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Abstract Wildfires in the southwestern United States are increasingly frequent and severe, but whether these trends exceed historical norms remains contested. Here we combine dendroecological records, satellite-derived burn severity, and field measured tree mortality to compare historical (1700-1880) and contemporary (1985-2020) fire regimes at tree-ring fire-scar sites in Arizona and New Mexico. We found that contemporary fire frequency, including recent, record fire years, is still

The factors that affect the progression of prostatic carcinoma are poorly understood, but it is known that carbohydrate antigens on the tumour cell surface play a role in the transforming and metastatic processes. The present report aimed to perform a comparative, lectin-histochemical study of benign and carcinomatous prostates, using a battery of lectins, in combination with monoclonal antibodies against Lewis antigens, and a semi quantitative study, to investigate the changes in glycosylation patterns that occur in prostatic carcinoma. Blocks from 27 necropsy cases of prostatic carcinoma were sectioned and stained with H+E, fifteen biotinylated lectins chosen to probe for a wide range of oligosaccharide sequences within several categories of glycoprotein glycans, using a lectin-biotin avidin-peroxidase method, and monoclonal antibodies against Lewisa, sialyl Lewisa and sialyl Lewisx antigens. The glycophenotype of prostatic carcinoma differed from that of the noncancerous prostate in revealing more intense staining with the following lectins (AAA, UEA-1, DBA, WFA, VVA, HPA, BSA-1B4, MPA, ECA, AHA, and CTA), while the binding patterns of (GNA and NPA) were almost similar in both prostatic carcinoma and the noncancerous prostate. Lewis antigens are found to be expressed in prostatic carcinomas but not in the noncancerous prostate. The observations of this study suggest that the gylcophenotype of transformed prostatic cells was modified. It showed a moderate increase in, and changing patterns of, fucosylation and galactosylation, increased branching of side chains and sharp rise in 2 deoxy, 2 acetamido galactosylation and masking process by sialylation, especially by Îą2-3 and Îą2-6 linkages. All these changes in the glycosylation pattern of the transformed prostatic cells were observed on O-glycans, no changes were observed on N-glycans.

Introduction: The respiratory system is both a route of entry and exit for toxins and injurious agents, as well as being a target for chemical substances and pathogens. Therefore, an understanding of the structure and function of the migratory cell populations of pulmonary tissues including alveolar macrophages is central in a number of important disease processes. This study aimed to identify and specify the glycotypes of alveolar macrophages in fibrotic lung disorders. Methods: Sections of paraffin-embedded tissue from 40 cases in both normal human lung and fibrotic lung disorders were studied by immunohistology and by lectin histochemistry with a panel of 27 biotinylated lectins. Results: The findings of this study showed that ten lectins (AHA, PTL-II, AAA, , LTA, UEA-I, BSA-1B4, VVA, SBA, DBA, PTL-I) did not bind to the alveolar macrophages in any of the cases, whereas 17 lectins (GNA, NPA, HHA, l-PHA, e-PHA, LCA, PSA, ConA, LEA, PAA, s-WGA, ECA, MPA,HPA, WFA, SNA, MAA( bound from moderately to strongly. In contrast, in fibrotic lung disorders some glycans were somewhat more marked or changed. Conclusion: Glycans terminating in -galactose, terminal Gal1,3GalNAc and subsets of GalNAc also appeared in alveolar macrophages of fibrotic lung disorders. L-fucosylated and terminal -linked galactosyl glycans were also detected in diseases states. Subsets of N-glycans were either changed minimally or not at all.

