The Suppression of Immune System Disorders by Passive Attrition

Exposure to infectious diseases has an unexpected benefit of inhibiting autoimmune diseases and allergies. This is one of many fundamental fitness tradeoffs associated with immune system architecture. The immune system attacks pathogens, but also may (inappropriately) attack the host. Exposure to pathogens can suppress the deleterious response, at the price of illness and the decay of immunity to previous diseases. This “hygiene hypothesis” has been associated with several possible underlying biological mechanisms. This study focuses on physiological constraints that lead to competition for survival between immune system cell types. Competition maintains a relatively constant total number of cells within each niche. The constraint implies that adding cells conferring new immunity requires loss (passive attrition) of some cells conferring previous immunities. We consider passive attrition as a mechanism to prevent the initial proliferation of autoreactive cells, thus preventing autoimmune disease. We see that this protection is a general property of homeostatic regulation and we look specifically at both the IL-15 and IL-7 regulated niches to make quantitative predictions using a mathematical model. This mathematical model yields insight into the dynamics of the “Hygiene Hypothesis,” and makes quantitative predictions for experiments testing the ability of passive attrition to suppress immune system disorders. The model also makes a prediction of an anti-correlation between prevalence of immune system disorders and passive attrition rates

Acute Respiratory Distress Syndrome after Onyx Embolization of Arteriovenous Malformation

Purpose. We report a case of a 60-year-old male who underwent sequential Onyx embolizations of a cerebral arteriovenous malformation (AVM) which we implicate as the most likely etiology of subsequent acute respiratory distress syndrome (ARDS). Methods. Case report and literature review. Results. Shortly after the second Onyx embolization procedure, the patient declined from respiratory failure secondary to pulmonary edema. Clinical entities typically responsible for pulmonary edema including cardiac failure, renal failure, iatrogenic volume overload, negative-pressure pulmonary edema, and infectious etiologies were evaluated and excluded. The patient required mechanical ventilatory support for several days, delaying operative resection. The patient met clinical and radiographic criteria for ARDS. After excluding other etiologies of ARDS, we postulate that ARDS developed as a result of Onyx administration. The Onyx copolymer is dissolved in dimethyl sulfoxide (DMSO), a solvent excreted through the lungs and has been implicated in transient pulmonary side effects. Additionally, a direct toxic effect of the Onyx copolymer is postulated. Conclusion. Onyx embolization and DMSO toxicity are implicated as the etiology of ARDS given the lack of other inciting factors and the close temporal relationship. A strong physiologic rationale provides further support. Clinicians should consider this uncommon but important complication

Genotype Effects and Genotype by Environment Interactions for Traits of Elite Switchgrass Populations

Switchgrass (Panicum virgatum L.) is used as a forage species and has shown potential for use in production of fuel ethanol from cellulosic biomass. Objectives of this research were to determine performance differences between elite switchgrass populations for agronomic, forage quality, and biofuel traits and to determine the magnitude of genotype × environment (G × E) interactions for these traits across midwestern environments.Twenty elite switchgrass populations, consisting of cultivars and advanced breeding populations, were planted in sward trials at Mead, NE, Ames, IA, and West Lafayette, IN, during 1990 and were evaluated in 1991 and 1992. Forage samples were taken at a vegetative growth stage, at heading, and at the end of the season. Plots were harvested for forage yield at heading and at the end of the growing season. Forage composition and in vitro dry matter digestibility was determined using near infrared reflectance spectroscopy. Significant differences (P \u3c 0.05) between populations for forage yield were found at individual locations but not across locations, except at the P = 0.10 probability level, because of G × E interactions. Genotype × environment interactions were significant for hemicellulose plus cellulose (holocellulose) yield, a potentially important biofuel trait. In vitro dry matter digestibility was more stable than both forage yield and holocellulose yield. Despite large G × E interaction effects, a few populations consistently ranked high in forage yield and holocellulose yield. Multiple location, multiple year sward trials will be needed to develop switchgrasses broadly adapted to the midwest

Genotypic Variability and Genotype × Environment Interactions among Switchgrass Accessions from the Midwestern USA

Genetic variation for economically important traits in switchgrass (Panicum virgatum L.) is needed to develop improved populations. Objectives of this research were to determine the genotypic variability, and the magnitude of genotype × enviromnent (G × E) interaction for agronomic, forage quality, and biofuel feedstock traits among switchgrass accessions collected from remnant midwestern prairies. A total of 23 accessions and five check strains were evaluated in space planted nurseries at Mead, NE; Ames, IA; and West Lafayette, IN, during 1991 and 1992. Forage quality traits were measured at a vegetative growth stage and at heading. Disease ratings were taken just prior to forage harvest at heading. Forage composition was determined by near infrared reflectance spectroscopy. Across locations and years, significant variation among accessions was observed for forage yield at heading, vegetative in vitro dry matter digestibility (IVDMD), and heading date. Some accessions, such as IA34, were comparable in forage yield at heading to check strains and should be useful genetic sources of variation for this trait. Except for disease rating, G × E interactions were important for all traits. Selection among accessions for forage yield at heading followed by selection for IVDMD within such accessions should be an effective approach in utilizing genetic variation in switchgrasses from remnant prairie sites

Evaluate the safety and efficacy of dura sealant patch in reducing cerebrospinal fluid leakage following elective cranial surgery (ENCASE II): study protocol for a randomized, two-arm, multicenter trial

