissipative process that from the same input may produce different outcomes, thus conformational heterogeneity of folded proteins is the rule and not the exception. Local changes in the intracellular environment promote variation in protein folding. Hence protein folding requires "supervision" by a host of chaperones and co-chaperones that help their client proteins to achieve the folding that is most stable according to the local environment. Such environmental influence on protein folding is continuously transduced with the help of the cellular stress responses (CSRs) and this may lead to changes in the rules of engagement between proteins, so that the corresponding protein interactome could be modified by the environment leading to an alternative cellular phenotype. This allows for a phenotypic plasticity useful for adapting to sudden and/or transient environmental changes at the cellular level. Starting from this perspective, hereunder we develop the argument that the presence of sustained cellular stress coupled to efficient CSRs may lead to the selection of an aberrant phenotype as the resulting adaptation of the cellular proteome (and the corresponding interactome) to such stressful conditions, and this can be a common epigenetic pathway to cancer.

Evaluating the feasibility of using augmented reality for tooth preparation.

OBJECTIVES: Tooth preparation is complicated because it requires the preparation of an abutment while simultaneously predicting the ideal shape of the tooth. This study aimed to develop and evaluate a system using augmented reality (AR) head-mounted displays (HMDs) that provide dynamic navigation capabilities for tooth preparation. METHODS: The proposed system utilizes optical see-through HMDs to overlay digital information onto the real world and enrich the user's environment. By integrating tracking algorithms and three-dimensional modeling, the system provides real-time visualization and navigation capabilities during tooth preparation by using two different visualization techniques. The experimental setup involved a comprehensive analysis of the distance to the surface and cross-sectional angles between the ideal and prepared teeth using three scenarios: traditional (without AR), overlay (AR-assisted visualization of the ideal prepared tooth), and cross-sectional (AR-assisted visualization with cross-sectional views and angular displays). RESULTS: A user study (N = 24) revealed that the cross-sectional approach was more effective for angle adjustment and reduced the occurrence of over-reduction. Additional questionnaires revealed that the AR-assisted approaches were perceived as less difficult, with the cross-sectional approach excelling in terms of performance. CONCLUSIONS: Visualization and navigation using cross-sectional approaches have the potential to support safer tooth preparation with less overreduction than traditional and overlay approaches do. The angular displays provided by the cross-sectional approach are considered helpful for tooth preparation. CLINICAL SIGNIFICANCE: The AR navigation system can assist dentists during tooth preparation and has the potential to enhance the accuracy and safety of prosthodontic treatment.

Constraints on Neutrino Natal Kicks from Black-Hole Binary VFTS 243.

The recently reported observation of VFTS 243 is the first example of a massive black-hole binary system with negligible binary interaction following black-hole formation. The black-hole mass (≈10M_{⊙}) and near-circular orbit (e≈0.02) of VFTS 243 suggest that the progenitor star experienced complete collapse, with energy-momentum being lost predominantly through neutrinos. VFTS 243 enables us to constrain the natal kick and neutrino-emission asymmetry during black-hole formation. At 68% confidence level, the natal kick velocity (mass decrement) is ≲10 km/s (≲1.0M_{⊙}), with a full probability distribution that peaks when ≈0.3M_{⊙} were ejected, presumably in neutrinos, and the black hole experienced a natal kick of 4 km/s. The neutrino-emission asymmetry is ≲4%, with best fit values of ∼0-0.2%. Such a small neutrino natal kick accompanying black-hole formation is in agreement with theoretical predictions.

Wiring Between Close Nodes in Molecular Networks Evolves More Quickly Than Between Distant Nodes.