Historically, Boswellia resin, commonly known as frankincense, has been used for a variety of applications, including medicinal purposes and in religious ceremonies. These practices continued into the modern era, in which the trade of resin has increased dramatically. The genus Boswellia contains many species that are not currently protected by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), but research has found that some of these populations are predicted to decrease by 50 % in the next two decades due to overexploitation (Bongers et al., 2019). This highlights the need for a method that can identify Boswellia resins. In this research, resin from nine different species of Boswellia were collected and analyzed in positive ion mode by Direct Analysis in Real Time Time-of-Flight mass spectrometry (DART TOFMS) by dissolving the resin in methanol to obtain a chemotype devoid of background noise. Chemometric analysis of the data indicated that positive ion spectra from the resins separated the species effectively, indicating that DART TOFMS can be used to identify resins in trade.

Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological functions of DSG2 holds promise to exploit this cell surface protein as a potential prognostic biomarker and/or target for better patient outcomes. This review explores the canonical and non-canonical functions of DSG2, as well as the context-dependent impacts of DSG2 in the realm of cancer.

OBJECTIVE: To identify and examine differences in pre-existing morbidity between injured and non-injured population-based cohorts. METHODS: Administrative health data from Manitoba, Canada, were used to select a population-based cohort of injured people and a sample of non-injured people matched on age, gender, aboriginal status and geographical location of residence at the date of injury. All individuals aged 18-64 years who had been hospitalized between 1988 and 1991 for injury (International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) code 800-995) (n = 21 032), were identified from the Manitoba discharge database. The matched non-injured comparison group comprised individuals randomly selected 1:1 from the Manitoba population registry. Morbidity data for the 12 months prior to the date of the injury were obtained by linking the two cohorts with all hospital discharge records and physician claims. RESULTS: Compared to the non-injured group, injured people had higher Charlson Comorbidity Index scores, 1.9 times higher rates of hospital admissions and 1.7 times higher rates of physician claims in the year prior to the injury. Injured people had a rate of admissions to hospital for a mental health disorder 9.3 times higher, and physician claims for a mental health disorder 3.5 times higher, than that of non-injured people. These differences were all statistically significant (P < 0.001). CONCLUSION: Injured people were shown to differ from the general non-injured population in terms of pre-existing morbidity. Existing population estimates of the attributable burden of injury that are obtained by extrapolating from observed outcomes in samples of injured cases may overestimate the magnitude of the problem.

Abstract  Prophylactic antibiotics are frequently withheld until cultures are obtained in revision total knee arthroplasty (TKA). We undertook a prospective study to determine whether prophylactic preoperative intravenous antibiotics would affect the results of cultures obtained intraoperatively. We enrolled 25 patients with 26 infected TKAs, a known preoperative infecting organism, and no recent antibiotic therapy. Reaspiration of the infected TKA was performed after anesthesia and sterile preparation. Intravenous antibiotic prophylaxis was then administered and the tourniquet inflated. Intraoperative culture swabs and tissue were obtained at arthrotomy. The timing of events was recorded. Pre- and postantibiotic culture data were analyzed to determine the effect of intravenous preoperative prophylactic antibiotics on cultures obtained intraoperatively. Infections were acute postoperative (four), chronic (19), and acute hematogenous (three). The most common infecting organism was cloxacillin-sensitive Staphylococcus aureus (nine knees [35%]). Preoperative prophylactic antibiotics did not affect the results of intraoperative cultures and we therefore believe should not be withheld before surgery for an infected TKA when an organism has been identified on aspiration preoperatively, and there has been no recent (4 weeks) antimicrobial therapy. Level of Evidence: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Deposition of amyloid β peptide in human brain in the form of senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). Levels of a phospholipid breakdown product, glycerophosphocholine (GPC), also increase in AD brain. The effect of GPC on amyloid β(1–40) peptide (Aβ) aggregation in PBS buffer was investigated by circular dichroism and fluoresence spectroscopy; interactions of Aβ and GPC with the intact erythrocyte membrane was examined by fluoresence spectroscopy. Fluorescamine labeled Aβ studies indicate GPC enhances Aβ aggregation. CD spectroscopy reveals that Aβ in the presence of GPC adopts 14% more β-sheet structure than does Aβ alone. Fluorescamine anisotropy measurements show that GPC and Aβ interact in the phospholipid head-group region of the erythrocyte membrane. In summary, both soluble Aβ and GPC insert into the phospholipid head-group region of the membrane where they interact leading to β-sheet formation in soluble Aβ which enhances Aβ aggregation. [ABSTRACT FROM AUTHOR]

