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Fatigue has become an increasing problem in our modern society. Using MATLAB as a generic modelling tool, a fatigue model was developed based on an existing one and compared with a commercial fatigue software for prediction of cognitive performance under total and partial sleep deprivation. The flexibility of our fatigue model allowed additions of new algorithms and mechanisms for non-sleep factors and countermeasures and thus improved model predictions and usability for both civilian and military applications. This was demonstrated by model simulations of various scenarios and comparison with experimental studies. Our future work will be focused on model validation and integration with other modelling tools. Practitioner Summary: Mental fatigue affects health, safety and quality of life in our modern society. In this paper, we reported a cognitive fatigue model based on existing models with newly incorporated components taking both the operator's state of alertness and task demand into account. The model provided the additional capability for prediction of cognitive performance in scenarios involving pharmaceutical countermeasures, different task demands and shift work.

Endothelial progenitor cells (EPCs) play a key role in neovascularization and have been linked to improved cardiovascular outcomes. Although there is a well-established inverse relationship between androgen levels and cardiovascular mortality in men, the role of androgens in EPC function is not fully understood. In this study, we investigated the effects of androgens on 2 subpopulations of EPCs, early EPCs (EEPCs) and late outgrowth EPCs (OECs), and their relationships with coronary collateralization. Early EPCs and OECs were isolated from the peripheral blood of young healthy men and treated with dihydrotestosterone (DHT) with or without androgen receptor (AR) antagonist, hydroxyflutamide, in vitro. Dihydrotestosterone treatment enhanced AR-mediated proliferation, migration, and tubulogenesis of EEPCs and OECs in a dose-dependent manner. Furthermore, DHT augmented EPC sensitivity to extracellular stimulation by vascular endothelial growth factor (VEGF) via increased surface VEGF receptor expression and AKT activation. In vivo, xenotransplantation of DHT pretreated human EPCs augmented blood flow recovery and angiogenesis in BALB/c nude male mice, compared to mice receiving untreated EPCs, following hindlimb ischemia. In particular, DHT pretreated human OECs exhibited higher reparative potential than EEPCs in augmenting postischemic blood flow recovery in mice. Furthermore, whole blood was collected from the coronary sinus of men with single vessel coronary artery disease (CAD) who underwent elective percutaneous intervention (n = 23). Coronary collateralization was assessed using the collateral flow index. Serum testosterone and EPC levels were measured. In men with CAD, circulating testosterone was positively associated with the extent of coronary collateralization and the levels of OECs. In conclusion, androgens enhance EPC function and promote neovascularization after ischemia in mice and are associated with coronary collateralization in men.

Cardiovascular morphogenesis involves cell behavior and cell identity changes that are activated by mechanical forces associated with heart function. Recently, advances in in vivo imaging, methods to alter blood flow, and computational modelling have greatly advanced our understanding of how forces produced by heart contraction and blood flow impact different morphogenetic processes. Meanwhile, traditional genetic approaches have helped to elucidate how endothelial cells respond to forces at the cellular and molecular level. Here we discuss the principles of endothelial mechanosensitity and their interplay with cellular processes during cardiovascular morphogenesis. We then discuss their implications in the field of cardiovascular tissue engineering. journal article review 2019 Aug 2019 10 03 imported

Mechanical forces are key modulators of valvulogenic developmental programs. However, the mechanosensitive gene network underlying this process remains unclear. It is well established that contractile and flow forces activate endocardial expression of the transcription factorklf2aduring valve morphogenesis. We report two novel transcription factors with a function in heart valve formation in zebrafish:egr1andklf2b. Genome-wide analysis of gene expression reveals that the endocardial transcriptional programs modulated byklf2a,klf2b, andegr1mainly contain non-redundant targets. Several of these targets have been implicated in endothelial-to-mesenchymal transition (EMT). Many of the deregulated genes exhibit changes in chromatin accessibility pointing to potential direct effects of these factors. Finally,in vivophenotypic analyses show that VEGF receptor 1 (flt1)is a target ofegr1andklf2bduring early valvulogenesis. These findings suggest thatklf2a,klf2b, andegr1cooperate for the activation of EMT program in response to mechanosensitive inputs. We propose that the combinatorial action of these factors mediates flow mechanotransduction to control the endocardial program, especially for valve development.

