Neutrophil extracellular traps promote immunopathogenesis of virus-induced COPD exacerbations.

Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.

The Wiser Strategy of Using Beta-Agonists in Asthma: Mechanisms and Rationales.

Concerns regarding the safety of beta-2 agonists have led to revisions of the major asthma guidelines to better address these issues. Although these updates allow for a combination of previous and current strategies, they may confuse clinical practitioners. Beta-2 agonists are vital for alleviating asthma symptoms by relaxing smooth muscles; however, they also pose significant risks by inducing pro-inflammatory mediators both in vitro and in vivo. In addition to the risks of overuse and symptom masking, the use of beta-agonists alone at therapeutic doses can worsen airway inflammation and enhance virus-induced inflammation during asthma exacerbation. Inhaled corticosteroids (ICS) can effectively prevent these adverse effects. With new insights into the mechanisms of these adverse events, reserving short-acting beta-agonists for acute symptom relief during exacerbations and only for those who are already on ICS or oral steroids represents a careful approach to using beta-agonists with least adverse effects in patients with asthma. However, a major drawback of this approach is the potential non-compliance with ICS, leading to beta-agonist use without the necessary counteraction by ICS. An optimal strategy, both during and outside exacerbations, would integrate beta-agonists into an anti-inflammatory regimen that includes ICS, ideally combined with the same inhaler to ensure their concurrent use where finances allow. This would maintain the beneficial effects of beta-agonists, such as bronchodilation, while preventing the adverse effects from the induction of inflammatory mediators. This method is aligned with diverse clinical settings, maximizes the safe use of beta-agonists, and supports a comprehensive guideline-compliant management strategy.

Beyond the Situation: Hanging Out with Peers now is Associated with Short-Term Mindsets Later.

It is well-established that unstructured unsupervised socializing with peers (UUS) motivates deviance while in that specific context. In this article, we extend this situational view by arguing that repeated UUS may also gradually shape adolescents' norms and decision making beyond the situation. Specifically, we argue that UUS promotes short-term mindsets, i.e., an increased focus on present rewards at the expense of considering future consequences. We test this hypothesis with fixed-effects models, using longitudinal data from a representative sample of 1,675 adolescents from Zurich, Switzerland. Consistent with our preregistered predictions, more frequent UUS is associated with increased short-term mindsets. Thus, our finding suggests that the effects of UUS on later deviance might be driven by becoming more present-oriented. This link offers new insights into the developmental pathways toward adolescent delinquency and offers a potential target for intervention. Supplementary Information: The online version contains supplementary material available at 10.1007/s40865-024-00249-2.

High-cell-density fed-batch strategy to manufacture tailor-made P(HB-co-HHx) by engineered Ralstonia eutropha at laboratory scale and pilot scale.

The transition towards a sustainable bioeconomy requires the development of highly efficient bioprocesses that enable the production of bulk materials at a competitive price. This is particularly crucial for driving the commercialization of polyhydroxyalkanoates (PHAs) as biobased and biodegradable plastic substitutes. Among these, the copolymer poly(hydroxybutyrate-co-hydroxyhexanoate) (P(HB-co-HHx)) shows excellent material properties that can be tuned by regulating its monomer composition. In this study, we developed a high-cell-density fed-batch strategy using mixtures of fructose and canola oil to modulate the molar composition of P(HB-co-HHx) produced by Ralstonia eutropha Re2058/pCB113 at 1-L laboratory scale up to 150-L pilot scale. With cell densities >100 g L-1 containing 70-80 wt% of PHA with tunable HHx contents in the range of 9.0-14.6 mol% and productivities of up to 1.5 g L-1 h-1, we demonstrate the tailor-made production of P(HB-co-HHx) at an industrially relevant scale. Ultimately, this strategy enables the production of PHA bioplastics with defined material properties on the kilogram scale, which is often required for testing and adapting manufacturing processes to target diverse applications.

Real-world performance of Uromonitor® in urothelial bladder cancer detection: a multicentric trial.

