Higher Landing Accuracy in Expert Pilots is Associated with Lower Activity in the Caudate Nucleus

The most common lethal accidents in General Aviation are caused by improperly executed landing approaches in which a pilot descends below the minimum safe altitude without proper visual references. To understand how expertise might reduce such erroneous decision-making, we examined relevant neural processes in pilots performing a simulated landing approach inside a functional MRI scanner. Pilots (aged 20–66) were asked to “fly” a series of simulated “cockpit view” instrument landing scenarios in an MRI scanner. The scenarios were either high risk (heavy fog–legally unsafe to land) or low risk (medium fog–legally safe to land). Pilots with one of two levels of expertise participated: Moderate Expertise (Instrument Flight Rules pilots, n = 8) or High Expertise (Certified Instrument Flight Instructors or Air-Transport Pilots, n = 12). High Expertise pilots were more accurate than Moderate Expertise pilots in making a “land” versus “do not land” decision (CFII: d′ = 3.62±2.52; IFR: d′ = 0.98±1.04; p<.01). Brain activity in bilateral caudate nucleus was examined for main effects of expertise during a “land” versus “do not land” decision with the no-decision control condition modeled as baseline. In making landing decisions, High Expertise pilots showed lower activation in the bilateral caudate nucleus (0.97±0.80) compared to Moderate Expertise pilots (1.91±1.16) (p<.05). These findings provide evidence for increased “neural efficiency” in High Expertise pilots relative to Moderate Expertise pilots. During an instrument approach the pilot is engaged in detailed examination of flight instruments while monitoring certain visual references for making landing decisions. The caudate nucleus regulates saccade eye control of gaze, the brain area where the “expertise” effect was observed. These data provide evidence that performing “real world” aviation tasks in an fMRI provide objective data regarding the relative expertise of pilots and brain regions involved in it.     

Assessment of Survival and Body Size Variation of Culicoides imicola (Diptera: Ceratopogonidae) as Functions of “Candidatus Cardinium” (Bacteroidetes) Infection Status

“Candidatus Cardinium hertigii” (Bacteroidetes) is a maternally inherited endosymbiont known from several arthropods. Its mechanisms for persistence in host populations are mostly reproductive manipulation, though it has been occasionally reported to improve fitness parameters in several hosts. In Culicoides (Diptera: Ceratopogonidae) biting midges, the prevalence of “Candidatus Cardinium” infection was documented as moderate, with no detectable sex bias. We therefore investigated whether “Candidatus Cardinium” affects important fitness parameters, such as survival and body size, in Culicoides imicola, a dominant vector species. Field-collected midges were trapped and analyzed for survival under different environmental conditions and antibiotic treatment, taking into account “Candidatus Cardinium” infection status and parity status (i.e., parous or nulliparous). Additionally, wing lengths were measured as a proxy parameter for body size and analyzed together with “Candidatus Cardinium” infection data. The findings revealed no difference in survival of Culicoides infected with “Candidatus Cardinium” and that of uninfected midges in both parity states and under all tested conditions: optimal, starvation, heat, and antibiotic treatment. Beyond survival, no wing length difference was found for “Candidatus Cardinium”-infected versus uninfected midges. In aggregate, these findings support our conclusion that “Candidatus Cardinium” does not have an overt effect on the survival and size of adult C. imicola midges. “Candidatus Cardinium” may affect immature stages or may alter adult reproductive performance.     

The Efficacy of Hyperbaric Oxygen Therapy on Middle Cerebral Artery Occlusion in Animal Studies: A Meta-Analysis

Background

Inconsistent results have been reported for hyperbaric oxygen therapy (HBO) for acute stroke. We conducted a systematic review and meta-analysis to evaluate the benefit of HBO in animal studies of middle cerebral artery occlusion (MCAO).

