A perceived recent increase in global jellyfish abundance has been portrayed as a symptom of degraded oceans. This perception is based primarily on a few case studies and anecdotal evidence, but a ...formal analysis of global temporal trends in jellyfish populations has been missing. Here, we analyze all available long-term datasets on changes in jellyfish abundance across multiple coastal stations, using linear and logistic mixed models and effect-size analysis to show that there is no robust evidence for a global increase in jellyfish. Although there has been a small linear increase in jellyfish since the 1970s, this trend was unsubstantiated by effect-size analysis that showed no difference in the proportion of increasing vs. decreasing jellyfish populations over all time periods examined. Rather, the strongest nonrandom trend indicated jellyfish populations undergo larger, worldwide oscillations with an approximate 20-y periodicity, including a rising phase during the 1990s that contributed to the perception of a global increase in jellyfish abundance. Sustained monitoring is required over the next decade to elucidate with statistical confidence whether the weak increasing linear trend in jellyfish after 1970 is an actual shift in the baseline or part of an oscillation. Irrespective of the nature of increase, given the potential damage posed by jellyfish blooms to fisheries, tourism, and other human industries, our findings foretell recurrent phases of rise and fall in jellyfish populations that society should be prepared to face.
Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard ...chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.
ABSTRACTMacDonald, GZ, Penney, MDH, Mullaley, ME, Cuconato, AL, Drake, CDJ, Behm, DG, and Button, DC. An acute bout of self-myofascial release increases range of motion without a subsequent decrease ...in muscle activation or force. J Strength Cond Res 27(3)812–821, 2013. Foam rolling is thought to improve muscular function, performance, overuse, and joint range of motion (ROM); however, there is no empirical evidence demonstrating this. Thus, the objective of the study was to determine the effect of self-myofascial release (SMR) via foam roller application on knee extensor force and activation and knee joint ROM. Eleven healthy male (height 178.9 ± 3.5 cm, mass 86.3 ± 7.4 kg, age 22.3 ± 3.8 years) subjects who were physically active participated. Subjectsʼ quadriceps maximum voluntary contraction force, evoked force and activation, and knee joint ROM were measured before, 2 minutes, and 10 minutes after 2 conditions(a) 2, 1-minute trials of SMR of the quadriceps via a foam roller and (b) no SMR (Control). A 2-way analysis of variance (condition × time) with repeated measures was performed on all dependent variables recorded in the precondition and postcondition tests. There were no significant differences between conditions for any of the neuromuscular dependent variables. However, after foam rolling, subjectsʼ ROM significantly (p < 0.001) increased by 10° and 8° at 2 and 10 minutes, respectively. There was a significant (p < 0.01) negative correlation between subjectsʼ force and ROM before foam rolling, which no longer existed after foam rolling. In conclusion, an acute bout of SMR of the quadriceps was an effective treatment to acutely enhance knee joint ROM without a concomitant deficit in muscle performance.
Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ ...from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.
Recently Assef et al. presented two catalogs of active galactic nucleus (AGN) candidates over 30,093 deg2 selected from the Wide-field Infrared Survey Explorer (WISE) observations. From their most ...reliable sample, Assef et al. identified 45 AGN candidates with the highest variability levels in the AllWISE catalog but that are not blazars. Here we present new spectroscopic observations of some of these targets to further constrain their nature. We also study their optical light curves using observations from the Catalina Real-Time Transient Survey (CRTS) and find that only seven show significant optical variability, and that five of those seven are spectroscopically classified as AGNs. In one of them, WISEA J094806.56+031801.7 (W0948+0318), we identify a transient event in the CRTS light curve. We present a detailed analysis of this transient and characterize it through its CRTS light curve and its multiwavelength spectral energy distribution obtained from GALEX, Pan-STARRS, and WISE observations. We find that the most likely source of the transient is a superluminous supernova (SLSN) in W0948+0318. We estimate the total radiated energy to be E = (1.6 0.3) × 1052 erg, making it one of the most energetic SLSNe observed. Based on the lack of change in mid-IR color throughout and after the transient event, we speculate that the location of the SLSN is within the torus of the AGN. We identify nine possible analogs to W0948+0318 based on their WISE light curves. None show optically detected transients and hence suggest significant dust obscuration. Finally, we estimate a rate of >2 × 10−7 yr−1 per AGN for these transients under the conservative assumption that none of the identified analogs have a common origin with the transient in W0948+0318.
Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have ...previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.
To examine the association between soluble tumor necrosis factor receptor 1 (sTNFR1) levels and kidney disease progression in Indigenous Australians at high risk of kidney disease.