Cells need to sense their mechanical environment during the growth of developing tissues and maintenance of adult tissues. The concept of force-sensing mechanisms that act through cell–cell and cell–matrix adhesions is now well established and accepted. Additionally, it is widely believed that force sensing can be mediated through cilia. Yet, this hypothesis is still debated. By using primary cilia sensing as a paradigm, we describe the physical requirements for cilium-mediated mechanical sensing and discuss the different hypotheses of how this could work. We review the different mechanosensitive channels within the cilium, their potential mode of action and their biological implications. In addition, we describe the biological contexts in which cilia are acting – in particular, the left–right organizer – and discuss the challenges to discriminate between cilium-mediated chemosensitivity and mechanosensitivity. Throughout, we provide perspectives on how quantitative analysis and physics-based arguments might help to better understand the biological mechanisms by which cells use cilia to probe their mechanical environment.

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose–mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.

Although N-acetyl groups are common in nature, N-glycolyl groups are rare. Mammals express two major sialic acids, N-acetylneuraminic acid and N-glycolylneuraminic acid (Neu5Gc). Although humans cannot produce Neu5Gc, it is detected in the epithelial lining of hollow organs, endothelial lining of the vasculature, fetal tissues, and carcinomas. This unexpected expression is hypothesized to result via metabolic incorporation of Neu5Gc from mammalian foods. This accumulation has relevance for diseases associated with such nutrients, via interaction with Neu5Gc-specific antibodies. Little is known about how ingested sialic acids in general and Neu5Gc in particular are metabolized in the gastrointestinal tract. We studied the gastrointestinal and systemic fate of Neu5Gc-containing glycoproteins (Neu5Gc-glycoproteins) or free Neu5Gc in the Neu5Gc-free Cmah−/− mouse model. Ingested free Neu5Gc showed rapid absorption into the circulation and urinary excretion. In contrast, ingestion of Neu5Gc-glycoproteins led to Neu5Gc incorporation into the small intestinal wall, appearance in circulation at a steady-state level for several hours, and metabolic incorporation into multiple peripheral tissue glycoproteins and glycolipids, thus conclusively proving that Neu5Gc can be metabolically incorporated from food. Feeding Neu5Gc-glycoproteins but not free Neu5Gc mimics the human condition, causing tissue incorporation into human-like sites in Cmah−/− fetal and adult tissues, as well as developing tumors. Thus, glycoproteins containing glycosidically linked Neu5Gc are the likely dietary source for human tissue accumulation, and not the free monosaccharide. This human-like model can be used to elucidate specific mechanisms of Neu5Gc delivery from the gut to tissues, as well as general mechanisms of metabolism of ingested sialic acids.

Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene α, interleukin (IL)-10, IL-7, transforming growth factor β1 and tumor necrosis factor-α, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential roles for Siglec-11 in ovarian physiology and human evolution.

After CNS injuries, axon growth inhibitors from the myelin and the scar tissue at the injury site are considered major impediments to axon regeneration. The presence of several classes of inhibitors with multiple members in each class suggests functional redundancy in growth inhibition. To test redundancy within the myelin inhibitory pathway, we analyzed raphe spinal serotonergic (5-HT) axon regeneration in mice deficient in two major myelin inhibitors, Nogo and MAG, and their common receptor NgR1 (or NgR). After a complete transection spinal cord injury, there was no significant enhancement of 5-HT axon regeneration beyond the injury site in either Nogo/MAG/NgR1 triple mutants or NgR1 single mutants. Occasional, genotype-independent traversal of 5-HT axons through GFAP-positive tissue bridges at the injury site implicates GFAP-negative lesion areas as especially inhibitory to 5-HT axons. To assess the contribution of class 3 Semaphorins that are expressed by GFAP-negative meningeal fibroblasts at the injury site, we analyzed mice deficient in PlexinA3 and PlexinA4, two key receptors for class 3 Semaphorins, with or without additional NgR1 deletion. No enhanced regeneration of 5-HT or corticospinal axons was detected in PlexinA3/PlexinA4 double mutants or PlexinA3/PlexinA4/NgR1 triple mutants through a complete transection injury. In contrast with previous reports, these data demonstrate that attenuating myelin or Semaphorin-mediated inhibition of axon growth is insufficient to promote 5-HT axon regeneration and further indicate that even attenuating both classes of inhibitory influences is insufficient to promote regeneration of injured axons through a complete transection spinal cord injury.

