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Objectives: It has been widely accepted in the literature that various forms of physical exercise, even in a single session, enhance positive mood. It has also been shown that physical exercise may sometimes enhance creative thinking, but the evidence is inconclusive. Positive moods can favour creative thinking, but the opposite has also been reported and these relations are unclear. There is a large anecdotal literature suggesting that creative people sometimes use bodily movement to help overcome "blocks". The aim of this study was to establish whether post-exercise creative thinking was attributable to improved mood.Methods: The responses of 63 participants to an exercise (aerobic workout or aerobic dance) and a "neutral" video watching condition were compared. Mood was measured using an adjective list, and creative thinking was tested by three measures of the Torrance test.Results: Analysis of variance showed a large and significant increase in positive mood after exercise (P < 0.001) and a significant decrease in positive mood after video watching (P < 0.001). A significant increase between the creative thinking scores of the two conditions was found on the flexibility (variety of responses) measure (P < 0.05). A multifactorial analysis of all data failed to show a significant covariance of creative thinking with the two measures of mood (P > 0.05).Conclusions: These results suggest that mood and creativity were improved by physical exercise independently of each other. [ABSTRACT FROM AUTHOR]

Importance: Head and neck cancers (HNCs) are often diagnosed at advanced clinical stages during their symptomatic phase, leading to a reduced treatment window and poor survival. Screening programs have been suggested as a mitigation strategy., Objective: To examine the effectiveness of current HNC screening programs in improving diagnosis and survival in adults., Evidence Review: This Preferred Reporting Items for Systematic Reviews and Meta-analyses-guided systematic review involved use of peer-reviewed, English-language journal articles identified from MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials between January 1, 2001, and July 15, 2022. Snowballing was applied to retrieve more studies. Eligible articles were original clinical trials and observational studies presenting a universal or risk-targeted screening program of primary HNC in the adult population. Reporting quality was assessed using the JBI's critical appraisal tools., Findings: Database searches yielded 3646 unique citations with an additional 8 studies found via snowballing. Five reviewers assessed the full text of 106 studies. Sixteen articles were ultimately included in the review, involving 4.7 million adults (34.1%-100% male; median age, 30-59 years). Fifteen studies were based in Asia and 1 in Europe (Portugal). Five reported data from randomized clinical trials. An oral inspection conducted once or once every 2 to 3 years was described in 11 studies for screening oral cancer, while multistep screening involving Epstein-Barr virus serologic testing for nasopharyngeal carcinoma delivered every 1 to 4 years was presented in 5. In 4 trials and 6 observational studies, screening significantly increased the detection of localized (stage I/II) tumor or was associated with an increased proportion of diagnoses, respectively, regardless of the population and cancer subsites. Universal screening of asymptomatic adults improved 3- to 5-year overall survival but did not increase cancer-specific survival in 4 trials. Targeted screening improved overall and cancer-specific survival or was associated with improved survival outcomes in 2 trials and 2 observational studies, respectively. Studies had low to medium risks of bias., Conclusions and Relevance: Evidence from the existing literature suggests that a risk-targeted screening program for oral and nasopharyngeal cancers could improve diagnosis and patient survival. Screening adherence, societal cost-effectiveness, and optimal risk stratification of such a program warrant future research, especially in low-incidence settings outside Asia.

Background: Square knots can be difficult to construct in deep body cavities. The reversing half-hitch alternating post (RHAP) surgical knot has noninferior tensile strength and performance characteristics in deep body cavities. We compared the enterotomy repairs of novice learners in simulated deep body cavities using RHAP versus square knots after proficiency-based training., Methods: Undergraduate students were randomized to RHAP (n = 10) or square knot (n = 10) groups and trained to defined proficiency. They then performed hand-sewn enterotomy repairs of cadaveric porcine small bowels on flat surfaces and in simulated deep body cavities. We recorded time to knot-tying proficiency and to enterotomy repair, and burst pressures for the repair., Results: Mean time-to-proficiency in knot tying was equivalent between the RHAP and square knot groups (23 [standard deviation (SD) 3] v. 21 [SD 2] min, p = 0.33). Mean time for enterotomy repair in deep cavities was shorter for the RHAP group (16 [SD 2] min v. 21 [SD 1] min, p = 0.02). Mean burst pressures for enterotomy repair were equivalent on flat surfaces (128 [SD 41] v. 101 [SD 36] mm Hg, p = 0.31), and were significantly higher for the RHAP group in simulated deep body cavities (32 [SD 13] v. 105 [SD 37] mm Hg, p = 0.05)., Conclusion: The RHAP knots appear to have superior performance versus square knots when tied in a deep body cavity by novice learners. Future work should focus on demonstrating the clinical relevance and broad utility of the RHAP knot in abdominal surgery. Both knot types should be taught to novice learners., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors.)

