A Neural Circuit for Angular Velocity Computation

In one of the most remarkable feats of motor control in the animal world, some Diptera, such as the housefly, can accurately execute corrective flight maneuvers in tens of milliseconds. These reflexive movements are achieved by the halteres, gyroscopic force sensors, in conjunction with rapidly tunable wing steering muscles. Specifically, the mechanosensory campaniform sensilla located at the base of the halteres transduce and transform rotation-induced gyroscopic forces into information about the angular velocity of the fly's body. But how exactly does the fly's neural architecture generate the angular velocity from the lateral strain forces on the left and right halteres? To explore potential algorithms, we built a neuromechanical model of the rotation detection circuit. We propose a neurobiologically plausible method by which the fly could accurately separate and measure the three-dimensional components of an imposed angular velocity. Our model assumes a single sign-inverting synapse and formally resembles some models of directional selectivity by the retina. Using multidimensional error analysis, we demonstrate the robustness of our model under a variety of input conditions. Our analysis reveals the maximum information available to the fly given its physical architecture and the mathematics governing the rotation-induced forces at the haltere's end knob

Biological constraints limit the use of rapamycin-inducible FKBP12-Inp54p for depleting PIP2 in dorsal root ganglia neurons

Background: Rapamycin-induced translocation systems can be used to manipulate biological processes with precise temporal control. These systems are based on rapamycin-induced dimerization of FK506 Binding Protein 12 (FKBP12) with the FKBP Rapamycin Binding (FRB) domain of mammalian target of rapamycin (mTOR). Here, we sought to adapt a rapamycin-inducible phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phosphatase (Inp54p) system to deplete PIP2 in nociceptive dorsal root ganglia (DRG) neurons. Results: We genetically targeted membrane-tethered CFP-FRBPLF (a destabilized FRB mutant) to the ubiquitously expressed Rosa26 locus, generating a Rosa26-FRBPLF knockin mouse. In a second knockin mouse line, we targeted Venus-FKBP12-Inp54p to the Calcitonin gene-related peptide-alpha (CGRPα) locus. We hypothesized that after intercrossing these mice, rapamycin treatment would induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in CGRP+ DRG neurons. In control experiments with cell lines, rapamycin induced translocation of Venus-FKBP12-Inp54p to the plasma membrane, and subsequent depletion of PIP2, as measured with a PIP2 biosensor. However, rapamycin did not induce translocation of Venus-FKBP12-Inp54p to the plasma membrane in FRBPLF-expressing DRG neurons (in vitro or in vivo). Moreover, rapamycin treatment did not alter PIP2-dependent thermosensation in vivo. Instead, rapamycin treatment stabilized FRBPLF in cultured DRG neurons, suggesting that rapamycin promoted dimerization of FRBPLF with endogenous FKBP12. Conclusions: Taken together, our data indicate that these knockin mice cannot be used to inducibly deplete PIP2 in DRG neurons. Moreover, our data suggest that high levels of endogenous FKBP12 could compete for binding to FRBPLF, hence limiting the use of rapamycin-inducible systems to cells with low levels of endogenous FKBP12

Doppler evaluation of left ventricular diastolic filling in children with systemic hypertension

To assess left ventricular (LV) diastolic function in children with systemic hypertension, 11 patients with hypertension (mean blood pressure 99 mm Hg) and 7 normal patients (mean blood pressure 78 mm Hg) underwent M-mode echocardiography and pulsed Doppler examination of the LV inflow. From a digitized trace of the LV endocardium and a simultaneous phonocardiogram, echocardiographic diastolic time intervals, peak rate of increase in LV dimension (dD/dt), and dD/dt normalized for LV end-diastolic dimension (dD/dt) were measured. Doppler diastolic time intervals, peak velocities at rapid filling (E velocity) and atrial contraction (A velocity), and the ratio of E and A velocities were measured. The following areas under the Doppler curve and their percent of the total area were determined: first 33% of diastole (0.33 area), first 50% of diastole, triangle under the A velocity (A area), and the triangle under the E velocity (E area). The A velocity (patients with HYPERTENSION = 0.68 +/- 0.11 m/s, normal SUBJECTS = 0.49 +/- 0.08 m/s), the 0.33 area/total area (patients with HYPERTENSION = 0.49 +/- 0.09, normal SUBJECTS = 0.58 +/- 0.08), the A area (patients with HYPERTENSION = 0.17 +/- 0.05, normal SUBJECTS = 0.12 +/- 0.03), and the A area/total area (patients with HYPERTENSION = 0.30 +/- 0.11, normal SUBJECTS = 0.20 +/- 0.07) were significantly different between groups (p < 0.05). M-mode and Doppler time intervals, dt/D, E velocity, and the remaining Doppler areas were not significantly different between groups. The normal subjects and patients with hypertension did not differ significantly in echocardiographic LV size and thickness or in percent shortening fraction. This study shows that abnormal patterns of LV diastolic filling occur in children with mild systemic hypertension. These diastolic abnormalities are detectable by mitral valve Doppler ultrasound examination when standard M-mode echocardiographic indexes of diastolic function are still normal and before the development of systolic function abnormalities or LV hypertrophy on the M-mode echocardiogram.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25489/1/0000030.pd

