cis-Inhibition of Notch by Endogenous Delta Biases the Outcome of Lateral Inhibition

SummaryLateral inhibition mediated by Delta/Notch (Dl/N) signaling is used throughout development to limit the number of initially equivalent cells that adopt a particular fate [1–3]. Although adjacent cells express both Dl ligand and N receptor, signaling between them ultimately occurs in only one direction. Classically, this has been explained entirely by feedback: activated N can downregulate Dl, amplifying even slight asymmetries in the Dl or N activities of adjacent cells [1–5]. Here, however, we present an example of lateral inhibition in which unidirectional signaling depends instead on Dl's ability to inhibit N within the same cell, a phenomenon known as cis-inhibition [6–11]. By genetically manipulating individual R1/R6/R7 photoreceptor precursors in the Drosophila eye, we show that loss of Dl-mediated cis-inhibition reverses the direction of lateral signaling. Based on our finding that Dl in R1/R6s requires endocytosis to trans-activate but not to cis-inhibit N, we reexamine previously published data from other examples of lateral inhibition. We conclude that cis-inhibition generally influences the direction of Dl/N signaling and should therefore be included in standard models of lateral inhibition

Primate Energy eExpenditure and Life History

Humans and other primates are distinct among placental mammals in having exceptionally slow rates of growth, reproduction, and aging. Primates’ slow life history schedules are generally thought to reflect an evolved strategy of allocating energy away from growth and reproduction and toward somatic investment, particularly to the development and maintenance of large brains. Here we examine an alternative explanation: that primates’ slow life histories reflect low total energy expenditure (TEE) (kilocalories per day) relative to other placental mammals. We compared doubly labeled water measurements of TEE among 17 primate species with similar measures for other placental mammals. We found that primates use remarkably little energy each day, expending on average only 50% of the energy expected for a placental mammal of similar mass. Such large differences in TEE are not easily explained by differences in physical activity, and instead appear to reflect systemic metabolic adaptation for low energy expenditures in primates. Indeed, comparisons of wild and captive primate populations indicate similar levels of energy expenditure. Broad interspecific comparisons of growth, reproduction, and maximum life span indicate that primates’ slow metabolic rates contribute to their characteristically slow life histories

Intratesticular Abscess in a Solitary Testicle: The Case for Testicle Sparing Management

We present the case of a 24-year-old immunocompromised man with an intratesticular abscess. The patient presented with one week of left scrotal pain and swelling. Workup included scrotal ultrasonography which revealed a large fluid collection within the tunica albuginea of the left testis. Surgical exploration of the left testis evacuated a significant amount of purulent fluid. The residual viable testicular parenchyma was salvaged. Intraoperative cultures grew Morganella morganii. Follow-up ultrasonography showed resolution of the testicular fluid collection, and the patient was discharged home with oral antibiotics. Intratesticular abscesses are a rare clinical entity which often result in orchiectomy

Comparing the EQ-5D-3 L and EQ-5D-5 L:studying measurement and scores in Indonesian type 2 diabetes mellitus patients

BACKGROUND: The EuroQoL five-dimensional instrument (EQ-5D) is the favoured preference-based instrument to measure health-related quality of life (HRQoL) in several countries. Two versions of the EQ-5D are available: the 3-level version (EQ-5D-3 L) and the 5-level version (EQ-5D-5 L). This study aims to compare specific measurement properties and scoring of the EQ-5D-3 L (3 L) and EQ-5D-5 L (5 L) in Indonesian type 2 diabetes mellitus (T2DM) outpatients.METHODS: A survey was conducted in a hospital and two primary healthcare centres on Sulawesi Island. Participants were asked to complete the two versions of the EQ-5D instruments. The 3 L and 5 L were compared in terms of distribution and ceiling, discriminative power and test-retest reliability. To determine the consistency of the participants' answers, we checked the redistribution pattern, i.e., the consistency of a participant's scores in both versions.RESULTS: A total of 198 T2DM outpatients (mean age 59.90 ± 11.06) completed the 3 L and 5 L surveys. A total of 46 health states for 3 L and 90 health states for 5 L were reported. The '11121' health state was reported most often: 17% in the 3 L and 13% in the 5 L. The results suggested a lower ceiling effect for 5 L (11%) than for 3 L (15%). Regarding redistribution, only 6.1% of responses were found to be inconsistent in this study. The 5 L had higher discriminative power than the 3 L version. Reliability as reflected by the index score was 0.64 for 3 L and 0.74 for 5 L. Pain/discomfort was the dimension mostly affected, whereas the self-care dimension was the least affected.CONCLUSIONS: This study suggests that the 5 L-version of the EQ-5D instrument performs better than the 3 L-version in T2DM outpatients in Indonesia, regarding measurement and scoring properties. As such, our study supports the use of the 5 L as the preferred health-related quality of life measurement tool. We did not do a trial but this study was approved by the Medical Ethics Committee of Universitas Gadjah Mada Yogyakarta, Indonesia (document number KE/FK/1188/EC, 12 November 2014, amended 16 March 2015).</p