Methods

A systematic search of the literature published prior to September 2015 was performed using Embase, Medline (OvidSP), Web of Science and PubMed. Keywords included “hyperoxia” OR “hyperbaric oxygen” OR “HBO” AND “isch(a)emia” OR “focal cerebral ischemia” OR “stroke” OR “infarct” OR “middle cerebral artery occlusion (MCAO).” The primary endpoints were the infarct size and/or neurological outcome score evaluated after HBO treatment in MCAO. Heterogeneity was analyzed using Cochrane Library’s RevMan 5.3.5.

Results

Fifty-one studies that met the inclusion criteria were identified among the 1198 studies examined. When compared with control group data, HBO therapy resulted in infarct size reduction or improved neurological function (32% decrease in infarct size; 95% confidence interval (CI), range 28%–37%; p < 0.00001). Mortality was 18.4% in the HBO group and 26.7% in the control group (RR 0.72, 95% CI, 0.54–0.98; p = 0.03). Subgroup analysis showed that a maximal neuro-protective effect was reached when HBO was administered immediately after MCAO with an absolute atmospheric pressure (ATA) of 2.0 (50% decrease; 95% CI, 43% -57% decrease; p < 0.0001) and more than 6 hours HBO treatment (53% decrease; 95% CI, 41% -64% decrease; p = 0.0005).

Conclusions

HBO had a neuro-protective effect and improved survival in animal models of MCAO, especially in animals given more than 6 hours of HBO and when given immediately after MCAO with 2.0 ATA.     

Computer Simulation of Radial Immunodiffusion: II. Selection of an Algorithm for the Antibody-Antigen Reaction in Gels

An algorithm needed for computer simulation of immunodiffusion has been deduced from existing theories of the in vitro reaction between antibody and antigen. The “Goldberg most probable polymer distribution” theory provides a formula that gives the amount of free antibody, free antigen, and diffusible complexes from extreme antibody excess through extreme antigen excess for any valences of antibody and antigen. As is shown here, that formula can be used even for those reactions producing complexes, cyclical or otherwise, that may precipitate as well as for those reactions involving heterogeneity of binding avidities. It is necessary, however, to specify an extent of reaction parameter. Five limiting expressions for this parameter are proposed as options for the basic algorithm. These are identified as: (a) the “Heidelberger-Kendall complete reaction” option, (b) the “Singer-Campbell constant avidity” option, (c) the “Hudson extensive antibody heterogeneity” option, (d) a new “extensive antigen heterogeneity” option, and (e) the “Goldberg critical extent of reaction” option. Literature data showing need for the various options are presented.     

Economic Analysis of the Impact of Overseas and Domestic Treatment and Screening Options for Intestinal Helminth Infection among US-Bound Refugees from Asia

BackgroundMany U.S.-bound refugees travel from countries where intestinal parasites (hookworm, Trichuris trichuria, Ascaris lumbricoides, and Strongyloides stercoralis) are endemic. These infections are rare in the United States and may be underdiagnosed or misdiagnosed, leading to potentially serious consequences. This evaluation examined the costs and benefits of combinations of overseas presumptive treatment of parasitic diseases vs. domestic screening/treating vs. no program.MethodsAn economic decision tree model terminating in Markov processes was developed to estimate the cost and health impacts of four interventions on an annual cohort of 27,700 U.S.-bound Asian refugees: 1) “No Program,” 2) U.S. “Domestic Screening and Treatment,” 3) “Overseas Albendazole and Ivermectin” presumptive treatment, and 4) “Overseas Albendazole and Domestic Screening for Strongyloides”. Markov transition state models were used to estimate long-term effects of parasitic infections. Health outcome measures (four parasites) included outpatient cases, hospitalizations, deaths, life years, and quality-adjusted life years (QALYs).ResultsThe “No Program” option is the least expensive ($165,923 per cohort) and least effective option (145 outpatient cases, 4.0 hospitalizations, and 0.67 deaths discounted over a 60-year period for a one-year cohort). The “Overseas Albendazole and Ivermectin” option ($418,824) is less expensive than “Domestic Screening and Treatment” ($3,832,572) or “Overseas Albendazole and Domestic Screening for Strongyloides” ($2,182,483). According to the model outcomes, the most effective treatment option is “Overseas Albendazole and Ivermectin,” which reduces outpatient cases, deaths and hospitalization by around 80% at an estimated net cost of $458,718 per death averted, or $2,219/$24,036 per QALY/life year gained relative to “No Program”.DiscussionOverseas presumptive treatment for U.S.-bound refugees is a cost-effective intervention that is less expensive and at least as effective as domestic screening and treatment programs. The addition of ivermectin to albendazole reduces the prevalence of chronic strongyloidiasis and the probability of rare, but potentially fatal, disseminated strongyloidiasis.     

