The Forgotten Intermediate Condylar Canal: Anatomic Study with Application to Skull Base Surgery.

BACKGROUND: The intermediate condylar canal, which lies lateral to the occipital condyles and medial to the jugular foramen, is rarely mentioned in textbooks, even those devoted to the skull base. Therefore the present anatomic study was performed to better elucidate these structures. METHODS: We studied 100 adult skulls (200 sides) to better understand the prevalence and anatomy of the intermediate condylar canal. RESULTS: An intermediate canal was found on 6 of 200 sides (3%). On average, these canals traveled 7.1 mm lateral to the occipital condyle and had a mean of 2.2 mm posteromedial to the jugular foramen. Anteriorly, these canals opened into the external surface of the hypoglossal canal and, when present, were just medial to a paracondylar process for which there was a strong positive correlation. The length of the canals ranged from 5 to 7.8 mm. In all, there were 3 partial canals and 3 complete canals. One left canal communicated anteriorly at the confluence of the inferior opening of a septated (bifurcated) hypoglossal canal and an unnamed foramen medial to the jugular foramen. These canals were distinct from posterior condylar canals when the latter was present. CONCLUSIONS: Knowledge of the anatomic variants at the base of the skull may help minimize complications during surgical procedures that employ a paracondylar or transcondylar approach or approaches to the jugular foramen.

Changes in Serum, Red Blood Cell, and Colonic Fatty Acids in a Personalized Omega-3 Fatty Acid Supplementation Trial.

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E2 (PGE2), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2-10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE2. Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE2 was change in red blood cell ω-3 HUFA (ρ = -0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE2 vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.

Ultra-low-density digitally architected carbon with a strutted tube-in-tube structure.

Porous materials with engineered stretching-dominated lattice designs, which offer attractive mechanical properties with ultra-light weight and large surface area for wide-ranging applications, have recently achieved near-ideal linear scaling between stiffness and density. Here, rather than optimizing the microlattice topology, we explore a different approach to strengthen low-density structural materials by designing tube-in-tube beam structures. We develop a process to transform fully dense, three-dimensional printed polymeric beams into graphitic carbon hollow tube-in-tube sandwich morphologies, where, similar to grass stems, the inner and outer tubes are connected through a network of struts. Compression tests and computational modelling show that this change in beam morphology dramatically slows down the decrease in stiffness with decreasing density. In situ pillar compression experiments further demonstrate large deformation recovery after 30-50% compression and high specific damping merit index. Our strutted tube-in-tube design opens up the space and realizes highly desirable high modulus-low density and high modulus-high damping material structures.

An Adaptive Bayesian Design for Personalized Dosing in a Cancer Prevention Trial.

INTRODUCTION: In biomarker-driven clinical trials, translational strategies typically involve moving findings from animal experiments to human trials. Typically, the translation is static, using a fixed model derived from animal experiments for the duration of the trial. Bayesian designs, capable of incorporating information external to the experiment, provide a dynamic translational strategy. This article demonstrates an example of such a dynamic Bayesian strategy in a clinical trial. METHODS: This study explored the effect of a personalized dose of fish oil for reducing prostaglandin E2, an inflammatory marker linked to colorectal cancer. A Bayesian design was implemented for the dose-finding algorithm that adaptively updated a dose-response model derived from a previously completed animal study during the clinical trial. In the initial stages of the trial, the dose-response model parameters were estimated from the rodent data. The model was updated following a Bayesian algorithm after data on every 10‒15 subjects were obtained until the model stabilized. Subjects were enrolled in the study between 2013 and 2015, and the data analysis was carried out in 2016. RESULTS: The 3 dosing models were used for groups of 16, 15, and 15 subjects. The mean target dose significantly decreased from 6.63 g/day (Model 1) to 4.06 g/day (Model 3) (p=0.001). Compared with the static strategy of dosing with a single model, the dynamic modeling reduced the dose significantly by about 1.38 g/day on average. CONCLUSIONS: A Bayesian design was effective in adaptively revising the dosing algorithm, resulting in a lower pill burden. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01860352.

