Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

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Reductions in ozone at high concentrations of stratospheric halogens

An increase in the concentration of inorganic chlorine to levels comparable to that of oxidized reactive nitrogen could cause a significant change in the chemistry of the lower stratosphere leading to a reduction potentially larger than 15% in the column density of ozone. This could occur, for example by the middle of the next century, if emissions of man-made chlorocarbons were to grow at a rate of 3% per year. Ozone could be further depressed by release of industrial bromocarbon

Can the outcome of pelvic-floor rehabilitation in patients with fecal incontinence be predicted?

Purpose: Pelvic-floor rehabilitation does not provide the same degree of relief in all fecal incontinent patients. We aimed at studying prospectively the ability of tests to predict the outcome of pelvic-floor rehabilitation in patients with fecal incontinence. Materials and methods: Two hundred fifty consecutive patients (228 women) underwent medical history and a standardized series of tests, including physical examination, anal manometry, pudendal nerve latency testing, anal sensitivity testing, rectal capacity measurement, defecography, endoanal sonography, and endoanal magnetic resonance imaging. Subsequently, patients were referred for pelvic-floor rehabilitation. Outcome of pelvic-floor rehabilitation was quantified by the Vaizey incontinence score. Linear regression analyses were used to identify candidate predictors and to construct a multivariable prediction model for the posttreatment Vaizey score. Results: After pelvic-floor rehabilitation, the mean baseline Vaizey score (18, SD±3) was reduced with 3.2 points (p<0.001). In addition to the baseline Vaizey score, three elements from medical history were significantly associated with the posttreatment Vaizey score (presence of passive incontinence, thin stool consistency, primary repair of a rupture after vaginal delivery at childbed) (R2, 0.18). Th

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR-Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms

A reafferent and feed-forward model of song syntax generation in the Bengalese finch

Adult Bengalese finches generate a variable song that obeys a distinct and individual syntax. The syntax is gradually lost over a period of days after deafening and is recovered when hearing is restored. We present a spiking neuronal network model of the song syntax generation and its loss, based on the assumption that the syntax is stored in reafferent connections from the auditory to the motor control area. Propagating synfire activity in the HVC codes for individual syllables of the song and priming signals from the auditory network reduce the competition between syllables to allow only those transitions that are permitted by the syntax. Both imprinting of song syntax within HVC and the interaction of the reafferent signal with an efference copy of the motor command are sufficient to explain the gradual loss of syntax in the absence of auditory feedback. The model also reproduces for the first time experimental findings on the influence of altered auditory feedback on the song syntax generation, and predicts song- and species-specific low frequency components in the LFP. This study illustrates how sequential compositionality following a defined syntax can be realized in networks of spiking neurons

Exploring the effect of pelvic belt configurations upon athletic lumbopelvic pain

Background: Lumbopelvic injuries are often refractory to treatment and can limit return to sport. Research shows that 50 Newtons (N) of force applied transversely to the pelvis improves lumbopelvic stability and pain. This study applies transverse and diagonal forces to the pelvis in athletes with lumbopelvic pain, and investigates effects on pain and function. Objective: To investigate the effects of transverse and diagonal compressive forces applied to the pelvis of athletes with lumbopelvic pain Study Design: A randomized, repeated measures design using 20 athletes with lumbopelvic pain. Methods: No belt and four pelvic belt configurations (50 N force) were tested. Outcome measures were: resting pain, pain on active straight leg raise (ASLR), resisted hip adduction force and pain on 1-metre broad jump. Force on the adduction test was determined via load cell. Results: Data were analyzed using repeated measures ANOVA. Squeeze test showed significant effect of condition F (4, 76) = 2.7, P < 0.05. On ASLR ipsilateral to the side of pain, pain decreased across conditions (F (4, 76) = 2.5 P = 0.05). Conclusion: Results suggest application of diagonal forces towards the site of pain may have additional benefits in improving pain and function. Such information may inform the development of an orthosis. Clinical relevance The results may be used clinically to determine the effectiveness of different belt placements (with belts or straps) in managing athletic lumbopelvic pain. The results offer an alternative to the application of transverse belts, and may inform new approaches in the development of orthotics

Synthetic biology approaches in drug discovery and pharmaceutical biotechnology

Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder

Future global warming from atmospheric trace gases

Human activity this century has increased the concentrations of atmospheric trace gases, which in turn has elevated global surface temperatures by blocking the escape of thermal infrared radiation. Natural climate variations are masking this temperature increase, but further additions of trace gases during the next 65 years could double or even quadruple the present effects, causing the global average temperature to rise by at least 1 °C and possibly by more than 5 °C. If the rise continues into the twenty-second century, the global average temperature may reach higher values than have occurred in the past 10 million years. © 1986 Nature Publishing Group