Comprehensive analysis of locomotion dynamics in the protochordate Ciona intestinalis reveals how neuromodulators flexibly shape its behavioral repertoire

Vertebrate nervous systems can generate a remarkable diversity of behaviors. However, our understanding of how behaviors may have evolved in the chordate lineage is limited by the lack of neuroethological studies leveraging our closest invertebrate relatives. Here, we combine high-throughput video acquisition with pharmacological perturbations of bioamine signaling to systematically reveal the global structure of the motor behavioral repertoire in the Ciona intestinalis larvae. Most of Ciona’s postural variance can be captured by 6 basic shapes, which we term “eigencionas.” Motif analysis of postural time series revealed numerous stereotyped behavioral maneuvers including “startle-like” and “beat-and-glide.” Employing computational modeling of swimming dynamics and spatiotemporal embedding of postural features revealed that behavioral differences are generated at the levels of motor modules and the transitions between, which may in part be modulated by bioamines. Finally, we show that flexible motor module usage gives rise to diverse behaviors in response to different light stimuli.

Vertebrate nervous systems can generate a remarkable diversity of behaviors, but how did these evolve in the chordate lineage? A study of the protochordate Ciona intestinalis reveals novel insights into how a simple chordate brain uses neuromodulators to control its behavioral repertoire.     

Bed Rest versus Early Ambulation with Standard Anticoagulation in The Management of Deep Vein Thrombosis: A Meta-Analysis

Introduction

Bed rest has been considered as the cornerstone of management of deep vein thrombosis (DVT) for a long time, though it is not evidence-base, and there is growing evidence favoring early ambulation.

Methods

Electronic databases including Medline, PubMed, Cochrane Library and three Chinese databases were searched with key words of “deep vein thrombosis”, “pulmonary embolism”, “venous thrombosis”, “bed rest”, “immobilization”, “mobilization” and “ambulation”. We considered randomized controlled trials, prospective or retrospective cohort studies that compared the outcomes of acute DVT patients managed with early ambulation versus bed rest, in addition to standard anticoagulation. Meta-analysis pertaining to the incidence of new pulmonary embolism (PE), progression of DVT, and DVT related deaths were conducted, as well as the extent of remission of pain and edema.

Results

13 studies were included with a total of 3269 patients. Compared to bed rest, early ambulation was not associated with a higher incidence of new PE, progression of DVT, or DVT related deaths (RD −0.03, 95% CI −0.05∼ −0.02; Z = 1.24, p = 0.22; random effect model, Tau² = 0.01). Moreover, if the patients suffered moderate or severe pain initially, early ambulation was related to a better outcome, with respect to remission of acute pain in the affected limb (SMD 0.42, 95%CI 0.09∼0.74; Z = 2.52, p = 0.01; random effect model, Tau² = 0.04). Meta-analysis of alleviation of edema cannot elicit a solid conclusion because of significant heterogeneity among the few studies.

Conclusions

Compared to bed rest, early ambulation of acute DVT patients with anticoagulation was not associated with a higher incidence of new PE, progression of DVT, and DVT related deaths. Furthermore, for the patients suffered moderate or severe pain initially, a better outcome can be seen in early ambulation group, regarding to the remission of acute pain in the affected limb.     