The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.

Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men. © 2010 Sieveking et al.

The intent of this project was to develop and test a database of questions that could be used to assess information exchange within a team-of-teams operating in a Joint, Interagency, Multinational, and Public (JIMP) environment. This work involved an initial identification of question categories (performance, effectiveness, efficiency, conditions, processes, and products) based on a review of the literature relevant to information exchange and performance in teams-of-teams. Question categories and sample questions were reviewed by scientific Subject-Matter Experts (SMEs) and modifications were made in accordance with the feedback received. A complete inventory of questions for each question category was developed and an online version of the questionnaire was pilot tested. Recommendations for future work include refinement and subsequent validation of the questionnaire and the use of supplementary measures of information exchange performance, in combination with the questionnaire, to get a more complete picture of information exchange.

This paper uses a case study approach to compare applications of Mission, Function and Task Analysis (MFTA) and Hierarchical Goal Analysis (HGA) to identify requirements for systems design in a military context. The two approaches were used to analyze three tactical positions in the Operations Room of a Halifax Class naval frigate. MFTA produced a four-level hierarchy; the bottom level of which specified tasks to be performed by the three naval operators. HGA produced a hierarchy that ranged from four to eight levels; every level specified goals, each assigned to an operator and each associated with a controlled variable. MFTA was found easier to apply, as job positions and time were used as frames of reference to identify tasks. HGA was found harder to apply, as goals were not defined by position, organizational structure, or time. MFTA successfully identified operator tasks, while HGA successfully identified both operator tasks and interactions that could benefit from technological support.

In the developing nervous system, cell diversification depends on the ability of neural progenitor cells to divide asymmetrically to generate daughter cells that acquire different identities. While much work has recently focused on the mechanisms controlling self-renewing asymmetric divisions producing a differentiating daughter and a progenitor, little is known about mechanisms regulating how distinct differentiating cell types are produced at terminal divisions. Here we study the role of the endocytic adaptor protein Numb in the developing mouse retina. Using clonalnumbinactivation in retinal progenitor cells (RPCs), we show that Numb is required for normal cell-cycle progression at early stages, but is dispensable for the production of self-renewing asymmetric cell divisions. At late stages, however, Numb is no longer required for cell-cycle progression, but is critical for the production of terminal asymmetric cell divisions. In the absence of Numb, asymmetric terminal divisions that generate a photoreceptor and a non-photoreceptor cell are decreased in favor of symmetric terminal divisions generating two photoreceptors. Using live imaging in retinal explants, we show that a Numb fusion protein is asymmetrically inherited by the daughter cells of some late RPC divisions. Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions.

Striking sex differences exist not only in the incidence of cardiovascular disease, but also in the clinical outcomes. Although cardiovascular events occur earlier in men, in women, it appears they have poorer short-term and long-term outcomes following these events compared to men. Thus, intrinsic sex differences may exist not only in atherogenesis, but also with respect to cardiovascular adaptation/repair in response to ischemia and/or infarction. Angiogenesis, the growth of new blood vessels, is essential for organ development and is critical to cardiovascular repair/regeneration. Although the effect of estrogen on angiogenesis has been studied extensively, the role of androgens has remained largely unexplored.Multiple lines of evidence now suggest an important role for androgens in cardiovascular repair and regeneration. Studies suggest that androgens stimulate angiogenesis via vascular endothelial growth factor-related mechanisms and by the stimulation of erythropoietin production. Furthermore, endothelial progenitor cells, important in angiogenesis, appear to be hormonally regulated and an important target of androgen action.Given the age-related decline in androgens, the findings discussed here have implications for therapeutic angiogenesis and androgen replacement therapies in aging and hypogonadal men.

