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The landscape theory of food web architecture (LTFWA) describes relationships among body size, trophic position, mobility, and energy channels that serve to couple heterogenous habitats, which in turn promotes long-term system stability. However, empirical tests of the LTFWA are rare and support differs among terrestrial, freshwater, and marine systems. Further, it is unclear whether the theory applies in highly altered ecosystems dominated by introduced species such as the Laurentian Great Lakes. Here, we provide an empirical test of the LTFWA by relating body size, trophic position, and the coupling of different energy channels using stable isotope data from species throughout the Lake Michigan food web. We found that body size was positively related to trophic position, but for a given trophic position, organisms predominately supported by pelagic energy had smaller body sizes than organisms predominately supported by nearshore benthic energy. We also found a hump-shaped trophic relationship in the food web where there is a gradual increase in the coupling of pelagic and nearshore energy channels with larger body sizes as well as higher trophic positions. This highlights the important role of body size and connectivity among habitats in structuring food webs. However, important deviations from expectations are suggestive of how species introductions and other anthropogenic impacts can affect food web structure in large lakes. First, native top predators appear to be flexible couplers that may provide food web resilience, whereas introduced top predators may confer less stability when they specialize on a single energy pathway. Second, some smaller bodied prey fish and invertebrates, in addition to mobile predators, coupled energy from pelagic and nearshore energy channels, which suggests that some prey species may also be important integrators of energy pathways in the system. We conclude that patterns predicted by the LTFWA are present in the face of species introductions and other anthropogenic stressors to a degree, but time-series evaluations are needed to fully understand the mechanisms that promote stability., (© 2024 The Author(s). Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Ultra-high dose rate ("FLASH") radiotherapy (>40-60 Gy/s) is a promising new radiation modality currently in human clinical trials. Previous studies showed that FLASH proton radiotherapy (FR) improves toxicity of normal tissues compared to standard proton radiotherapy (SR) without compromising anti-tumor effects. Understanding this normal tissue sparing effect may offer insight into how toxicities from cancer therapy can be improved. Here, we show that compared to SR, FR resulted in improved acute weight recovery and survival in mice after whole-abdomen irradiation. Improved morbidity and mortality after FR were associated with greater proliferation of damage-induced epithelial progenitor cells followed by improved tissue regeneration. FR led to the accelerated differentiation of revival stem cells (revSCs), a rare damage-induced stem cell required for intestinal regeneration, and to qualitative and quantitative changes in activity of signaling pathways important for revSC differentiation and epithelial regeneration. Specifically, FR resulted in greater infiltration of macrophages producing TGF-β, a cytokine important for revSC induction, that was coupled to augmented TGF-β signaling in revSCs. In pericryptal fibroblasts, FR resulted in greater type I IFN (IFN-I) signaling, which directly stimulates production of FGF growth factors supporting revSC proliferation. Accordingly, the ability of FR to improve epithelial regeneration and morbidity was dependent on IFN-I signaling. In the context of SR, however, IFN-I had a detrimental effect and promoted toxicity. Thus, a tissue-level signaling network coordinated by differences in IFN-I signaling and involving stromal cells, immune cells, and revSCs underlies the ability of FLASH to improve normal tissue toxicity without compromising anti-tumor efficacy.

In aquatic systems, food web linkages are often assessed using diet contents, stable isotope ratios, and, increasingly, fatty acid composition of organisms. Some correlations between different trophic metrics are assumed to be well-supported; for example, particular stable isotope ratios and fatty acids seem to reflect reliance on benthic or pelagic energy pathways. However, understanding whether the assumed correlations between different trophic metrics are coherent and consistent across species represents a key step toward their effective use in food web studies. To assess links among trophic markers, we compared relationships between major diet components, fatty acids, and stable isotope ratios in three fishes: yellow perch (Perca flavescens), round goby (Neogobius melanostomus), and spottail shiner (Notropis hudsonius) collected from nearshore Lake Michigan. Yellow perch and spottail shiner are native in this system, while round goby are a relatively recent invader. We found some evidence for agreement between different trophic metrics, especially between diet components, n-3:n-6 fatty acid ratios, and stable isotope ratios (δ13C and δ15N). However, we also observed significant variation in observed relationships among markers and species, potentially due to taxonomic variation in the specific diet items consumed (e.g., chydorid microcrustaceans and Dreissena mussels) and species-specific biochemical processes. In many of these latter cases, the invasive species differed from the native species. Understanding the effects of taxonomic variation on prey and predator signatures could significantly improve the usefulness of fatty acids in food web studies, whereas diet contents and stable isotopes appear to be reliable indicators of trophic niche in aquatic food webs., Competing Interests: The authors have declared that no competing interests exist.