M tuberculosis in the Adjuvant Modulates Time of Appearance of CNS-Specific Effector T Cells in the Spleen through a Polymorphic Site of TLR2

DC deliver information regulating trafficking of effector T cells along T-cell priming. However, the role of pathogen-derived motives in the regulation of movement of T cells has not been studied. We hereinafter report that amount of M tuberculosis in the adjuvant modulates relocation of PLP139-151 specific T cells. In the presence of a low dose of M tuberculosis in the adjuvant, T cells (detected by CDR3 BV-BJ spectratyping, the so-called “immunoscope”) mostly reach the spleen by day 28 after immunization (“late relocation”) in the SJL strain, whereas T cells reach the spleen by d 14 with a high dose of M tuberculosis (“early relocation”). The C57Bl/6 background confers a dominant “early relocation” phenotype to F1 (SJL×C57Bl/6) mice, allowing early relocation of T cells in the presence of low dose M tuberculosis. A single non-synonymous polymorphism of TLR2 is responsible for “early/late” relocation phenotype. Egress of T lymphocytes is regulated by TLR2 expressed on T cells. Thus, pathogens engaging TLR2 on T cells regulate directly T-cell trafficking, and polymorphisms of TLR2 condition T-cell trafficking upon a limiting concentration of ligand.     

Network modeling of dynamic brain interactions predicts emergence of neural information that supports human cognitive behavior

How cognitive task behavior is generated by brain network interactions is a central question in neuroscience. Answering this question calls for the development of novel analysis tools that can firstly capture neural signatures of task information with high spatial and temporal precision (the “where and when”) and then allow for empirical testing of alternative network models of brain function that link information to behavior (the “how”). We outline a novel network modeling approach suited to this purpose that is applied to noninvasive functional neuroimaging data in humans. We first dynamically decoded the spatiotemporal signatures of task information in the human brain by combining MRI-individualized source electroencephalography (EEG) with multivariate pattern analysis (MVPA). A newly developed network modeling approach—dynamic activity flow modeling—then simulated the flow of task-evoked activity over more causally interpretable (relative to standard functional connectivity [FC] approaches) resting-state functional connections (dynamic, lagged, direct, and directional). We demonstrate the utility of this modeling approach by applying it to elucidate network processes underlying sensory–motor information flow in the brain, revealing accurate predictions of empirical response information dynamics underlying behavior. Extending the model toward simulating network lesions suggested a role for the cognitive control networks (CCNs) as primary drivers of response information flow, transitioning from early dorsal attention network-dominated sensory-to-response transformation to later collaborative CCN engagement during response selection. These results demonstrate the utility of the dynamic activity flow modeling approach in identifying the generative network processes underlying neurocognitive phenomena.

How is cognitive task behavior generated by brain network interactions? This study describes a novel network modeling approach and applies it to source electroencephalography data. The model accurately predicts future information dynamics underlying behavior and (via simulated lesioning) suggests a role for cognitive control networks as key drivers of response information flow.     

Resuscitation of the terminally ill

The CMA believes that there are conditions of ill health and inevitable death for which a “no resuscitation” order, signed by the attending physician, is appropriate and ethically acceptable. The association encourages physicians who are faced with the decision of writing a “no resuscitation” or “do not resuscitate” order to consider the clinical criteria and procedural guidelines in the Joint Statement on Terminal Illness. This protocol is intended as a basic, national guideline for those involved in the care of the terminally ill. Individual institutions may wish to develop their own directives as an adjunct to the national statement.     

The Power of the Picture: How Narrative Film Captures Attention and Disrupts Goal Pursuit

Narrative transportation is described as a state of detachment that arises when one becomes immersed in the narrative of a story. Participants viewed either an intact version of an engaging 20 min film, “Bang You’re Dead!,” (1961) by Alfred Hitchcock (contiguous condition), or a version of the same film with scenes presented out of order (noncontiguous condition). In this latter condition, the individual scenes were intact but were presented out of chronological order. Participants were told a cover story that we were interested in the amount of gun violence depicted in films. Both groups were given the goal to remember to lift their hand every time they heard the word “gun” spoken during the film. Results revealed that participants were significantly less likely to remember to execute their goal in the contiguous condition, presumably because this narrative transported viewers’ attention and thereby “hijacked” processing resources away from internal goals.     