Sex differences in impulsivity in adult rats are mediated by organizational actions of neonatal gonadal hormones and not by hormones acting at puberty or in adulthood.

Males as compared to females display increased impulsivity and inefficient inhibitory control and are more frequently diagnosed with disorders characterized by impulsivity. We previously demonstrated male rats make more impulsive action responses (i.e. premature responding) than females on the 5-choice serial reaction time task (5-CSRTT). Furthermore, pre-pubertal male rats make more impulsive choice responses (i.e. choosing an immediate small reward over a delayed larger reward) than females on a delayed-based reward T-maze task. The goal of the current work was to determine if gonadal hormones impact sex differences in impulsivity in adult rats. In an initial experiment, male and female rats underwent sham surgeries or were gonadectomized either pre-pubertally or during adulthood and tested on the 5-CSRTT in adulthood. Males displayed more impulsive action responses than females regardless of hormone status. In a second experiment, females received testosterone or vehicle injections on postnatal days 1 and 2. Males received vehicle injections. All rats were gonadectomized prior to puberty and tested on the 5-CSRTT in adulthood. Females treated neonatally with testosterone and control males made more impulsive action responses than control females. In another set of experiments, manipulation of gonadal hormones led to no differences in performance on the delayed-based reward T-maze task in males and females. Results indicate that no sex difference is apparent in impulsive choice on a delayed-base reward task in adult rats. They also reveal that adult sex differences on a task of impulsive action is mediated by organizational effects of gonadal hormones acting during the neonatal period and not impacted by hormones acting during puberty or adulthood.

Retrieving Decadal Climate Change from Satellite Radiance Observations-A 100-year CO2 Doubling OSSE Demonstration.

Preparing for climate change depends on the observation and prediction of decadal trends of the environmental variables, which have a direct impact on the sustainability of resources affecting the quality of life on our planet. The NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission is proposed to provide climate quality benchmark spectral radiance observations for the purpose of determining the decadal trends of climate variables, and validating and improving the long-range climate model forecasts needed to prepare for the changing climate of the Earth. The CLARREO will serve as an in-orbit, absolute, radiometric standard for the cross-calibration of hyperspectral radiance spectra observed by the international system of polar operational satellite sounding sensors. Here, we demonstrate that the resulting accurately cross-calibrated polar satellite global infrared spectral radiance trends (e.g., from the Metop IASI instrument considered here) can be interpreted in terms of temperature and water vapor profile trends. This demonstration is performed using atmospheric state data generated for a 100-year period from 2000-2099, produced by a numerical climate model prediction that was forced by the doubling of the global average atmospheric CO2 over the 100-year period. The vertical profiles and spatial distribution of temperature decadal trends were successfully diagnosed by applying a linear regression profile retrieval algorithm to the simulated hyperspectral radiance spectra for the 100-year period. These results indicate that it is possible to detect decadal trends in atmospheric climate variables from high accuracy all-sky satellite infrared radiance spectra using the linear regression retrieval technique.

Stiff isotropic lattices beyond the Maxwell criterion.

Materials with a stochastic microstructure, like foams, typically exhibit low mechanical stiffness, whereas lattices with a designed microarchitecture often show notably improved stiffness. These periodic architected materials have previously been designed by rule, using the Maxwell criterion to ensure that their deformation is dominated by the stretching of their struts. Classical designs following this rule tend to be anisotropic, with stiffness depending on the load orientation, but recently, isotropic designs have been reported by superimposing complementary anisotropic lattices. We have designed stiff isotropic lattices de novo with topology optimization, an approach based on continuum finite element analysis. Here, we present results of experiments on these lattices, fabricated by additive manufacturing, that validate predictions of their performance and demonstrate that they are as efficient as those designed by rule, despite appearing to violate the Maxwell criterion. These findings highlight the enhanced potential of topology optimization to design materials with unprecedented properties.

Dietary polyunsaturated fatty acids modulate adipose secretome and is associated with changes in mammary epithelial stem cell self-renewal.

