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• Impacts of climate change on aquatic macroinvertebrates are complex. • Causal modelling is used to integrate data and models from various sources. • Macroinvertebrates' response to climate change-induced disturbances is predicted. • Optimal use of existing data and merits of models in the field can be made. • Policymaking may benefit from causal models' ability to answer 'what if' questions. Climate change is projected to threaten ecological communities through changes in temperature, rainfall, runoff patterns, and mediated changes in other environmental variables. Their combined effects are difficult to comprehend without the mathematical machinery of causal modelling. Using piecewise structural equation modelling, we aim to predict the responses of aquatic macroinvertebrate total abundance and richness to disturbances generated by climate change. Our approach involves integrating an existing hydroclimate-salinity model for the Murray-Darling Basin, Australia, into our recently developed statistical models for macroinvertebrates using long-term monitoring data on macroinvertebrates, water quality, climate, and hydrology, spanning 2,300 km of the Murray River. Our exercise demonstrates the potential of causal modelling for integrating data and models from different sources. As such, optimal use of valuable existing data and merits of previously developed models in the field can be made for exploring the effects of future climate change and management interventions. [ABSTRACT FROM AUTHOR]

Abstract: Recent advances in causal modeling have made it possible to build and test structural equation models without any restriction on the functional forms or error distributions of the structural equations. We propose here a method for building and testing causal models that uses ordination axes arising from multivariate species data. This is demonstrated through the analysis of macrobenthic species abundance data observed at multiple times before and after the 1978 Amoco Cadiz oil spill (Dauvin, 1982). The available data consist of 21 quarterly observations on 257 species during the period 1977–1982. A causal model of the impact and subsequent recovery was built and tested using distance-based redundancy analysis (dbRDA). In addition, to predict the time required for recovery of the community, nonlinear models were fitted to the first two PCO axes, and the fitted nonlinear models were used to generate predictions for 20years beyond the last observation in the data set. These predictions were found to compare favorably with the results from longer term studies carried out by Dauvin (1998). The methods described here are sufficiently well established to be used in ecological research, and will allow ecologists to move towards plausible causal models and generate stronger inferences from observational multivariate community data than has been achieved to date. [Copyright &y& Elsevier]

Abstract: We describe a composite hydroxyapatite (HA)–silk fibroin scaffold designed to induce and support the formation of mineralized bone matrix by human mesenchymal stem cells (hMSCs) in the absence of osteogenic growth factors. Porous three-dimensional silk scaffolds were extensively used in our previous work for bone tissue engineering and showed excellent biodegradability and biocompatibility. However, silk is not an osteogenic material and has a compressive stiffness significantly lower than that of native bone. In the present study, we explored the incorporation of silk sponge matrices with HA (bone mineral) micro-particles to generate highly osteogenic composite scaffolds capable of inducing the in vitro formation of tissue-engineered bone. Different amounts of HA were embedded in silk sponges at volume fractions of 0%, 1.6%, 3.1% and 4.6% to enhance the osteoconductive activity and mechanical properties of the scaffolds. The cultivation of hMSCs in the silk/HA composite scaffolds under perfusion conditions resulted in the formation of bone-like structures and an increase in the equilibrium Young’s modulus (up to 4-fold or 8-fold over 5 or 10 weeks of cultivation, respectively) in a manner that correlated with the initial HA content. The enhancement in mechanical properties was associated with the development of the structural connectivity of engineered bone matrix. Collectively, the data suggest two mechanisms by which the incorporated HA enhanced the formation of tissue engineered bone: through osteoconductivity of the material leading to increased bone matrix production, and by providing nucleation sites for new mineral resulting in the connectivity of trabecular-like architecture. [Copyright &y& Elsevier]

Tissue engineering is expected to help us outlive the failure of our organs by enabling the creation of tissue substitutes capable of fully restoring the original tissue function. Degenerative joint disease, which affects one-fifth of the US population and is the country''s leading cause of disability, drives current research of actively growing, functional tissue grafts for joint repair. Toward this goal, living cells are used in conjunction with biomaterial scaffolds (serving as instructive templates for tissue development) and bioreactors (providing environmental control and molecular and physical regulatory signals). In this review, we discuss the requirements for engineering customized, anatomically-shaped, stratified grafts for joint repair and the challenges of designing these grafts to provide immediate functionality (load bearing, structural support) and long-term regeneration (maturation, integration, remodeling). [Copyright &y& Elsevier]

Abstract: The Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a disease susceptibility gene for Parkinson''s disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950–3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation. [Copyright &y& Elsevier]

Phagocytosis of IgG-opsonized pathogens by Fc), receptors requires extensive remodeling of the actin cytoskeleton, a process regulated by the small GTPase Rac. Vav was thought to be the guanine nucleotide exchange factor responsible for the activation of Rac, but recent evidence indicates that Fcy receptor-mediated phagocytosis is unaffected in macrophages lacking all three isoforms of Vav. We therefore tested whether another GEF, DOCK180, participates in Fcy receptor-initiated phagocytosis. DOCK180 associates with the adaptor protein Crk, which mediates recruitment of the GEF to sites of tyrosine phosphorylation. CrkII and DOCK180 were found to accumulate at the phagocytic cup. Knockdown of Crk or DOCK180 in murine macrophages using small interfering RNA inhibited phagocytosis of IgG-opsonized particles. Moreover, transfection of dominant negative CrkII prevented both recruitment of DOCK180 and the activation of Rac at the phagocytic cup. This is the first report of a role for either Crk or DOCK180 in Fcy receptor-mediated phagocytosis. The Crk-DOCK180 complex is involved in the clearance of apoptotic cells, which unlike the ingestion of IgG-opsonized particles, is an anti-inflammatory process. The finding that CrkII-DOCK180 is also responsible, at least in part, for the effects of Fcγ receptors implies that additional, parallel pathways must account for the associated pro-inflammatory effect. [ABSTRACT FROM AUTHOR]

Abstract: Ruddiman [2006. What is the timing of orbital-scale monsoon changes? Quaternary Science Reviews 25, 657–658.] interprets early climate model sensitivity tests as indicating that the timing of Northern Hemisphere (NH) summer monsoon strength has, or should have, near-zero phase relative to maxima of NH precession-driven radiation. Ruddiman used this “zero-phase hypothesis” to tune the Vostok methane record to mid-July 30°N insolation with the assumption that tropical (monsoonal) sources control the orbital-scale variation of methane []. In contrast, we and others have measured the monsoon-related response in the Indian Ocean and find that the strongest monsoons occur about 8000 years after precession-driven NH radiation maxima when analyzed over the last 350,000 years. We interpret this resultant −120° phase as a combined response to multiple forcing mechanisms including NH and Southern-Hemisphere (SH) radiation as well as global ice volume. Here, we assess four issues raised by the Ruddiman Viewpoint: (1) the validity of Arabian Sea monsoon proxies, (2) the analogy between phase at the annual cycle (month) and phase at the precessional cycle (ka), (3) the phase implications of the early Kutzbach climate model sensitivity tests, and (4) the phase of ice core and speleothem records cited by Ruddiman in support of his zero-phase hypothesis. [Copyright &y& Elsevier]