Excessive proliferation and apoptosis-resistance are hallmarks of cancer. Increased dynamin-related protein 1 (Drp1)-mediated mitochondrial fission is one of the mediators of this phenotype. Mitochondrial fission that accompanies the nuclear division is called mitotic fission and occurs when activated Drp1 binds partner proteins on the outer mitochondrial membrane. We examine the role of Drp1-binding partners, mitochondrial dynamics protein of 49 and 51 kDa (MiD49 and MiD51), as drivers of cell proliferation and apoptosis-resistance in non-small cell lung cancer (NSCLC) and invasive breast carcinoma (IBC). We also evaluate whether inhibiting MiDs can be therapeutically exploited to regress cancer. We show that MiD levels are pathologically elevated in NSCLC and IBC by an epigenetic mechanism (decreased microRNA-34a-3p expression). MiDs silencing causes cell cycle arrest through (a) increased expression of cell cycle inhibitors, p27 Kip1 and p21 Waf1 , (b) inhibition of Drp1, and (c) inhibition of the Akt-mTOR-p70S6K pathway. Silencing MiDs leads to mitochondrial fusion, cell cycle arrest, increased apoptosis, and tumor regression in a xenotransplant NSCLC model. There are positive correlations between MiD expression and tumor size and grade in breast cancer patients and inverse correlations with survival in NSCLC patients. The microRNA-34a-3p-MiDs axis is important to cancer pathogenesis and constitutes a new therapeutic target., (© 2020 Federation of American Societies for Experimental Biology.)

Objective: To provide family physicians with an updated approach to diagnosis and treatment of pharyngitis, detailing key symptoms, methods of investigation, and a summary of common causes., Sources of Information: The approach described is based on the authors' clinical practice and peer-reviewed literature from 1989 to 2018., Main Message: Sore throat caused by pharyngitis is commonly seen in family medicine clinics and is caused by inflammation of the pharynx and surrounding tissues. Pharyngitis can be caused by viral, bacterial, or fungal infections. Viral causes are often self-limiting, while bacterial and fungal infections typically require antimicrobial therapy. Rapid antigen detection tests and throat cultures can be used with clinical findings to identify the inciting organism. Pharyngitis caused by Streptococcus pyogenes is among the most concerning owing to its associated severe complications such as acute rheumatic fever and glomerulonephritis. Hence, careful diagnosis of pharyngitis is necessary to provide targeted treatment., Conclusion: A thorough history is key to diagnosing pharyngitis. Rapid antigen detection tests should be reserved for concerns about antibiotic initiation. Physicians should exercise restraint in antibiotic initiation for pharyngitis, as restraint does not delay recovery or increase the risk of S pyogenes infections., (Copyright© the College of Family Physicians of Canada.)

Objective: To provide family physicians with an updated approach to the diagnosis and management of Ménière disease (MD), detailing the natural course of MD and describing how to initiate medical therapy while awaiting consultation with otolaryngology-head and neck surgery., Sources of Information: The approach is based on the authors' clinical practices and review articles from 1989 to 2018. Most of the cited studies provided level II or III evidence., Main Message: Ménière disease is an uncommon disorder of the inner ear causing vertigo attacks with associated unilateral hearing loss, tinnitus, and aural fullness. It has a degenerative course that often results in permanent sensorineural hearing loss. On average, MD stabilizes with no further vestibular attacks by about 8 years after the onset of symptoms; however, this is highly variable. Vertigo symptoms can be controlled through a combination of dietary salt restriction, stress reduction, and medical therapy (betahistine, diuretics, or both). These can be initiated by family physicians before consultation with otolaryngology-head and neck surgery. Symptoms refractory to such strategies can be treated using nonablative, and occasionally ablative, therapies., Conclusion: A thorough history is key to the approach to and management of MD and permits differentiating MD from other vestibular and nonvestibular conditions., (Copyright© the College of Family Physicians of Canada.)

