The transcription of genes that support memory processes are likely to be impacted by the normal aging process. Because Arc is necessary for memory consolidation and enduring synaptic plasticity, we examined Arc transcription within the aged hippocampus. Here, we report that Arc transcription is reduced within the aged hippocampus compared to the adult hippocampus during both “off line” periods of rest, and following spatial behavior. This reduction is observed within ensembles of CA1 “place cells”, which make less mRNA per cell, and in the dentate gyrus (DG) where fewer granule cells are activated by behavior. In addition, we present data suggesting that aberrant changes in methylation of the Arc gene may be responsible for age-related decreases in Arc transcription within CA1 and the DG. Given that Arc is necessary for normal memory function, these subregion-specific epigenetic and transcriptional changes may result in less efficient memory storage and retrieval during aging.
A novel mechanism is found by which Drosophila male germline stem cells (GSCs) slow their cell cycle under limited nutrient conditions. Upon culturing in poor media, GSCs misorient their centrosomes with respect to the stem cell niche, activating the centrosome orientation checkpoint and leading to slowdown of the cell cycle.
Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.
AIM: To understand the demographic characteristics of patients in Southwestern Ontario, Canada with ulcerative colitis (UC) in order to predict disease severity.
METHODS: Records from 1996 to 2001 were examined to create a database of UC patients seen in the London Health Sciences Centre South Street Hospital Inflammatory Bowel Disease Clinic. To be included, patients’ charts were required to have information of their disease presentation and a minimum of 5 years of follow-up. Charts were reviewed using standardized data collection forms. Disease severity was generated during the chart review process, and non-endoscopic Mayo Score criteria were collected into a composite.
RESULTS: One hundred and two consecutive patients’ data were entered into the database. Demographic analyses revealed that 51% of the patients were male, the mean age at diagnosis was 39 years, 13.7% had a first degree relative with inflammatory bowel disease (IBD), 61.8% were nonsmokers and 24.5% were ex-smokers. In 22.5% of patients the disease was limited to the rectum, in 21.6% disease was limited to the sigmoid colon, in 22.5% disease was limited to the left colon, and 32.4% of patients had pancolitis. Standard multiple regression analysis which regressed a composite of physician global assessment of disease severity, average number of bowel movements, and average amount of blood in bowel movements on year of diagnosis and age at time of diagnosis was significant, R2 = 0.306, F (7, 74) = 4.66, P < 0.01. Delay from symptoms to diagnosis of UC, gender, family history of IBD, smoking status and disease severity at the time of diagnosis didnot significantly predict the composite measure.
CONCLUSION: UC severity is associated with younger age at diagnosis and year of diagnosis in a longitudinal cohort of UC patients, and may identify prognostic UC indicators.
Demographic; Disease severity; Prognosis; Ulcerative colitis
PCR was used to evaluate the occurrence of Toxoplasma gondii parasitemia by detection of the B1 gene in blood samples in two groups of immunosuppressed patients (148 subjects) suspected of having cerebral or extracerebral infection, respectively. Group I consisted of 52 patients with AIDS with suspected cerebral toxoplasmosis. The diagnosis was clinically proven in 15 cases. Parasitemia was detected by PCR in only two of these patients (13.3%), both showing evidence of disseminated infection. Group II consisted of 96 immunocompromised patients, either with AIDS or receiving iatrogenic immunosuppressive therapy. Of these patients, 65 (34 with AIDS and 31 others) showed abnormalities only in chest radiography and were first screened for the presence of Toxoplasma DNA in bronchoalveolar lavage fluid. Blood was then analyzed when the parasite was detected in the bronchoalveolar lavage fluid. The remaining 31 subjects (22 with AIDS and 9 others) were suspected of having extracerebral, pulmonary, or disseminated toxoplasmosis, and blood was studied directly in these cases. Among the nine patients with clinically diagnosed extracerebral infection in group II, the parasite was detected by PCR in the blood of five patients (55.5%), all having pulmonary toxoplasmosis. If all patients with clinical manifestations of extracerebral toxoplasmosis (from both groups) who had not received antitoxoplasma therapy when the samples were collected are considered, PCR detected parasitemia in seven of the nine cases (77.8%). The present study indicates that examination of blood by PCR may be valuable in cases of extracerebral toxoplasmosis because of the disseminated nature of the disease. Since most cases of cerebral toxoplasmosis result from the local reactivation of latent brain cysts, detection of parasitemia by PCR is useful only in cases associated with severe cerebral infection or dissemination of this disease.