Abstract Transfection of chondrocytes with microRNA-451(miR-451), present in growth zone cartilage of the growth plate, upregulates production of enzymes association with extracellular matrix degradation. miR-451 is also present in articular cartilage and exacerbates IL-1β effects in articular chondrocytes. Moreover, when osteoarthritis (OA) was induced in Sprague Dawley rats via bilateral anterior cruciate ligament transection (ACLT), miR-451 expression was increased in OA cartilage compared to control, suggesting its inhibition might be used to prevent or treat OA. To examine the prophylactic and therapeutic potential of inhibiting miR-451, we evaluated treatment with miR-451 power inhibitor (451-PI) at the onset of joint trauma and treatment after OA had developed. The prophylactic animal cohort received twice-weekly intra-articular injections of either 451-PI or a negative control (NC-PI) beginning on post-surgical day 3. OA was allowed to develop for 24 days in the therapeutic cohort before beginning injections. All rats were killed on day 45. Micro-CT, histomorphometrics, OARSI scoring, and muscle force testing were performed on samples. 451-PI mitigated OA progression compared to NC-PI limbs in the prophylactic cohort based on histomorphometric analysis and OARSI scoring, but no differences were detected by micro-CT. 451-PI treatment beginning 24 days post-surgery was not able to reduce OA severity. Prophylactic administration of 451-PI mitigates OA progression in a post-trauma ACLT rat model supporting its potential to prevent OA development following an ACLT injury clinically.

ABSTRACT: The Atlantic Johne's Disease Initiative (AJDI) aims to control Mycobacterium avium ssp. paratuberculosis infection by using veterinary-administered risk assessments to identify high-risk management practices and prompt changes in management behavior. Objectives for this study were to measure producer satisfaction with the veterinary-administered risk assessment and management plan (RAMP) process in a voluntary Johne's disease (JD) control program, compare RAMP-specific satisfaction results based on herd JD status, and measure knowledge transfer from certified veterinarians to producers during the RAMP. A satisfaction questionnaire was adapted to the RAMP process in the AJDI to measure producer satisfaction. The questionnaire included 9 RAMP-specific producer satisfaction items, 1 global RAMP satisfaction item, and 16 questions to assess producer knowledge and knowledge translation about JD, bovine viral diarrhea (BVD), and bovine leukosis virus (BLV) during the RAMP (BVD and BLV used for comparison purposes). A total of 133 dairy producers in the AJDI (79.6% response rate) completed the questionnaire by telephone. The RAMP-specific satisfaction was high among the AJDI producers surveyed, and these results were not found to differ based on herd JD status. The lowest satisfaction scores and the highest number of “unable to assess” responses were for the item relating to cost. Factors that contributed to RAMP-specific producer satisfaction were not identified from the demographic and herd information available in this study. The knowledge scores indicated moderate knowledge about JD and fair knowledge about BVD and BLV. Evidence of knowledge translation from the RAMP was mixed in this study. Bovine viral diarrhea knowledge scores were not found to differ based on whether or not the certified veterinarian discussed BVD during the preceding RAMP, but BLV knowledge scores were higher among dairy producers that discussed BLV during the preceding RAMP. Strengths and gaps in producer knowledge about these 3 infectious diseases were identified. By using this producer questionnaire, interventions aimed at improving the content, delivery, and satisfaction of RAMP in JD control programs, such as the AJDI, can be developed.