Abstract: Human mesenchymal stem cells (hMSCs) have great potential in bone tissue engineering, and hydroxyapatite (HA), a natural component of human hard tissues, is believed to support hMSC growth and osteogenic differentiation. In this study, two types of biomimetic composite materials, chitosan–gelatin (CG) and hydroxyapatite/chitosan–gelatin (HCG), were fabricated and compared to examine the effects of HA on hMSC adhesion and 3-D construct development. The 2-D membranes were prepared to examine the influence of HA on adhesion efficiency of hMSCs, while 3-D porous scaffolds were produced to investigate the effects of HA on material adsorption properties and 3-D hMSC construct development. HA was found to promote protein and calcium ion adsorption of the 3-D porous scaffolds in the complete tissue culture media. HMSCs exhibited higher initial cell adhesion efficiency to 2-D HCG membranes, and maintained higher proliferation rates in the 3-D porous HCG than CG scaffolds with 3.3 times higher final DNA amount in HCG scaffolds over a 35-day period. Colony forming unit-fibroblast (CFU-F) assays showed that higher percentages of cells maintained their progenicity in the 3-D porous HCG scaffolds over the 35-day culture period. Differentiation assays indicated that the multi-lineage differentiation potential of the hMSCs was preserved in both 3-D porous scaffolds. However, higher alkaline phosphate activity was detected in the 3-D porous HCG scaffolds upon osteogenic induction indicating improved osteogenic differentiation potential. The results demonstrate that enhanced protein and calcium ion adsorption properties of HA in the CG polymer network improve initial cell adhesion and long-term growth, favor osteogenic differentiation upon induction, as well as maintain the progenicity of the 3-D hMSC constructs. [Copyright &y& Elsevier]

In 1997, The American Heart Association in association with representatives of the International Committee on Resuscitation (ILCOR) published recommended guidelines for reviewing, reporting and conducting in-hospital cardiopulmonary resuscitation (CPR) outcomes using the “Utstein style”. Using these guidelines, we developed two Microsoft Office® based database management programs that may be useful to the resuscitation community. We developed a user-friendly spreadsheet based on MS Office Excel®. The user enters patient variables such as name, age, and diagnosis. Then, event resuscitation variables such as time of collapse and CPR team arrival are entered from a “code flow sheet”. Finally, outcome variables such as patient condition at different time points are recorded. The program then makes automatic calculations of average response times, survival rates and other important outcome measurements . Also using the Utstein style, we developed a database program based on MS Office Access®. To promote free public access to these programs, we established at http://www.cproutcomes.org a website. These programs will help hospitals track, analyze, and present their CPR outcomes data. Clinical CPR researchers might also find the programs useful because they are easily modified and have statistical functions. [Copyright &y& Elsevier]

Phagocytosis is central to the microbicidal function of neutrophils. Pathogens are initially engulfed into a plasma membrane-derived vacuole, the phagosome, which proceeds to acquire degradative properties by a complex process termed maturation. In this chapter, we discuss the current knowledge of the molecular mechanisms underlying phagosome formation and maturation in neutrophils. [Copyright &y& Elsevier]

Five summer-monsoon proxies from the Northern Arabian Sea are combined using stacking and principal components analysis (PCA) to create two very similar multi-proxy records of summer-monsoon variability. The five individual proxies all respond to monsoon variability but are largely independent in terms of the processes that complicate their interpretation as summer-monsoon indicators (e.g. preservation, dissolution, diagenesis, sediment reworking). As such, stacking and PCA average out non-monsoon variance, yielding a more pure monsoon signal. These stacked and PCA records (hereafter summer-monsoon stack and summer-monsoon factor) allow evaluation of relative monsoon strength through time as well as the relative concentration of variance within orbital bands; these two parameters are less reliable when estimated from individual proxy records. In fact, the summer-monsoon factor (SMF) accounts for only 33% of the total variance in the five records, suggesting that relative amplitude variations in each individual proxy time series are influenced by non-monsoon processes. The summer-monsoon stack (SMS) and SMF are spectrally very similar, dominated by variance in the 41-k.y. (obliquity) and 23-k.y. (precession) bands; there is very little variance at the 100-k.y. (eccentricity) band associated with large-scale changes in global ice-volume. Indeed, equally strong monsoons occur in both glacial and interglacial intervals. Within the 23-k.y. precession cycle, monsoon maxima fall at −121° relative to precession minima (June 21 perihelion, maximum Northern Hemisphere (NH) summer insolation). This phase falls midway between δ18O minima (−78°) and December 21 perihelion (−180°) indicating that two mechanisms exert equal influence in determining the timing of strong summer monsoons within the precession band: (1) sensible heating of the Asian Plateau which is maximized at times of ice-volume minima (−78°), and (2) latent heat export from the southern subtropical Indian Ocean which is maximized at times of December 21 perihelion (−180°). The seasonal cycle at December 21 perihelion is characterized by warm Southern Hemisphere (SH) summers followed by cold SH winters, a combination that preconditions the ocean to export latent heat during the boreal summer-monsoon season. Summer-monsoon winds transport this latent heat into Asia where it is released during precipitation, enhancing the Asian monsoon low. Within the 41-k.y. obliquity cycle, monsoon maxima are in phase with obliquity maxima. This indicates that two mechanisms, quite similar to those in the precession band, influence the timing of strong summer-monsoons in the obliquity band: (1) sensible heating of the Asian Plateau but with no ice-volume delay, and (2) latent heat export from the southern subtropical Indian Ocean which is maximized at times of obliquity maxima. Again, the seasonal cycle at obliquity maximum is characterized by warm SH summers followed by cold SH winters, ideal for maximizing latent heat export during the boreal summer monsoon. [Copyright &y& Elsevier]

Protein interface hot spots, as revealed by alanine scanning mutagenesis, continue to stimulate interest in the biophysical basis of molecular recognition. Although these regions apparently constitute fertile grounds for intermolecular interactions, no general algorithm has yet been developed that can predict hot spots based solely on their shape or composition. The discovery of structural plasticity in hot spot regions indicates that dynamic simulation techniques may be essential for achieving a predictive understanding of binding interface energetics. Future progress will depend as much on the application of new computational approaches for dissecting protein interfaces as on expanding our empirical databank of mutagenic substitutions and their effects. Despite our current theoretical shortcomings, recent methodological advances provide efficient experimental means of probing hot spots and enable immediate applications for hot spots in drug discovery. [Copyright &y& Elsevier]