As species diverge, a wide range of evolutionary processes lead to changes in protein-protein interaction (PPI) networks and metabolic networks. The rate at which molecular networks evolve is an important question in evolutionary biology. Previous empirical work has focused on interactomes from model organisms to calculate rewiring rates, but this is limited by the relatively small number of species and sparse nature of network data across species. We present a proxy for variation in network topology: variation in drug-drug interactions (DDIs), obtained by studying drug combinations (DCs) across taxa. Here, we propose the rate at which DDIs change across species as an estimate of the rate at which the underlying molecular network changes as species diverge. We computed the evolutionary rates of DDIs using previously published data from a high-throughput study in gram-negative bacteria. Using phylogenetic comparative methods, we found that DDIs diverge rapidly over short evolutionary time periods, but that divergence saturates over longer time periods. In parallel, we mapped drugs with known targets in PPI and cofunctional networks. We found that the targets of synergistic DDIs are closer in these networks than other types of DCs and that synergistic interactions have a higher evolutionary rate, meaning that nodes that are closer evolve at a faster rate. Future studies of network evolution may use DC data to gain larger-scale perspectives on the details of network evolution within and between species.

Impact of Recombinant VSV-HIV Prime, DNA-Boost Vaccine Candidates on Immunogenicity and Viremia on SHIV-Infected Rhesus Macaques.

Currently, no effective vaccine to prevent human immunodeficiency virus (HIV) infection is available, and various platforms are being examined. The vesicular stomatitis virus (VSV) vaccine vehicle can induce robust humoral and cell-mediated immune responses, making it a suitable candidate for the development of an HIV vaccine. Here, we analyze the protective immunological impacts of recombinant VSV vaccine vectors that express chimeric HIV Envelope proteins (Env) in rhesus macaques. To improve the immunogenicity of these VSV-HIV Env vaccine candidates, we generated chimeric Envs containing the transmembrane and cytoplasmic tail of the simian immunodeficiency virus (SIV), which increases surface Env on the particle. Additionally, the Ebola virus glycoprotein was added to the VSV-HIV vaccine particles to divert tropism from CD4 T cells and enhance their replications both in vitro and in vivo. Animals were boosted with DNA constructs that encoded matching antigens. Vaccinated animals developed non-neutralizing antibody responses against both the HIV Env and the Ebola virus glycoprotein (EBOV GP) as well as systemic memory T-cell activation. However, these responses were not associated with observable protection against simian-HIV (SHIV) infection following repeated high-dose intra-rectal SHIV SF162p3 challenges.

Injectable Nanoengineered Adhesive Hydrogel for Treating Enterocutaneous Fistulas.

Enterocutaneous fistula (ECF) is a severe medical condition where an abnormal connection forms between the gastrointestinal tract and skin. ECFs are, in most cases, a result of surgical complications such as missed enterotomies or anastomotic leaks. The constant leakage of enteric and fecal contents from the fistula site leads to skin breakdown and increases the risk of infection. Despite advances in surgical techniques and postoperative management, ECF accounts for significant mortality rates, estimated between 15-20%, and causes debilitating morbidity. Therefore, there is a critical need for a simple and effective method to seal and heal ECF. Injectable hydrogels with combined properties of robust mechanical properties and cell infiltration/proliferation have the potential to block and heal ECF. Herein, we report the development of an injectable nanoengineered adhesive hydrogel (INAH) composed of a synthetic nanosilicate (Laponite®) and a gelatin-dopamine conjugate for treating ECF. The hydrogel undergoes fast cross-linking using a co-injection method, resulting in a matrix with improved mechanical and adhesive properties. INAH demonstrates appreciable blood clotting abilities and is cytocompatible with fibroblasts. The adhesive properties of the hydrogel are demonstrated in ex vivo adhesion models with skin and arteries, where the volume stability in the hydrated internal environment facilitates maintaining strong adhesion. In vivo assessments reveal that the INAH is biocompatible, supporting cell infiltration and extracellular matrix deposition while not forming fibrotic tissue. These findings suggest that this INAH holds promising translational potential for sealing and healing ECF.

Assessing Ecogeographic Rules in Two Sigmodontine Rodents along an Elevational Gradient in Central Chile.

