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An expanding body of research asserts that the gut microbiota has a role in bone metabolism and the pathogenesis of osteoporosis. This review considers the human gut microbiota composition and its role in osteoclastogenesis and the bone healing process, specifically in the case of osteoporosis. Although the natural physiologic processes of bone healing and the pathogenesis of osteoporosis and bone disease are now relatively well known, recent literature suggests that a healthy microbiome is tied to bone homeostasis. Nevertheless, the mechanism underlying this connection is still somewhat enigmatic. Based on the literature, a relationship between the microbiome, osteoblasts, osteoclasts, and receptor activator of nuclear factor-kappa-Β ligand (RANKL) is contemplated and explored in this review. Studies have proposed various mechanisms of gut microbiome interaction with osteoclastogenesis and bone health, including micro-RNA, insulin-like growth factor 1, and immune system mediation. However, alterations to the gut microbiome secondary to pharmaceutical and surgical interventions cannot be discounted and are discussed in the context of clinical therapeutic consideration. The literature on probiotics and their mechanisms of action is examined in the context of bone healing. The known and hypothesized interactions of common osteoporosis drugs and the human gut microbiome are examined. Since dysbiosis in the gut microbiota can function as a biomarker of bone metabolic activity, it may also be a pharmacological and nutraceutical (i.e., pre- and probiotics) therapeutic target to promote bone homeostasis.

The emergence of COVID-19 virus has led to a pandemic with staggering morbidity and mortality. There is evidence showing that pre-existing conditions and environmental factors are associated with worse COVID-19 outcomes. Among these conditions, altitude is of particular interest. Altitude has been shown to influence the morbidity and mortality of multiple chronic pathologies such as cardiovascular disease, chronic obstructive pulmonary disease and lung cancer. COVID-19 fatality rate has been associated with as altitude as well, but findings are disputed. Therefore, we revisit this assessment with a comprehensive analysis of the relationship between COVID-19 fatality rates and altitude for the Mountain region of the United States while considering the effect of additional comorbidities and sociodemographic factors. A Generalized Additive Model (GAM) approach using one year of county data adjusted by population density was performed to evaluate associations within states and for the whole region. Our analysis revealed a consistent effect where COVID-19 case-fatality rate is decreased with higher altitude, even when controlling for pre-existing conditions and certain demographic variables. In summary, the work presented provides evidence that suggests that the protective effects of high altitude are likely to be influenced by physiologic factors but demographic trends that are associated with life at high altitude must also be considered.

Clostridium novyi has demonstrated selective efficacy against solid tumors largely due to the microenvironment contained within dense tumor cores. The core of a solid tumor is typically hypoxic, acidic, and necrotic—impeding the penetration of current therapeutics. C . novyi is attracted to the tumor microenvironment and once there, can both lyse and proliferate while simultaneously re-activating the suppressed immune system. C . novyi systemic toxicity is easily mitigated by knocking out the phage DNA plasmid encoded alpha toxin resulting in C . novyi -NT; but, after intravenous injection spores are quickly cleared by phagocytosis before accomplishing significant tumor localization. C . novyi -NT could be designed to accomplish intravenous delivery with the potential to target all solid tumors and their metastases in a single dose. This study characterizes CRISPR/Cas9 modified C . novyi- NT to insert the gene for RGD, a tumor targeting peptide, expressed within the promoter region of a spore coat protein. Expression of the RGD peptide on the outer spore coat of C . novyi- NT indicates an increased capacity for tumor localization of C . novyi upon intravenous introduction based on the natural binding of RGD with the α v β 3 integrin commonly overexpressed on the epithelial tissue surrounding a tumor, and lead to immune stimulation.

Nearly 1.3 million total joint replacement procedures are performed in the United States annually, with numbers projected to rise exponentially in the coming decades. Although finite infection rates for these procedures remain consistently low, device-related infections represent a significant cause of implant failure, requiring secondary or revision procedures. Revision procedures manifest several-fold higher infection recurrence rates. Importantly, many revision surgeries, infected or not, require bone void fillers to support the host bone and provide a sufficient tissue bed for new hardware placement. Antibiotic-eluting bone void fillers (ABVF), providing both osteoconductive and antimicrobial properties, represent one approach for reducing rates of orthopedic device-related infections. Using a solvent-free, molten-cast process, a polymer-controlled antibiotic-eluting calcium carbonate hydroxyapatite (HAP) ceramic composite BVF (ABVF) was fabricated, characterized, and evaluated in vivo using a bacterial challenge in a rabbit radial defect window model. ABVF loaded with tobramycin eliminated the infectious burden in rabbits challenged with a clinically relevant strain of Staphylococcus aureus (inoculum as high as 10⁷ CFU). Histological, microbiological, and radiographic methods were used to detail the effects of ABVF on microbial challenge to host bone after 8 weeks in vivo. In contrast to the HAP/BVF controls, which provided no antibiotic protection and required euthanasia 3 weeks post-operatively, tobramycin-releasing ABVF animals showed no signs of infection (clinical, microbiological, or radiographic) when euthanized at the 8-week study endpoint. ABVF sites did exhibit fibrous encapsulation around the implant at 8 weeks. Local antibiotic release from ABVF to orthopedic sites requiring bone void fillers eliminated the periprosthetic bacterial challenge in this 8-week in vivo study, confirming previous in vitro results.

Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections, resulting in increased mortality. In the face of this rising epidemic, antibiotic drug discovery, which has long been overlooked by big pharma, is reaching a critical low. Thus, the development of an infection-responsive drug delivery system, which may mitigate multidrug resistance and preserve the lifetime of our current antibiotic arsenal, has garnered the attention of both popular science and funding agencies. The present work describes the development of a thrombin-sensitive linker embedded into a recombinant spider silk copolymer to create a nanosphere drug delivery vehicle. Recent studies have suggested that there is an increase in thrombin-like activity during Staphylococcus aureus infection; thus, drug release from this new “smart” nanosphere can be triggered in the presence of infection. A thrombin sensitive peptide (TSP) was synthesized, and the thrombin cleavage sensitivity was determined by HPLC. The results showed no cleavage of the peptide when exposed to human serum whereas the peptide was cleaved when incubated with S. aureus exudate. Subsequently, the peptide was coupled with a silk copolymer via EDC-NHS chemistry and formulated into nanospheres encapsulating antibiotic vancomycin. These nanospheres were evaluated for in vitro infection-responsive drug release and antimicrobial activity. Finally, the drug responsive nanospheres were assessed for efficacy in an in vivo septic arthritis model. Our study provides evidence that the protein conjugate was enzyme responsive and can be used to formulate targeted drug release to combat infections against multidrug-resistant bacterial strains.

Infection remains one of the largest threats to global health. Among those infections that are especially troublesome, osteomyelitis, or inflammation of the bone, typically due to infection, is a particularly difficult condition to diagnose and treat. This difficulty stems not only from the biological complexities of opportunistic infections designed to avoid the onslaught of both the host immune system as well as exogenous antibiotics, but also from changes in the host vasculature and the heterogeneity of infectious presentations. While several groups have attempted to classify and stage osteomyelitis, controversy remains, often delaying diagnosis and treatment. Despite a host of preclinical treatment advances being incubated in academic and company research and development labs worldwide, clinical treatment strategies remain relatively stagnant, including surgical debridement and lengthy courses of intravenous antibiotics, both of which may compromise the overall health of the bone and the patient. This manuscript reviews the current methods for diagnosing and treating osteomyelitis and then contemplates the role that nanotechnology might play in the advancement of osteomyelitis treatment.

Autoimmune (AI) diseases, which present in a multitude of systemic manifestations, have been connected to many underlying factors. These factors include the environment, genetics, individual microbiomes, and diet. An individual’s gut microbiota is an integral aspect of human functioning, as it is intimately integrated into the metabolic, mechanical, immunological, and neurologic pathways of the body. The microbiota dynamically changes throughout our lifetimes and is individually unique. While the gut microbiome is ever-adaptive, gut dysbiosis can exert a significant influence on physical and mental health. Gut dysbiosis is a common factor in various AI, and diets with elevated fat and sugar content have been linked to gut microbiome alterations, contributing to increased systemic inflammation. Additionally, multiple AI’s have increased levels of certain inflammatory markers such as TNF-a, IL-6, and IL-17 that have been shown to contribute to arthropathy and are also linked to increased levels of gut dysbiosis. While chronic inflammation has been shown to affect many physiologic systems, this review explores the connection between gut microbiota, bone metabolism, and the skeletal and joint destruction associated with various AI, including psoriatic arthritis, systemic lupus erythematosus, irritable bowel disease, and rheumatoid arthritis. This review aims to define the mechanisms of microbiome crosstalk between the cells of bone and cartilage, as well as to investigate the potential bidirectional connections between AI, bony and cartilaginous tissue, and the gut microbiome. By doing this, the review also introduces the concept of altering an individual’s specific gut microbiota as a form of regenerative medicine and potential tailored therapy for joint destruction seen in AI. We hope to show multiple, specific ways to target the microbiome through diet changes, rebalancing microbial diversity, or decreasing specific microbes associated with increased gut permeability, leading to reduced systemic inflammation contributing to joint pathology. Additionally, we plan to show that diet alterations can promote beneficial changes in the gut microbiota, supporting the body’s own endogenous processes to decrease inflammation and increase healing. This concept of microbial alteration falls under the definition of regenerative medicine and should be included accordingly. By implementing microbial alterations in regenerative medicine, this current study could lend increasing support to the current research on the associations of the gut microbiota, bone metabolism, and AI-related musculoskeletal pathology.

Despite the significant advances in antibiotic treatments and therapeutics, Staphylococcus aureus (S. aureus) remains a formidable pathogen, primarily due to its rapid acquisition of antibiotic resistance. Known for its array of virulence factors, including surface proteins that promote adhesion to host tissues, enzymes that break down host barriers, and toxins that contribute to immune evasion and tissue destruction, S. aureus poses a serious health threat. Both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) classify S. aureus as an ESKAPE pathogen, recognizing it as a critical threat to global health. The increasing prevalence of drug-resistant S. aureus underscores the need for new therapeutic strategies. This review discusses a promising approach that combines monoclonal antibodies targeting multiple S. aureus epitopes, offering synergistic efficacy in treating infections. Such strategies aim to reduce the capacity of the pathogen to develop resistance, presenting a potent adjunct or alternative to conventional antibiotic treatments.

Spiders and silkworms provide a model of superior processing for multifunctional and highly versatile high-performance fibers. Mimicking the spider's complex control system for chemical and mechanical gradients has remained an ongoing obstacle for synthetic silk production. In this study, the use of hydrodynamic fluid focusing within a 3D printed biomimetic spinning system to recapitulate the biological spinneret is explored and shown to produce predictable, small diameter fibers. Mirroring in silico fluid flow simulations using a hydrodynamic microfluidic spinning technique, we have developed a model correlating spinning rates, solution viscosity and fiber diameter outputs that will significantly advance the field of synthetic silk fiber production. The use of hydrodynamic focusing to produce controlled output fiber diameter simulates the natural silk spinning process and continues to build upon a 3D printed biomimetic spinning platform.

Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley’s Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to “hijack” typical host–pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed “domestication”, of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria–host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as “prophylactic”, may even be able to prevent or “derail” tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria–host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria.