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In callichthyid catfishes, the posterior intestine is modified to function as an air breathing organ by being air-filled, thin-walled and highly vascularized. These modifications make it unsuitable for digestive functions and digesta has to be transported quickly through this region to minimize disruption of vital respiratory functions. However, the weak muscles of the wall of the respiratory intestine make this problematic. It is hypothesized that the unidirectional ventilatory air current within the respiratory intestine is responsible for the quick transport of digesta through the respiratory intestine. To verify this, movement of digesta through the alimentary tract was examined in Hoplosternum littorale and Corydoras aeneus that were either allowed to breathe air or prevented from air breathing. When air breathing was prevented, digesta was not transported to the rectum in H. littorale and there was a 94% reduction in the amount of digesta in the rectum of C. aeneus. This study suggests that the anterior digestive intestine facilitates the passage of air although it is filled with digesta. The anterior digestive intestine packages digesta into a string of slightly compressed boluses, creating an air channel in the digestive intestine thus allowing air to pass unimpeded.[PUBLICATION ABSTRACT]

Newly hatched larval Hoplosternum littorale do not exhibit bimodal respiration upon hatching but depend initially on branchial respiration. As the respiratory intestine develops, its increasing length leads to an increasing dependence on aerial respiration. The respiratory intestine first appears when the fish is 9 days old but is microscopic at this age and becomes detectable by gross morphological examination at 13 days old. Development of the gut for the remainder of the juvenile period (up to 32 days old) consists of increasing length, mucosal folding, concentration of taste buds, gastric glands, mucous glands and goblet cells. Stage 1 commenced with newly hatched larvae until the larval fish were 11 days old. During this stage the fish did not have the capacity to air-breathe and thus behaved as oxygen conformers. Stage 2 extended from day 12 to day 23 and the fish had the capacity to air-breathe although the respiratory intestine was still developing. Stage 3 began from day 24 to day 32 and at this point the respiratory intestine was well-developed and functioned efficiently. The rate of oxygen consumption of the larval fish was found to be related to dissolved oxygen concentration, age of the larval fish and various interactions of these two factors.[PUBLICATION ABSTRACT]

In callichthyid catfishes, the posterior intestine is modified to function as an air breathing organ by being air-filled, thin-walled and highly vascularised. These modifications make it unsuitable for digestive functions and digesta has to be transported quickly through this region to minimise disruption of vital respiratory functions. However, the weak muscles of the wall of the respiratory intestine make this problematic. It is hypothesised that the unidirectional ventilatory air current within the respiratory intestine is responsible for the quick transport of digesta through the respiratory intestine. To verify this, movement of digesta through the alimentary tract was examined in Hoplosternum littorale and Corydoras aeneus that were either allowed to breathe air or prevented from air breathing. When air breathing was prevented, digesta was not transported to the rectum in H. littorale and there was a 94% reduction in the amount of digesta in the rectum of C. aeneus. This study suggests that the anterior digestive intestine facilitates the passage of air although it is filled with digesta. The anterior digestive intestine packages digesta into a string of slightly compressed boluses, creating an air channel in the digestive intestine thus allowing air to pass unimpeded.

In callichthyid catfishes, the posterior intestine is modified to function as an air breathing organ by being air-filled, thin-walled and highly vascularized. These modifications make it unsuitable for digestive functions and digesta has to be transported quickly through this region to minimize disruption of vital respiratory functions. However, the weak muscles of the wall of the respiratory intestine make this problematic. It is hypothesized that the unidirectional ventilatory air current within the respiratory intestine is responsible for the quick transport of digesta through the respiratory intestine. To verify this, movement of digesta through the alimentary tract was examined in Hoplosternum littorale and Corydoras aeneus that were either allowed to breathe air or prevented from air breathing. When air breathing was prevented, digesta was not transported to the rectum in H. littorale and there was a 94% reduction in the amount of digesta in the rectum of C. aeneus. This study suggests that the anterior digestive intestine facilitates the passage of air although it is filled with digesta. The anterior digestive intestine packages digesta into a string of slightly compressed boluses, creating an air channel in the digestive intestine thus allowing air to pass unimpeded.

Chronic noncancer pain includes any painful condition that persists for at least three months and is not associated with malignant disease. According to seven national surveys conducted between 1994-2008, 15%-19% of Canadian adults live with chronic noncancer pain. Chronic noncancer pain interferes with activities of daily living, has a major negative impact on quality of life and physical function, and is the leading cause of health resource utilization and disability among working-age adults. Here, Busse et al inform the prescribing of opioids for adults with chronic noncancer pain.

Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI. Protein kinases have emerged as critical regulators of disease pathogenesis. Here, the authors have utilized kinome-wide screening approaches to reveal a pathogenic role of CDKL5 kinase in acute kidney injury, which is dependent on suppression of a SOX9-associated transcriptional network.

Although clinical trials have shown that RAF inhibitors prolong the survival of patients with BRAF-mutant melanoma, resistance inevitably develops; resistance is shown here to be frequently mediated by the expression of splicing variants of mutant BRAF. Mechanism of RAF inhibitor resistance Although recent clinical trials have shown the efficacy of B-RAF inhibitors in the treatment of melanomas with activating B-RAF mutations, the patients inevitably develop resistance. David Solit and colleagues now identify a mechanism of acquired resistance conferred by a structural change in B-RAF itself. The expression of a 61-kilodalton splice variant of mutant B-RAF leads to enhanced B-RAF dimerization, rendering it resistant to kinase inhibitors. This variant was found to be expressed in 6 of 19 patients who had developed resistance to the B-RAF inhibitor PLX4032. Activated RAS promotes dimerization of members of the RAF kinase family 1 , 2 , 3 . ATP-competitive RAF inhibitors activate ERK signalling 4 , 5 , 6 , 7 by transactivating RAF dimers 4 . In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E) 8 . However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4–8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS–GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.

The International AIDS Society Towards a Cure Working Group lays out its scientific strategy to achieve a cure for HIV. Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.

Objective:Late life depression (LLD) refers to a diagnosis of major depressive disorder in people older than 60, and has been linked to significant cognitive impairment and increased risk of Alzheimer's disease. Although anxiety and depression are highly comorbid, the impact of anxiety on cognition in LLD is far less researched. This is important given that over 20% of middle aged and older adults endorse clinically significant chronic worry. Generalized anxiety disorder in older adults with major depression is associated with poorer cognition and worse treatment outcomes compared with those without anxiety. Therefore, the purpose of the study is to examine the role of anxiety on memory in LLD. We hypothesized that presence of anxiety among older depressed adults would be associated with worse cognitive performance over time.Participants and Methods:Participants included 124 individuals (69.4% female, 90.3% Caucasian) aged 60 or above (M = 71.5, SD = 7.4) who met criteria for major depression, single episode or recurrent. They completed the State Trait Anxiety Inventory, Montgomery Asberg Depression Rating Scale, and a measure of verbal episodic memory (WMS-IV Logical Memory) as part of a larger neuropsychological battery. Data were collected from baseline to three years as part of a larger NIMH-supported longitudinal study. Two-level linear mixed-effect models were fitted to predict memory. State and trait anxiety were used as time-varying predictors. The between-person (level 2) and within-person (level 1) effects of anxiety on memory were assessed controlling for the time trend, age, education, gender, race, and change in depression over time.Results:Plot trajectories across variables revealed a negative correlation such that as anxiety decreased, memory improved over time. Hierarchical linear mixed-effect models revealed that average state anxiety was a marginally significant between-person (level2) predictor for memory [B=-0.041, t(128)=-1.8, p=0.083]. Individuals with greater average state anxiety were more likely to experience memory decline compared to those with lower average state anxiety. In addition, the within-person effect (level 1) of state anxiety was significant [B=-0.096, t(253)=-2.7, p=0.007]. As an individual's anxiety increased over time, their memory declined. Trait anxiety showed a significant within-person effect on memory [B=-0.087, t(254)=-2.0, p=0.048], but a non-significant between-person effect [B=-0.005, t(124)=-0.06, p=0.95].Conclusions:Anxiety appears to increase the risk of memory decline in older adults with major depression, a cohort who are already at risk of cognitive decline. Changes in anxiety increased risk of memory decline even when accounting for changes in depression over time. Although the causal link between anxiety and cognitive impairment remains unclear, it is possible that anxiety and worry may compete for cognitive resources necessary for demanding tasks and situations, detracting from abilities, such as attention and working memory. Older adults with depression may also have difficulty coping adaptively with anxiety, which may negatively affect cognition. Finally, presence of anxiety may represent a form of mild behavioral impairment, a prodrome of cognitive decline leading to dementia. Overall, the present study highlights the negative impact of anxiety on memory performance, indicating that treatment interventions targeting anxiety in older adults are essential to help prevent cognitive decline.