Chronic low-grade adipose inflammation, characterized by aberrant adipokine production and pro-inflammatory macrophage activation/polarization is associated with increased risk of breast cancer. Adipocyte fatty acid composition is influenced by dietary availability and may regulate adipokine secretion and adipose inflammation. After feeding F344 rats for 20 weeks with a Western diet or a fish oil-supplemented diet, we cultured primary rat adipose tissue in a three-dimensional explant culture and collected the conditioned medium. The rat adipose tissue secretome was assayed using the Proteome Profiler Cytokine XL Array, and adipose tissue macrophage polarization (M1/M2 ratio) was assessed using the iNOS/ARG1 ratio. We then assessed the adipokine's effects upon stem cell self-renewal using primary human mammospheres from normal breast mammoplasty tissue. Adipose from rats fed the fish oil diet had an ω-3:ω-6 fatty acid ratio of 0.28 compared to 0.04 in Western diet rats. The adipokine profile from the fish oil-fed rats was shifted toward adipokines associated with reduced inflammation compared to the rats fed the Western diet. The M1/M2 macrophage ratio decreased by 50% in adipose of fish oil-fed rats compared to that from rats fed the Western diet. Conditioned media from rats fed the high ω-6 Western diet increased stem cell self-renewal by 62%±9% (X¯%±SD) above baseline compared to only an 11%±11% increase with the fish oil rat adipose. Modulating the adipokine secretome with dietary interventions therefore may alter stromal-epithelial signaling that plays a role in controlling mammary stem cell self-renewal.

Automated detection and sorting of microencapsulation via machine learning.

Microfluidic-based microencapsulation requires significant oversight to prevent material and quality loss due to sporadic disruptions in fluid flow that routinely arise. State-of-the-art microcapsule production is laborious and relies on experts to monitor the process, e.g. through a microscope. Unnoticed defects diminish the quality of collected material and/or may cause irreversible clogging. To address these issues, we developed an automated monitoring and sorting system that operates on consumer-grade hardware in real-time. Using human-labeled microscope images acquired during typical operation, we train a convolutional neural network that assesses microencapsulation. Based on output from the machine learning algorithm, an integrated valving system collects desirable microcapsules or diverts waste material accordingly. Although the system notifies operators to make necessary adjustments to restore microencapsulation, we can extend the system to automate corrections. Since microfluidic-based production platforms customarily collect image and sensor data, machine learning can help to scale up and improve microfluidic techniques beyond microencapsulation.

Interactions of fatty acids, nonsteroidal anti-inflammatory drugs, and coxibs with the catalytic and allosteric subunits of cyclooxygenases-1 and -2.

Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis-the conversion of arachidonic acid to prostaglandin endoperoxide H2 Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates-COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved.

A seven-step plan for becoming a moderately rich and famous biochemist.

Omega-6 polyunsaturated fatty acids were identified as essential nutrients in 1930. Their essentiality is largely due to their function as prostaglandin (PG) precursors. I spent most of my career in biochemistry determining how PG biosynthesis is regulated. PGs are lipid mediators formed in response to certain circulating hormones and cytokines. PGs act near their sites of synthesis to signal neighboring cells to coordinate their responses (e.g. when platelets interact with blood vessels). The committed step in PG synthesis is the conversion of a 20-carbon omega-6 fatty acid called arachidonic acid to prostaglandin endoperoxide H2 (PGH2). Depending on the tissue and the hormone or cytokine stimulus, this reaction is catalyzed by either cyclooxygenase-1 or cyclooxygenase-2 (COX-1 or COX-2). Once formed, PGH2 is converted, again depending on the context, to one of several downstream PG subtypes that act via specific G protein-coupled receptors. Nonsteroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen, and naproxen) block PG synthesis by inhibiting COX-1 and COX-2. COX-2 is also inhibited by COX-2-selective inhibitors. Inhibition of COX-1 by low-dose aspirin prevents thrombosis. COX-2 inhibition reduces inflammation and pain. Investigating the mysteries of COXs anchored my scientific career. I attribute my successes to the great good fortune of having been surrounded by people who helped me make the most of my talents. I have written this reflection in a light-hearted fashion as a self-help essay, while highlighting the people and factors that most impacted me during my upbringing and then during my maturation and evolution as a biochemist.

Field responsive mechanical metamaterials.