Infant rats must learn to identify their mother’s diet-dependent odor. Once learned, maternal odor controls pups’ approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver.
Maternal odor; Olfactory bulb; Norepinephrine; Attachment; Locus coeruleus; Amygdala
Members of the Rhabdoviridae infect a wide variety of animals and plants, and are the causative agents of many important diseases. Rhabdoviruses enter host cells following internalization into endosomes, with the glycoprotein (G protein) mediating both receptor binding to host cells and fusion with the cellular membrane. The recently solved crystal structure of vesicular stomatitis virus G has allowed considerable insight into the mechanism of rhabdovirus entry, in particular the low pH-dependent conformational changes that lead to fusion activation. Rhabdovirus entry shows several distinct features compared with other enveloped viruses; first, the entry process appears to consist of two distinct fusion events, initial fusion into vesicles within endosomes followed by back-fusion into the cytosol; second, the conformational changes in the G protein that lead to fusion activation are reversible; and third, the G protein is structurally distinct from other viral fusion proteins and is not proteolytically cleaved. The internalization and fusion mechanisms of rhabdoviruses are discussed in this article, with a focus on viral systems where the G protein has been studied extensively: vesicular stomatitis virus and rabies virus, as well as viral hemorrhagic septicemia virus.
membrane fusion; rabies; viral receptor; virus entry; VSV
Neutrophils are innate immune cells that counter pathogens by many mechanisms including release of antimicrobial proteins such as calprotectin to inhibit bacterial growth. Calprotectin sequesters essential micronutrient metals such as zinc, thereby limiting their availability to microbes, a process termed nutritional immunity. We find that while calprotectin is induced by neutrophils during infection with the gut pathogen Salmonella Typhimurium, calprotectin-mediated metal sequestration does not inhibit S. Typhimurium proliferation. Remarkably, S. Typhimurium overcomes calprotectin-mediated zinc chelation by expressing a high affinity zinc transporter (ZnuABC). A S. Typhimurium znuA mutant impaired for growth in the inflamed gut was rescued in the absence of calprotectin. ZnuABC was also required to promote the growth of S. Typhimurium over that of competing commensal bacteria. Thus, our findings indicate that Salmonella thrives in the inflamed gut by overcoming the zinc sequestration of calprotectin and highlight the importance of zinc acquisition in bacterial intestinal colonization.
The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug–induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs.
Two distinct preparations of amphiphilic diblock copolymer vesicles (i.e. polymersomes), composed of (poly(ethylene oxide)-poly(butadiene)) (PEO-PBD), with molecular weights of 1.8 kDa and 10.4 kDa, offering different hydrophobic membrane thicknesses, were used to encapsulate the oxygen (O2) storage and transport protein hemoglobin (Hb) for possible application as a red blood cell (RBC) substitute. Key biophysical properties as well as the kinetics of polymersome encapsulated Hb (PEH) interaction with physiologically important gaseous ligands (O2, carbon monoxide and nitric oxide) were measured as a function of the hydrophobic membrane thickness of the PEH particle. Taken together, the results of this work show that PEHs exhibit biophysical properties and retarded ligand binding/release kinetics (compared to cell-free Hb), which are similar to the behavior of RBCs. Therefore, PEHs have the potential to serve as safe and efficacious RBC substitutes for use in transfusion medicine.
