Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

Jumping in lantern bugs (Hemiptera, Fulgoridae).

Lantern bugs are amongst the largest of the jumping hemipteran bugs, with body lengths reaching 44 mm and masses reaching 0.7 g. They are up to 600 times heavier than smaller hemipterans that jump powerfully using catapult mechanisms to store energy. Does a similar mechanism also propel jumping in these much larger insects? The jumping performance of two species of lantern bugs (Hemiptera, Auchenorrhyncha, family Fulgoridae) from India and Malaysia was therefore analysed from high-speed videos. The kinematics showed that jumps were propelled by rapid and synchronous movements of both hind legs, with their trochantera moving first. The hind legs were 20-40% longer than the front legs, which was attributable to longer tibiae. It took 5-6 ms to accelerate to take-off velocities reaching 4.65 m s-1 in the best jumps by female Kalidasa lanata. During these jumps, adults experienced an acceleration of 77 g, required an energy expenditure of 4800 µJ and a power output of 900 mW, and exerted a force of 400 mN. The required power output of the thoracic jumping muscles was 21,000 W kg-1, 40 times greater than the maximum active contractile limit of muscle. Such a jumping performance therefore required a power amplification mechanism with energy storage in advance of the movement, as in their smaller relatives. These large lantern bugs are near isometrically scaled-up versions of their smaller relatives, still achieve comparable, if not higher, take-off velocities, and outperform other large jumping insects such as grasshoppers.

Adhesive latching and legless leaping in small, worm-like insect larvae.

Jumping is often achieved using propulsive legs, yet legless leaping has evolved multiple times. We examined the kinematics, energetics and morphology of long-distance jumps produced by the legless larvae of gall midges (Asphondylia sp.). They store elastic energy by forming their body into a loop and pressurizing part of their body to form a transient 'leg'. They prevent movement during elastic loading by placing two regions covered with microstructures against each other, which likely serve as a newly described adhesive latch. Once the latch releases, the transient 'leg' launches the body into the air. Their average takeoff speeds (mean: 0.85 m s-1; range: 0.39-1.27 m s-1) and horizontal travel distances (up to 36 times body length or 121 mm) rival those of legged insect jumpers and their mass-specific power density (mean: 910 W kg-1; range: 150-2420 W kg-1) indicates the use of elastic energy storage to launch the jump. Based on the forces reported for other microscale adhesive structures, the adhesive latching surfaces are sufficient to oppose the loading forces prior to jumping. Energetic comparisons of insect larval crawling versus jumping indicate that these jumps are orders of magnitude more efficient than would be possible if the animals had crawled an equivalent distance. These discoveries integrate three vibrant areas in engineering and biology - soft robotics, small, high-acceleration systems, and adhesive systems - and point toward a rich, and as-yet untapped area of biological diversity of worm-like, small, legless jumpers.

The Boltzmann project.

The International Committee for Weights and Measures (CIPM), at its meeting in October 2017, followed the recommendation of the Consultative Committee for Units (CCU) on the redefinition of the kilogram, ampere, kelvin and mole. For the redefinition of the kelvin, the Boltzmann constant will be fixed with the numerical value 1.380 649 × 10-23 J K-1. The relative standard uncertainty to be transferred to the thermodynamic temperature value of the triple point of water will be 3.7 × 10-7, corresponding to an uncertainty in temperature of 0.10 mK, sufficiently low for all practical purposes. With the redefinition of the kelvin, the broad research activities of the temperature community on the determination of the Boltzmann constant have been very successfully completed. In the following, a review of the determinations of the Boltzmann constant k, important for the new definition of the kelvin and performed in the last decade, is given.

Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Enterobacter aerogenes Hormaeche and Edwards 1960 (Approved Lists 1980) and Klebsiella mobilis Bascomb et al. 1971 (Approved Lists 1980) share the same nomenclatural type (ATCC 13048) on the Approved Lists and are homotypic synonyms, with consequences for the name Klebsiella mobilis Bascomb et al. 1971 (Approved Lists 1980).