Bergmann's and Allen's rules are two classic ecogeographic rules concerning the physiological mechanisms employed by endotherm vertebrates for heat conservation in cold environments, which correlate with adaptive morphological changes. Thus, larger body sizes (Bergmann's rule) and shorter appendages and limbs (Allen's rule) are expected in mammals inhabiting cold environments (higher latitudes). Both rules may also apply to elevational gradients, due to the decrease in external temperature as elevation increases. In this study, we evaluated whether these patterns were true in two coexisting sigmodontine rodents across an elevational gradient in central Chile. We analyzed whether the size of the skull, body, and appendages of Abrothrix olivacea (n = 70) and Phyllotis darwini (n = 58) correlated with elevation, as predicted by these rules in a range between 154 and 2560 m. Our data revealed weak support for the Bergmann and Allen predictions. Moreover, we observed opposite patterns when expectations of Bergmann's rules were evaluated, whereas Allen's rule just fitted for ear size in both rodent species. Our results suggest that morphological changes (cranial, body, and appendage sizes) may play a minor role in the thermoregulation of these two species at high elevations, although behavioral strategies could be more critical. Other ecological and environmental variables could explain the morphological trends observed in our study. These hypotheses should be assessed in future studies to consider the relative contribution of morphology, behavior, and physiological mechanisms to the thermal adaptation of these two rodent species at high elevations.

Autokinesis Reveals a Threshold for Perception of Visual Motion.

In natural viewing conditions, the brain can optimally integrate retinal and extraretinal signals to maintain a stable visual perception. These mechanisms, however, may fail in circumstances where extraction of a motion signal is less viable such as impoverished visual scenes. This can result in a phenomenon known as autokinesis in which one may experience apparent motion of a small visual stimulus in an otherwise completely dark environment. In this study, we examined the effect of autokinesis on visual perception of motion in human observers. We used a novel method with optical tracking in which the visual motion was reported manually by the observer. Experiment results show at lower speeds of motion, the perceived direction of motion was more aligned with the effect of autokinesis, whereas in the light or at higher speeds in the dark, it was more aligned with the actual direction of motion. These findings have important implications for understanding how the stability of visual representation in the brain can affect accurate perception of motion signals.

Gastric outlet obstruction due to an intragastric balloon in a patient returning from the Caribbean.

Key Clinical Message: Gastric outlet obstruction can be a dangerous complication of intragastric balloons, as it can result in severe metabolic alkalosis. As weight loss procedures and medical tourism become more popular, physicians should have a high index of suspicion for complications of invasive procedures, particularly in returning travelers. Abstract: Intragastric balloons for weight loss have decreased in frequency in the United States. However, they are still frequent in low- and middle-income countries. Severe complications occur in less than 3% of patients who undergo this procedure. Herein, we present a case of gastric outlet obstruction, severe metabolic alkalosis, and refeeding syndrome in a patient returning from the Dominican Republic. She presented with 2 weeks of emesis and obstipation, followed by a pre-syncope and altered mental status. An intragastric mass was observed on computerized tomography, which was characterized as an intragastric balloon and retrieved endoscopically. All metabolic derangements were corrected, and the patient improved without sequelae. As weight loss procedures and medical tourism become more popular, physicians should have a high index of suspicion for complications of invasive procedures, particularly in returning travelers.

Outcomes after surgical revascularization in diabetic patients.