Dekkera bruxellensis can outcompete Saccharomyces cerevisiae in environments with low sugar concentrations. It is usually regarded as a spoilage yeast but has lately been identified as an alternative ethanol production organism. In this study, global gene expression in the industrial isolate D. bruxellensis CBS 11270 under oxygen and glucose limitation was investigated by whole transcriptome sequencing using the AB SOLiD technology. Among other observations, we noted expression of respiratory complex I NADH-ubiquinone reductase although D. bruxellensis is a Crabtree positive yeast. The observed higher expression of NADH-generating enzymes compared to NAD+-generating enzymes might be the reason for the previously observed NADH imbalance and resulting Custer effect in D. bruxellensis. Low expression of genes involved in glycerol production is probably the molecular basis for high efficiency of D. bruxellensis metabolism under nutrient limitation. No D. bruxellensis homologs to the genes involved in the final reactions of glycerol biosynthesis were detected. A high number of expressed sugar transporter genes is consistent with the hypothesis that the competitiveness of D. bruxellensis is due to a higher affinity for the limiting substrate.
Widespread temperature stress has caused catastrophic coral bleaching events that have been devastating for coral reefs. Here, we evaluate whether coral fluorescence could be utilized as a noninvasive assessment for coral health. We conducted cold and heat stress treatments on the branching coral Acropora yongei, and found that green fluorescent protein (GFP) concentration and fluorescence decreased with declining coral health, prior to initiation of bleaching. Ultimately, cold-treated corals acclimated and GFP concentration and fluorescence recovered. In contrast, heat-treated corals eventually bleached but showed strong fluorescence despite reduced GFP concentration, likely resulting from the large reduction in shading from decreased dinoflagellate density. Consequently, GFP concentration and fluorescence showed distinct correlations in non-bleached and bleached corals. Green fluorescence was positively correlated with dinoflagellate photobiology, but its closest correlation was with coral growth suggesting that green fluorescence could be used as a physiological proxy for health in some corals.
Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing.
We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology.
Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.
Complex traits such as obesity are manifestations of intricate interactions of multiple genetic factors. However, such relationships are difficult to identify. Thanks to the recent advance in high-throughput technology, a large amount of data has been collected for various complex traits, including obesity. These data often measure different biological aspects of the traits of interest, including genotypic variations at the DNA level and gene expression alterations at the RNA level. Integration of such heterogeneous data provides promising opportunities to understand the genetic components and possibly genetic architecture of complex traits. In this paper, we propose a machine learning based method, module-guided Random Forests (mgRF), to integrate genotypic and gene expression data to investigate genetic factors and molecular mechanism underlying complex traits. mgRF is an augmented Random Forests method enhanced by a network analysis for identifying multiple correlated variables of different types. We applied mgRF to genetic markers and gene expression data from a cohort of F2 female mouse intercross. mgRF outperformed several existing methods in our extensive comparison. Our new approach has an improved performance when combining both genotypic and gene expression data compared to using either one of the two types of data alone. The resulting predictive variables identified by mgRF provide information of perturbed pathways that are related to body weight. More importantly, the results uncovered intricate interactions among genetic markers and genes that have been overlooked if only one type of data was examined. Our results shed light on genetic mechanisms of obesity and our approach provides a promising complementary framework to the “genetics of gene expression” analysis for integrating genotypic and gene expression information for analyzing complex traits.
Obesity has become a perilous global epidemic that can lead to complex diseases, such as diabetes and cardiovascular diseases. Much effort has been devoted to the studies of the genetic mechanisms that pillow the manifestation of obesity. Although a large quantity of experimental data has been accumulated lately using high-throughput techniques, our understanding of genetic mechanisms of obesity is still limited. The proposed method is motivated to address three critical issues that have impeded the existing methods. The first is the curse of dimensionality in selecting a subset of genetic elements related to the traits of interest from a large number of candidates. The second is genetic multiplicity underlying non-Mendelian traits, in which multiple genes are in interplay. The third issue is the integration of data from multiple sources in light of genetic multiplicity and curse of dimensionality. Here, we propose a new method, which augments the Random Forests method with a network-based analysis, to integrate genotypic and gene expression information and identify correlated multiple genetic elements underlying mouse weight. Our results shed light on complex genetic interactions underlying obesity, which can form viable hypotheses worthy of further investigation.