A quantitative analysis of the voltage-current relationships of fixed charge membranes and the associated property of "punch-through"

A theoretical analysis of the voltage-current relationship is carried out in a membrane consisting of two fixed charge regions, of opposite sign, in contact. This is achieved by applying the diffusion equations to this system in conjunction with the Poisson-Boltzmann equation. The latter has been successfully applied by Mauro to determine the profiles of the electrostatic potential in his treatment of the capacitative property of such a system. It is shown that the system displays the property of rectification and is very similar in many respects to a solid state P-N junction diode. It is also shown that for the case of reverse bias, an electrical breakdown phenomena can occur. This is referred to as the “punch-through” effect. “Punch-through” was observed in experiments on the electrical characteristics of the membranes of Chara australis and Nitella sp. The experimental results are discussed in relation to the theoretical analysis.     

Characterization of the Denitrification-Associated Phosphorus Uptake Properties of “Candidatus Accumulibacter phosphatis” Clades in Sludge Subjected to Enhanced Biological Phosphorus Removal

To characterize the denitrifying phosphorus (P) uptake properties of “Candidatus Accumulibacter phosphatis,” a sequencing batch reactor (SBR) was operated with acetate. The SBR operation was gradually acclimated from anaerobic-oxic (AO) to anaerobic-anoxic-oxic (A2O) conditions by stepwise increases of nitrate concentration and the anoxic time. The communities of “Ca. Accumulibacter” and associated bacteria at the initial (AO) and final (A2O) stages were compared using 16S rRNA and polyphosphate kinase genes and using fluorescence in situ hybridization (FISH). The acclimation process led to a clear shift in the relative abundances of recognized “Ca. Accumulibacter” subpopulations from clades IIA > IA > IIF to clades IIC > IA > IIF, as well as to increases in the abundance of other associated bacteria (Dechloromonas [from 1.2% to 19.2%] and “Candidatus Competibacter phosphatis” [from 16.4% to 20.0%]), while the overall “Ca. Accumulibacter” abundance decreased (from 55.1% to 29.2%). A series of batch experiments combined with FISH/microautoradiography (MAR) analyses was performed to characterize the denitrifying P uptake properties of the “Ca. Accumulibacter” clades. In FISH/MAR experiments using slightly diluted sludge (∼0.5 g/liter), all “Ca. Accumulibacter” clades successfully took up phosphorus in the presence of nitrate. However, the “Ca. Accumulibacter” clades showed no P uptake in the presence of nitrate when the sludge was highly diluted (∼0.005 g/liter); under these conditions, reduction of nitrate to nitrite did not occur, whereas P uptake by “Ca. Accumulibacter” clades occurred when nitrite was added. These results suggest that the “Ca. Accumulibacter” cells lack nitrate reduction capabilities and that P uptake by “Ca. Accumulibacter” is dependent upon nitrite generated by associated nitrate-reducing bacteria such as Dechloromonas and “Ca. Competibacter.”     

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all “single mutant active” with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of “single mutant active” ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) “double mutant active” ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities (“singe mutant active” versus “double mutant active”) rather than the loosely-defined “generational” (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.     

Plant intelligence: Why,why not or where?

The concept of plant intelligence, as proposed by Anthony Trewavas, has raised considerable discussion. However, plant intelligence remains loosely defined; often it is either perceived as practically synonymous to Darwinian fitness, or reduced to a mere decorative metaphor. A more strict view can be taken, emphasizing necessary prerequisites such as memory and learning, which requires clarifying the definition of memory itself. To qualify as memories, traces of past events have to be not only stored, but also actively accessed. We propose a criterion for eliminating false candidates of possible plant intelligence phenomena in this stricter sense: an “intelligent” behavior must involve a component that can be approximated by a plausible algorithmic model involving recourse to stored information about past states of the individual or its environment. Re-evaluation of previously presented examples of plant intelligence shows that only some of them pass our test.