We describe the multi-decadal delayed effects of flood on macroinvertebrate community structure using 33 years of monitoring data on macroinvertebrates, water quality, and climate, and 51 years of hydrological data, spanning 2300 km of the Murray River, Australia. We used distributed lag nonlinear models in a four-step analytical process, including 1) modelling macroinvertebrate community structure, represented as a set of principle coordinate axes, as a function of a lagged hydrologic index and other environmental variables using distance-based redundancy analysis 2) visualizing the patterns of delayed effects of flows on the PCO axes, 3) modelling the abundances of groups of taxa along individual PCO axes, and 4) combining the two sets of models in a counterfactual analysis to predict the community structure under flood and no-flood scenarios to describe the multi-decadal trajectory of the community following a flood. Our findings show an increase in abundance of most taxa of filtering-gathering collectors, scrapers, and shredders in the long term that implicates an influx of organic matter of all sizes, from particulate organic matter to coarse and large woody debris, that serves directly or indirectly as a food resource and/or habitat. Our approach enabled the isolation of a flood impact from the confounding effects of other flow events and environmental variables, overcoming a substantial challenge in ecohydrological studies. Unlabelled Image • Large floods could have decadal impacts on macroinvertebrate community structure. • Small and medium flows have indiscernible effects on the community structure. • Floods may cause an increase in all functional feeding groups. • Community succession suggests the involvement of influx of organic matter by floods. [ABSTRACT FROM AUTHOR]

The alteration of normal dermal fibroblast function that leads to the development of hypertrophic scar after thermal injury is unknown. To determine functional differences that might explain this process, fibroblasts were cultured from biopsies of post-thermal injury mature hypertrophic scars and patient-matched normal skin. The mitogenic responses of scar cells to fetal bovine serum, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and tumor necrosis factor α (TNFα) were determined and compared to normal skin cells. Collagen synthetic rate was also compared in the presence and absence of transforming growth factor β1 (TGFβ1). Whereas both scar and normal cells responded with increased thymidine uptake to serum and cytokines, the stimulation to EGF and serum was significantly lower in scar cells. In contrast, synthesis of collagen, but not of non-collagenous proteins, was increased in scar relative to normal cells, both basally and when stimulated with low doses of TGFβ1. Additionally, the fraction of protein synthesized as collagen was significantly higher in scar fibroblasts. These results suggest that fibroblasts from hypertrophic scars demonstrate stable phenotypic differences in cytokine responsiveness in comparison to cells from unaffected skin. The increased rate of collagen synthesis and decreased responsiveness to mitogens are consistent with the increased extracellular matrix content and decreased cellularity of hypertrophic scars. [ABSTRACT FROM AUTHOR]

Summary: The LAC+USC Burn Center has admitted 3118 patients for treatment in the last 10 years. A majority of patients were young adults (1868), with the second largest group being small children (543). The ethnicity of the patients reflects the diverse nature of the population of Los Angeles County. Forty-eight percent of injuries were less than 5% TBSA and approximately 2% were greater than 60% TBSA. Eighty-two percent were accidental injuries. Sixty percent of admitted patients underwent skin grafting. Mortality was negligible in the group with burns over less than 10% of their body and very high (15/19), 79% in the most severely burned group. Further, there was a high correlation between age and mortality. Complications during treatment included: deep venous thrombosis 1% per year; pulmonary emboli in 5 patients; endotracheal tube dislodgment early or self-extubation about 1 month (11.3 per year); 4.5 patients per year who developed acute renal failure; abdominal compartment syndrome developed in 4.7 patients each year; heterotopic ossification was seen in 4 patients (0.4%); 4 patients (0.4%) developed stage II–IV pressure sores; hypothermia was present in 0.8% of patients. [Copyright &y& Elsevier]

This randomized trial of fractionation after breast reconstruction (FABREC) sought to compare quality-of-life (QOL) and clinical outcomes of hypofractionated (HF) vs. conventionally-fractionated (CF) postmastectomy radiation therapy (PMRT) in the setting of immediate prosthetic reconstruction. Between 3/2018 and 11/2021, 400 patients at 18 centers with Stage 0-III breast cancer and immediate placement of tissue expander (TE) or implant (I) after mastectomy were randomized 1:1 to HF or CF photon PMRT. Respective doses in the two arms were 42.56 Gy/16 fractions to the chest wall (CW), with or without axillary/supraclavicular lymph node (LN) radiation (39.9 Gy/15 fractions) and 50 Gy in 25 fractions to CW (46-50 Gy to axillary LNs). A boost was not permitted; bolus was used at physician discretion. CW toxicity was defined as any grade ≥3 adverse event (CTCAE) after PMRT initiation. Patients were censored at study withdrawal or at diagnosis of distant recurrence. Participants completed QOL instruments (FACT-B, BREAST-Q, Lymph-ICF) at baseline, 6, 12 and 18-months from PMRT initiation. Questions regarding financial burden were included with the 6-month survey. Primary endpoint of the study was improvement in the Physical Well-Being (PWB) domain of FACT-B at 6 months with pre-specified stratification by age (younger than 45 vs. 45 years or older). QOL scores were compared using Student's t-test. Median follow-up for the 385 patients analyzed was 31.8 months (range, 6.9-54.4); median age was 47.0 years (range, 23-79). Preoperative chemotherapy was used in 67.8% and preoperative endocrine therapy (ET) in 21.5% of the cohort. There were 16 distant (8 in each arm), and 2 local-regional (1 in each arm) recurrences. CW toxicity occurred in 35 patients (19 HF, 16 CF, p=0.58) at medians of 3.4 and 4.8 months after RT initiation in the HF and CF arms, respectively (p=0.82). Post-operative infection before RT (HR=3.31, p=0.03), irradiation of TE vs I (HR=7.74, p=0.046), preoperative endocrine therapy (HR=3.45, p=0.0007) and number of LNs removed (HR=1.06/node, p=0.02) were significant for developing CW toxicity on multivariate analysis, while fractionation was not (HF HR=1.19, p=0.63). There was no significant difference in overall change in PWB scores at 6 months between the two treatment arms (p=0.71) or separately in younger (p=0.15) and older cohorts (p=0.27). However, HF patients younger than 45 were less bothered by side-effects of treatment (p=0.045) and nausea (p=0.02) vs. CF patients younger than 45. Among patients who took unpaid time off from work during treatment (n=51), those receiving HF required fewer hours off than those receiving CF (73.7 vs. 125.8, p=0.046). Physical well-being and overall toxicity profile of HF PMRT were comparable between HF and CF PMRT. HF was associated with better 6-month QOL in some domains among younger patients. Our early results support the use of HF PMRT in the setting of TE- or implant-based breast reconstruction. [ABSTRACT FROM AUTHOR]

Highlights: [•] Severe influenza is characterized by acute lung injury. [•] Influenza virus can induce pulmonary endothelial leak via cytopathic and paracrine effects. [•] Drugs that enhance endothelial barrier integrity may decrease mortality from influenza. [Copyright &y& Elsevier]