Microplastics are present in aquatic ecosystems the world over and may influence the feeding, growth, reproduction, and survival of freshwater and marine biota; however, the extent and magnitude of potential effects of microplastics on aquatic organisms is poorly understood. In the current study, we conducted a meta-analysis of published literature to examine impacts of exposure to microplastics on consumption (and feeding), growth, reproduction, and survival of fish and aquatic invertebrates. While we did observe within-taxa negative effects for all four categories of responses, many of the effects summarized in our study were neutral, indicating that the effects of exposure to microplastics are highly variable across taxa. The most consistent effect was a reduction in consumption of natural prey when microplastics were present. For some taxa, negative effects on growth, reproduction and even survival were also evident. Organisms that serve as prey to larger predators, e.g., zooplankton, may be particularly susceptible to negative impacts of exposure to microplastic pollution, with potential for ramifications throughout the food web. Future work should focus on whether microplastics may be affecting aquatic organisms more subtly, e.g., by influencing exposure to contaminants and pathogens, or by acting at a molecular level., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Interest in granulation processes using twin screw extrusion machines is rapidly growing. The primary objectives of this study were to develop a continuous granulation process for direct production of granules using this technique with glyceryl behenate as a binder, evaluate the properties of the resulting granules and develop controlled release tablets containing tramadol HCl. In addition, the granulation mechanism was probed and the polymorphic form of the lipid and drug release rate were evaluated on stability. Granules were prepared using a Leistritz NANO16 twin screw extruder operated without a constricting die. The solid state of the granules were characterized by differential scanning calorimetry and X-ray diffraction. Formulated tablets were studied in 0.1N HCl containing 0-40% ethanol to investigate propensity for alcohol induced dose dumping. The extrusion barrel temperature profile and feed rate were determined to be the primary factors influencing the particle size distribution. Granules were formed by a combination immersion/distribution mechanism, did not require subsequent milling, and were observed to contain desirable polymorphic forms of glyceryl behenate. Drug release from tablets was complete and controlled over 16 h and the tablets were determined to be resistant to alcohol induced dose dumping. The drug release rate from the tablets was found to be stable at 40°C and 75% relative humidity for the duration of a 3 month study., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Matrix metalloprotease-1 (MMP1) has been implicated in many human disease processes, however the lack of a well characterized murine homologue has significantly limited the study of MMP1 and the development of MMP-targeted therapeutics. The discovery of murine Mmp1a in 2001, the functional mouse homologue of MMP1, offers a valuable tool for modeling MMP1-mediated processes in mice. Variation in physiologic expression levels of Mmp1a in mice as compared to MMP1 in humans highlights the importance of understanding the similarities and differences between the homologues. Recent studies have demonstrated tumor growth-, invasion-, and angiogenesis-promoting functions of Mmp1a in lung cancer models, consistent with the analogous functions observed for human MMP1. Biochemical investigations have shown that point mutations in the pro-domain of mouse Mmp1a weaken docking between the pro- and catalytic domains, generating an unstable zymogen primed for activation. The difficulty to effectively maintain Mmp1a in the zymogen form may account for the tight control of Mmp1a expression and reduced expression in normal tissue as compared to inflammatory states or cancer. This discovery raises important questions about the activation mechanisms and regulation of the MMP family in general., (© 2014 Wiley Periodicals, Inc.)