OBJECTIVES: Patients with diabetes mellitus (DM) undergoing coronary artery bypass grafting (CABG) have been repeatedly demonstrated to have worse clinical outcomes compared to patients without DM. The objective of this study was to evaluate the impact of DM on 1-year clinical outcomes after isolated CABG. METHODS: The European DuraGraft registry included 1130 patients (44.6%) with and 1402 (55.4%) patients without DM undergoing isolated CABG. Intra-operatively, all free venous and arterial grafts were treated with an endothelial damage inhibitor. Primary end point in this analysis was the incidence of a major adverse cardiac event (MACE), a composite of all-cause death, repeat revascularization or myocardial infarction at 1 year post-CABG. To balance between differences in baseline characteristics (n = 1072 patients in each group), propensity score matching was used. Multivariable Cox proportional hazards regression was performed to identify independent predictors of MACE. RESULTS: Diabetic patients had a higher cardiovascular risk profile and EuroSCORE II with overall more comorbidities. Patients were comparable in regard to surgical techniques and completeness of revascularization. At 1 year, diabetics had a higher MACE rate {7.9% vs 5.5%, hazard ratio (HR) 1.43 [95% confidence interval (CI) 1.05-1.95], P = 0.02}, driven by increased rates of death [5.6% vs 3.5%, HR 1.61 (95% CI 1.10-2.36), P = 0.01] and myocardial infarction [2.8% vs 1.4%, HR 1.99 (95% CI 1.12-3.53) P = 0.02]. Following propensity matching, no statistically significant difference was found for MACE [7.1% vs 5.7%, HR 1.23 (95% CI 0.87-1.74) P = 0.23] or its components. Age, critical operative state, extracardiac arteriopathy, ejection fraction ≤50% and left main disease but not DM were identified as independent predictors for MACE. CONCLUSIONS: In this study, 1-year outcomes in diabetics undergoing isolated CABG were comparable to patients without DM.

Anti-Citrullinated Protein Antibodies With Multiple Specificities Ameliorate Collagen Antibody-Induced Arthritis in a Time-Dependent Manner.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs. METHODS: We expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme-linked immunosorbent assays. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n = 9) were tested in the collagen antibody-induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation. RESULTS: Recombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto-cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype-matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model. CONCLUSION: Recombinant patient-derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis.

Amphotericin B-loaded natural latex dressing for treating Candida albicans wound infections using Galleria mellonella model.

Amphotericin B (AmB) is the gold standard for antifungal drugs. However, AmB systemic administration is restricted because of its side effects. Here, we report AmB loaded in natural rubber latex (NRL), a sustained delivery system with low toxicity, which stimulates angiogenesis, cell adhesion and accelerates wound healing. Physicochemical characterizations showed that AmB did not bind chemically to the polymeric matrix. Electronic and topographical images showed small crystalline aggregates from AmB crystals on the polymer surface. About 56.6% of AmB was released by the NRL in 120 h. However, 33.6% of this antifungal was delivered in the first 24 h due to the presence of AmB on the polymer surface. The biomaterial's excellent hemo- and cytocompatibility with erythrocytes and human dermal fibroblasts (HDF) confirmed its safety for dermal wound application. Antifungal assay against Candida albicans showed that AmB-NRL presented a dose-dependent behavior with an inhibition halo of 30.0 ± 1.0 mm. Galleria mellonella was employed as an in vivo model for C. albicans infection. Survival rates of 60% were observed following the injection of AmB (0.5 mg.mL-1) in G. mellonella larvae infected by C. albicans. Likewise, AmB-NRL (0.5 mg.mL-1) presented survival rates of 40%, inferring antifungal activity against fungus. Thus, NRL adequately acts as an AmB-sustained release matrix, which is an exciting approach, since this antifungal is toxic at high concentrations. Our findings suggest that AmB-NRL is an efficient, safe, and reasonably priced ($0.15) dressing for the treatment of cutaneous fungal infections.

Interatrial Septum Stenting for Hypoplastic Left Heart Syndrome in Ex Utero Intrapartum Therapy.

Patients with hypoplastic left heart syndrome (HLHS) with intact atrial septum have an increased mortality rate. This presentation occurs in 6% to 10% of cases. We present a patient with fetal diagnosis of HLHS with restrictive atrial septum. We performed a cesarean section at 37 weeks of gestation, and under ex utero intrapartum treatment proceeded with a median sternotomy and transatrial stenting for left atrial decompression due to findings of intact atrial septum on the fetal echocardiogram performed during the procedure. Subsequently, the patient underwent hybrid stage I palliation followed by a comprehensive stage II procedure at five months of age, but unfortunately died from postoperative complications.