Purpose: Vertebral compression fracture is a common complication of spinal stereotactic body radiation therapy. Development of an in vivo model is crucial to fully understand how focal radiation treatment affects vertebral integrity and biology at various dose fractionation regimens. We present a clinically relevant animal model to analyze the effects of localized, high-dose radiation on vertebral microstructure and mechanical integrity. Using this model, we test the hypothesis that fractionation of radiation dosing can reduce focused radiation therapy's harmful effects on the spine.Methods and Materials: The L5 vertebra of New Zealand white rabbits was treated with either a 24-Gy single dose of focused radiation or 3 fractionated 8-Gy doses over 3 consecutive days via the Small Animal Radiation Research Platform. Nonirradiated rabbits were used as controls. Rabbits were euthanized 6 months after irradiation, and their lumbar vertebrae were harvested for radiologic, histologic, and biomechanical testing.Results: Localized single-dose radiation led to decreased vertebral bone volume and trabecular number and a subsequent increase in trabecular spacing and thickness at L5. Hypofractionation of the radiation dose similarly led to reduced trabecular number and increased trabecular spacing and thickness, yet it preserved normalized bone volume. Single-dose irradiated vertebrae displayed lower fracture loads and stiffness compared with those receiving hypofractionated irradiation and with controls. The hypofractionated and control groups exhibited similar fracture load and stiffness. For all vertebral samples, bone volume, trabecular number, and trabecular spacing were correlated with fracture loads and Young's modulus (P < .05). Hypocellularity was observed in the bone marrow of both irradiated groups, but osteogenic features were conserved in only the hypofractionated group.Conclusions: Single-dose focal irradiation showed greater detrimental effects than hypofractionation on the microarchitectural, cellular, and biomechanical characteristics of irradiated vertebral bodies. Correlation between radiologic measurements and biomechanical properties supported the reliability of this animal model of radiation-induced vertebral compression fracture, a finding that can be applied to future studies of preventative measures. [ABSTRACT FROM AUTHOR]

Abstract: Enhancing human mesenchymal stem cell (hMSC) differentiation via RNA interference (RNAi) could provide an effective way of controlling cell fate for tissue engineering, but a safe and effective delivery vehicle must first be developed. Here, we evaluated an array of synthetic end-modified poly(beta-amino ester) (PBAE)-based nanoparticles to optimize siRNA delivery into hMSCs. In general, cystamine-terminated polymers caused the most knockdown, with the best polymer achieving 91% knockdown 20 days post-transfection. Binding studies revealed that the cystamine-terminated polymer bound siRNA tightly at lower weight ratios of polymer to siRNA but then efficiently released siRNA upon exposure to a reducing environment, suggesting that this class of PBAEs can form tight initial interactions with its cargo and then cause efficient, environmentally-triggered release in the cytoplasm. Finally, we tested a functional application of this system by transfecting hMSCs with siRNA against an inhibitor of osteogenesis, B-cell lymphoma (Bcl)-like protein 2 (BCL2L2). This resulted in enhanced osteogenesis over 4 weeks as evidenced by Alizarin Red S staining and calcium quantification. The bioreducible PBAE/siRNA nanoparticles developed here can provide a means of safe and effective control of hMSC differentiation for a wide variety of applications. [Copyright &y& Elsevier]

An excessive amount of matrix metalloproteinase-9 (MMP-9) has been well documented in inflammatory diseases, including chronic wounds and cancers. Secreted as a zymogen, proMMP-9 can be irreversibly converted to a mature form through cleavage of the N-terminal propeptide domain. Although the converting enzyme for proMMP-9 in human tissues is unknown, we previously found that tumor necrosis factor-α (TNF-α) promotes activation of proMMP-9 in human skin, and characterized the converting activities as tissue-associated chymotrypsin-like proteinases. On the other hand, the pathophysiologic inhibitor to prevent proMMP-9 maturation also remains elusive. In this regard, we observed the presence of the inhibitory property in burn blister fluid that abrogates the skin extract–mediated activation of proMMP-9. Then we determined that α-1-antichymotrypsin (α-ACT), an acute-phase factor abundantly present in the blister, effectively inhibited proMMP-9 activation in human and rodent skin. In contrast, the aminophenylmercuric acetate-induced “cysteine switch” and activation of proMMP-9 were not affected by α-ACT. TNF-α-induced activation of proMMP-9 by the explants of human skin was inhibited by α-ACT but not by related α-1-antitrypsin. α-ACT specifically attenuated maturation of proMMP-9 but not proMMP-2 or proMMP-13. Furthermore, short peptides that mimic the reactive center loop (RCL) of α-ACT were sufficient to inhibit the conversion. Mutation analysis demonstrated that a conserved leucine within the RCL was critical for α-ACT-exerted inhibition. In chronic wounds, a large amount of mature MMP-9 was associated with fragmentation and inactivation of α-ACT. Taken together, these results demonstrate that, to the best of our knowledge, α-ACT is a previously unreported pathophysiologic inhibitor that controls proMMP-9 activation in skin tissue.Journal of Investigative Dermatology (2008) 128, 2334–2342; doi:10.1038/jid.2008.77; published online 10 April 2008 [ABSTRACT FROM AUTHOR]

Abstract: A cyclohexanemonocarboxylic acid-capped 15-crown-5 ether was synthesized and found to be effective as an ionophore for Pb2+ and Cd2+, transporting them across a phospholipid bilayer membrane. Transport studies were carried out using 1-palmitoyl-2-oleoyl-sn-glycerophosphatidylcholine (POPC) vesicles containing the chelating indicator 2-([2-bis(carboxymethyl)amino-5-methylphenoxy]methyl)-6-methoxy-8-bis(carboxymethyl)aminoquinoline (Quin-2). Data obtained at pH 7.0 using this system, show that the synthetic ionophore transports divalent cations with the selectivity sequence Pb2+ >Cd2+ ≫Zn2+ >Mn2+ >Co2+ >Ni2+ >Ca2+ >Sr2+. Selectivity factors, based on the ratio of individual initial cation transport rates, are 280 (Pb2+/Ca2+), 62 (Pb2+/Zn2+), 68 (Cd2+/Ca2+), and 16 (Cd2+/Zn2+). Plots of log initial rate versus logM n+ or log ionophore concentration suggest that Pb2+ and Cd2+ are transported primarily as a 1:1 cation–ionophore complex, but that complexes with other stoichiometries may also be present. The ionophore transports Pb2+ and Cd2+ by a predominantly electrogenic mechanism, based upon an enhanced rate of transport that is produced by agents which dissipate transmembrane potentials. The rate of Pb2+ transport shows a biphasic pH dependence with the maximum occurring at pH∼6.5. The high selectivity for Pb2+ and Cd2+ displayed by the cyclohexanecarboxylic acid-capped 15-crown-5 ether suggests potential applications of this ionophore for the treatment of Pb and Cd intoxication, and removal of these heavy metals from wastewater. [Copyright &y& Elsevier]