Enterobacter aerogenes Hormaeche and Edwards 1960 (Approved Lists 1980) and Klebsiella mobilis Bascomb et al. 1971 (Approved Lists 1980) were placed on the Approved Lists of Bacterial Names and were based on the same nomenclatural type, ATCC 13048. Consequently they are to be treated as homotypic synonyms. However, the names of homotypic synonyms at the rank of species normally are based on the same epithet. Examination of the Rules of the International Code of Nomenclature of Bacteria in force at the time indicates that the epithet mobilis in Klebsiella mobilis Bascomb et al. 1971 (Approved Lists 1980) was illegitimate at the time the Approved Lists were published and according to the Rules of the current International Code of Nomenclature of Prokaryotes continues to be illegitimate.

Muscle-spring dynamics in time-limited, elastic movements.

Muscle contractions that load in-series springs with slow speed over a long duration do maximal work and store the most elastic energy. However, time constraints, such as those experienced during escape and predation behaviours, may prevent animals from achieving maximal force capacity from their muscles during spring-loading. Here, we ask whether animals that have limited time for elastic energy storage operate with springs that are tuned to submaximal force production. To answer this question, we used a dynamic model of a muscle-spring system undergoing a fixed-end contraction, with parameters from a time-limited spring-loader (bullfrog: Lithobates catesbeiana) and a non-time-limited spring-loader (grasshopper: Schistocerca gregaria). We found that when muscles have less time to contract, stored elastic energy is maximized with lower spring stiffness (quantified as spring constant). The spring stiffness measured in bullfrog tendons permitted less elastic energy storage than was predicted by a modelled, maximal muscle contraction. However, when muscle contractions were modelled using biologically relevant loading times for bullfrog jumps (50 ms), tendon stiffness actually maximized elastic energy storage. In contrast, grasshoppers, which are not time limited, exhibited spring stiffness that maximized elastic energy storage when modelled with a maximal muscle contraction. These findings demonstrate the significance of evolutionary variation in tendon and apodeme properties to realistic jumping contexts as well as the importance of considering the effect of muscle dynamics and behavioural constraints on energy storage in muscle-spring systems.

Take-off speed in jumping mantises depends on body size and a power-limited mechanism.

Many insects such as fleas, froghoppers and grasshoppers use a catapult mechanism to jump, and a direct consequence of this is that their take-off velocities are independent of their mass. In contrast, insects such as mantises, caddis flies and bush crickets propel their jumps by direct muscle contractions. What constrains the jumping performance of insects that use this second mechanism? To answer this question, the jumping performance of the mantis Stagmomantis theophila was measured through all its developmental stages, from 5 mg first instar nymphs to 1200 mg adults. Older and heavier mantises have longer hind and middle legs and higher take-off velocities than younger and lighter mantises. The length of the propulsive hind and middle legs scaled approximately isometrically with body mass (exponent=0.29 and 0.32, respectively). The front legs, which do not contribute to propulsion, scaled with an exponent of 0.37. Take-off velocity increased with increasing body mass (exponent=0.12). Time to accelerate increased and maximum acceleration decreased, but the measured power that a given mass of jumping muscle produced remained constant throughout all stages. Mathematical models were used to distinguish between three possible limitations to the scaling relationships: first, an energy-limited model (which explains catapult jumpers); second, a power-limited model; and third, an acceleration -: limited model. Only the model limited by muscle power explained the experimental data. Therefore, the two biomechanical mechanisms impose different limitations on jumping: those involving direct muscle contractions (mantises) are constrained by muscle power, whereas those involving catapult mechanisms are constrained by muscle energy.

Estimates of the difference between thermodynamic temperature and the International Temperature Scale of 1990 in the range 118 K to 303 K.