The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) has listed over 100 species of trees whose trade is primarily in timber, and whose existence may be endangered due to either indiscriminate or illegal logging. Species determination of timber is essential for enforcing logging quotas and species protections laws, but it is a challenging endeavor. Here we present a technique that relies on mass spectra chemotypes for species assignment and demonstrate that it provides high reliability.The reliability of timber identification by mass spectrometry relies on multiple factors: 1) access to a robust wood spectra database (e.g., ForeST ©: Forensic Spectra of Trees) derived from a curated xylarium, 2) analysis of the correct wood tissue (i.e., heartwood vs sapwood), 3) reproducibility of the spectra, 4) repeatability of the analysis and 5) skill in interpreting the data. The goal of timber identification is to assign wood products to species, but in some cases the precision of the analysis will be to the genus or even family level. This may be due, for example, to shared chemotypes among closely related tree species. These higher taxa assignments do not represent an error (false positive or false negative), but rather reflect the complexity of wood chemistry in relation to phylogeny. Such higher taxa determinations are often sufficient for enforcement purposes, as many timber trees are protected at the genus or above.

Abstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.

RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.

Reduced skeletal loading associated with many conditions, such as neuromuscular injuries, can lead to bone fragility and may threaten the success of implant therapy. Our group has developed a botulinum toxin A (botox) injection model to imitate disease-reduced skeletal loading and reported that botox dramatically impaired the bone formation and osseointegration of titanium implants. Semaphorin 3A (sema3A) is an osteoprotective factor that increases bone formation and inhibits bone resorption, indicating its potential therapeutic role in improving osseointegration in vivo. We first evaluated the sema3A effect on whole bone morphology following botox injections by delivering sema3A via injection. We then evaluated the sema3A effect on the osseointegration of titanium implants with two different surface topographies by delivering sema3A to cortical bone defect sites prepared for implant insertion and above the implants after insertion using a copper-free click hydrogel that polymerizes rapidly in situ. Implants had hydrophobic smooth surfaces (PT) or multiscale biomimetic micro/nano topography (SLAnano). Sema3A rescued the botox-impaired bone formation. Furthermore, biomimetic Ti implants improved the bone-to-implant contact (BIC) and mechanical properties of the integrated bone in the botox-treated rats, which sema3A enhanced. This study demonstrated the value of biomimetic approaches combining multiscale topography and biologics in improving the clinical outcomes of implant therapy.

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

Volumetric muscle loss (VML) is the acute loss of muscle mass due to trauma. Such injuries occur primarily in the extremities and are debilitating, as there is no clinical treatment to restore muscle function. Pro-inflammatory advanced glycation end-products (AGEs) and the soluble receptor for advanced glycation end-products (RAGE) are known to increase in acute trauma patient’s serum and are correlated with increased injury severity. However, it is unclear whether AGEs and RAGE increase in muscle post-trauma. To test this, we used decellularized muscle matrix (DMM), a pro-myogenic, non-immunogenic extracellular matrix biomaterial derived from skeletal muscle. We delivered adipose-derived stromal cells (ASCs) and primary myoblasts to support myogenesis and immunomodulation (N = 8 rats/group). DMM non-seeded and seeded grafts were compared to empty defect and sham controls. Then, 56 days after surgery muscle force was assessed, histology characterized, and protein levels for AGEs, RAGE, p38 MAPK, and myosin heavy chains were measured. Overall, our data showed improved muscle regeneration in ASC-treated injury sites and a regulation of RAGE and p38 MAPK signaling, while myoblast-treated injuries resulted in minor improvements. Taken together, these results suggested that ASCs combined with DMM provides a pro-myogenic microenvironment with immunomodulatory capabilities and indicates further exploration of RAGE signaling in VML.

Urbanization and scarce income-earning opportunities have led to increasing commercialization of non-timber forest products in southern Africa, including the nutritious mopane worm 'Imbrasia (=Gonimbrasia) belina'. The mopane worm contributes substantially to incomes and food security in households across the region, but little research has addressed its use within South Africa. Using semi-structured interviews with harvesters and resource managers, this paper compares the management of mopane worm resources under public, private, and communal governance systems to explore the ability of each to provide users with sustainable access to the resource. Results show that governance is weaker in the communal property regime compared to the public and private property regimes. Weak control over access and high demand for mopane worms in urban and rural centres may be leading to a concentration of harvesting pressures in communally managed areas, increasing competition for a resource already scarce after years of drought and land-use change.

Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve’s role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE’s effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.

Psychology students delivered stress and coping workshops to homeless adolescent mothers as part of a college service-learning project. In this vulnerable and underserved population, stress reduction is critical. Service-learning was used as an avenue to enhance student learning and growth while helping meet this need in our community. The psychology students developed deeper learning, professional skills, and social awareness. The adolescent mothers developed stress reduction skills that they were able to successfully implement. Challenges and recommendations for the implementation of similar service-learning projects are discussed.

Decellularized tissues are biocompatible materials that engraft well, but the age of their source has not been explored for clinical translation. Advanced glycation end products (AGEs) are chemical cross-links that accrue on skeletal muscle collagen in old age, stiffening the matrix and increasing inflammation. Whether decellularized biomaterials derived from aged muscle would suffer from increased AGE collagen cross-links is unknown. We characterized gastrocnemii of 1-, 2-, and 20-month-old C57BL/6J mice before and after decellularization to determine age-dependent changes to collagen stiffness and AGE cross-linking. Total and soluble collagen was measured to assess if age-dependent increases in collagen and cross-linking persisted in decellularized muscle matrix (DMM). Stiffness of aged DMM was determined using atomic force microscopy. AGE levels and the effect of an AGE cross-link breaker, ALT-711, were tested in DMM samples. Our results show that age-dependent increases in collagen amount, cross-linking, and general stiffness were observed in DMM. Notably, we measured increased AGE-specific cross-links within old muscle, and observed that old DMM retained AGE cross-links using ALT-711 to reduce AGE levels. In conclusion, deleterious age-dependent modifications to collagen are present in DMM from old muscle, implying that age matters when sourcing skeletal muscle extracellular matrix as a biomaterial.

Abstract Conservation plans aiming to reduce the threat of illegal wildlife trade increasingly recognize the need for multifaceted approaches that include both enhanced enforcement and demand reduction initiatives. Both are complex issues that involve understanding consumer motives. Pangolins represent some of the most heavily trafficked species, largely due to high consumer demand for their scales for use in traditional medicines. Recent media reports also suggest that demand is related to the purported presence of the analgesic tramadol in scales. We examined chemotypes of scales from 104 individual pangolins representing all extant species. None of the specimens demonstrated the presence of tramadol. Given that demand for pangolins and their parts is decimating wild populations, it is imperative that such false claims be rectified. These results could be incorporated into demand reduction campaigns in areas where this misinformation is perpetuated.

Products developed for skeletal muscle regeneration frequently incorporate allogeneic and xenogeneic materials to elicit a regenerative response to heal skeletal muscle wounds. To avoid graft rejection in preclinical studies, immunodeficient rodents are used. Whether the immunodeficiency alters the host response to the material in skeletal muscle has not been studied. In this study, we hypothesized that an allogeneic acellular skeletal muscle grafts implanted in an immunodeficient rat (RNU, Foxn1-deficient) would exhibit better new muscle fiber formation compared to grafts implanted in immunocompetent Sprague Dawley (SD) rats. Decellularized SD skeletal muscle matrix (DMM) was implanted in the gastrocnemius (N = 8 rats/group). 56 days after surgery, animal gait was examined and animals were euthanized. Muscle force was assessed and fiber number as well as immune cell infiltrate was measured by histomorphometry and immunohistochemistry. Animal gait and percent recovery of muscle force were unchanged in both groups, but newly regenerated muscle fibers increased in RNU rats. Macrophage staining for CD68 was higher in RNU rats than in SD rats. These data show differences in muscle regeneration between animal models using the same biomaterial treatment, but these differences could not be ascribed to the immune response. Overall, our data provide awareness that more studies are needed to understand how host responses to biomaterials differ based on the animal model used.

