Leishmania manipulation of sand fly feeding behavior results in enhanced transmission.

In nature the prevalence of Leishmania infection in whole sand fly populations can be very low (<0.1%), even in areas of endemicity and high transmission. It has long since been assumed that the protozoan parasite Leishmania can manipulate the feeding behavior of its sand fly vector, thus enhancing transmission efficiency, but neither the way in which it does so nor the mechanisms behind such manipulation have been described. A key feature of parasite development in the sand fly gut is the secretion of a gel-like plug composed of filamentous proteophosphoglycan. Using both experimental and natural parasite-sand fly combinations we show that secretion of this gel is accompanied by differentiation of mammal-infective transmission stages. Further, Leishmania infection specifically causes an increase in vector biting persistence on mice (re-feeding after interruption) and also promotes feeding on multiple hosts. Both of these aspects of vector behavior were found to be finely tuned to the differentiation of parasite transmission stages in the sand fly gut. By experimentally accelerating the development rate of the parasites, we showed that Leishmania can optimize its transmission by inducing increased biting persistence only when infective stages are present. This crucial adaptive manipulation resulted in enhanced infection of experimental hosts. Thus, we demonstrate that behavioral manipulation of the infected vector provides a selective advantage to the parasite by significantly increasing transmission

Combining epidemiology with basic biology of sand flies, parasites, and hosts to inform leishmaniasis transmission dynamics and control.

Quantitation of the nonlinear heterogeneities in Leishmania parasites, sand fly vectors, and mammalian host relationships provides insights to better understand leishmanial transmission epidemiology towards improving its control. The parasite manipulates the sand fly via production of promastigote secretory gel (PSG), leading to the "blocked sand fly" phenotype, persistent feeding attempts, and feeding on multiple hosts. PSG is injected into the mammalian host with the parasite and promotes the establishment of infection. Animal models demonstrate that sand flies with the highest parasite loads and percent metacyclic promastigotes transmit more parasites with greater frequency, resulting in higher load infections that are more likely to be both symptomatic and efficient reservoirs. The existence of mammalian and sand fly "super-spreaders" provides a biological basis for the spatial and temporal clustering of clinical leishmanial disease. Sand fly blood-feeding behavior will determine the efficacies of indoor residual spraying, topical insecticides, and bed nets. Interventions need to have sufficient coverage to include transmission hot spots, especially in the absence of field tools to assess infectiousness. Interventions that reduce sand fly densities in the absence of elimination could have negative consequences, for example, by interfering with partial immunity conferred by exposure to sand fly saliva. A deeper understanding of both sand fly and host biology and behavior is essential to ensuring effectiveness of vector interventions

Robotic partial nephrectomy for posterior tumors through a retroperitoneal approach offers decreased length of stay compared with the transperitoneal approach: A propensity-matched analysis

INTRODUCTION: We sought to compare surgical outcomes between transperitoneal and retroperitoneal robotic partial nephrectomy (RPN) for posterior tumors. PATIENTS AND METHODS: Using our multi-institutional RPN database, we reviewed 610 consecutive cases for posterior renal masses treated between 2007 and 2015. Primary outcomes were complications, operative time, length of stay (LOS), surgical margin status, and estimated glomerular filtration rate (eGFR) preservation. Secondary outcomes were estimated blood loss, warm ischemia time (WIT), disease recurrence, and disease-specific mortality. Due to significant differences in treatment year and tumor size between approaches, retroperitoneal cases were matched 1:4 to transperitoneal cases based on propensity scores using the greedy algorithm. Outcomes were compared between approaches using the chi-square and Mann-Whitney U tests. RESULTS: After matching, 296 transperitoneal and 74 retroperitoneal cases were available for analysis, and matched groups were well balanced in terms of treatment year, age, gender, race, American Society of Anesthesiologists physical status classification (ASA) score, body mass index, tumor laterality, tumor size, R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to the collecting system or sinus, anterior/posterior, location relative to polar lines) score, and hilar location. Compared with transperitoneal, the retroperitoneal approach was associated with significantly shorter mean LOS (2.2 vs 2.6 days, p = 0.01), but longer mean WIT (21 vs 19 minutes, p = 0.01). Intraoperative (p = 0.35) and postoperative complications (p = 0.65), operative time (p = 0.93), positive margins (p = 1.0), and latest eGFR preservation (p = 0.25) were not significantly different between approaches. No differences were detected in the other outcomes. CONCLUSIONS: Among high-volume surgeons, transperitoneal and retroperitoneal RPN achieved similar outcomes for posterior renal masses, although with slight differences in LOS and WIT. Retroperitoneal RPN may be an effective option for the treatment of certain small posterior renal masses

β2 Adrenergic Receptor Fluorescent Protein Fusions Traffic to the Plasma Membrane and Retain Functionality

Green fluorescent protein (GFP) has proven useful for the study of protein interactions and dynamics for the last twenty years. A variety of new fluorescent proteins have been developed that expand the use of available excitation spectra. We have undertaken an analysis of seven of the most useful fluorescent proteins (XFPs), Cerulean (and mCerulean3), Teal, GFP, Venus, mCherry and TagRFP657, as fusions to the archetypal G-protein coupled receptor, the β2 adrenergic receptor (β2AR). We have characterized these β2AR::XFP fusions in respect to membrane trafficking and G-protein activation. We noticed that in the mouse neural cell line, OP 6, that membrane bound β2AR::XFP fusions robustly localized in the filopodia identical to gap::XFP fusions. All β2ARR::XFP fusions show responses indistinguishable from each other and the non-fused form after isoprenaline exposure. Our results provide a platform by which G-protein coupled receptors can be dissected for their functionality

Effects of the Orion Launch Abort Vehicle Plumes on Aerodynamics and Controllability