Using exceptionally accurate measurements of the speed of sound in argon, we have made estimates of the difference between thermodynamic temperature, T, and the temperature estimated using the International Temperature Scale of 1990, T90, in the range 118 K to 303 K. Thermodynamic temperature was estimated using the technique of relative primary acoustic thermometry in the NPL-Cranfield combined microwave and acoustic resonator. Our values of (T-T90) agree well with most recent estimates, but because we have taken data at closely spaced temperature intervals, the data reveal previously unseen detail. Most strikingly, we see undulations in (T-T90) below 273.16 K, and the discontinuity in the slope of (T-T90) at 273.16 K appears to have the opposite sign to that previously reported.

Phase shift between joint rotation and actuation reflects dominant forces and predicts muscle activation patterns.

During behavior, the work done by actuators on the body can be resisted by the body's inertia, elastic forces, gravity, or viscosity. The dominant forces that resist actuation have major consequences on the control of that behavior. In the literature, features and actuation of locomotion, for example, have been successfully predicted by nondimensional numbers (e.g. Froude number and Reynolds number) that generally express the ratio between two of these forces (gravitational, inertial, elastic, and viscous). However, animals of different sizes or motions at different speeds may not share the same dominant forces within a behavior, making ratios of just two of these forces less useful. Thus, for a broad comparison of behavior across many orders of magnitude of limb length and cycle period, a dimensionless number that includes gravitational, inertial, elastic, and viscous forces is needed. This study proposes a nondimensional number that relates these four forces: the phase shift (ϕ) between the displacement of the limb and the actuator force that moves it. Using allometric scaling laws, ϕ for terrestrial walking is expressed as a function of the limb length and the cycle period at which the limb steps. Scale-dependent values of ϕ are used to explain and predict the electromyographic (EMG) patterns employed by different animals as they walk.

The diagnostic utility of hypophosphatemia for differentiating generalized tonic-clonic seizures from syncope in dogs: A case control study.

Transient hypophosphatemia is often detected in humans following generalized tonic-clonic seizures (GTCS), and serum phosphorus concentration (sPi) serves as a marker to differentiate GTCS from syncope. The objective of this retrospective study was to assess the usefulness of hypophosphatemia as a diagnostic marker for GTCS in dogs. Eighty-seven and 26 client-owned dogs with GTCS or syncope, respectively, were enrolled. Dogs were included if the episode occurred ≤ 3 h from presentation, and if sPi and serum creatinine (sCr) were measured. Dogs were excluded if aged < 1 year or if sCr exceeded 176.8 µmol/L. There were no group differences in sCr. Hypophosphatemia (sPi ≤ 0.97 mmol/L) occurred in 28 dogs (32%) in the seizure group, and in no dogs in the syncope group. Median sPi was significantly (P < 0.001) lower in the seizure group (1 mmol/L, [range, 0.31-2.87 mmol/L]) compared to the syncope group (1.35 mmol/L [range, 0.97-2.71 mmol/L]). Furthermore, in dogs presented while seizing (n = 24/87; 28%) median sPi was significantly lower compared to those that were not (0.9 mmol/L [range, 0.3-1.74 mmol/L] vs. 1 mmol/L [range, 0.33-2.18 mmol/L], P = 0.050). ROC analysis of sPi as a marker of GTCS yielded an AUC of 0.757 (95% confidence interval 0.667-0.847), with an optimum cutoff point of 0.97 mmol/L, corresponding to specificity and sensitivity levels of 100% and 44%, respectively. In conclusion, sPi may, in certain cases, serve as an additional diagnostic tool to differentiate GTCS from syncope in dogs. Hypophosphatemia, especially with sPi < 0.97 mmol/L, may be useful in clinical practice to rule in GTCS.

Spring and latch dynamics can act as control pathways in ultrafast systems.