OBJECTIVES: To compare Uromonitor® (U-Monitor Lda, Porto, Portugal), a multitarget DNA assay that detects mutated proto-oncogenes (telomerase reverse transcriptase [TERT], fibroblast growth factor receptor 3 [FGFR-3], Kirsten rat sarcoma viral oncogene homologue [KRAS]), with urine cytology in the urine-based diagnosis of urothelial carcinoma of the bladder (UCB) within a multicentre real-world setting. PATIENTS AND METHODS: This multicentre, prospective, double-blind study was conducted across four German urological centres from 2019 to 2024. We evaluated the diagnostic performance of Uromonitor compared to urine cytology in a cohort of patients with UCB and in healthy controls within a real-world setting. Sensitivity, specificity, positive-predictive value (PPV), negative-predictive value (NPV), and accuracy of the tests were measured, in addition to multivariate analyses to assess the ability of individual proto-oncogene mutations in detecting UCB. The biometric sample size was designed to achieve a 10% difference in sensitivity. RESULTS: Patients with UCB comprised 63.7% (339/532) of the study group. Uromonitor showed a sensitivity, specificity, PPV, NPV, accuracy, and an area-under-the-curve of 49.3%, 93.3%, 92.8%, 51.1%, 65.2%, and 0.713%, respectively. These metrics did not demonstrate statistical superiority over urine cytology in terms of sensitivity (44.6%; P = 0.316). Moreover, the comparison of additional test parameters, as well as the comparison within various sensitivity analyses, yielded no significant disparity between the two urinary tests. Multivariate logistic regression underscored the significant predictive value of a positive Uromonitor for detecting UCB (odds ratio [OR] 9.03; P < 0.001). Furthermore, mutations in TERT and FGFR-3 were independently associated with high odds of UCB detection (OR 13.30 and 7.04, respectively), while KRAS mutations did not exhibit predictive capability. CONCLUSION: Despite its innovative approach, Uromonitor fell short of confirming the superior results anticipated from previous studies in this real-world setting. The search for an optimal urine-based biomarker for detecting and monitoring UCB remains ongoing. Results from this study highlight the complexity of developing non-invasive diagnostic tools and emphasise the importance of continued research efforts to refine these technologies.

Quantifying NOx point sources with Landsat and Sentinel-2 satellite observations of NO2 plumes.

We show that the Landsat and Sentinel-2 satellites can detect NO2 plumes from large point sources at 10 to 60 m pixel resolution in their blue and ultrablue bands. We use the resulting NO2 plume imagery to quantify nitrogen oxides (NOx) emission rates for several power plants in Saudi Arabia and the United States, including a 13-y analysis of 132 Landsat plumes from Riyadh power plant 9 from 2009 through 2021. NO2 in the plumes initially increases with distance from the source, likely reflecting recovery from ozone titration. The fine pixel resolutions of Landsat and Sentinel-2 enable separation of individual point sources and stacks, including in urban background, and the long records enable examination of multidecadal emission trends. Our inferred NOx emission rates are consistent with previous estimates to within a precision of about 30%. Sources down to ~500 kg h-1 can be detected over bright, quasi-homogeneous surfaces. The 2009 to 2021 data for Riyadh power plant 9 show a strong summer peak in emissions, consistent with increased power demand for air conditioning, and a marginal slow decrease following the introduction of Saudi Arabia's Ambient Air Standard 2012.

A comparison of two versus five epineural sutures to achieve successful polyethylene glycol (PEG) nerve fusion in a rat sciatic nerve repair model.