Patient understanding of radiotherapy (RT) processes and data regarding optimal approaches to patient education (PE) within radiation oncology (RO) are limited. Our objective was to evaluate PE practices and preferences of interprofessional RO providers to inform recommendations for delivering inclusive, accessible, and patient-centered education. An anonymous 17-item online survey, approved by an ethics review board, was administered to all members of the Radiation Oncology Education Collaborative Study Group (ROECSG) between 10/5/22 to 11/23/22. Respondent demographics, provider practices/preferences, and institutional practices were collected. Qualitative items explored key strategies, challenges, and desired resources for PE. Descriptive statistics summarized survey responses. Fisher's exact test compared PE practices by provider role and PE timing. Thematic analysis was used for qualitative responses. A total of 123 ROECSG members, including RO attendings (64%), RO trainees (21%), medical physicists (7%), physician assistants/nurses (2%), and radiation therapists (2%), completed the survey (31% response rate). Most practiced in an academic setting (86%) in North America (82%). The most common PE resources used were custom created institution-specific (61%) and electronic health system generated materials (38%). PE was delivered primarily by one-on-one teaching (72%), paper handouts (69%), and organizational websites (21%) (e.g., RTanswers.org). Almost half (41%) reported that PE practices differed based on type of clinical encounter, for example paper handouts for in-person visits and multimedia for virtual visits. The majority (86%) stated that their institution has disease site-specific PE materials, with nearly all having breast cancer materials (91%). Only 58% reported access to non-English PE materials. RO attendings/trainees were more likely than other team members to deliver PE at consultation (98% vs 71%, p = 0.03). PE practices amongst radiation oncologists differed according to the timing along the RT care path (consultation vs simulation vs first fraction, respectively): one-on-one teaching: 89% vs 49% vs 56%, p<0.01 and paper handouts: 69% vs 28% vs 16%, p<0.01. Key PE strategies included incorporating multimedia resources, personalizing delivery, and repetition at multiple timepoints by the interprofessional team. Limited time, inadequate administrative support, and lack of customized resources were identified as challenges in PE delivery. Interprofessional RO providers engage in PE, with most utilizing institution-specific materials. PE practices differ according to the type of clinical encounter and timing in the RT care path. Increased adoption of multimedia materials and partnerships with patients to tailor PE resources based on language, learning styles, and cultural preferences are needed to foster high-quality, patient-centered PE delivery. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a highcapacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP- 9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP- 9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis. [ABSTRACT FROM AUTHOR]

The accumulation of low-density lipoproteins (LDL) in the arterial wall plays a pivotal role in the initiation and pathogenesis of atherosclerosis. Conversely, the removal of cholesterol from the intima by cholesterol efflux to high density lipoproteins (HDL) and subsequent reverse cholesterol transport shall confer protection against atherosclerosis. To reach the subendothelial space, both LDL and HDL must cross the intact endothelium. Traditionally, this transit is explained by passive filtration. This dogma has been challenged by the identification of several rate-limiting factors namely scavenger receptor SR-BI, activin like kinase 1, and caveolin-1 for LDL as well as SR-BI, ATP binding cassette transporter G1, and endothelial lipase for HDL. In addition, estradiol, vascular endothelial growth factor, interleukins 6 and 17, purinergic signals, and sphingosine-1-phosphate were found to regulate transendothelial transport of either LDL or HDL. Thorough understanding of transendothelial lipoprotein transport is expected to elucidate new therapeutic targets for the treatment or prevention of atherosclerotic cardiovascular disease and the development of strategies for the local delivery of drugs or diagnostic tracers into diseased tissues including atherosclerotic lesions. Image 1 • The endothelium limits the entry and exit of lipoproteins into and from the arterial wall, respectively. • SR-BI, activin like kinase 1, and caveolin-1 as well as GPER and sphingosine-1-phosphate regulate the transcytosis of LDL. • SR-BI, ABCG1, endothelial lipase, the ecto-ATPase/P2Y-receptor axis, VEGF, IL-6/17, and S1P regulate HDL transcytosis. [ABSTRACT FROM AUTHOR]

Background: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is an autoimmune condition with significant morbidity and mortality.Methods: A retrospective review was performed at a single institution. All patients admitted to the LAC+USC burn unit from May 1st 2015-January 1st 2018 with a histologic diagnosis of SJS/TEN were reviewed. Patient characteristics and outcomes were recorded. These outcomes were compared to our previously published cohort.Results: Thirteen total consecutive SJS/TEN patients were treated with etanercept. Compared to non-etanercept treated patients, etanercept-treated patients did not experience a significant difference in mortality (15.4% vs. 10%, P=0.58), ICU days (6.9 vs. 15.1, P=0.08), length-of-stay (9.8 vs 16.4, P=0.11), or infections (38.5% vs. 57.5%, P=0.58). The standardized mortality ratio in etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65). In general, etanercept-treated patients had higher SCORTENs (3 vs. 2, P=0.03) and longer delays to presentation (5.2 vs. 2.7 days, P<0.01).Conclusions: Etanercept can be considered in the treatment of SJS/TEN patients in addition to IVIg, and supportive care in a burn unit. [ABSTRACT FROM AUTHOR]

We demonstrate the effect of varying Al-Zr chemistry on the morphology, microstructure, intermetallic reactions and ignition temperature of powders prepared using arrested reactive ball milling in hexane. Upon slow heating in Ar, 3Al:Zr, Al:Zr, and Al:3Zr (at.%) produces 19 ± 2.6 kJ/mol 22.0 ± 1.6 kJ/mol, and 14.0 ± 2.6 kJ/mol of heat respectively. When rapidly heated in air 3Al:Zr powders did not ignite, while Al:Zr and Al:3Zr had ignition temperatures of 461 ± 25 °C and 475 ± 25 °C, suggesting Zr oxidation is aiding ignition. To reduce cold welding of 3Al:Zr during milling, acetonitrile replaced a fraction of hexane. 3Al:Zr milled with 6.25 vol% and 12.5 vol% acetonitrile had smaller particles, higher heats and lower ignition temperatures compared to 0 vol%. 3Al:Zr with 6.25 vol% demonstrated the lowest ignition temperatures (433 ± 34 °C). 3Al:Zr with 12.5 vol% had the smallest mean diameter, largest surface area, smallest Zr inclusion areas, and highest heats, but had higher ignition temperatures (492 ± 27 °C), likely due to ZrC inhibiting the reaction of Zr with N and O. [Display omitted] • Planetary ball milling of varying Al-Zr compositions. • Ignition temperature of various Al-Zr compositions in planetary ball milled powders. • Planetary ball milled aluminum zirconium with immiscible process control agents. [ABSTRACT FROM AUTHOR]