Abstract Objective: To describe the practical issues that need to be overcome to conduct national data linkage projects in Australia and propose recommendations to improve efficiency. Methods: Review of the processes, documentation and applications required to conduct national data linkage in Australia. Results: The establishment of state and national data linkage centres in Australia has placed Australia at the forefront of research linking health‐related administrative data collections. However, improvements are needed to reduce the clerical burden on researchers, simplify the process of obtaining ethics approval, improve data accessibility, and thus improve the efficiency of data linkage research. Conclusions: While a sound state and national data linkage infrastructure is in place, the current complexity, duplication and lack of cohesion undermines any attempts to conduct research involving national record linkage in a timely manner. Implications: Data linkage applications and Human Research Ethics Committee approval processes need to be streamlined and duplication removed, in order to reduce the administrative and financial burden on researchers if national data linkage research is to be viable.

Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique “open” and classical “closed” conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas “open-like” IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a “double hit” cytokine receptor blockade.

Persistent or chronic pain is prevalent in many developed countries, with estimates ranging from 10% to higher than 50%, and is a major economic burden to individuals and societies. However, the variation in pain outcomes after acute orthopedic trauma and treatment confronts treating physicians with uncertainty in providing prognostic advice regarding long-term recovery. Although several previous reviews have addressed the determinants of chronic pain outcomes secondary to acute trauma, they have primarily focused on specific injury samples and, furthermore, lack consistency with respect to the important prognostic factors, which limits the generalizability of findings. This review, however, aimed specifically to identify the early prognostic factors associated with variation in persistent pain outcomes following acute orthopedic trauma presenting with a spectrum of pathologies.

The factors that affect the progression of prostatic carcinoma are poorly understood, but it is known that carbohydrateantigens on the tumour cell surface play a role in the transforming and metastatic processes. The present reportaimed to perform a comparative, lectin-histochemical study of benign and carcinomatous prostates, using a battery oflectins, in combination with monoclonal antibodies against Lewis antigens, and a semi quantitative study, to investigate thechanges in glycosylation patterns that occur in prostatic carcinoma. Blocks from 27 necropsy cases of prostatic carcinomawere sectioned and stained with H+E, fifteen biotinylated lectins chosen to probe for a wide range of oligosaccharidesequences within several categories of glycoprotein glycans, using a lectin-biotin avidin-peroxidase method, and monoclonalantibodies against Lewisa, sialyl Lewisa and sialyl Lewisx antigens. The glycophenotype of prostatic carcinoma differedfrom that of the noncancerous prostate in revealing more intense staining with the following lectins (AAA, UEA-1,DBA, WFA, VVA, HPA, BSA-1B4, MPA, ECA, AHA, and CTA), while the binding patterns of (GNA and NPA) were almostsimilar in both prostatic carcinoma and the noncancerous prostate. Lewis antigens are found to be expressed in prostatic carcinomasbut not in the noncancerous prostate. The observations of this study suggest that the gylcophenotype of transformedprostatic cells was modified. It showed a moderate increase in, and changing patterns of, fucosylation and galactosylation,increased branching of side chains and sharp rise in 2 deoxy, 2 acetamido galactosylation and masking process by sialylation,especially by α2-3 and α2-6 linkages. All these changes in the glycosylation pattern of the transformed prostatic cellswere observed on O-glycans, no changes were observed on N-glycans.

The development of vascular grafts requires thematching of material and viscoelastic properties tothose of native artery. The hypothesis of this studywas to subject electrospun tissue engineeringscaffolds composed of polydioxanone, elastin, andcollagen to cyclic loading in order to quantify thehysteretic properties, uniaxial tensile mechanicalproperties of conditioned scaffolds, and stressrelaxation properties over a period of 400 cycleswhen compared to ePTFE, one of the most popularvascular prosthetic materials, and decellularized pigartery. In the electrospun graft, polydioxanone wouldprovide a mechanical backbone, providing tensilesupport and preventing vessel rupture; while theelastin would provide elasticity and collagen wouldprovide bioactivity (promote regeneration in vitro/insitu).