Humans are genetically unable to synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc). However, Neu5Gc can be metabolically incorporated and covalently expressed on cultured human cell surfaces. Meanwhile, humans express varying and sometimes high titers of polyclonal anti-Neu5Gc antibodies. Here, a survey of human tissues by immunohistochemistry with both a monospecific chicken anti-Neu5Gc antibody and with affinity-purified human anti-Neu5Gc antibodies demonstrates endothelial expression of Neu5Gc, likely originating from Neu5Gc-rich foods like red meats. We hypothesized that the combination of Neu5Gc incorporation and anti-Neu5Gc antibodies can induce endothelial activation. Indeed, the incubation of high-titer human sera with Neu5Gc-fed endothelial cells led to Neu5Gc-dependent antibody binding, complement deposition, endothelial activation, selectin expression, increased cytokine secretion, and monocyte binding. The proinflammatory cytokine tumor necrosis factor-α also selectively enhanced human anti-Neu5Gc antibody reactivity. Anti-Neu5Gc antibodies affinity-purified from human serum also directed Neu5Gc-dependent complement deposition onto cultured endothelial cells. These data indicate a novel human-specific mechanism in which Neu5Gc-rich foods deliver immunogenic Neu5Gc to the endothelium, giving anti-Neu5Gc antibody- and complement-dependent activation, and potentially contributing to human vascular pathologies. In the case of atherosclerosis, Neu5Gc is present both in endothelium overlying plaques and in subendothelial regions, providing multiple pathways for accelerating inflammation in this disease.

Motion of the keys was measured in a transverse flute while beginner, amateur and professional flutists played a range of exercises. The time taken for a key to open or close is typically 10 ms when pushed by a finger or 16 ms when moved by a spring. Delays between the motion of the fingers were typically tens of ms, with longer delays as more fingers are involved. Because the opening and closing of keys will never be exactly simultaneous, transitions between notes that involve the movement of multiple fingers can occur via several possible pathways with different intermediate fingerings. A transition is classified as `safe' if it is possible to be slurred from the initial to final note with little perceptible change in pitch or volume. Some transitions are `unsafe' and possibly involve a transient change in pitch or a decrease in volume. In transitions with multiple fingers, players, on average, used safe transitions more frequently than unsafe transitions. Professionals exhibited smaller average delays between the motion of fingers than did amateurs.

Conclusion: Echocardiography is underutilised in acute PE in some regional hospitals in Australia. Elevated troponin levels are associated with increased short term morbidity inacutePE.There is ahighproportionof accompanying DVT with acute PE. doi:10.1016/j.hlc.2011.05.025

Background: The relationship between androgens and cardiovascular disease (CVD) remains poorly understood. While low testosterone levels in men are associated with increased mortality from CVD, the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, is unknown. Methods: We assessed the effect of the nonaromatisable androgen dihydrotestosterone (DHT) on key angiogenic events in male and female-donor endothelial cells (ECs). In vivo angiogenesis was assessed using 2 models: Matrigel plug; and hindlimb ischemia (HI) assays in castrate/ovariectomised and sham-operated male and female C57Bl6/J mice±DHT. Results: DHT induced a dose-dependent increase in migration, proliferation and tubulogenesis in male (P 0.05).Androgen Receptor (AR) antagonism and siRNA-knockdown abrogated DHT effects in male ECs. Gonadectomy markedly decreased Matrigel plug vascularisation in both sexes (P< 0.0001). However, this was reversed byDHT treatment in males (P < 0.02) but NOT females (Fig. 1). In males, blood-flow recovery fromHIwas impairedwith castration (P< 0.05), a finding also reversed by DHT (P< 0.01). DHT also increased mobilisation of erythroidand endothelial progenitor cells (P< 0.01). Conclusion:Androgensstimulatekeyangiogenicevents in males but NOT females in vitro and in vivo via AR. Androgens also stimulate progenitor cell mobilisation in males. These findings suggest that androgens may modulate vascular regeneration with implications for the role of androgen replacement in men.

Mastering a wind instrument requires not only expert blowing and embouchure, but also many hours of practice of exercises that improve the fingering speed, regularity and coordination. Many note transitions involve the motion of several fingers, often in opposite directions. The order of finger movement can sometimes affect the transitions between notes and produce short, spurious notes between the original and destination notes. We adapted a transverse flute for real time measurement (with a resolution of 3 ms) of all key positions using reflected light sensors. Beginner and advanced players were asked to perform a phrase including multifinger transitions. The detailed motion, average speed and intervals between finger motion were analysed. The comparison among players is not surprising: an experienced player was found to have more regular time intervals between fingers moving in a same direction (within 10 ms) than an amateur (within 25 ms). Contrary fingering motions are slightly less regular (15 ms for an experienced player against 50 ms for an amateur), but still unperceptible to the ear in the case of the experienced musician. A range of details will be reported, for instance the influence of scale exercises.