Background: We compared rates of successful polyethylene glycol (PEG) nerve fusion between two epineural suture repairs (2SR) and five epineural suture repairs (5SR) in a rat sciatic nerve transection neurorrhaphy model. We hypothesise that the two and five epineural neural suture repair groups will achieve a similar rate of PEG fusion. Methods: Twenty-five Lewis rats underwent bilateral sciatic nerve transection. Primary neurorrhaphy (PN) consisting of 2SR in one hind limb and 5SR in the contralateral hind limb was performed utilizing PEG fusion. Successful PEG fusion was confirmed by a distal muscle twitch after nerve stimulation proximal to the nerve fusion site. Sciatic nerve conduction velocity (SNCV) across the repair site and the force generated by tibialis anterior muscle (TAM) contraction were also compared between the 2SR and 5SR groups. Results: Success rates were 100% for the 2SR and the 5SR groups. No statistically significant differences in SNCV (P = 0.444) or isometric tetanic TAM contractile force (P = 0.820) were observed between 2SR and 5SR in the setting of PEG fusion. Conclusion: These findings demonstrate no significant difference in successful PEG fusion between the 2SR and 5SR groups. In addition, the findings demonstrate no statistically significant differences in SNCV or isometric tetanic TAM contractile force following sciatic nerve transection when performing a 2SR or 5SR PN in the setting of PEG fusion. Successful PEG fusion can be achieved acutely with either a two or five-epineural suture repair in a rat model.

Echinacea Reduces Antibiotics by Preventing Respiratory Infections: A Meta-Analysis (ERA-PRIMA).

Respiratory tract infections (RTIs) are the leading cause of antibiotic prescriptions, primarily due to the risk for secondary bacterial infections. In this study, we examined whether Echinacea could reduce the need for antibiotics by preventing RTIs and their complications, and subsequently investigated its safety profile. A comprehensive search of EMBASE, PubMed, Google Scholar, Cochrane DARE and clinicaltrials.gov identified 30 clinical trials (39 comparisons) studying Echinacea for the prevention or treatment of RTIs in 5652 subjects. Echinacea significantly reduced the monthly RTI occurrence, risk ratio (RR) 0.68 (95% CI 0.61-0.77) and number of patients with ≥1 RTI, RR = 0.75 [95% CI 0.69-0.81] corresponding to an odds ratio 0.53 [95% CI 0.42-0.67]. Echinacea reduced the risk of recurrent infections (RR = 0.60; 95% CI 0.46-0.80), RTI complications (RR = 0.44; 95% CI 0.36-0.54) and the need for antibiotic therapy (RR = 0.60; 95% CI 0.39-0.93), with total antibiotic therapy days reduced by 70% (IRR = 0.29; 95% CI 0.11-0.74). Alcoholic extracts from freshly harvested Echinacea purpurea were the strongest, with an 80% reduction of antibiotic treatment days, IRR 0.21 [95% CI 0.15-0.28]. An equal number of adverse events occurred with Echinacea and control treatment. Echinacea can safely prevent RTIs and associated complications, thereby decreasing the demand for antibiotics. Relevant differences exist between Echinacea preparations.

Post-COVID-19 Neurological Sequelae of Polyneuropathy and Encephalitis: A Comprehensive Case Report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, commonly known as COVID-19, has been associated with various neurological complications. However, the mechanisms underlying these neurological manifestations remain incompletely understood. We present a case of a 63-year-old male who was admitted to the intensive care unit with severe COVID-19 pneumonia. Following recovery from respiratory symptoms, he was found to have weakness in the limbs. Months later, he also developed altered mental status, hallucinations, and behavioral changes. Neurological examination revealed signs consistent with polyneuropathy and autoimmune encephalitis. Further investigations, including nerve conduction studies, cerebrospinal fluid analysis, and response to steroids, supported the diagnosis of COVID-19-related polyneuropathy and autoimmune encephalitis. This is a rare presentation of COVID-19 and has only been described in a few case reports. Further research is warranted to elucidate the pathophysiological mechanisms underlying neurological sequelae of COVID-19 and to develop targeted therapeutic strategies.

Transplant nephrectomy: indication, surgical approach and complications-experiences from a single transplantation center.