protein degradation; hydrophobic tagging; undruggable proteome; chemical biology; proteostasis
Repeated stress releases dynorphins and causes subsequent activation of kappa opioid receptors (KORs) in limbic brain regions. The serotonergic dorsal raphe nucleus (DRN) has previously been found to be an important site of action for the dysphoric effects of dynorphin-kappa opioid receptor system activation during stress-evoked behaviors, and KOR-induced activation of p38α MAP kinase in serotonergic neurons was found to be a critical mediator of the aversive properties of stress. Yet, how dynorphins and KORs functionally regulate the excitability of serotonergic DRN neurons both in adaptive and pathological stress states is poorly understood. Here we report that acute KOR activation by the selective agonist U69,593 inhibits serotonergic neuronal excitability within the DRN through both pre-synaptic inhibition of excitatory synaptic transmission and post-synaptic activation of G-protein gated inwardly rectifying potassium channels (GIRK) electrophysiologically recorded in brain slices. Repeated swim stress sessions of C57Bl/6 mice significantly reduced KOR mediated GIRK currents recorded in serotonergic neurons in DRN post-synaptically, without significantly affecting pre-synaptic KOR-mediated regulation of excitatory transmission. This effect was blocked by genetic excision of p38α MAPK selectively from serotonergic neurons. An increase in phospho-immunoreactivity suggests that this functional dysregulation may be a consequence of tyrosine phosphorylation of GIRK (KIR3.1) channels. These data elucidate a mechanism for stress-induced dysregulation of the excitability of neurons in the DRN and identify a functional target of stress-induced p38α MAPK activation that may underlie some of the negative effects of pathological stress exposure.
dorsal raphe; stress; dynorphin; kappa opioid receptor; p38 MAPK
Individuals with cardiovascular disease (CVD) living in Health Professional Shortage Areas (HPSA) may receive less preventive care than others. The Reasons for Geographic And Racial Differences in Stroke Study (REGARDS) surveyed 30,221 African American (AA) and White individuals older than 45 years of age between 2003–2007. We compared medication use for CVD prevention by HPSA and insurance status, adjusting for sociodemographic factors, health behaviors, and health status. Individuals residing in partial HPSA counties were excluded. Mean age was 64±9 years, 42% were AA, 55% were women, and 93% had health insurance; 2,545 resided in 340 complete HPSA counties and 17,427 in 1,145 non-HPSA counties. Aspirin, beta-blocker, and ACE-inhibitor use were similar by HPSA and insurance status. Compared with insured individuals living in non-HPSA counties, statin use was lower among uninsured participants living in non-HPSA and HPSA counties. Less medication use for CVD prevention was not associated with HPSA status, but less statin use was associated with lack of insurance.
Health Professional Shortage Areas; cardiovascular disease; prevention; insurance status
Host-microbe interactions at the intestinal mucosal-luminal interface (MLI) are critical factors in the biology of inflammatory bowel disease (IBD).
To address this issue, we performed a series of investigations integrating analysis of the bacteria and metaproteome at the MLI of Crohn’s disease, ulcerative colitis, and healthy human subjects. After quantifying these variables in mucosal specimens from a first sample set, we searched for bacteria exhibiting strong correlations with host proteins. This assessment identified a small subset of bacterial phylotypes possessing this host interaction property. Using a second and independent sample set, we tested the association of disease state with levels of these 14 “host interaction” bacterial phylotypes.
A high frequency of these bacteria (35%) significantly differentiated human subjects by disease type. Analysis of the MLI metaproteomes also yielded disease classification with exceptional confidence levels. Examination of the relationships between the bacteria and proteins, using regularized canonical correlation analysis (RCCA), sorted most subjects by disease type, supporting the concept that host-microbe interactions are involved in the biology underlying IBD. Moreover, this correlation analysis identified bacteria and proteins that were undetected by standard means-based methods such as ANOVA, and identified associations of specific bacterial phylotypes with particular protein features of the innate immune response, some of which have been documented in model systems.