Comparing the EQ-5D-3 L and EQ-5D-5 L:studying measurement and scores in Indonesian type 2 diabetes mellitus patients

BACKGROUND: The EuroQoL five-dimensional instrument (EQ-5D) is the favoured preference-based instrument to measure health-related quality of life (HRQoL) in several countries. Two versions of the EQ-5D are available: the 3-level version (EQ-5D-3 L) and the 5-level version (EQ-5D-5 L). This study aims to compare specific measurement properties and scoring of the EQ-5D-3 L (3 L) and EQ-5D-5 L (5 L) in Indonesian type 2 diabetes mellitus (T2DM) outpatients. METHODS: A survey was conducted in a hospital and two primary healthcare centres on Sulawesi Island. Participants were asked to complete the two versions of the EQ-5D instruments. The 3 L and 5 L were compared in terms of distribution and ceiling, discriminative power and test-retest reliability. To determine the consistency of the participants' answers, we checked the redistribution pattern, i.e., the consistency of a participant's scores in both versions. RESULTS: A total of 198 T2DM outpatients (mean age 59.90 ± 11.06) completed the 3 L and 5 L surveys. A total of 46 health states for 3 L and 90 health states for 5 L were reported. The '11121' health state was reported most often: 17% in the 3 L and 13% in the 5 L. The results suggested a lower ceiling effect for 5 L (11%) than for 3 L (15%). Regarding redistribution, only 6.1% of responses were found to be inconsistent in this study. The 5 L had higher discriminative power than the 3 L version. Reliability as reflected by the index score was 0.64 for 3 L and 0.74 for 5 L. Pain/discomfort was the dimension mostly affected, whereas the self-care dimension was the least affected. CONCLUSIONS: This study suggests that the 5 L-version of the EQ-5D instrument performs better than the 3 L-version in T2DM outpatients in Indonesia, regarding measurement and scoring properties. As such, our study supports the use of the 5 L as the preferred health-related quality of life measurement tool. We did not do a trial but this study was approved by the Medical Ethics Committee of Universitas Gadjah Mada Yogyakarta, Indonesia (document number KE/FK/1188/EC, 12 November 2014, amended 16 March 2015)

Cetaceans have complex brains for complex cognition

MEDLINE® is the source for the citation and abstract of this record.Peer reviewedPublisher PD

Pericyte actomyosin-mediated contraction at the cell-material interface can modulate the microvascular niche

Pericytes physically surround the capillary endothelium, contacting and communicating with associated vascular endothelial cells via cell–cell and cell–matrix contacts. Pericyte–endothelial cell interactions thus have the potential to modulate growth and function of the microvasculature. Here we employ the experimental finding that pericytes can buckle a freestanding, underlying membrane via actin-mediated contraction. Pericytes were cultured on deformable silicone substrata, and pericyte-generated wrinkles were imaged via both optical and atomic force microscopy (AFM). The local stiffness of subcellular domains both near and far from these wrinkles was investigated by using AFM-enabled nanoindentation to quantify effective elastic moduli. Substratum buckling contraction was quantified by the normalized change in length of initially flat regions of the substrata (corresponding to wrinkle contour lengths), and a model was used to relate local strain energies to pericyte contractile forces. The nature of pericyte-generated wrinkling and contractile protein-generated force transduction was further explored by the addition of pharmacological cytoskeletal inhibitors that affected contractile forces and the effective elastic moduli of pericyte domains. Actin-mediated forces are sufficient for pericytes to exert an average buckling contraction of 38% on the elastomeric substrata employed in these in vitro studies. Actomyosin-mediated contractile forces also act in vivo on the compliant environment of the microvasculature, including the basement membrane and other cells. Pericyte-generated substratum deformation can thus serve as a direct mechanical stimulus to adjacent vascular endothelial cells, and potentially alter the effective mechanical stiffness of nonlinear elastic extracellular matrices, to modulate pericyte–endothelial cell interactions that directly influence both physiologic and pathologic angiogenesis.National Science Foundation (U.S.) (CAREER Award)National Science Foundation (U.S.) (Chemical, Bioengineering, Environmental, and Transport Systems-0644846)National Institutes of Health (U.S.) (EY 19533)National Institutes of Health (U.S.) (EY 15125