PURPOSE: Management of a failed kidney allograft, and the question whether it should be removed is a challenging task for clinicians. The reported risks for transplant nephrectomy (TN) vary, and there is no clear recommendation on indications or surgical approach that should be used. This study gives an overview of indications, compares surgical techniques, and identifies risk factors for higher morbidity. METHODS: Retrospective analysis was conducted on all transplant nephrectomies performed between 2005 and 2020 at Charité Hospital Berlin, Department of Urology. Patient demographics, laboratory parameters, graft survival data, indication for TN, and surgical complications were extracted from medical reports. RESULTS: A total of 195 TN were performed, with graft intolerance syndrome being the most common indication in 52 patients (26.7%), acute rejection in 36 (18.5%), acute infection in 30 (15.4%), and other reasons to stop immunosuppression in 26 patients (13.3%). Rare indications were vascular complications in 16 (8.2%) and malignancies in the allograft in six (3.1%) cases. Extracapsular surgical approach was significantly more often used in cases of vascular complications and earlier allograft removal, but there was no difference in complication rates between extra- and intracapsular approach. Acute infection was identified as an independent risk factor for a complication grade IIIb or higher according to Clavien-Dindo classification, with a HR of 12.3 (CI 2.2-67.7; p = 0.004). CONCLUSION: Transplant nephrectomy should only be performed when there is a good indication, and non-elective surgery should be avoided, when possible, as it increases morbidity.

Synthesis and Photopatterning of Synthetic Thiol-Norbornene Hydrogels.

Hydrogels are a class of soft biomaterials and the material of choice for a myriad of biomedical applications due to their biocompatibility and highly tunable mechanical and biochemical properties. Specifically, light-mediated thiol-norbornene click reactions between norbornene-modified macromers and di-thiolated crosslinkers can be used to form base hydrogels amenable to spatial biochemical modifications via subsequent light reactions between pendant norbornenes in the hydrogel network and thiolated peptides. Macromers derived from natural sources (e.g., hyaluronic acid, gelatin, alginate) can cause off-target cell signaling, and this has motivated the use of synthetic macromers such as poly(ethylene glycol) (PEG). In this study, commercially available 8-arm norbornene-modified PEG (PEG-Nor) macromers were reacted with di-thiolated crosslinkers (dithiothreitol, DTT) to form synthetic hydrogels. By varying the PEG-Nor weight percent or DTT concentration, hydrogels with a stiffness range of 3.3 kPa-31.3 kPa were formed. Pendant norbornene groups in these hydrogels were used for secondary reactions to either increase hydrogel stiffness (by reacting with DTT) or to tether mono-thiolated peptides to the hydrogel network. Peptide functionalization has no effect on bulk hydrogel mechanics, and this confirms that mechanical and biochemical signals can be independently controlled. Using photomasks, thiolated peptides can also be photopatterned onto base hydrogels, and mesenchymal stem cells (MSCs) attach and spread on RGD-functionalized PEG-Nor hydrogels. MSCs encapsulated in PEG-Nor hydrogels are also highly viable, demonstrating the ability of this platform to form biocompatible hydrogels for 2D and 3D cell culture with user-defined mechanical and biochemical properties.

Evaluation of Antibiotic Biodegradation by a Versatile and Highly Active Recombinant Laccase from the Thermoalkaliphilic Bacterium Bacillus sp. FNT.

Laccases are industrially relevant enzymes that have gained great biotechnological importance. To date, most are of fungal and mesophilic origin; however, enzymes from extremophiles possess an even greater potential to withstand industrial conditions. In this study, we evaluate the potential of a recombinant spore-coat laccase from the thermoalkaliphilic bacterium Bacillus sp. FNT (FNTL) to biodegrade antibiotics from the tetracycline, ß-lactams, and fluoroquinolone families. This extremozyme was previously characterized as being thermostable and highly active in a wide range of temperatures (20-90 °C) and very versatile towards several structurally different substrates, including recalcitrant environmental pollutants such as PAHs and synthetic dyes. First, molecular docking analyses were employed for initial ligand affinity screening in the modeled active site of FNTL. Then, the in silico findings were experimentally tested with four highly consumed antibiotics, representatives of each family: tetracycline, oxytetracycline, amoxicillin, and ciprofloxacin. HPLC results indicate that FNTL with help of the natural redox mediator acetosyringone, can efficiently biodegrade 91, 90, and 82% of tetracycline (0.5 mg mL-1) in 24 h at 40, 30, and 20 °C, respectively, with no apparent ecotoxicity of the products on E. coli and B. subtilis. These results complement our previous studies, highlighting the potential of this extremozyme for application in wastewater bioremediation.