Tissue engineering strategies to treat patients with volumetric muscle loss (VML) aim to recover the structure and contractile function of lost muscle tissue. Here, we assessed the capacity of novel electrospun fibrin hydrogel scaffolds seeded with murine myoblasts to regenerate the structure and function of damaged muscle within VML defects to the mouse tibialis anterior muscle. The electrospun fibrin scaffolds provide pro-myogenic alignment and stiffness cues, myomimetic hierarchical structure, suturability, and scale-up capabilities. Myoblast-seeded scaffolds enabled remarkable muscle regeneration with high myofiber and vascular densities after 2 and 4 weeks, mimicking that of native skeletal muscle, while acellular scaffolds lacked muscle regeneration. Both myoblast-seeded and acellular scaffolds fully recovered muscle contractile function to uninjured values after 2 and 4 weeks. Electrospun scaffolds pre-vascularized with co-cultured human endothelial cells and human adipose-derived stem cells implanted into VML defects for 2 weeks anastomosed with host vasculature and were perfused with host red blood cells. These data demonstrate the significant potential of electrospun fibrin scaffolds seeded with myoblasts to fully regenerate the structure and function of volumetric muscle defects and these scaffolds offer a promising treatment option for patients with VML. [ABSTRACT FROM AUTHOR]

Post-mastectomy radiotherapy (PMRT) is associated with increased risk of implant-based breast reconstruction complications. We sought to examine the relationship between clinical/dosimetric factors and implant reconstruction complications. We conducted a retrospective study of breast cancer patients (pts) who underwent simulation for PMRT from 2012 to 2015 following single-stage or two-stage implant-based reconstruction. Demographic, disease, treatment, and reconstruction outcomes data were collected. Major reconstruction complication (MRC) was defined as any complication requiring unplanned reoperation or removal. Clinical/dosimetric factors associated with MRC were determined by Cox regression. Cutpoints for dosimetric variables were determined by the Contal and O'Quigley method. We identified 111 pts who underwent PMRT following implant-based reconstruction. 91% underwent two-stage reconstruction with PMRT to a tissue expander (TE) and 9% underwent single-stage reconstruction with PMRT to the permanent implant (PI). All pts were treated using 3D-CRT with conventional fractionation (1.8-2 Gy/day) for the majority of their treatment. 11 pts (10%) received hypofractionated (2.1-3 Gy) treatment for the last 2-5 fractions for scheduling reasons and were excluded from dosimetric analysis. 44% received a chest wall boost (4-10 Gy). At a median follow-up of 6.6 years, 45 pts (41%) experienced an MRC (8 had MRC while TE was in place, 7%; 37 had MRC while PI was in place, 33%). Following MRC, at time of last follow-up/death, 15 pts lacked replacement reconstruction and 12 had autologous reconstruction. Median time from end of PMRT to MRC was 1.6 yrs. The most common types of MRC were contracture (31%), infection (22%), asymmetry (18%), and threatened exposure of the PI (7%). On univariate analysis, there was no significant difference between pts with or without MRC with respect to age, race, smoking history, menopause status, chemotherapy or hormonal therapy, or reconstruction timing. Obesity (P = 0.03; HR 2.26, 1.08-4.76) and infection occurring after mastectomy and within 30 days after PMRT (P < 0.0001; HR 7.37, 2.78-19.55) were significantly associated with MRC. Dosimetric characteristics (excluding boost), including maximum chest wall hot spot ≥ 5464 cGy (P = 0.003; HR 4.08, 1.60-10.41), D 2cc ≥ 5410 cGy (P = 0.01; HR 3.51, 1.37-8.95), D 0.03cc ≥ 5420 cGy (P = 0.01; HR 4.73, 1.46-15.33), V100% ≥ 640 cc (P = 0.01; HR 2.72, 1.26-5.91), V105% ≥ 250 cc (P = 0.003; 2.58, 1.39-4.77), and V108% ≥ 3.5 cc (P = 0.01; HR 2.97, 1.25-7.07) were significantly associated with MRC. Patients undergoing PMRT and implant-based reconstruction are at significant risk of MRC. Obesity, infection within 30 days of PMRT, increased treatment volume, and plan heterogeneity further increase this risk. Additional studies are needed to validate these findings and determine dosimetric constraints or other prophylactic measures that can limit complication risk. [ABSTRACT FROM AUTHOR]

Oxygen diffusion limitations within nascent tissue engineered (TE) grafts lead to the development of hypoxic regions, cell death, and graft failure. Previous efforts have been made to deliver oxygen within TE scaffolds, including peroxide-doping, perfluorocarbons, and hyperbaric oxygen therapy, to mitigate these effects and help maintain post transplantation cell viability, but these have suffered from significant drawbacks. Here we present a novel approach utilizing polymeric hollow-core microspheres that can be hyperbarically loaded with oxygen and subsequently provide prolonged oxygen delivery. These oxygen carriers are termed, microtanks . With an interest in orthopedic applications, we combined microtanks within polycaprolactone to form solid phase constructs with oxygen delivery capabilities. The mathematical laws governing oxygen delivery from microtank-loaded constructs are developed along with empirical validation. Constructs achieved periods of oxygen delivery out to 6 days, which was shown to prolong the survival of human adipose derived stem cells (hASCs) and human umbilical vein endothelial cells (HUVECs) as well as to enhance their cellular morphology under anoxic conditions. The results of this study suggest the microtank approach may be a feasible means of maintaining cell viability in TE scaffolds during the critical period of vascularization in vivo . [ABSTRACT FROM AUTHOR]

In 1978, the 3rd International Sun–Earth Explorer (ISEE-3) became the first libration-point mission, about the Sun–Earth L1 point. Four years later, a complex series of lunar swingbys and small propulsive maneuvers ejected ISEE-3 from the Earth–Moon system, to fly by a comet (Giacobini–Zinner) for the first time in 1985, as the rechristened International Cometary Explorer (ICE). In its heliocentric orbit, ISEE-3/ICE slowly drifted around the Sun to return to the Earth׳s vicinity in 2014. Maneuvers in 1986 targeted a 2014 August 10th lunar swingby to recapture ISEE-3 into Earth orbit. In 1999, ISEE-3/ICE passed behind the Sun; after that, tracking of the spacecraft ceased and its control center at Goddard was shut down. In 2013, meetings were held to assess the viability of “re-awakening” ISEE-3. The goal was to target the 2014 lunar swingby, to recapture the spacecraft back into a halo-like Sun–Earth L1 orbit. However, special hardware for communicating with the spacecraft via NASA׳s Deep Space Network stations was discarded after 1999, and NASA had no funds to reconstruct the lost equipment. After ISEE-3׳s carrier signal was detected on March 1st with the 20 m antenna at Bochum, Germany, Skycorp, Inc. decided to initiate the ISEE-3 Reboot Project, to use software-defined radio with a less costly S-band transmitter that was purchased with a successful RocketHub crowdsourcing effort. NASA granted Skycorp permission to command the spacecraft. Commanding was successfully accomplished using the 300 m radio telescope at Arecibo. New capture trajectories were computed, including trajectories that would target the August lunar swingby and use a second Δ V (velocity change) that could target later lunar swingbys that would allow capture into almost any desired final orbit, including orbits about either the Sun–Earth L1 or L2 points, a lunar distant retrograde orbit, or targeting a flyby of the Earth-approaching active Comet Wirtanen in 2018. A tiny spinup maneuver was performed on July 2nd, the first since 1987. A 7 m/s Δ V maneuver was attempted on July 8th, to target the August lunar swingby. But the maneuver failed; telemetry showed that only about 0.15 m/s of Δ V was accomplished, then the thrust quickly decayed. The telemetry indicated that the nitrogen pressurant was gone so hydrazine could not be forced to the thrusters. The experience showed how a spacecraft can survive 30 years of space weather. The spacecraft flew 18 thousand km from the Moon, resulting in a heliocentric orbit that will return near the Earth in 2029. [ABSTRACT FROM AUTHOR]