Matrix metalloprotease-1 (MMP1) is an important mediator of tumorigenesis, inflammation and tissue remodeling through its ability to degrade critical matrix components. Recent studies indicate that stromal-derived MMP1 may exert direct oncogenic activity by signaling through protease-activated receptor-1 (PAR1) in carcinoma cells; however, this has not been established in vivo. We generated an Mmp1a knockout mouse to ascertain whether stromal-derived Mmp1a affects tumor growth. Mmp1a-deficient mice are grossly normal and born in Mendelian ratios; however, deficiency of Mmp1a results in significantly decreased growth and angiogenesis of lung tumors. Coimplantation of lung cancer cells with wild-type Mmp1a(+/+) fibroblasts completely restored tumor growth in Mmp1a-deficient animals, highlighting the critical role of stromal-derived Mmp1a. Silencing of PAR1 expression in the lung carcinoma cells phenocopied stromal Mmp1a-deficiency, thus validating tumor-derived PAR1 as an Mmp1a target. Mmp1a secretion is controlled by the ability of its prodomain to facilitate autocleavage, whereas human MMP1 is efficiently secreted because of stable pro- and catalytic domain interactions. Taken together, these data demonstrate that stromal Mmp1a drives in vivo tumorigenesis and provide proof of concept that targeting the MMP1-PAR1 axis may afford effective treatments of lung cancer.

Matrix metalloprotease-1 (MMP1), a collagenase and activator of the G protein-coupled protease activated receptor-1 (PAR1), is an emerging new target implicated in oncogenesis and metastasis in diverse cancers. However, the functional mouse homologue of MMP1 in cancer models has not yet been clearly defined. We report here that Mmp1a is a functional MMP1 homologue that promotes invasion and metastatic progression of mouse lung cancer and melanoma. LLC1 (Lewis lung carcinoma) and primary mouse melanoma cells harboring active BRAF express high levels of endogenous Mmp1a, which is required for invasion through collagen. Silencing of either Mmp1a or PAR1 suppressed invasive stellate growth of lung cancer cells in three-dimensional matrices. Conversely, ectopic expression of Mmp1a conferred an invasive phenotype in epithelial cells that do not express endogenous Mmp1a. Consistent with Mmp1a acting as a PAR1 agonist in an autocrine loop, inhibition or silencing of PAR1 resulted in a loss of the Mmp1a-driven invasive phenotype. Knockdown of Mmp1a on tumor cells resulted in significantly decreased tumorigenesis, invasion, and metastasis in xenograft models. Together, these data demonstrate that cancer cell-derived Mmp1a acts as a robust functional homologue of MMP1 by conferring protumorigenic and metastatic behavior to cells.

Population structure dictates the evolution of each population, and thus, the species as a whole. Incorporating spatial variables with population genetic statistics allows for greater discovery beyond traditional population genetics alone and can inform management decisions. The understanding of population structure in Hessian fly, Mayetiola destructor (Say), a pest of wheat, has been limited in the past. We scored 14 microsatellite loci from 12 collections of Hessian fly in the southeastern United States. Through Bayesian clustering analysis, we found two major populations of Hessian fly covering the entire southeastern United States. We evaluated correlations between agriculturally significant spatial variables and population genetic differentiation to test if genetic structure has an ecological component in a wheat agro-ecosystem. Our results suggest the total amount of alternative host plants in the county may be driving some genetic differentiation. Although planting date may also be influential, geographic distance, mean annual temperature, and harvested wheat for grain do not seem to be contributing factors. The ecological or spatial component to population structure, however, may be minimal compared to factors such as genetic drift.

RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF-alpha stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.

Despite the compelling reasons for advance directives and their endorsement by the public and medical professions, little is known about their actual use and impact on site of death. This study was conducted to examine the role of advance directives and other "drivers" of hospitalization of the long-term care end-of-life patient. The medical records of 100 deceased consecutive nursing home residents, stratified by site of death (skilled nursing facility or acute care hospital), were reviewed by a team of geriatric researchers to obtain patient information in the following domains: sociodemographic, advance directives, transfer and death information, patient diagnoses at admission, discharge, and other time intervals; medication usage and signs and symptoms precipitating death. Severity of illness was assessed using the Cumulative Illness Rating Scale-G (CIRS-G). In testing for differences between patients by site of death, sociodemographic variables (gender, age, race, payer at discharge, cognitive capacity) did not significantly differ between the two groups of patients. Strong similarities between the groups were also found in terms of severity of illness and medication usage. Significantly higher proportions of patients dying in the nursing home had specific advance directives (do not resuscitate, do not intubate, do not artificially feed, do not hydrate, and do not hospitalize), as opposed to those dying in the hospital. The findings of this study demonstrate the impact of the explicit advance directive on the decision to transfer the patient to the acute care setting at the end of life.

Background: In this period of cost constraints, any indicator, such as nutritional status, which may predict the outcome of rehabilitation for a common problem, such as hip fractures, merits evaluation., Methods: Nutritional indices--serum albumin, cholesterol, and body mass index--were assessed in 114 subacute rehabilitation hip fracture patients., Results: Hypoalbuminemia was very common, occurring in 101 of 114 patients (88.6%). Using a forward stepwise regression model which considered age, total protein count, albumin, cholesterol, weight, height, and body mass index, serum albumin was the only variable that was significantly correlated with the length of stay (b=-0.23; p<.015). A scatterplot showed that almost all the albumin values in this elderly group fell between 2.4 mg/dl and 3.2 mg/dl, relatively low values, with a significant negative linear relationship between serum albumin and length of stay in this range. The average length of stay at 3.2 mg/dl was 44 days and at 2.4 mg/dl was 56 days., Conclusion: Hypoalbuminemia remains an important indicator of poor health outcome. Early biomedical monitoring of elderly subacute patients may lead to a reduction in length of stay and consequently reduce the costs of rehabilitation.

Two derivatives of a tungstate cluster containing 11 tungsten atoms (W11PO39SiR4-) have been synthesized which enable them to be covalently attached to biomolecules at specific sites. The tungstate cluster is 1.0 nm in diameter, electron dense, and visible in the electron microscope. One derivative is a W11-sulfonyl chloride, reactive with amines and sulfhydryls. The second compound is a W11-thiosulfonate which can be used to label sulfhydryl groups. These new labels are beam resistant and provide significantly higher resolution then most other electron microscopy (EM) markers. Labeling of the protein albumin is described as an example.

The impressive rise in the number of elderly persons (65 years and over) will continue in the next two to three decades. Urinary incontinence is a common problem in the elderly, adversely affecting medical, social, and "quality of life" aspects. The cost of urinary incontinence is substantial and is expected to escalate enormously (e.g., by 160% from 1980 to 2040). An aggressive approach toward the diagnosis and management of urinary incontinence can result in an impressive reduction in health care costs and improvement in the quality of life.

An 11 gold atom (undecagold) cluster was covalently attached to specific sites on Fab', F(ab')2 and whole IgG molecules such that each carried 11-33 gold atoms without significant loss of native immunospecificity. Gold cluster labeled 17-1A monoclonal F(ab')2 antibody fragments showed 80% immunoreactivity compared to native antibody fragments in binding to human colon carcinoma cells in vitro. Radioactive gold in vivo biodistributions in nude mice with human tumors are also reported. By using clusters, potentially a larger destructive payload can be carried per antibody.

A pharmacist collected data in an active geriatric outpatient program on 140 patients admitted consecutively over a 1-year period. Compliance was monitored by patient statement, pill counting, and daily written record-keeping of all medications with the help of a pocket diary provided in the program. Weekly pharmacist counseling sessions were then initiated for all patients. After four compliance sessions, two subgroups of patients were identified: 120 compliant patients and 20 patients showing persistent 50% noncompliance. Patients were interviewed by a psychiatrist to develop a profile of the noncompliant patient. This profile may be useful in identifying other noncompliant geriatric patients. Early recognition of this special group of patients in need of directed counseling may help reduce medical misjudgment in prescribing for the frail elderly population.