Rationale: Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMCs). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably hydrogen peroxide (H 2 O 2 ) ([H 2 O 2 ] mito ). Decreases in [H 2 O 2 ] mito elevate pulmonary vascular tone by increasing intracellular calcium ([Ca 2+ ] i ) through reduction-oxidation regulation of ion channels. Although HPV is mimicked by the Complex I inhibitor, rotenone, the molecular identity of the O 2 sensor is unknown., Objective: To determine the role of Ndufs2 (NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 2), Complex I's rotenone binding site, in pulmonary vascular oxygen-sensing., Methods and Results: Mitochondria-conditioned media from pulmonary and renal mitochondria isolated from normoxic and chronically hypoxic rats were infused into an isolated lung bioassay. Mitochondria-conditioned media from normoxic lungs contained more H 2 O 2 than mitochondria-conditioned media from chronic hypoxic lungs or kidneys and uniquely attenuated HPV via a catalase-dependent mechanism. In PASMC, acute hypoxia decreased H 2 O 2 within 112±7 seconds, followed, within 205±34 seconds, by increased intracellular calcium concentration, [Ca 2+ ] i . Hypoxia had no effects on [Ca 2+ ] i in renal artery SMC. Hypoxia decreases both cytosolic and mitochondrial H 2 O 2 in PASMC while increasing cytosolic H 2 O 2 in renal artery SMC. Ndufs2 expression was greater in PASMC versus renal artery SMC. Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I. In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H 2 O 2 , prevented hypoxic increases in [Ca 2+ ] i , and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD + ) ratio and decreasing expression of the O 2 -sensitive ion channel, Kv1.5. Knocking down another Fe-S center within Complex I (Ndufs1, NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 1) or other mitochondrial subunits proposed as putative oxygen sensors (Complex III's Rieske Fe-S center and COX4i2 [cytochrome c oxidase subunit 4 isoform 2] in Complex IV) had no effect on hypoxic increases in [Ca 2+ ] i . In vivo, siNdufs2 significantly decreased hypoxia- and rotenone-induced constriction while enhancing phenylephrine-induced constriction., Conclusions: Ndufs2 is essential for oxygen-sensing and HPV.

Background: Proficiency-based knot-tying curricula have been developed for square knots for medical students, but, to our knowledge, no such curriculum exists for the reverse half hitch alternating-post (RHAP) knot. We aimed to compare medical students' knot-tying proficiency, knot-tying self-confidence and final knot characteristics for RHAP and square knots in a simulated deep body cavity., Methods: We performed a within-subject prospective crossover study of novice medical students who received 30 minutes of training in tying both RHAP and square knots. Participant performance was assessed via a knot-tying checklist, and knot configuration, tensile strength, tightness (loop circumference) and mechanism of failure were also assessed. Participants' self-reported confidence in knot tying was captured., Results: Twenty-one students participated in the study. Mean scores on the knot-tying checklist were significantly higher for RHAP knots than for square knots (6.9 [standard deviation (SD) 2.1] v. 5.2 [SD 2.3], p < 0.01), and RHAP knots were significantly tighter than square knots (46.8 mm [SD 0.4 mm] v. 49.3 mm [SD 0.7 mm], p < 0.05). There were no differences between RHAP and square knots in correct knot configuration, breaking strength or mechanism of failure. Reverse half hitch alternating-post knots were easier to tie within a deep-body cavity, whereas square knots were easier to learn., Conclusion: Novice medical students were more proficient in tying RHAP knots than square knots in a simulated deep body cavity. Students were able to construct RHAP knots more securely and reported increased confidence in tying RHAP knots at depth compared to square knots., Competing Interests: None declared., (© 2018 Joule Inc. or its licensors)