Association between polymorphisms on chromosome 17q12-q21 and rhinovirus-induced interferon responses.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes on chromosome 17q12-q21 are associated with childhood-onset asthma and rhinovirus-induced wheeze. There are few mechanistic data linking chromosome 17q12-q21 to wheezing illness. OBJECTIVE: We investigated whether 17q12-q21 risk alleles were associated with impaired interferon responses to rhinovirus. METHODS: In a population-based birth cohort of European ancestry, we stimulated peripheral blood mononuclear cells with rhinovirus A1 (RV-A1) and rhinovirus A16 (RV-A16) and measured IFN and IFN-induced C-X-C motif chemokine ligand 10 (aka IP10) responses in supernatants. We investigated associations between virus-induced cytokines and 6 SNPs in 17q12-q21. Bayesian profile regression was applied to identify clusters of individuals with different immune response profiles and genetic variants. RESULTS: Five SNPs (in high linkage disequilibrium, r2 ≥ 0.8) were significantly associated with RV-A1-induced IFN-ß (rs9303277, P = .010; rs11557467, P = .012; rs2290400, P = .006; rs7216389, P = .008; rs8079416, P = .005). A reduction in RV-A1-induced IFN-ß was observed among individuals with asthma risk alleles. There were no significant associations for RV-A1-induced IFN-α or CXCL10, or for any RV-A16-induced IFN/CXCL10. Bayesian profile regression analysis identified 3 clusters that differed in IFN-ß induction to RV-A1 (low, medium, high). The typical genetic profile of the cluster associated with low RV-A1-induced IFN-ß responses was characterized by a very high probability of being homozygous for the asthma risk allele for all SNPs. Children with persistent wheeze were almost 3 times more likely to be in clusters with reduced/average RV-A1-induced IFN-ß responses than in the high immune response cluster. CONCLUSIONS: Polymorphisms on chromosome 17q12-q21 are associated with rhinovirus-induced IFN-ß, suggesting a novel mechanism-impaired IFN-ß induction-links 17q12-q21 risk alleles with asthma/wheeze.

Revealing Early Spatial Patterns of Cellular Responsivity in Fiber-Reinforced Microenvironments.

Fiber-reinforcement approaches have been used to replace aligned tissues with engineered constructs after injury or surgical resection, strengthening soft biomaterial scaffolds and replicating anisotropic, load-bearing properties. However, most studies focus on the macroscale aspects of these scaffolds, rarely considering the cell-biomaterial interactions that govern remodeling and extracellular matrix organization toward aligned neo-tissues. As initial cell-biomaterial responses within fiber-reinforced microenvironments likely influence the long-term efficacy of repair and regeneration strategies, here we elucidate the roles of spatial orientation, substrate stiffness, and matrix remodeling on early cell-fiber interactions. Bovine mesenchymal stromal cells (MSCs) were cultured in soft fibrin gels reinforced with a stiff 100 µm polyglycolide-co-caprolactone fiber. Gel stiffness and remodeling capacity were modulated by fibrinogen concentration and aprotinin treatment, respectively. MSCs were imaged at 3 days and evaluated for morphology, mechanoresponsiveness (nuclear Yes-associated protein [YAP] localization), and spatial features including distance and angle deviation from fiber. Within these constructs, morphological conformity decreased as a function of distance from fiber. However, these correlations were weak (R2 = 0.01043 for conformity and R2 = 0.05542 for nuclear YAP localization), illustrating cellular heterogeneity within fiber-enforced microenvironments. To better assess cell-fiber interactions, we applied machine-learning strategies to our heterogeneous dataset of cell-shape and mechanoresponsive parameters. Principal component analysis (PCA) was used to project 23 input parameters (not including distance) onto 5 principal components (PCs), followed by agglomerative hierarchical clustering to classify cells into 3 groups. These clusters exhibited distinct levels of morpho-mechanoresponse (combination of morphological conformity and YAP signaling) and were classified as high response (HR), medium response (MR), and low response (LR) clusters. Cluster distribution varied spatially, with most cells (61%) closest to the fiber (0-75 µm) belonging to the HR cluster, and most cells (55%) furthest from the fiber (225-300 µm) belonging to the LR cluster. Modulation of gel stiffness and fibrin remodeling showed differential effects for HR cells, with stiffness influencing the level of mechanoresponse and remodeling capacity influencing the location of responding cells. Together, these novel findings demonstrate early trends in cellular patterning of the fiber-reinforced microenvironment, showing how spatial orientation, substrate biophysical properties, and matrix remodeling may guide the amplitude and localization of cellular mechanoresponses. These trends may guide approaches to optimize the design of microscale scaffold architecture and substrate properties for enhancing organized tissue assembly at the macroscale.