These findings suggest that computational mining of mucosa-associated bacteria for host interaction provides an unsupervised strategy to uncover networks of bacterial taxa and host processes relevant to normal and disease states.
metaproteome; microbiome; mucosal luminal interface; rRNA genes
Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)–induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.
apoptosis, autophagy; chloroquine; erbB inhibitor; malignant peripheral nerve sheath tumor
Ulnar-sided wrist pain is a common problem and can be difficult to manage due to the wide range of etiologies, and the fact that significant pain can be present without radiographic evidence. A common cause of ulnar-sided wrist pain is ulnar impaction syndrome, for which several factors must be considered when choosing from among the many available treatment options. Ulnar shortening osteotomy is the most commonly performed surgical procedure for ulnar impaction syndrome at the largest hand surgery unit in Canada. In addition to objective radiological and range of motion measurements, this study used a visual analogue scale and the Disabilities of the Arm and Shoulder survey to characterize self-reported outcomes of ulnar shortening osteotomy.
Ulnar-sided wrist pain is a common problem in the upper extremity. It affects a broad patient population and can be difficult to treat. Ulnar impaction syndrome (UIS) is major cause of ulnar-sided wrist pain and a number of different operations have been used to correct it, including ulnar shortening osteotomy (USO).
To retrospectively review functional outcomes and complication rates of USO for UIS at the Hand and Upper Limb Centre (London, Ontario) over a two-year period.
Twenty-eight patients who underwent USO between 2007 and 2009 participated in the present study. Ulnar variance pre- and post-surgery was assessed using standard radiographic examination. Patient-rated outcomes were measured using a visual analogue scale (VAS) for pain and the Disabilities of the Arm, Shoulder and Hand (DASH) survey for functional outcomes. Objective grip strength and range of motion were compared with the contralateral extremity.
On average, USO achieved a 3.11 mm reduction in ulnar variance. Nonunion occurred in five patients and required a secondary bone grafting procedure. All USO eventually healed. Overall, pain improved by 47.2% and the mean DASH score after surgery was 37.21. Flexion, extension and supination range of motion decreased by 10° compared with the unaffected side. Eleven patients (39%) elected to undergo a second surgery for hardware removal. Patients receiving compensation from the Workplace Safety and Insurance Board experienced significantly higher residual pain (VSA 5.24 versus 1.97) and disability levels (DASH 60.23 versus 25.70). Smokers also experienced worse outcomes in terms of pain (VSA 4.43 versus 2.36) and disability (DASH 51.06 versus 29.67). In this cohort, smoking was not associated with a higher rate of nonunion.
USO is effective in reducing pain in UIS and improves disability, at the price of a small decrease in range of motion. Smokers and people receiving compensation from the Workplace Safety and Insurance Board, however, have significantly worse subjective outcomes (VAS and DASH), but similar objective outcomes (range of motion).
Ulnar impaction syndrome (UIS); Ulnar shortening osteotomy (USO); Ulnar wrist pain
Patient handoffs are common during residency and are often performed with little or no training. We devised a simple intervention to improve the readiness of interns to perform handoffs.
We administered a 90-minute interactive workshop during intern orientation in 2009 and 2010. It consisted of a discussion, a case presentation, and a trigger video, followed by debriefing and a role-play exercise. The workshop required minimal technology and materials. Interns were surveyed on their readiness to perform handoffs before and after the workshop as well as 3 to 6 months after the workshop.
Eighty-nine interns participated in the workshop during a 2-year period. Seventy-four survey responses were collected. Self-reported readiness to perform a handoff increased by 26%. A total of 91% and 81% of respondents in 2010 and 2009, respectively, reported using aspects of the workshop up to 6 months later.
A brief workshop can improve interns' readiness to perform handoffs.
The patatin-related phospholipase A (pPLA) hydrolyzes membrane glycerolipids to produce monoacyl compounds and free fatty acids. Phospholipids are cleaved by pPLAIIα at the sn-1 and sn-2 positions, and galactolipids, including those containing oxophytodienoic acids, can also serve as substrates. Ablation of pPLAIIα decreased lysophosphatidylcholine and lysophosphatidylethanolamine levels, but increased free linolenic acid. pPLAIIα-deficient plants displayed a higher level of jasmonic acid and methyl jasmonate, as well as the oxylipin-biosynthetic intermediates 13-hydroperoxylinolenic acid and 12-oxophytodienoic acid than wild-type (WT) plants. The expression of genes involved in oxylipin production was also higher in the pPLAIIα-deficient mutant than in WT plants. The mutant plants lost water more quickly than WT plants. The stomata of WT and mutant plants responded similarly to abscisic acid. In response to desiccation, the mutant and WT leaves produced abscisic acid at the same rate, but, after 4 h of desiccation, the jasmonic acid level was much higher in mutant than WT leaves. These results indicate that pPLAIIα negatively regulates oxylipin production and suggest a role in the removal of oxidatively modified fatty acids from membranes.