Typically, mechanical metamaterial properties are programmed and set when the architecture is designed and constructed, and do not change in response to shifting environmental conditions or application requirements. We present a new class of architected materials called field responsive mechanical metamaterials (FRMMs) that exhibit dynamic control and on-the-fly tunability enabled by careful design and selection of both material composition and architecture. To demonstrate the FRMM concept, we print complex structures composed of polymeric tubes infilled with magnetorheological fluid suspensions. Modulating remotely applied magnetic fields results in rapid, reversible, and sizable changes of the effective stiffness of our metamaterial motifs.

Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin-E2 concentrations after dietary supplementation with ω-3 fatty acids.

This study evaluated whether mRNA expression of major genes regulating formation of prostaglandin (PG)E2 in the colon and colonic fatty acid concentrations are associated with the reduction in colonic mucosal PGE2 after dietary supplementation with omega-3 (ω-3) fatty acids. Supplementation with ω-3 fatty acids was done for 12 weeks using personalized dosing that was expected to reduce colonic PGE2 by 50%. In stepwise linear regression models, the ω-3 fatty acid dose and baseline BMI explained 16.1% of the inter-individual variability in the fold change of colonic PGE2 post-supplementation. Increases in mRNA gene expression after supplementation were, however, modest and were not associated with changes in PGE2. When baseline expression of PTGS1, PTGS2 and HPGD genes was included in the linear regression model containing dose and BMI, only PTGS2, the gene coding for the inducible form cyclooxygenase, was a significant predictor. Higher relative expression of PTGS2 predicted greater decreases in colonic PGE2, accounting for an additional 13.6% of the inter-individual variance. In the final step of the regression model, greater decreases in total colonic fatty acid concentrations predicted greater decreases in colonic PGE2, contributing to an additional 18.7% of the variance. Overall, baseline BMI, baseline expression of PTGS2 and changes in colonic total fatty acids together accounted for 48% of the inter-individual variability in the change in colonic PGE2. This is consistent with biochemical data showing that fatty acids which are not substrates for cyclooxygenases can activate cyclooxygenase-2 allosterically. Further clinical trials are needed to elucidate the factors that regulate the fatty acid milieu of the human colon and how this interacts with key lipid metabolizing enzymes. Given the central role of PGE2 in colon carcinogenesis, these pathways may also impact on colon cancer prevention by other dietary and pharmacological approaches.

The lifecycle of anvil clouds and the top-of-atmosphere radiation balance over the tropical west Pacific.

Observations from a geostationary satellite are used to describe the lifecycle of mesoscale convective systems (MCS), their associated anvil clouds, and their effects on the radiation balance over the warm pool of the tropical west Pacific Ocean. In their developing stages, MCS primarily consist of clouds that are optically thick and have a negative net cloud radiative effect (CRE). As MCS age, ice crystals in the anvil become larger, the cloud top lowers somewhat, and clouds with neutral and positive net CRE become more common. Shading from anvils causes cool anomalies in the underlying sea surface temperature (SST) of up to -0.6 °C. MCS often occur in clusters that are embedded within large westward-propagating disturbances, so shading from anvils can cool SSTs over regions spanning hundreds of kilometers. Triggering of convection is more likely to follow a warm SST anomaly than a cold SST anomaly on timescales of several days. This information is used to test hypotheses on why, over the warm pool, the average shortwave and longwave CRE are individually large but nearly cancel. The results are consistent with the hypothesis that the cancelation in CRE is caused by feedbacks between cloud albedo, large-scale circulation, and SST.

A Prototype Method for Diagnosing High Ice Water Content Probability Using Satellite Imager Data.