Monitorización del grado de satisfacción tras intervención nutricional en pacientes con cáncer / Monitoring satisfaction level after nutritional intervention in cancer patients

Introducción: La identificación temprana de la angustiapsicosocial y el impacto de la caquexia permiten intervencio-nes oportunas para mejorar los síntomas.Los PREM (Patient-Reported Experience Measures) aportanvalor a pacientes y organizaciones sanitarias. El poder real delos mismos se encuentra en la posibilidad de cruzarlos con da-tos clínicos. Esto permite identificar puntos críticos y áreas demejora de la calidad asistencial de los procesos. La intervención nutricional en pacientes seleccionadosbrinda un beneficio significativo para algunos aspectos comoel funcionamiento emocional, la disnea, la pérdida de apetitoy el estado de salud global.Por ello, se propone evaluar el grado de satisfacción de lospacientes en los que se ha realizado una intervención nutri-cional durante el tratamiento oncológico activo.Metodología: Estudio retrospectivo, exploratorio, delgrado de satisfacción, en referencia a la intervención nutricio-nal, en pacientes tratados por cáncer en el Hospital de Día deOncología del hospital Universitario Doctor Peset de Valencia,entre enero de 2022 y enero de 2023. Resultados: Se incluyeron un total de 93 pacientes. Seelaboró un cuestionario de 15 preguntas que se ofreció a los50 últimos pacientes incluidos. Respondieron de forma volun-taria y anónima 28 (56%). En el 95% de los casos la inter-vención nutricional se valoró de forma satisfactoria.Conclusiones: La identificación temprana de la desnutri-ción y la intervención oportuna tienen un impacto favorableen el grado de satisfacción del paciente.(AU)

Introduction: Early identification of psychosocial distressand the impact of cachexia allows for timely interventions toimprove symptoms. Patient-Reported Experience Measures(PREMs) add value to patients and healthcare organizations.Their true power lies in the ability to cross-reference themwith clinical data. This enables the identification of criticalpoints and areas for improving the quality of care processes.Nutritional intervention in selected cancer patients providessignificant benefits for aspects such as emotional functioning,dyspnea, loss of appetite, and overall health status. Therefore, we propose to evaluate the satisfaction level ofpatients who have undergone nutritional intervention duringactive oncological treatment. Methodology: Retrospective exploratory study of satisfac-tion levels regarding nutritional intervention in cancer patientstreated at the Oncology Day Hospital of the UniversityHospital Doctor Peset in Valencia, between January 2022 andJanuary 2023.Results: A total of 93 patients were included. A question-naire consisting of 15 questions was developed and offered tothe last 50 included patients. Twenty-eight (56%) respondedvoluntarily and anonymously. In 95% of cases, nutritional in-tervention was evaluated satisfactorily.Conclusions: Early identification of malnutrition andtimely intervention have a favorable impact on patient satis-faction levels.(AU)

Engineering transcriptional regulation for cell-based therapies.