Serosurveys are useful for assessing population susceptibility to vaccine-preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system's analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Square knots are the gold standard in hand-tie wound closure, but are difficult to reproduce in deep cavities, inadvertently resulting in slipknots. The reversing half-hitch alternating post (RHAP) knot has been suggested as an alternative owing to its nonslip nature and reproducibility in limited spaces. We explored whether the RHAP knot is noninferior to the square knot by assessing tensile strength., Methods: We conducted 10 trials for each baseline and knot configuration, using 3-0 silk and 3-0 polyglactin 910 sutures. We compared tensile strength between knot configurations at the point of knot failure between slippage and breakage., Results: Maximal failure strength (mean ± SD) in square knots was reached with 4-throw in both silk (30 ± 1.5 N) and polyglactin 910 (39 ± 12 N). For RHAP knots, maximal failure strength was reached at 5-throw for both silk (31 ± 1.5 N) and polyglactin 910 (41 ± 13 N). In both sutures, there were no strength differences between 3-throw square and 4-throw RHAP, between 4-throw square and 5-throw RHAP, or between 5-throw square and 6-throw RHAP knots. Polyglactin 910 sutures, in all knot configurations, were more prone to slippage than silk sutures ( p < 0.001)., Conclusion: The difference in mean tensile strength could be attributed to the proportion of knot slippage versus breakage, which is material-dependent. Future studies can re-evaluate findings in monofilament sutures and objectively assess the reproducibility of square and RHAP knots in deep cavities. Our results indicate that RHAP knots composed of 1 extra throw provide equivalent strength to square knots and may be an alternative when performing hand-ties in limited cavities with either silk or polyglactin 910 sutures.

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po 2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient's disease state to achieve optimal diagnostic and therapeutic outcomes.

Nanoparticles are suitable platforms for cancer targeting and diagnostic applications. Typically, less than 10% of all systemically administered nanoparticles accumulate in the tumour. Here we explore the interactions of blood components with nanoparticles and describe how these interactions influence solid tumour targeting. In the blood, serum proteins adsorb onto nanoparticles to form a protein corona in a manner dependent on nanoparticle physicochemical properties. These serum proteins can block nanoparticle tumour targeting ligands from binding to tumour cell receptors. Additionally, serum proteins can also encourage nanoparticle uptake by macrophages, which decreases nanoparticle availability in the blood and limits tumour accumulation. The formation of this protein corona will also increase the nanoparticle hydrodynamic size or induce aggregation, which makes nanoparticles too large to enter into the tumour through pores of the leaky vessels, and prevents their deep penetration into tumours for cell targeting. Recent studies have focused on developing new chemical strategies to reduce or eliminate serum protein adsorption, and rescue the targeting potential of nanoparticles to tumour cells. An in-depth and complete understanding of nanoparticle-blood interactions is key to designing nanoparticles with optimal physicochemical properties with high tumour accumulation. The purpose of this review article is to describe how the protein corona alters the targeting of nanoparticles to solid tumours and explains current solutions to solve this problem.

Understanding the principles governing the design of nanoparticles for tumor targeting is essential for the effective diagnosis and treatment of solid tumors. There is currently a poor understanding of how to rationally engineer nanoparticles for tumor targeting. Here, we engineered different-sized spherical gold nanoparticles to discern the effect of particle diameter on passive (poly(ethylene glycol)-coated) and active (transferrin-coated) targeting of MDA-MB-435 orthotopic tumor xenografts. Tumor accumulation of actively targeted nanoparticles was found to be 5 times faster and approximately 2-fold higher relative to their passive counterparts within the 60 nm diameter range. For 15, 30, and 100 nm, we observed no significant differences. We hypothesize that such enhancements are the result of an increased capacity to penetrate into tumors and preferentially associate with cancer cells. We also use computational modeling to explore the mechanistic parameters that can impact tumor accumulation efficacy. We demonstrate that tumor accumulation can be mediated by high nanoparticle avidity and are weakly dependent on their plasma clearance rate. Such findings suggest that empirical models can be used to rapidly screen novel nanomaterials for relative differences in tumor targeting without the need for animal work. Although our findings are specific to MDA-MB-435 tumor xenografts, our experimental and computational findings help to enrich knowledge of design considerations that will aid in the optimal engineering of spherical gold nanoparticles for cancer applications in the future.