This longitudinal ...observational study examined participants aged ≥18 years recruited from >20 sites across diabetes and/or kidney function strata. Baseline measures included sTNFR1, serum creatinine, urine albumin-to-creatinine ratio (uACR), HbA
, C-reactive protein (CRP), waist-to-hip ratio, systolic blood pressure, and medical history. Linear regression was used to estimate annual change in estimated glomerular filtration rate (eGFR) for increasing sTNFR1, and Cox proportional hazards were used to estimate the hazard ratio (HR) and 95% CI for developing a combined renal outcome (first of a ≥30% decline in eGFR with a follow-up eGFR <60 mL/min/1.73 m
, progression to renal replacement therapy, or renal death) for increasing sTNFR1.
Over a median of 3 years, participants with diabetes (
= 194) in the highest compared with the lowest quartile of sTNFR1 experienced significantly greater eGFR decline (-4.22 mL/min/1.73 m
/year 95% CI -7.06 to -1.38;
= 0.004), independent of baseline age, sex, eGFR, and uACR. The adjusted HR (95% CI) for participants with diabetes per doubling of sTNFR1 for the combined renal outcome (
= 32) was 3.8 (1.1-12.8;
= 0.03). No association between sTNFR1 and either renal outcome was observed for those without diabetes (
= 259).
sTNFR1 is associated with greater kidney disease progression independent of albuminuria and eGFR in Indigenous Australians with diabetes. Further research is required to assess whether TNFR1 operates independently of other metabolic factors associated with kidney disease progression.
During the past several decades, high numbers of gelatinous Zooplankton species have been reported in many estuarine and coastal ecosystems. Coupled with media-driven public perception, a paradigm ...has evolved in which the global ocean ecosystems are thought to he heading toward being dominated by “nuisance” jellyfish. We question this current paradigm by presenting a broad overview of gelatinous Zooplankton in a historical context to develop the hypothesis that population changes reflect the human-mediated alteration of global ocean ecosystems. To this end, we synthesize information related to the evolutionary context of contemporary gelatinous Zooplankton blooms, the human frame of reference for changes in gelatinous Zooplankton populations, and whether sufficient data are available to have established the paradigm. We conclude that the current paradigm in which it is believed that there has been a global increase in gelatinous Zooplankton is unsubstantiated, and we develop a strategy for addressing the critical questions about long-term, human-related changes in the sea as they relate to gelatinous Zooplankton blooms.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Aim
To evaluate GI safety of celecoxib compared with 2 nonselective (ns) NSAIDs, as a secondary objective of a large trial examining multiorgan safety.
Methods
This randomised, double‐blind ...controlled trial analysed 24 081 patients. Osteoarthritis or rheumatoid arthritis patients, needing ongoing NSAID treatment, were randomised to receive celecoxib 100‐200 mg b.d., ibuprofen 600‐800 mg t.d.s. or naproxen 375‐500 mg b.d. plus esomeprazole, and low‐dose aspirin or corticosteroids if already prescribed. Clinically significant GI events (CSGIE—bleeding, obstruction, perforation events from stomach downwards or symptomatic ulcers) and iron deficiency anaemia (IDA) were adjudicated blindly.
Results
Mean treatment and follow‐up durations were 20.3 and 34.1 months. While on treatment or 30 days after, CSGIE occurred in 0.34%, 0.74% and 0.66% taking celecoxib, ibuprofen and naproxen. Hazard ratios (HR) were 0.43 (95% CI 0.27‐0.68, P = 0.0003) celecoxib vs ibuprofen and 0.51 (0.32‐0.81, P = 0.004) vs naproxen. There was also less IDA on celecoxib: HR 0.43 (0.27‐0.68, P = 0.0003) vs ibuprofen; 0.40 (0.25‐0.62, P < 0.0001) vs naproxen. Even taken with low‐dose aspirin, fewer CSGIE occurred on celecoxib than ibuprofen (HR 0.52 0.29‐0.94, P = 0.03), and less IDA vs naproxen (0.42 0.23‐0.77, P = 0.005). Corticosteroid use increased total GI events and CSGIE. H. pylori serological status had no influence.
Conclusions
Arthritis patients taking NSAIDs plus esomeprazole have infrequent clinically significant gastrointestinal events. Co‐prescribed with esomeprazole, celecoxib has better overall GI safety than ibuprofen or naproxen at these doses, despite treatment with low‐dose aspirin or corticosteroids.
Linked ContentThis article is linked to Laine, Yeomans and Graham, and Scarpignato and Blandizzi papers. To view these articles visit https://doi.org/10.1111/apt.14642, https://doi.org/10.1111/apt.14656 and https://doi.org/10.1111/apt.14810.
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