Water Vapor Measurements by Howard University Raman Lidar during the WAVES 2006 Campaign

Retrieval of water vapor mixing ratio using the Howard University Raman Lidar is presented with emphasis on three aspects: i) performance of the lidar against collocated radiosondes and Raman lidar, ii) investigation of the atmospheric state variables when poor agreement between lidar and radiosondes values occurred and iii) a comparison with satellite-based measurements. The measurements were acquired during the Water Vapor Validation Experiment Sondes/Satellites 2006 field campaign. Ensemble averaging of water vapor mixing ratio data from ten night-time comparisons with Vaisala RS92 radiosondes shows on average an agreement within 10 % up to approx. 8 km. A similar analysis of lidar-to-lidar data of over 700 profiles revealed an agreement to within 20 % over the first 7 km (10 % below 4 km). A grid analysis, defined in the temperature - relative humidity space, was developed to characterize the lidar - radiosonde agreement and quantitatively localizes regions of strong and weak correlations as a function of altitude, temperature or relative humidity. Three main regions of weak correlation emerge: i) regions of low relative humidity and low temperature, ii) moderate relative humidity at low temperatures and iii) low relative humidity at moderate temperatures. Comparison of Atmospheric InfraRed Sounder and Tropospheric Emission Sounder satellites retrievals of moisture with that of Howard University Raman Lidar showed a general agreement in the trend but the formers miss a lot of the details in atmospheric structure due to their low resolution. A relative difference of about 20 % is usually found between lidar and satellites measurements

Gain-of-function mutation in ubiquitin ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues

The start codon c.1A>G mutation in KLHL24, encoding ubiquitin ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation and ultimately causing epidermolysis bullosa simplex (EBS). The majority of patients with EBS are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homolog of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human-induced pluripotent stem cell–derived (hiPSC-derived) cardiomyocytes from 2 patients and 3 nonfamilial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients’ explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values, and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, which can be prevented by restoring desmin protein levels

A Solvable Regime of Disorder and Interactions in Ballistic Nanostructures, Part I: Consequences for Coulomb Blockade

We provide a framework for analyzing the problem of interacting electrons in a ballistic quantum dot with chaotic boundary conditions within an energy $E_T$ (the Thouless energy) of the Fermi energy. Within this window we show that the interactions can be characterized by Landau Fermi liquid parameters. When $g$, the dimensionless conductance of the dot, is large, we find that the disordered interacting problem can be solved in a saddle-point approximation which becomes exact as $g\to\infty$ (as in a large-N theory). The infinite $g$ theory shows a transition to a strong-coupling phase characterized by the same order parameter as in the Pomeranchuk transition in clean systems (a spontaneous interaction-induced Fermi surface distortion), but smeared and pinned by disorder. At finite $g$, the two phases and critical point evolve into three regimes in the $u_m-1/g$ plane -- weak- and strong-coupling regimes separated by crossover lines from a quantum-critical regime controlled by the quantum critical point. In the strong-coupling and quantum-critical regions, the quasiparticle acquires a width of the same order as the level spacing $\Delta$ within a few $\Delta$'s of the Fermi energy due to coupling to collective excitations. In the strong coupling regime if $m$ is odd, the dot will (if isolated) cross over from the orthogonal to unitary ensemble for an exponentially small external flux, or will (if strongly coupled to leads) break time-reversal symmetry spontaneously.Comment: 33 pages, 14 figures. Very minor changes. We have clarified that we are treating charge-channel instabilities in spinful systems, leaving spin-channel instabilities for future work. No substantive results are change