Recent studies have found that flight through deep convective storms and ingestion of high mass concentrations of ice crystals, also known as high ice water content (HIWC), into aircraft engines can adversely impact aircraft engine performance. These aircraft engine icing events caused by HIWC have been documented during flight in weak reflectivity regions near convective updraft regions that do not appear threatening in onboard weather radar data. Three airborne field campaigns were conducted in 2014 and 2015 to better understand how HIWC is distributed in deep convection, both as a function of altitude and proximity to convective updraft regions, and to facilitate development of new methods for detecting HIWC conditions, in addition to many other research and regulatory goals. This paper describes a prototype method for detecting HIWC conditions using geostationary (GEO) satellite imager data coupled with in-situ total water content (TWC) observations collected during the flight campaigns. Three satellite-derived parameters were determined to be most useful for determining HIWC probability: 1) the horizontal proximity of the aircraft to the nearest overshooting convective updraft or textured anvil cloud, 2) tropopause-relative infrared brightness temperature, and 3) daytime-only cloud optical depth. Statistical fits between collocated TWC and GEO satellite parameters were used to determine the membership functions for the fuzzy logic derivation of HIWC probability. The products were demonstrated using data from several campaign flights and validated using a subset of the satellite-aircraft collocation database. The daytime HIWC probability was found to agree quite well with TWC time trends and identified extreme TWC events with high probability. Discrimination of HIWC was more challenging at night with IR-only information. The products show the greatest capability for discriminating TWC ≥ 0.5 g m-3. Product validation remains challenging due to vertical TWC uncertainties and the typically coarse spatio-temporal resolution of the GEO data.

Calibration Changes to Terra MODIS Collection-5 Radiances for CERES Edition 4 Cloud Retrievals.

Previous research has revealed inconsistencies between the Collection 5 (C5) calibrations of certain channels common to the Terra and Aqua MODerate-resolution Imaging Spectroradiometers (MODIS). To achieve consistency between the Terra and Aqua MODIS radiances used in the Clouds and the Earth's Radiant Energy System (CERES) Edition 4 (Ed4) cloud property retrieval system, adjustments were developed and applied to the Terra C5 calibrations for channels 1-5, 7, 20, and 26. These calibration corrections were developed independently of those used for MODIS Collection 6 (C6) data, which became available after the CERES Ed4 processing had commenced. The comparisons demonstrate that the corrections applied to the Terra C5 data for CERES Edition 4 generally resulted in Terra-Aqua radiance consistency that is as good as or better than that of the C6 datasets. The C5 adjustments resulted in more consistent Aqua and Terra cloud property retrievals than seen in the previous CERES edition. Other calibration artifacts were found in one of the corrected channels and in some of the uncorrected thermal channels after Ed4 began. Where corrections were neither developed nor applied, some artifacts are likely to have been introduced into the Ed4 cloud property record. For example, the degradation in the Aqua MODIS 0.65-µm channel in both the C5 and C6 datasets affects trends in cloud optical depth retrievals. Thus, despite the much-improved consistency achieved for the Terra and Aqua datasets in Ed4, the CERES Ed4 cloud property datasets should be used cautiously for cloud trend studies because of those remaining calibration artifacts.

Flipping the cyclooxygenase (Ptgs) genes reveals isoform-specific compensatory functions.

Two prostaglandin (PG) H synthases encoded by Ptgs genes, colloquially known as cyclooxygenase (COX)-1 and COX-2, catalyze the formation of PG endoperoxide H2, the precursor of the major prostanoids. To address the functional interchangeability of these two isoforms and their distinct roles, we have generated COX-2>COX-1 mice whereby Ptgs2 is knocked in to the Ptgs1 locus. We then "flipped" Ptgs genes to successfully create the Reversa mouse strain, where knock-in COX-2 is expressed constitutively and knock-in COX-1 is lipopolysaccharide (LPS) inducible. In macrophages, flipping the two Ptgs genes has no obvious impact on COX protein subcellular localization. COX-1 was shown to compensate for PG synthesis at high concentrations of substrate, whereas elevated LPS-induced PG production was only observed for cells expressing endogenous COX-2. Differential tissue-specific patterns of expression of the knock-in proteins were evident. Thus, platelets from COX-2>COX-1 and Reversa mice failed to express knock-in COX-2 and, therefore, thromboxane (Tx) production in vitro and urinary Tx metabolite formation in COX-2>COX-1 and Reversa mice in vivo were substantially decreased relative to WT and COX-1>COX-2 mice. Manipulation of COXs revealed isoform-specific compensatory functions and variable degrees of interchangeability for PG biosynthesis in cells/tissues.