The increasing use of nanomaterials raises concerns about the long-term effects of chronic nanoparticle exposure on human health. However, nanoparticle exposure is difficult to evaluate non-invasively using current measurement techniques. Here we show that the skin is an important site of nanoparticle accumulation following systemic administration. Mice injected with high doses of gold nanoparticles have visibly blue skin while quantum dot-treated animals fluoresce under ultraviolet excitation. More importantly, elemental analysis of excised skin correlates with the injected dose and nanoparticle accumulation in the liver and spleen. We propose that skin analysis may be a simple strategy to quantify systemic nanoparticle exposure and predict nanoparticle fate in vivo. Our results suggest that in the future, dermal accumulation may also be exploited to trigger the release of ultraviolet and visible light-sensitive therapeutics that are currently impractical in vivo due to limits in optical penetration of tissues at these wavelengths.

Nanomaterials are used for numerous biomedical applications, but the selection of optimal properties for maximum delivery remains challenging. Thus, there is a significant interest in elucidating the nano-bio interactions underlying tissue accumulation. To date, researchers have relied on cell culture or animal models to study nano-bio interactions. However, cell cultures lack the complexity of biological tissues and animal models are prohibitively slow and expensive. Here we report a tumour-on-a-chip system where incorporation of tumour-like spheroids into a microfluidic channel permits real-time analysis of nanoparticle (NP) accumulation at physiological flow conditions. We show that penetration of NPs into the tissue is limited by their diameter and that retention can be improved by receptor targeting. NP transport is predominantly diffusion-limited with convection improving accumulation mostly at the tissue perimeter. A murine tumour model confirms these findings and demonstrates that the tumour-on-a-chip can be useful for screening optimal NP designs prior to in vivo studies.

The development of a rapid and sensitive infectious disease diagnostic platform would enable one to select proper treatment and to contain the spread of the disease. Here we examined the feasibility of using quantum dot (QD) barcodes to detect genetic biomarkers of the bloodborne pathogens HIV, malaria, hepatitis B and C, and syphilis. The genetic fragments from these pathogens were detected in less than 10 min at a sample volume of 200 μL and with a detection limit in the femtomol range. A next step for the advancement of QD barcode technology to the clinic will require validation of the technology with human samples to assess for matrix effects, head-to-head comparison with existing detection method, development of techniques to automate the assay and detection process, and simplification of analytical device for the read-out of the barcode signal. Our study provides an important intermediate step in the translation of QD barcode technology for screening infectious disease agents in the developed and developing world.

Intercellular (between cell) communication networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. Despite the importance of intercellular networks in stem cell biology, their rules, structure and molecular components are poorly understood. Herein, we describe the structure and dynamics of intercellular and intracellular networks in a stem cell derived, hierarchically organized tissue using experimental and theoretical analyses of cultured human umbilical cord blood progenitors. By integrating high-throughput molecular profiling, database and literature mining, mechanistic modeling, and cell culture experiments, we show that secreted factor-mediated intercellular communication networks regulate blood stem cell fate decisions. In particular, self-renewal is modulated by a coupled positive-negative intercellular feedback circuit composed of megakaryocyte-derived stimulatory growth factors (VEGF, PDGF, EGF, and serotonin) versus monocyte-derived inhibitory factors (CCL3, CCL4, CXCL10, TGFB2, and TNFSF9). We reconstruct a stem cell intracellular network, and identify PI3K, Raf, Akt, and PLC as functionally distinct signal integration nodes, linking extracellular, and intracellular signaling. This represents the first systematic characterization of how stem cell fate decisions are regulated non-autonomously through lineage-specific interactions with differentiated progeny.