Ultrafast movements propelled by springs and released by latches are thought limited to energetic adjustments prior to movement, and seemingly cannot adjust once movement begins. Even so, across the tree of life, ultrafast organisms navigate dynamic environments and generate a range of movements, suggesting unrecognized capabilities for control. We develop a framework of control pathways leveraging the non-linear dynamics of spring-propelled, latch-released systems. We analytically model spring dynamics and develop reduced-parameter models of latch dynamics to quantify how they can be tuned internally or through changing external environments. Using Lagrangian mechanics, we test feedforward and feedback control implementation via spring and latch dynamics. We establish through empirically-informed modeling that ultrafast movement can be controllably varied during latch release and spring propulsion. A deeper understanding of the interconnection between multiple control pathways, and the tunability of each control pathway, in ultrafast biomechanical systems presented here has the potential to expand the capabilities of synthetic ultra-fast systems and provides a new framework to understand the behaviors of fast organisms subject to perturbations and environmental non-idealities.

A buckling region in locust hindlegs contains resilin and absorbs energy when jumping or kicking goes wrong.

If a hindleg of a locust slips during jumping, or misses its target during kicking, energy generated by the two extensor tibiae muscles is no longer expended in raising the body or striking a target. How, then, is the energy in a jump (4100-4800 µJ) or kick (1700 µJ) dissipated? A specialised buckling region found in the proximal hind-tibia where the bending moment is high, but not present in the other legs, buckled and allowed the distal part of the tibia to extend. In jumps when a hindleg slipped, it bent by a mean of 23±14 deg at a velocity of 13.4±9.5 deg ms(-1); in kicks that failed to contact a target it bent by 32±16 deg at a velocity of 32.9±9.5 deg ms(-1). It also buckled 8.5±4.0 deg at a rate of 0.063±0.005 deg ms(-1) when the tibia was prevented from flexing fully about the femur in preparation for both these movements. By experimentally buckling this region through 40 deg at velocities of 0.001-0.65 deg ms(-1), we showed that one hindleg could store about 870 µJ on bending, of which 210 µJ was dissipated back to the leg on release. A band of blue fluorescence was revealed at the buckling region under UV illumination that had the two key signatures of the elastic protein resilin. A group of campaniform sensilla 300 µm proximal to the buckling region responded to imposed buckling movements. The features of the buckling region show that it can act as a shock absorber as proposed previously when jumping and kicking movements go wrong.

Biomechanics: Passive forces set the stage for stick insects.

For small animals like insects, passive elastic forces within their joints are extremely important to control of limb motion. A new study shows that these passive forces are tuned to the needs of individual joints.

Quantity over quality? Prey-field characteristics influence the foraging decisions of little penguins (Eudyptula minor).

Quantifying prey characteristics is important for understanding the foraging behaviour of predators, which ultimately influence the structure and function of entire ecosystems. However, information available on prey is often at magnitudes which cannot be used to infer the fine-scale behaviour of predators, especially so in marine environments where direct observation of predator-prey interactions is rarely possible. In the present study, animal-borne video data loggers were used to determine the influence of prey type and patch density on the foraging behaviour of the little penguin (Eudyptula minor), an important predator in southeastern Australia. We found that numerical density positively influenced time spent foraging at a patch. However, when accounting for calorific value in density estimates, individuals spent longer at dense patches of low-quality prey. This may reflect a trade-off between capture effort and calorific gain as lower quality prey were captured at higher rates. During the breeding season, foraging trip distance and duration is constrained by the need to return to the colony each day to feed offspring. The results of the study suggest that, under these spatio-temporal constraints, little penguins maximize foraging performance by concentrating efforts at larger quantities of prey, irrespective of their calorific quality.

Analysis of biochemical parameters in canine fetal fluids during the second half of pregnancy.