A major aim in the field of synthetic biology is developing tools capable of responding to user-defined inputs by activating therapeutically relevant cellular functions. Gene transcription and regulation in response to external stimuli are some of the most powerful and versatile of these cellular functions being explored. Motivated by the success of chimeric antigen receptor (CAR) T-cell therapies, transmembrane receptor-based platforms have been embraced for their ability to sense extracellular ligands and to subsequently activate intracellular signal transduction. The integration of transmembrane receptors with transcriptional activation platforms has not yet achieved its full potential. Transient expression of plasmid DNA is often used to explore gene regulation platforms in vitro. However, applications capable of targeting therapeutically relevant endogenous or stably integrated genes are more clinically relevant. Gene regulation may allow for engineered cells to traffic into tissues of interest and secrete functional proteins into the extracellular space or to differentiate into functional cells. Transmembrane receptors that regulate transcription have the potential to revolutionize cell therapies in a myriad of applications, including cancer treatment and regenerative medicine. In this review, we will examine current engineering approaches to control transcription in mammalian cells with an emphasis on systems that can be selectively activated in response to extracellular signals. We will also speculate on the potential therapeutic applications of these technologies and examine promising approaches to expand their capabilities and tighten the control of gene regulation in cellular therapies.

Mesenchymal stem cells enhance targeted bone growth from injectable hydrogels with BMP-2 peptides.

Osteoporosis is the most common chronic metabolic bone disease, and the prevalence of osteoporotic fractures is rapidly increasing with the aging population. While bisphosphonates can reduce bone loss and risk of fracture, these drugs are systemic, rely on long-term use, and patient compliance is low. Recombinant human bone morphogenetic protein-2 (BMP-2) is an FDA-approved protein that can offer a more targeted therapeutic than systemic treatments. DWIVA is a peptide sequence corresponding to the wrist epitope of BMP-2, and DWIVA-functionalized hydrogels feature osteoinductive propertiesin vitro and in vivo. This study reports that self-forming DWIVA-functionalized hydrogels injected into the intramedullary canal of rat femurs induce a local increase in trabecular bone in as little as 2 weeks. Increases in bone volume, trabecular thickness, and trabeculae count from DWIVA-laden hydrogels persist for at least 4 weeks, and the inclusion of mesenchymal stem cells (MSCs) significantly enhances the development of mineralized bone. Histological analysis of decalcified femurs also shows that hydrogel injections containing DWIVA peptide and MSCs stimulate unmineralized bone tissue formation and induce an increased count of osteoblasts and osteoclasts at the injection site after 4 weeks. Overall, the MSC-laden DWIVA peptide-functionalized hydrogels presented rapidly induce targeted bone formation and have the potential to form nascent bone within bones in jeopardy of an osteoporotic fracture such as the femur.

Microbially synthesized poly(hydroxybutyrate-co-hydroxyhexanoate) with low to moderate hydroxyhexanoate content: Properties and applications.

Plastic pollution is the biggest environmental concern of our time. Breakdown products like micro- and nano-plastics inevitably enter the food chain and pose unprecedented health risks. In this scenario, bio-based and biodegradable plastic alternatives have been given a momentum aiming to bridge a transition towards a more sustainable future. Polyhydroxyalkanoates (PHAs) are one of the few thermoplastic polymers synthesized 100 % via biotechnological routes which fully biodegrade in common natural environments. Poly(hydroxybutyrate-co-hydroxyhexanoate) [P(HB-co-HHx)] is a PHA copolymer with great potential for the commodity polymers industry, as its mechanical properties can be tailored through fine-tuning of its molar HHx content. We have recently developed a strategy that enables for reliable tailoring of the monomer content of P(HB-co-HHx). Nevertheless, there is often a lack of comprehensive investigation of the material properties of PHAs to evaluate whether they actually mimic the functionalities of conventional plastics. We present a detailed study of P(HB-co-HHx) copolymers with low to moderate hydroxyhexanoate content to understand how the HHx monomer content influences the thermal and mechanical properties and to link those to their abiotic degradation. By increasing the HHx fractions in the range of 2 - 14 mol%, we impart an extension of the processing window and application range as the melting temperature (Tm) and glass temperature (Tg) of the copolymers decrease from Tm 165 °C to 126 °C, Tg 4 °C to -5.9 °C, accompanied by reduced crystallinity from 54 % to 20 %. Elongation at break was increased from 5.7 % up to 703 % at 14 mol% HHx content, confirming that the range examined was sufficiently large to obtain ductile and brittle copolymers, while tensile strength was maintained throughout the studied range. Finally, accelerated abiotic degradation was shown to be slowed down with an increasing HHx fraction decreasing from 70 % to 55 % in 12 h.