The versatility of nanoparticle design has established nanotechnology as a potential "one-stop solution" to many biological and medical applications. The capacity to control nanoparticle size, shape, and surface chemistry has enabled their use as imaging contrast agents or carriers for drugs and other compounds. However, concerns of nanoparticle toxicity have surfaced that could limit their clinical translation. In order to overcome this challenge, researchers are starting to characterize how particle properties influence their interactions with biological systems. By identifying the specific nanoparticle parameters responsible for toxicity, it may be possible to engineer safer and nontoxic nanoparticles.

Communication networks between cells and tissues are necessary for homeostasis in multicellular organisms. Intercellular (between cell) communication networks are particularly relevant in stem cell biology, as stem cell fate decisions (self-renewal, proliferation, lineage specification) are tightly regulated based on physiological demand. We have developed a novel mathematical model of blood stem cell development incorporating cell-level kinetic parameters as functions of secreted molecule-mediated intercellular networks. By relation to quantitative cellular assays, our model is capable of predictively simulating many disparate features of both normal and malignant hematopoiesis, relating internal parameters and microenvironmental variables to measurable cell fate outcomes. Through integrated in silico and experimental analyses, we show that blood stem and progenitor cell fate is regulated by cell-cell feedback, and can be controlled non-cell autonomously by dynamically perturbing intercellular signalling. We extend this concept by demonstrating that variability in the secretion rates of the intercellular regulators is sufficient to explain heterogeneity in culture outputs, and that loss of responsiveness to cell-cell feedback signalling is both necessary and sufficient to induce leukemic transformation in silico.

Advances in nanotechnology research have led to the creation of new generation of contrast agents, therapeutics, and delivery systems. These applications are expected to significantly improve the diagnosis and treatment of a variety of diseases. Two nanotechnologies-semiconductor and metallic nanostructures-are the most advanced in this young field and have been extensively investigated for clinical use. These nanostructures are currently the "model" for the developments of many novel nanostructures. This review describes their chemical design, tunable properties, and utility in medicine. Furthermore, we will describe the current understanding of their toxicity, which could be barriers to their use for human.

The role of experimental psychology in the development of psychopharmacology has largely been ignored in recent historical accounts. In this article the authors attempt to redress that gap by outlining work in early experimental psychology that contributed significantly to the field. While psychiatrists focused on the therapeutic nature of drugs or their mimicry of psychopathology, experimental psychologists used psychoactive drugs as tools to study individual differences in normal behavior as well as to develop methodologies using behavior to study mechanisms of drug action. Experimental work by Kraepelin, Rivers, and Hollingworth was particularly important in establishing drug-screening protocols still used today. Research on nitrous oxide and on the effects of drug combinations is discussed to illustrate the importance of experimental psychology to psychopharmacology.

The Type A behaviour pattern is a well-documented, if controversial, risk factor for coronary heart disease. Surprisingly, relatively little work has been reported on ways of modifying this behaviour pattern. Aerobic exercise, with its demonstrated benefits for both cardiovascular reactivity and psychological 'well-being', is a promising treatment. The literature is reviewed and recommendations are made for practical applications and future research.

The amount of backward walking induced in mice by co-administration of clenbuterol, a beta-adrenoceptor agonist and putative antidepressant, and the benzodiazepine chlordiazepoxide was plotted as a three-dimensional surface, using modified Uniras software. The surface was compared with the theoretical surface to be expected if the interactions between the two drugs were merely additive. The difference between the theoretical and the obtained surfaces was plotted and a functional representation of statistical variability was 'draped' over the difference model. The computer methods can be applied to small amounts of irregularly distributed data, and results are apparent from simple inspection, e.g. the highest peak of backward walking is also the most reliable statistically. The technique is useful for both laboratory and clinical studies.

Drug combinations often yield results not readily predictable from those of their separate constituents. Computer programs have been developed to generate models of dual drug effects to analyse the results of experiments involving drug combinations. Single and combined dose-response results of rat locomotor activity are expressed as three-dimensional models. A manually plotted isobol diagram, showing eqi-active dose combinations of amylobarbitone and dexamphetamine, is compared with isobols constructed by the computer. A simple dose model theory is proposed which assumes that the two drugs have merely additive effects; differences between expectations from this theoretical model and the experimental results actually obtained were found by the computer. This computer approach allows detailed analysis of results. Three-dimensional dose response surfaces can provide a simple visual guide to dose combinations whose effects deviate significantly from those expected if the constituents were simply additive. Areas of special interest can thus be highlighted.