Characterization of the launch abort system of the Multi-purpose Crew Vehicle (MPCV) for control design and accurate simulation has provided a significant challenge to aerodynamicists and design engineers. The design space of the launch abort vehicle (LAV) includes operational altitudes from ground level to approximately 300,000 feet, Mach numbers from 0-9, and peak dynamic pressure near 1300psf during transonic flight. Further complicating the characterization of the aerodynamics and the resultant vehicle controllability is the interaction of the vehicle flowfield with the plumes of the two solid propellant motors that provide attitude control and the main propulsive impulse for the LAV. These interactions are a function of flight parameters such as Mach number, altitude, dynamic pressure, vehicle attitude, as well as parameters relating to the operation of the motors themselves - either as a function of time for the AM, or as a result of the flight control system requests for control torque from the ACM. This paper discusses the computational aerodynamic modeling of the aerodynamic interaction caused by main abort motor and the attitude control motor of the MPCV LAV, showing the effects of these interactions on vehicle controllability

In Vitro Mutational Analysis of the β2 Adrenergic Receptor, an In Vivo Surrogate Odorant Receptor

Many G-protein coupled receptors (GPCRs), such as odorant receptors (ORs), cannot be characterized in heterologous cells because of their difficulty in trafficking to the plasma membrane. In contrast, a surrogate OR, the GPCR mouse β2-adrenergic-receptor (mβ2AR), robustly traffics to the plasma membrane. We set out to characterize mβ2AR mutants in vitro for their eventual use in olfactory axon guidance studies. We performed an extensive mutational analysis of mβ2AR using a Green Fluorescent Protein-tagged mβ2AR (mβ2AR::GFP) to easily assess the extent of its plasma membrane localization. In order to characterize mutants for their ability to successfully transduce ligand-initiated signal cascades, we determined the half maximal effective concentrations (EC50) and maximal response to isoprenaline, a known mβ2AR agonist. Our analysis reveals that removal of amino terminal (Nt) N-glycosylation sites and the carboxy terminal (Ct) palmitoylation site of mβ2AR do not affect its plasma membrane localization. By contrast, when both the Nt and Ct of mβ2AR are replaced with those of M71 OR, plasma membrane trafficking is impaired. We further analyze three mβ2AR mutants (RDY, E268A, and C327R) used in olfactory axon guidance studies and are able to decorrelate their plasma membrane trafficking with their capacity to respond to isoprenaline. A deletion of the Ct prevents proper trafficking and abolishes activity, but plasma membrane trafficking can be selectively rescued by a Tyrosine to Alanine mutation in the highly conserved GPCR motif NPxxY. This new loss-of-function mutant argues for a model in which residues located at the end of transmembrane domain 7 can act as a retention signal when unmasked. Additionally, to our surprise, amongst our set of mutations only Ct mutations appear to lower mβ2AR EC50s revealing their critical role in G-protein coupling. We propose that an interaction between the Nt and Ct is necessary for proper folding and/or transport of GPCRs

How Captain Amerika uses neural networks to fight crime

Artificial neural network models can make amazing computations. These models are explained along with their application in problems associated with fighting crime. Specific problems addressed are identification of people using face recognition, speaker identification, and fingerprint and handwriting analysis (biometric authentication)

Initial Metabolic Profiles Are Associated with 7-Day Survival among Infants Born at 22-25 Weeks of Gestation.

OBJECTIVE:To evaluate the association between early metabolic profiles combined with infant characteristics and survival past 7 days of age in infants born at 22-25 weeks of gestation. STUDY DESIGN:This nested case-control consisted of 465 singleton live births in California from 2005 to 2011 at 22-25 weeks of gestation. All infants had newborn metabolic screening data available. Data included linked birth certificate and mother and infant hospital discharge records. Mortality was derived from linked death certificates and death discharge information. Each death within 7 days was matched to 4 surviving controls by gestational age and birth weight z score category, leaving 93 cases and 372 controls. The association between explanatory variables and 7-day survival was modeled via stepwise logistic regression. Infant characteristics, 42 metabolites, and 12 metabolite ratios were considered for model inclusion. Model performance was assessed via area under the curve. RESULTS:The final model included 1 characteristic and 11 metabolites. The model demonstrated a strong association between metabolic patterns and infant survival (area under the curve [AUC] 0.885, 95% CI 0.851-0.920). Furthermore, a model with just the selected metabolites performed better (AUC 0.879, 95% CI 0.841-0.916) than a model with multiple clinical characteristics (AUC 0.685, 95% CI 0.627-0.742). CONCLUSIONS:Use of metabolomics significantly strengthens the association with 7-day survival in infants born extremely premature. Physicians may be able to use metabolic profiles at birth to refine mortality risks and inform postnatal counseling for infants born at &lt;26 weeks of gestation

Atypical and Severe Nonsuicidal Self-Injury as an Indicator of Severe Psychopathology: Findings From a Sample of High-Risk Community Mental Health Clients

This study examined whether atypical/severe nonsuicidal self-injury (NSSI; e.g., foreign body ingestion, cutting necessitating sutures) serves as a marker of severe psychopathology among 467 adult community mental health clients (n = 33 with an atypical/severe NSSI history). Information regarding psychiatric risk indicators was extracted from participants’ psychiatric records. Generalized linear models with negative binomial distribution and log link function, as well as chi-square tests, were used to address study aims. Clients with a lifetime atypical/severe NSSI history met criteria for a significantly greater number of psychiatric risk indicators than clients with a lifetime history of common NSSI only; however, these clients were not significantly more likely to report recent suicidal actions. Individuals with an atypical/severe NSSI history may demonstrate more severe psychopathology than those with a history of common NSSI only. Thus, it may be clinically useful to consider individuals with an atypical/severe NSSI history as a high-risk subgroup