patatin-related phospholipase A; oxidative modified lipids; jasmonate synthesis; water loss; Arabidopsis thaliana
Structure–activity relationship studies on 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl) butan-1-one (SYA 013), a homopiperazine analog of haloperidol has resulted in an understanding of the effect of structural modifications on binding affinity at dopamine and serotonin receptor subtypes. Further exploration, using bioisosteric replacement strategies has led to the identification of several new agents including compounds 7, 8, 11 and 12 which satisfy the initial criteria for further exploration as new antipsychotic agents. In addition, compound 18, a D3 selective tropanol, has been identified as having the potential for further optimization into a useful drug which may combat neuropsychiatric diseases.
Antipsychotics; Haloperidol analogs; Structure–activity relationship studies; Atypical antipsychotics; Homopiperazine; Benzothiazole
The failure to consider the future consequences of one’s behavior is a major risk factor for aggression. Aggressive people tend to act first, and think later. Some people focus on the —here and now rather than on the future, a tendency measured by the Consideration of Future Consequences (CFC) scale (Strathman, Gleicher, Boninger, & Edwards, 1994). Alcohol intoxication is a neuro-biological variable that produces similar effects. Participants in the present experiment completed the CFC scale and then consumed either an alcohol or a placebo beverage. Next, they competed against a same-sex ostensible partner on an interpersonally adversarial competitive task in which the winner could administer electric shocks to the loser (the aggression measure). As expected, aggression was highest in intoxicated persons with low CFC scores. Being unconcerned about the future consequences of one’s actions, in conjunction with acute alcohol intoxication, combine in a pernicious manner to increase aggression.
Consideration of Future Consequences; alcohol; aggression
To date, no reliable serum marker for clear cell renal cell carcinoma (CCRCC) is available. The aim of this study was to evaluate the putative significance of circulating 20S proteasome levels.
Preoperative 20S proteasome serum levels were determined in 113 CCRCC patients and 15 healthy controls by a sandwich enzyme-linked immunosorbent assay. Associations with CCRCC, pathological variables, disease-specific survival (DSS), and response to sunitinib were evaluated.
Median 20S proteasome levels were higher in CCRCC patients than in healthy controls (4.66 vs 1.52 μg ml−1, P<0.0001). The area under the receiver operating characteristics curve curve was 87.1%. The 20S proteasome levels were associated with symptoms (P=0.0008), distant metastases (P=0.0011), grade (P=0.0247), and necrosis (P=0.0462). The 20S proteasome levels were identified as a prognostic factor for DSS in both univariable (hazards ratio 1.21, P<0.001) and multivariable (hazards ratio 1.17, P=0.0015) survival analysis. In patients responding to sunitinib, 20S proteasome levels were lower than in patients with stable disease and progressive disease.
This study demonstrates for the first time that increased 20S proteasome levels are associated with CCRCC, advanced disease, and poor prognosis. Routine use of this marker may allow better diagnosis, risk stratification, risk-adjusted follow-up, and identification of patients with a greater likelihood of response to targeted therapy.
20S proteasome; renal cancer; hypoxia; diagnosis; prognosis
To examine relationships between spiritual health locus of control beliefs and various health behaviors.
A cross-sectional survey of a national sample of African Americans assessed spiritual beliefs, fruit and vegetable consumption, physical activity, and alcohol consumption.
Active spiritual beliefs were positively associated with fruit consumption and negatively associated with alcohol consumption. Passive spiritual beliefs were associated with lower vegetable and increased alcohol consumption. Among male participants, passive spiritual beliefs were associated with higher alcohol consumption.
Findings suggest that dimensions of spiritual health locus of control beliefs have complex and varying relationships with health behaviors.
spirituality; spiritual health locus of control; African Americans; health behaviors