Although fetal fluids, amnion (AM) and allantois (AL), have been studied at the end of pregnancy in the bitch, little is known about their composition during gestation. The aim of this study was to characterize and compare the biochemical parameters of fetal fluids collected from healthy pregnant bitches in mid pregnancy. Fetal fluids were collected from 26 pregnant bitches between 35 and 62 days from ovulation based on ultrasonography. A total of 149 samples were analyzed; 94 samples of known origin (61 a.m. and 33 AL) from 17 dams, which included 17 paired samples (AM and AL from the same fetus; 34 samples), and 55 of unknown origin from nine dams. Reference ranges were formulated for 22 biochemical parameters in AM and AL based on the samples of known origin (n = 94). All parameters (creatinine, albumin, GGT and urea) significantly different between AM and AL were included (by mixed model ANOVA) in the analysis and an algorithm to predict the origin of the fluid was developed (by logistic regression). Overall, of the 94 samples, 79 samples (84%) were correctly identified by the algorithm. For the 33 allantois samples, and for the 61 amnion samples, 23 (69.7%) and 56 (91.8%) were correctly identified by the algorithm, respectively. Based on the algorithm, 31 of the unknown samples (58%) were classified as amnion and 22 samples (42%), as allantois fluid. For all the unknown samples, the average certainty was 86% (compared to 81% for the samples whose fluid type was known), showing the degree of precision of the classification.

Ovariectomy and genes encoding core circadian regulatory proteins in murine bone.

SUMMARY: This study investigated the influence of ovarian hormone deficiency on core circadian regulatory protein (CCRP) in the context of bone loss. Our data suggest that ovarian hormone deficiency disrupts diurnal rhythmicity and CCRP expression in bone. Further studies should determine if chronobiology provides a novel therapeutic target for osteoporosis intervention. INTRODUCTION: CCRP synchronize metabolic activities and display an oscillatory expression profile in murine bone. In vitro studies using bone marrow mesenchymal stromal/stem cells have demonstrated that the CCRP is present and can be regulated within osteoblast progenitors. In vivo studies have shown that the CCRP regulates bone mass via leptin/neuroendocrine pathways. The current study used an ovariectomized murine model to test the hypothesis that ovarian hormone deficiency is associated with either an attenuation and/or temporal phase shift of the CCRP oscillatory expression in bone and that these changes are correlated with the onset of osteoporosis. METHODS: Sham-operated controls and ovariectomized female C57BL/6 mice were euthanized at 4-h intervals 2 weeks post-operatively. RESULTS: Ovariectomy attenuated the oscillatory expression of CCRP mRNAs in the femur and vertebra relative to the controls and reduced the wheel-running activity profile. CONCLUSION: Ovarian hormone deficiency modulates the expression profile of the CCRP with potential impact on bone marrow mesenchymal stem cell lineage commitment.

Sorafenib in combination with weekly topotecan in recurrent ovarian cancer, a phase I/II study of the Hoosier Oncology Group.

OBJECTIVE: This trial determined the efficacy and tolerability of sorafenib and weekly topotecan in patients with platinum-resistant ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS: Primary endpoints were maximum tolerated dose of sorafenib with weekly topotecan (phase I) and response rate (phase II). Secondary endpoints were progression free survival (PFS), overall survival (OS), toxicity, and rate of clinical benefit. Eligibility included recurrent platinum-resistant OC or PPC, <3 prior regimens, normal end-organ function. 3+3 dose escalation was used for phase I, sorafenib being tested at 400mg and 800 mg orally daily. Topotecan dose was reduced from 4 mg/m(2) to 3.5mg/m(2) IV weekly. The phase II regimen was sorafenib 400mg daily and topotecan 3.5mg/m(2) weekly on days 1, 8, 15 of a 28 days cycle. RESULTS: 16 patients were enrolled in phase I and 14 patients in phase II. Median age was 52.5 years (range 35-79), 27 patients had OC, and 3 PPC. Median number of cycles administered was 2.5 (0-15). There were 5 partial responses (PR) (16.7%), and 14 patients (46.7%) with stable disease (SD). Four PRs were recorded during phase I and 1 during phase II. One of those PRs occurred in a patient with platinum-sensitive disease. Grade 3/4 toxicities included leukopenia/neutropenia (23%), thrombocytopenia (17%), anemia (10%), fatigue, nausea, vomiting (7% each). One case of grade 3 hand-foot syndrome was recorded. CONCLUSIONS: The combination of sorafenib and topotecan causes significant toxicity, precluding administration of full doses and resulting in modest clinical efficacy in platinum resistant OC or PPC.