The purpose of this study was to establish whether material properties of elastin co-electrospun with polydioxanone (PDO) would change over time in both the uncross-linked state and the cross-linked state. First, uncross-linked scaffolds were placed in phosphate buffered saline (PBS) for three separate time periods: 15 minutes, 1 hour, and 24 hours, and subsequently tested using uniaxial materials testing. Several cross-linking reagents were then investigated to verify their ability to crosslink elastin: 1-ethyl-3-(dimethylaminopropyl)-carbodiimide (EDC), ethylene glycol diglycidyl ether (EGDE), and genipin. Uniaxial tensile testing was performed on scaffolds cross-linked with EDC and genipin, yielding results that warranted further investigation for PDO-elastin blends. Material properties of the cross-linked scaffolds were then found within range of both pig femoral artery and human femoral artery. These results demonstrate PDO-elastin blends could potentially be favorable as vascular grafts, thus warranting future in vitro and in vivo studies.

Human interleukin-3 (hIL-3) is a polypeptide growth factor that regulates the proliferation, differentiation, survival and function of hematopoietic progenitors and many mature blood cell lineages. Although recombinant hIL-3 is a widely used laboratory reagent in hematology, standard methods for its preparation, including those employed by commercial suppliers, remain arduous owing to a reliance on refolding insoluble protein expressed in E. coli. In addition, wild-type hIL-3 is a poor substrate for radio-iodination, which has been a long-standing hindrance to its use in receptor binding assays. To overcome these problems, we developed a method for expression of hIL-3 in E. coli as a soluble protein, with typical yields of >3mg of purified hIL-3 per litre of shaking microbial culture. Additionally, we introduced a non-native tyrosine residue into our hIL-3 analog, which allowed radio-iodination to high specific activities for receptor binding studies whilst not compromising bioactivity. The method presented herein provides a cost-effective and convenient route to milligram quantities of a hIL-3 analog with wild-type bioactivity that, unlike wild-type hIL‑3, can be efficiently radio-iodinated for receptor binding studies.

Background. Including spouses in obesity treatment has been found to promote weight loss. We assessed whether spouses’ diet and activity changes impacted each other’s weight loss when both members attended an active weight loss program (TOGETHER) or only the primary participant attended treatment (ALONE). Methods. Heterosexual couples (N=132) enrolled in an 18-month randomized controlled weight loss trial were weighed and completed measures of dietary intake and physical activity at baseline and 6 months. We conducted dyadic data analyses using the Actor-Partner Interdependence Model. Results. Participants’ weight loss was not predicted by their partners’ behavior changes. However, partners’ weight loss was predicted by their participants’ changes in calorie and fat intake. When partners were coupled with a participant who did not reduce their own calorie and fat intake as much, these partners had higher weight loss when treated in the TOGETHER group but lower weight loss when they were untreated in the ALONE group. There were no reciprocal effects found with physical activity changes. Conclusions. Direct treatment had the greatest impact on participants and partners who were treated. Untreated partners’ weight losses were positively impacted by their spouses’ dietary changes, suggesting a ripple effect from treated spouses to their untreated partners.