Critical-sized midfacial bone defects present a unique clinical challenge due to their complex three-dimensional shapes and intimate associations with sensory organs. To address this challenge, a point-of-care treatment strategy for functional, long-term regeneration of 2 cm full-thickness segmental defects in the zygomatic arches of Yucatan minipigs is evaluated. A digital workflow is used to 3D-print anatomically precise, porous, biodegradable scaffolds from clinical-grade poly-ε-caprolactone and decellularized bone composites. The autologous stromal vascular fraction of cells (SVF) is isolated from adipose tissue extracts and infused into the scaffolds that are implanted into the zygomatic ostectomies. Bone regeneration is assessed up to 52 weeks post-operatively in acellular (AC) and SVF groups (BV/DV = 0.64 ± 0.10 and 0.65 ± 0.10 respectively). In both treated groups, bone grows from the adjacent tissues and restores the native anatomy. Significantly higher torque is required to fracture the bone-scaffold interface in the SVF (7.11 ± 2.31 N m) compared to AC groups (2.83 ± 0.23 N m). Three-dimensional microcomputed tomography analysis reveals two distinct regenerative patterns: osteoconduction along the periphery of scaffolds to form dense lamellar bone and small islands of woven bone deposits growing along the struts in the scaffold interior. Overall, this study validates the efficacy of using 3D-printed bioactive scaffolds with autologous SVF to restore geometrically complex midfacial bone defects of clinically relevant sizes while also highlighting remaining challenges to be addressed prior to clinical translation. [ABSTRACT FROM AUTHOR]

Low oxygen (O 2) diffusion into large tissue engineered scaffolds hinders the therapeutic efficacy of transplanted cells. To overcome this, we previously studied hollow, hyperbarically-loaded microtanks (μtanks) to serve as O 2 reservoirs. To adapt these for bone regeneration, we fabricated biodegradable μtanks from polyvinyl alcohol and poly (lactic- co -glycolic acid) and embedded them to form 3D-printed, porous poly-ε-caprolactone (PCL)-μtank scaffolds. PCL-μtank scaffolds were loaded with pure O 2 at 300–500 psi. When placed at atmospheric pressures, the scaffolds released O 2 over a period of up to 8 h. We confirmed the inhibitory effects of hypoxia on the osteogenic differentiation of human adipose-derived stem cells (hASCs and we validated that μtank-mediated transient hyperoxia had no toxic impacts on hASCs, possibly due to upregulation of endogenous antioxidant regulator genes. We assessed bone regeneration in vivo by implanting O 2 -loaded, hASC-seeded, PCL-μtank scaffolds into murine calvarial defects (4 mm diameters × 0.6 mm height) and subcutaneously (4 mm diameter × 8 mm height). In both cases we observed increased deposition of extracellular matrix in the O 2 delivery group along with greater osteopontin coverages and higher mineral deposition. This study provides evidence that even short-term O 2 delivery from PCL-μtank scaffolds may enhance hASC-mediated bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Hydrogels have been widely used for 3-dimensional (3D) cell culture and tissue regeneration due to their tunable biochemical and physicochemical properties as well as their high water content, which resembles the aqueous microenvironment of the natural extracellular matrix. While many properties of natural hydrogel matrices are modifiable, their intrinsic isotropic structure limits the control over cellular organization, which is critical to restore tissue function. Here we report a generic approach to incorporate alignment topography inside the hydrogel matrix using a combination of electrical and mechanical stretching. Hydrogel fibres with uniaxial alignment were prepared from aqueous solutions of natural polymers such as alginate, fibrin, gelatin, and hyaluronic acid under ambient conditions. The unique internal alignment feature drastically enhances the mechanical properties of the hydrogel microfibres. Furthermore, the facile, organic solvent-free processing conditions are amenable to the incorporation of live cells within the hydrogel fibre or on the fibre surface; both approaches effectively induce cellular alignment. This work demonstrates a versatile and scalable strategy to create aligned hydrogel microfibres from various natural polymers. [Copyright &y& Elsevier]

Purpose/objective(s): The COVID-19 pandemic posed challenges in resource allocation and breast cancer (BC) treatment decisions. Our study aims to understand changes in practice patterns of United States radiation oncologists (RO) treating BC during the COVID-19 pandemic.Materials/methods: An IRB-approved 58-question survey with 6 clinical scenarios was distributed between July 17 and November 8, 2020 to ASTRO directory members. The cases included 1) Low-grade ductal carcinoma in situ (DCIS), 2) Low-risk BC treated with lumpectomy, 3) Low-risk BC treated with mastectomy with reconstruction 4) BC treated with neoadjuvant chemotherapy and mastectomy with reconstruction 5) BC treated with mastectomy and adjuvant chemotherapy but without reconstruction 6) Metastatic BC with enlarging breast mass. RO were surveyed about treatment recommendations if cases were seen pre-pandemic (PP) and hypothetically during the peak of pandemic (DTPP). Chi-square and McNemar-Bowker tests were used to examine the significance of changes.Results: A total of 285 respondents from 48 states completed the survey and reported treating at least one patient with BC in the past 12 months. 45% primarily practice in university affiliated hospitals and 43% in private practice. 22% reported treating ≥ 1 COVID-positive BC patients. Moderate hypofractionation (2.31 - 3 Gy per fraction) in the PMRT and immediate reconstruction setting was recommended by 0.7% PP compared to 10.5% DTPP. In the low-risk PMRT setting, recommendation of no further treatment increased from 13% PP to 20% DTPP. Further, 56% changed their DCIS recommendations if the patient was seen DTPP. For low-risk BC, whole breast RT was preferred by 83.5% PP compared to 46.7% DTPP, and 35.1% recommended delay of RT DTPP compared to 0.4% PP (P < 0.05). Increase in ultra-hypofractionation (> 5 Gy per fraction) was significant for low-risk BC after lumpectomy as 0.4% reported its use PP compared to 3.8% DTPP. In addition, utilization of brachytherapy as PBI modality decreased from 23.9% to 17% among respondents PP and DTPP respectively. The Florence fractionation schedule for PBI was recommended by 46.2% for early-stage BC and by 51.7% for DCIS DTPP compared to 20% and 34.4% PP. Finally, 68.1% reported the use of 10-25 fractions PP for the palliative scenario. However, of those who would change their recommendation (48.8%), 62.8% reported recommendation of ≤ 5 fractions DTPP. Additional subset analysis by geographic region and practice type were notable for variable changes in treatment recommendations, and will be presented.Conclusion: This large survey of Breast RO clinical decision making demonstrates significant differences in recommendations and rapid adoption of unique fractionation. While likely reflective of intent to optimize resource allocations during the pandemic, maintenance of new practice patterns remains subject to future investigation. [ABSTRACT FROM AUTHOR]