A 61-year-old woman with a neuropathic joint was treated by total hip arthroplasty. Histologically, the absence of any osseous repair process in this hip is consistent with reports that neuropathic fractures of the femoral neck generally fail to unite. The fragments of necrotic bone found in the synovium are characteristic of the pathologic process. The above-described patient is typical of the preataxic stage. The seven-year successful result of total hip arthroplasty is most likely explained by the fact that the patient was not ataxic. Because of the unpredictability of neurosyphilis, seven years should not be considered the touchstone of success. From this experience there is no recommendation or even a suggestion that hip arthroplasty should be performed on ataxic patients.

During an 11-month period, 70 tube-fed patients aged 65 to 95 years were studied prospectively to determine the indications, benefits, and complications of enteral alimentation. Indications for alimentation were refusal to swallow (35 patients [50%], dysphagia without obstruction (33 [47%]), and esophageal obstruction (two [3%]). Nasogastric tubes (NGTs) were used initially in 69 patients; 15 of these subsequently required a gastrostomy tube (GT). One patient was treated initially with a gastrostomy. Indicators of nutritional status included weight, hemoglobin level, hematocrit, and serum albumin level. During the first two weeks the most common problems in the NGT group were agitation and self-extubation (36 patients [67%]) and aspiration pneumonia (23 [43%]). In GT patients the most common early problems were aspiration pneumonia (nine patients [56%]), tube dysfunction (eight [50%]), and agitation and extubation (seven [44%]). The common late problems were aspiration pneumonia (24 patients [44%] in the NGT group and nine [56%] in the GT group), and feeding tube dysfunction in six (38%) of the GT group. Self-extubation as a late problem was limited to the NGT group (21 patients [39%]). Twenty-eight (40%) of the 70 patients died during the study period.

At an active outpatient geriatric program the gerontological team observed that Alzheimer patients appear to have fewer physical ailments than other elderly patients. To test this hypothesis, we reviewed a sample of 348 clinic patients. One hundred forty-three had a normal mental status; 75 had Alzheimer's disease as defined by DSM-III criteria; 139 had an abnormal mental status attributed to other etiologies. The number of diagnoses was compiled in each of the three groups. The average number of diagnoses in the nondemented group was 5.0 in males, 5.4 in females. In the non-Alzheimer abnormal mental status group, the average number was 5.5 in males, 4.6 in females. In contrast, the number of diagnoses in the Alzheimer group was 2.9 in males and 2.8 in females (P less than 0.0001). Cardiovascular diseases, hypertension, and cerebrovascular accidents were less frequent in the Alzheimer population. This study suggests that Alzheimer patients are physically healthier than non-Alzheimer elderly patients.

The authors reviewed the results of annual laboratory screening (SMA 20, T3, T4, UA, EKG, chest x-ray) performed on a population of 500 institutionalized and ambulatory patients retrospectively followed from 1 to 19 years. With 30 laboratory values recorded for each annual exam, there were an average of 1.56 new abnormal laboratory findings per year per patient. A sample of 100 patients was further reviewed to determine the incidence of new diagnoses and treatment initiated by the appearance of new abnormal laboratory findings; 756 new abnormalities were recorded out of a possible 15,000, and 66 medical work-ups were initiated, which lead to new diagnoses in 21 cases and a treatment plan in 12 cases. The authors suggest that, in view of the rapid increase in the number of elderly persons and the consequent need to conserve limited health care resources, "standard" laboratory screening may not be warranted on a yearly basis in the elderly population.

In response to the challenge posed by falls in the elderly, the Jewish Institute for Geriatric Care established a Falls Clinic. The coordinated expertise of a geriatrician, neurologist, cardiologist, and physiatrist were combined with resources in audiology, ophthalmology, and podiatry. Thirty-six patients enrolled in the study had sustained a total of 36 falls, which resulted in 13 fractures and seven soft-tissue injuries. Falls were a daily occurrence for three patients, weekly for five patients, monthly for ten, semiannually for 14, and yearly for four patients. After a one-year follow-up, 77% of the patients experienced no further falls. We suggest that falls are a multidisciplinary issue and recommend a team approach for successful management.