Although GABA-A receptor-mediated inhibition of cerebellar Purkinje cells by molecular layer interneurons (MLIs) has been studied intensely on the cellular level, it has remained unclear how this inhibition regulates cerebellum-dependent behaviour. We have implemented two complementary approaches to investigate the function of the MLI-Purkinje cell synapse on the behavioral level. In the first approach we permanently disrupted inhibitory fast synaptic transmission at the synapse by genetically removing the postsynaptic GABA-A receptors from Purkinje cells (PC-Δγ2 mice). We found that chronic disruption of the MLI-Purkinje cell synapse strongly impaired cerebellar learning of the vestibular occular reflex (VOR), presumably by disrupting the temporal patterns of Purkinje cell activity. However, in PC-Δγ2 mice the baseline VOR reflex was only mildly affected; indeed PC-Δγ2 mice showed no ataxia or gait abnormalities suggesting that MLI control of Purkinje cell activity is either not involved in ongoing motor tasks or that the system has found a way to compensate for its loss. To investigate the latter possibility we have developed an alternative genetic technique; we made the MLI-Purkinje cell synapse selectively sensitive to rapid manipulation with the GABAA receptor modulator zolpidem (PC-γ2-swap mice). Minutes after intraperitoneal zolpidem injection, these PC-γ2-swap mice developed severe motor abnormalities, revealing a substantial contribution of the MLI-Purkinje cell synapse to real time motor control. The cell-type selective permanent knockout of synaptic GABAergic input, and the fast reversible modulation of GABAergic input at the same synapse illustrate how pursuing both strategies gives a fuller view.

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

Objective: This article aims to examine the impact of nursing workforce skill-mix (percentage of critical care registered nurses [CCRN]) in the intensive care unit (ICU) during a patient's stay., Design: Registry linked cohort study of the Australian and New Zealand Intensive Care Society Adult Patient Database and the Critical Health Resources Information System using real-time nursing workforce data., Settings: Fifteen public and 5 private hospital ICUs in Victoria, Australia., Participants: There were 16,618 adult patients admitted between 1 December 2021 and 30 September 2022., Main Outcome Measures: Primary outcome: in-hospital mortality. Secondary outcomes: in-ICU mortality, development of delirium, pressure injury, duration of stay in-ICU and hospital, after-hours discharge from ICU and readmission to ICU., Results: In total, 6563 (39.5%) patients were cared for in ICUs with >75% CCRN, 7695 (46.3%) in ICUs with 50-75% CCRN, and 2360 (14.2%) in ICUs with <50% CCRN. In-hospital mortality was 534 (8.1%) vs. 859 (11.2%) vs. 252 (10.7%) respectively. After adjusting for confounders, patients cared for in ICUs with 50-75% CCRN (adjusted OR 1.21 [95% CI 1.02-1.45]) were more likely to die compared to patients in ICUs with >75% CCRN. A similar but non-significant trend was seen in ICUs with <50% CCRN (adjusted OR 1.21 [95% CI 0.94-1.55]), when compared to patients in ICUs with >75% CCRN. In-ICU mortality, delirium, pressure injuries, after-hours discharge and ICU length of stay were lower in ICUs with CCRN>75%., Conclusion: The nursing skill-mix in ICU impacts outcomes and should be routinely monitored. Health system regulators, hospital administrators and ICU leaders should ensure nursing workforce planning and education align with these findings to maximise patient outcomes., (© 2024 The Authors.)

Background: Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were: 1) To evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; 2) To assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma., Methods: 1) African Green monkeys (AGM) received doxorubicin (30-60 mg/m 2 /biweekly IV, cumulative dose: 240 mg/m 2 ). Blinded histopathologic analyses of collagen deposition and cell vacuolization in the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to 5 age- and gender-matched healthy, untreated AGMs. 2) Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study. The primary outcome was change in maximal tissue-to-background ratio (TBRmax) of the thoracic aorta from baseline to their end-of-treatment clinical PET/CT., Results: In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin cohort 6.23±0.88% vs. controls 4.67±0.54%; p=0.01) and increased intracellular vacuolization (doxorubicin 66.3 ± 10.1 vs controls 11.5 ± 4.2 vacuoles/field, p<0.0001) than untreated controls.In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (pre-doxorubicin TBRmax 1.46±0.16 vs post-doxorubicin TBRmax 1.44±0.14, p=0.14). The absence of change in TBRmax was consistent across all univariate analyses., Conclusions: In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation.Further research is required to elucidate the mechanisms of anthracycline-related vascular harm.