Abstract: Dysregulation of the glutamatergic system has been implicated not only in the treatment of major depressive disorder (MDD), but also in the excitotoxic effects of stress and anxiety on the prefrontal cortex, which may precede the onset of a depressive episode. Our previous studies demonstrate marked deficits in prominent postsynaptic proteins involved in glutamate neurotransmission in the prefrontal cortex (PFC), Brodmann''s area 10 (BA 10) from subjects diagnosed with major depressive disorder (MDD). In the same group of subjects we have identified deficits in expression and phosphorylation level of key components of the mammalian target of rapamycin (mTOR) signaling pathway, known to regulate translation initiation. Based on our previous findings, we have postulated that glutamate-dependent dysregulation of mTOR-initiated protein synthesis in the PFC may underlie the pathology of MDD. The aim of this study was to use the NanoString nCounter System to perform analysis of genes coding for glutamate transporters, glutamate metabolizing enzymes, neurotrophic factors and other intracellular signaling markers involved in glutamate signaling that were not previously investigated by our group in the PFC BA 10 from subjects with MDD. We have analyzed a total of 200 genes from 16 subjects with MDD and 16 healthy controls. These are part of the same cohort used in our previous studies. Setting our cutoff p-value≤0.01, marked upregulation of genes coding for mitochondrial glutamate carrier (GC1; p=0.0015), neuropilin 1 (NRP-1; p=0.0019), glutamate receptor ionotropic N-methyl-d-aspartate-associated protein 1 (GRINA; p=0.0060), and fibroblast growth factor receptor 1 (FGFR-1; p=0.010) was identified. No significant differences in expression of the remaining 196 genes were observed between MDD subjects and controls. While upregulation of FGFR-1 has been previously shown in MDD; abnormalities in GC-1, GRINA, and NRP-1 have not been reported. Therefore, this postmortem study identifies GC1, GRINA, and NRP-1 as novel factors associated with MDD; however, future studies will be needed to address the significance of these genes in the pathophysiology of depression and antidepressant activity. [Copyright &y& Elsevier]

Background: High-frequency percussive ventilation (HFPV) is an effective rescue therapy in ventilated patients with acute lung injury. High levels of inspired oxygen (FiO2) are toxic to the lungs. The objective of this study was to review a low FiO2 (0.25)/HFPV protocol as a protective strategy in burn patients receiving mechanical ventilation greater than 10days. Methods: A single-center, retrospective study in burn patients between December 2002 and May 2005 at the LAC+USC Burn Center. Demographic and physiologic data were recorded from time of admission to extubation, 4weeks, or death. Results: 32 subjects were included in this study, 1 patient failed the protocol. 23 of 32 (72%) patients were men and mean age was 46±15years. Average TBSA burn was 30±20 with 9 of 32 (28%) having >40% TBSA involved. Average burn index was 76±21. 22 of 32 (69%) had inhalation injury and 23 of 32 (72%) had significant comorbidities. Average ventilator parameters included ventilator days 24±12, FiO2 0.28±0.03, PaO2 107±15Torr, PaCO2 42±4Torr, and PaO2/FiO2 ratio 395±69. 16 of 32 (50%) patients developed pneumonia and 9 of 32 (28%) died. No patient developed ARDS, barotrauma, or died from respiratory failure. There was no association between inhalation injury and mortality in this group of patients. Conclusion: A low FiO2/HFPV protocol is a safe and effective way to ventilate critically ill burn patients. Reducing the oxidative stress of high inspired oxygen levels may improve outcome. [Copyright &y& Elsevier]

Abstract: To quantify the effect of dynamic particle size changes and degradation and accumulation of suspended solids (SS) in influents to reactors on membrane fouling frequency in hybrid powder-activated carbon (PAC)–microfiltration (MF) reactors, we operated a PAC–MF system (hollow-fiber module) for more than five months to purify river water before and after pretreatment by a biofilter. The transmembrane pressure, backwashing pressure, resistance to filtration, and SS accumulation and degradation during these dynamic changes were evaluated. The initial dose of PAC was 40g/L of the reactor and no additional PAC was added during this continuous operational period. The presence of PAC reduced the membrane resistance to filtration even at the end of filtration period when the number of particles in the smallest range (>1.0–3.6μm) was the highest measured by the flow cytometer and microscopy image analysis. This resistance was reduced further when the river water was biofiltered prior to membrane filtration. This real-time study demonstrates that over time PAC and other particles coming into the reactors through the influents degrade and/or become smaller because of the turbulence caused by continuous aeration below the MF membrane fibers. The number of particles in the reactors with diameters less than 10μm increased with time, increasing the fouling frequency; however, the presence of PAC further reduced the particle enhanced fouling. The presence of PAC also increased SS degradation by up to 10%. The increased number of bacteria inside the PAC–MF systems did not contribute to the number of membrane fouling. Even though the particle sizes inside the reactors became smaller with time, the gradual increase in net accumulation of SS was also an important factor controlling the performance of the PAC–MF system. [Copyright &y& Elsevier]

Abnormal wound healing encompasses a wide spectrum, from chronic wounds to hypertrophic scars. Both conditions are associated with an abnormal cytokine profile in the wound bed. In this study, we sought to understand the dynamic relationships between myofibroblast differentiation and mechanical performance of the collagen matrix under tissue growth factor–β (TGF-β) and tumor necrosis factor–α (TNF-α) stimulation. We found TGF-β increased α-smooth muscle actin (α-SMA) and TNF-α alone decreased the basal α-SMA expression. When TGF-β1 and TNF-α were both added, the α-SMA expression was suppressed below the baseline. Real-time PCR showed that TNF-α suppresses TGF-β1-induced myofibroblast (fibroproliferative) phenotypic genes, for example, α-SMA, collagen type 1A, and fibronectin at the mRNA level. TNF-α suppresses TGF-β1-induced gene expression by affecting its mRNA stability. Our results further showed that TNF-α inhibits TGF-β1-induced Smad-3 phosphorylation via Jun N-terminal kinase signaling. Mechanical testing showed that TNF-α decreases the stiffness and contraction of the lattices after 5 days in culture. We proposed that changes in α-SMA, collagen, and fibronectin expression result in decreased contraction and stiffness of collagen matrices. Therefore, the balance of cytokines in a wound defines the mechanical properties of the extracellular matrix and optimal wound healing.Journal of Investigative Dermatology (2007) 127, 2645–2655; doi:10.1038/sj.jid.5700890; published online 31 May 2007 [ABSTRACT FROM AUTHOR]