The role of endogenous opioids in the cardiovascular response to mental stress was investigated in two controlled studies. In the first, cardiovascular, hormonal and psychological measures were made in a group of subjects before, during and after presentation of either a mental stress task or a non-stressful control task in the presence of naloxone (8 mg), an opiate antagonist, or an equal volume of saline. The study was carried out in random order and single(subject)-blind. Naloxone specifically enhanced the heart rate response to the stressful task but had no effect on blood pressure, plasma epinephrine or norepinephrine, or feelings of anxiety. Naloxone increased plasma cortisol and ACTH in both stressful and control tasks. A second, double-blind, study replicated the effect on heart rate. An endogenous opioid mechanism thus appears to inhibit the cardiovascular response to stress.

Forty regular male runners were divided into two similar groups and studied for six weeks. One group continued normal running, but the other stopped running for the middle two weeks of the study. Questionnaires were completed at the end of each week. Symptoms of depression were greater in the withdrawn than in the control group at the end of the second week of withdrawal. Somatic symptoms, anxiety, insomnia and feelings of being under strain were greater in the withdrawn group after both the first and second weeks of withdrawal. The groups did not differ in the final two weeks, when running had been resumed. These effects strengthen the view that stopping regular physical exercise produces a 'withdrawal syndrome', and that exercise might therefore be regarded as addictive. The increase in depression may reflect a more gradual loss of the antidepressive effect of exercise training.

Motor impairment, especially ataxia, is often mentioned as a 'side effect' of doses of psychoactive drugs which depress animal behaviour; it is difficult to determine it accurately from visual observation, but relatively few attempts have been made to measure it objectively and quantitatively. Mescaline, in moderate to large doses, can induce biphasic--depressant followed by stimulant--effects on learnt and other performance of laboratory rodents. Motor impairment, using three doses, was accordingly measured during the depressant phase by two methods. An 'ataxia' test, involving analyses of footprints, showed few irregularities of gait splay due to mescaline, but the drug markedly reduced the length of steps ('stride') in a dose-related manner. In a 'tilt plane' test for general motor control, the animals' ability to cling to a tilted plane decreased with 25 mg/kg mescaline, at 30 and 40 minutes after administration. Deficits of this kind can be relevant to interpreting drug actions on forms of behaviour which involve movements for responding, and they also have interesting potential in their own right.

A simple objective method using the irregularity of the spacing of rats' footprints to determine drug-induced locomotor ataxia has been adapted for mice and for computer analysis, by means of a digitizer-based program. Results obtained by the usual manual method of measuring and analyzing the records are compared with results of the computerized method. The computer method improves speed, and perhaps accuracy, of measurement and analysis, especially with large numbers of records, although manual scoring gives satisfactory results and remains essential for unusual records. Inter-observer agreement of the computerized method was high, and there was good agreement between measurements and subjective ratings of ataxia. The use of footprints to measure ataxia, with or without computer aid, is recommended as a routine test in laboratory evaluation of psychoactive drugs. Other uses discussed include determining changes in different characteristics of gait such as step width and step length in animal and human subjects affected not only by drugs, but also by movement disorders such as Parkinsonism.

The first symposium on endorphins and behavioural processes in Britain was held by the British Psychological Society in March 1985. Against a background of the explosive history of the discovery of endogenous opioids, problems of terminology, and basic mechanisms and concepts, five papers reflect the main fields in which outstanding progress has been made: analgesia, feeding, reward mechanisms, social behaviour and aggression, and addiction. A review of the literature on endorphins and exercise stresses both the value and limitations of trying to unravel a fashionable subject. Endorphin research is multi-disciplinary and highly complex, with tricky technical and conceptual problems and inevitable lack of consensus. Investigators should be more aware of the crucial role that outcomes of behaviour experiments play in the attribution of function to opioid systems.