BACKGROUND Cerebrospinal fluid (CSF) leakage is a frequent and challenging complication in neurosurgery, especially in the posterior fossa, with a prevalence of 8%. It is associated with substantial morbidity and increased healthcare costs. A novel dural sealant patch (LIQOSEAL) was developed for watertight dural closure. The objective of this study is to clinically assess the safety and effectiveness of LIQOSEAL as a means of reducing intra- as well as postoperative CSF leakage in patients undergoing elective posterior fossa intradural surgery with a dural closure procedure compared to the best currently available dural sealants. METHODS We will conduct a two-arm, randomized controlled, multicenter study with a 90-day follow-up. A total of 228 patients will be enrolled in 19 sites, of which 114 will receive LIQOSEAL and 114 an FDA-approved PEG sealant. The composite primary endpoint is defined as intraoperative CSF leakage at PEEP 20 cm H$_{2}$O, percutaneous CSF leakage within 90 days of, wound infection within 90 days of or pseudomeningocele of more than 20cc on MRI or requiring intervention. We hypothesize that the primary endpoint will not be reached by more than 10 patients (9%) in the investigational arm, which will demonstrate non-inferiority of LIQOSEAL compared to control. DISCUSSION This trial will evaluate whether LIQOSEAL is non-inferior to control as a means of reducing CSF leakage and safety TRIAL REGISTRATION: ClinicalTrials.gov NCT04086550 . Registered on 11 September 2019

Suspended-sediment induced stratification inferred from concentration and velocity profile measurements in the lower Yellow River, China

Despite a multitude of models predicting sediment transport dynamics in open‐channel flow, self‐organized vertical density stratification that dampens flow turbulence due to the interaction between fluid and sediment, has not been robustly validated with field observations from natural rivers. Turbulence‐suppressing density stratification can develop in channels with low channel‐bed slope and high sediment concentration. As the Yellow River, China, maintains one of the highest sediment loads in the world for a low sloping system, this location is ideal for documenting particle and fluid interactions that give rise to density stratification. Herein, we present analyses from a study conducted over a range of discharge conditions (e.g., low flow, rising limb, and flood peak) from a lower reach of the Yellow River, whereby water samples were collected at targeted depths to measure sediment concentration and, simultaneously, velocity measurements were collected throughout the flow depth. Importantly, sediment concentration varied by an order of magnitude between base and flood flows. By comparing measured concentration and velocity profiles to predictive models, we show that the magnitude of density stratification increases with sediment concentration. Furthermore, a steady‐state calculation of sediment suspension is used to determine that sediment diffusivity increases with grain size. Finally, we calculate concentration and velocity profiles, showing that steady‐state sediment suspensions are reliably predicted over a range of stratification conditions larger than had been previously documented in natural river flows. We determine that the magnitude of density stratification can be predicted by a function considering an entrainment parameter, sediment concentration, and bed slope

PAI-1 is a Critical Upstream Regulator of the TGF-β1/EGF-Induced Invasive Phenotype in Mutant p53 Human Cutaneous Squamous Cell Carcinoma

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-β synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-β/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-β1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-β1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies

Modeling deltaic lobe‐building cycles and channel avulsions for the Yellow River delta, China

River deltas grow by repeating cycles of lobe development punctuated by channel avulsions, so that over time, lobes amalgamate to produce a composite landform. Existing models have shown that backwater hydrodynamics are important in avulsion dynamics, but the effect of lobe progradation on avulsion frequency and location has yet to be explored. Herein, a quasi‐2‐D numerical model incorporating channel avulsion and lobe development cycles is developed. The model is validated by the well‐constrained case of a prograding lobe on the Yellow River delta, China. It is determined that with lobe progradation, avulsion frequency decreases, and avulsion length increases, relative to conditions where a delta lobe does not prograde. Lobe progradation lowers the channel bed gradient, which results in channel aggradation over the delta topset that is focused farther upstream, shifting the avulsion location upstream. Furthermore, the frequency and location of channel avulsions are sensitive to the threshold in channel bed superelevation that triggers an avulsion. For example, avulsions occur less frequently with a larger superelevation threshold, resulting in greater lobe progradation and avulsions that occur farther upstream. When the delta lobe length prior to avulsion is a moderate fraction of the backwater length (0.3–0.5L_b), the interplay between variable water discharge and lobe progradation together set the avulsion location, and a model capturing both processes is necessary to predict avulsion timing and location. While this study is validated by data from the Yellow River delta, the numerical framework is rooted in physical relationships and can therefore be extended to other deltaic systems

Suspended-sediment induced stratification inferred from concentration and velocity profile measurements in the lower Yellow River, China

Despite a multitude of models predicting sediment transport dynamics in open‐channel flow, self‐organized vertical density stratification that dampens flow turbulence due to the interaction between fluid and sediment, has not been robustly validated with field observations from natural rivers. Turbulence‐suppressing density stratification can develop in channels with low channel‐bed slope and high sediment concentration. As the Yellow River, China, maintains one of the highest sediment loads in the world for a low sloping system, this location is ideal for documenting particle and fluid interactions that give rise to density stratification. Herein, we present analyses from a study conducted over a range of discharge conditions (e.g., low flow, rising limb, and flood peak) from a lower reach of the Yellow River, whereby water samples were collected at targeted depths to measure sediment concentration and, simultaneously, velocity measurements were collected throughout the flow depth. Importantly, sediment concentration varied by an order of magnitude between base and flood flows. By comparing measured concentration and velocity profiles to predictive models, we show that the magnitude of density stratification increases with sediment concentration. Furthermore, a steady‐state calculation of sediment suspension is used to determine that sediment diffusivity increases with grain size. Finally, we calculate concentration and velocity profiles, showing that steady‐state sediment suspensions are reliably predicted over a range of stratification conditions larger than had been previously documented in natural river flows. We determine that the magnitude of density stratification can be predicted by a function considering an entrainment parameter, sediment concentration, and bed slope