Kapsula

Selections from the 2015 Conference of the Contemporary Art, Design and New Media Art Histories Masters Progra

Kapsula

Selections from the 2015 Conference of the Contemporary Art, Design and New Media Art Histories Masters Progra

A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer

Purpose: To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)–positive breast cancers from patients uniformly treated with adjuvant tamoxifen. Experimental Design: Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures. Results: Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR–based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior. Conclusion: The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points

Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

"Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.

Measurement of the Ratio of b Quark Production Cross Sections in Antiproton-Proton Collisions at 630 GeV and 1800 GeV

We report a measurement of the ratio of the bottom quark production cross section in antiproton-proton collisions at 630 GeV to 1800 GeV using bottom quarks with transverse momenta greater than 10.75 GeV identified through their semileptonic decays and long lifetimes. The measured ratio sigma(630)/sigma(1800) = 0.171 +/- .024 +/- .012 is in good agreement with next-to-leading order (NLO) quantum chromodynamics (QCD)

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Characterizing the Rhizosphere Microbial Community of Food Crops in a Changing Climate

In recent years, there have been increased occurrences of food-borne illness in Canada, which is not directly associated with animal-related products but is caused by the increasing prevalence of pathogenic outbreaks in fresh produce. This can have health and economic impacts on the agriculture industry in Canada. As such, it is essential to better understand the plant-microbe interactions of crops grown in Canada and determine how climate change may alter the relationship. Plants can promote the growth of beneficial bacteria in the rhizosphere, which can create protective competition between beneficial and pathogenic bacteria. Changes in the environment of the rhizosphere can lead to an imbalance in the community. They may allow pathogenic bacteria to infect plant tissue or become incorporated into the rhizosphere community, where the pathogenic bacteria can redistribute to the surrounding environment. Not only do different plant species promote the growth of different bacterial community compositions, but abiotic factors such as temperature, nutrient levels, and humidity also impact community profiles. By better understanding the microbial community dynamics under changing environmental conditions, we could promote the growth of diverse and abundant microbial communities to increase plant resilience against pathogenic bacteria and climate change, thereby supporting healthy crops for optimal food output. Using Community Level Physiological Profiling (CLPP) and Denaturing Gradient Gel Electrophoresis (DGGE) to assess the functional and structural fingerprint of the bacterial community, the metabolic fingerprints of microbial communities associated with kale, broccoli, cabbage, and spinach at two locations and temperatures were analysed. The crops were shown to have distinct metabolic and genetic communities that shifted with temperature increases, location, and across species. The microbial community of crops shared similar metabolic profiles in the rhizoplane regardless of species and cultivar but showed distinct groupings in the genetic profiles. As nutrient levels increased there was a loss of differentiation between the bulk soil and rhizosphere communities metabolically as the nutrients increased microbial activity in the bulk soil to rhizosphere levels. The increased temperature caused similar loss of metabolic distinction, as the stress on the plants caused the release of similar metabolites into the rhizoplane, increasing metabolic activity, diversity, and similarity between all crop microbial communities. Temperature caused similarity to increase genetically between rhizoplane fractions of the different crops. Potential foodborne pathogen presence was mostly unaffected by temperature and location, with the greatest difference occurring between fraction types. Overall, this research showed changes in metabolic and genetic profiles of microbial communities associated with Canadian food crops under different conditions in rising temperatures