“You were hurt?” Kumiko said, looking at the scar.Sally looked down. “Yeah.”“Why didn''t you have it removed?”“Sometimes it''s good to remember.”“Being hurt?”“Being stupid.”—(W. Gibson: Mona Lisa Overdrive)

Key words: intelligence, memory, learning, plant development, mathematical models, plant neurobiology, definition of terms     

Mutations in HPCA Cause Autosomal-Recessive Primary Isolated Dystonia

Reports of primary isolated dystonia inherited in an autosomal-recessive (AR) manner, often lumped together as “DYT2 dystonia,” have appeared in the scientific literature for several decades, but no genetic cause has been identified to date. Using a combination of homozygosity mapping and whole-exome sequencing in a consanguineous kindred affected by AR isolated dystonia, we identified homozygous mutations in HPCA, a gene encoding a neuronal calcium sensor protein found almost exclusively in the brain and at particularly high levels in the striatum, as the cause of disease in this family. Subsequently, compound-heterozygous mutations in HPCA were also identified in a second independent kindred affected by AR isolated dystonia. Functional studies suggest that hippocalcin might play a role in regulating voltage-dependent calcium channels. The identification of mutations in HPCA as a cause of AR primary isolated dystonia paves the way for further studies to assess whether “DYT2 dystonia” is a genetically homogeneous condition or not.     

Uncovering a Microbial Enigma: Isolation and Characterization of the Streamer-Generating,Iron-Oxidizing,Acidophilic Bacterium “Ferrovum myxofaciens”

A betaproteobacterium, shown by molecular techniques to have widespread global distribution in extremely acidic (pH 2 to 4) ferruginous mine waters and also to be a major component of “acid streamer” growths in mine-impacted water bodies, has proven to be recalcitrant to enrichment and isolation. A modified “overlay” solid medium was devised and used to isolate this bacterium from a number of mine water samples. The physiological and phylogenetic characteristics of a pure culture of an isolate from an abandoned copper mine (“Ferrovum myxofaciens” strain P3G) have been elucidated. “F. myxofaciens” is an extremely acidophilic, psychrotolerant obligate autotroph that appears to use only ferrous iron as an electron donor and oxygen as an electron acceptor. It appears to use the Calvin-Benson-Bassham pathway to fix CO₂ and is diazotrophic. It also produces copious amounts of extracellular polymeric materials that cause cells to attach to each other (and to form small streamer-like growth in vitro) and to different solid surfaces. “F. myxofaciens” can catalyze the oxidative dissolution of pyrite and, like many other acidophiles, is tolerant of many (cationic) transition metals. “F. myxofaciens” and related clone sequences form a monophyletic group within the Betaproteobacteria distantly related to classified orders, with genera of the family Nitrosomonadaceae (lithoautotrophic, ammonium-oxidizing neutrophiles) as the closest relatives. On the basis of the phylogenetic and phenotypic differences of “F. myxofaciens” and other Betaproteobacteria, a new family, “Ferrovaceae,” and order, “Ferrovales,” within the class Betaproteobacteria are proposed. “F. myxofaciens” is the first extreme acidophile to be described in the class Betaproteobacteria.     

Diversity of “Candidatus Liberibacter asiaticus,” Based on the omp Gene Sequence

Huanglongbing (yellow dragon disease) is a destructive disease of citrus. The etiological agent is a noncultured, phloem-restricted alpha-proteobacterium, “Candidatus Liberibacter africanus” in Africa and “Candidatus Liberibacter asiaticus” in Asia. In this study, we used an omp-based PCR-restriction fragment length polymorphism (RFLP) approach to analyze the genetic variability of “Ca. Liberibacter asiaticus” isolates. By using five different enzymes, each the 10 isolates tested could be associated with a specific combination of restriction profiles. The results indicate that the species “Ca. Liberibacter asiaticus,” even within a given region, may comprise several different variants. Thus, omp-based PCR-RFLP analysis is a simple method for detecting and differentiating “Ca. Liberibacter asiaticus” isolates.