Mammalian life shows huge diversity, but most groups remain nocturnal in their activity pattern. A key unresolved question is whether mammal species that have diversified into different diel niches ...occupy unique regions of functional trait space. For 5,104 extant mammals we show here that daytime-active species (cathemeral or diurnal) evolved trait combinations along different gradients from those of nocturnal and crepuscular species. Hypervolumes of five major functional traits (body mass, litter size, diet, foraging strata, habitat breadth) reveal that 30% of diurnal trait space is unique, compared to 55% of nocturnal trait space. Almost half of trait space (44%) of species with apparently obligate diel niches is shared with those that can switch, suggesting that more species than currently realised may be somewhat flexible in their activity patterns. Increasingly, conservation measures have focused on protecting functionally unique species; for mammals, protecting functional distinctiveness requires a focus across diel niches.
The conversion of mechanical force to chemical signals is critical for many biological processes, including the senses of touch, pain, and hearing. Mechanosensitive ion channels play a key role in ...sensing the mechanical stimuli experienced by various cell types and are present in organisms from bacteria to mammals. Bacterial mechanosensitive channels are characterized thoroughly, but less is known about their counterparts in vertebrates. Piezos have been recently established as ion channels required for mechanotransduction in disparate cell types in vitro and in vivo. Overexpression of Piezos in heterologous cells gives rise to large mechanically activated currents; however, it is unclear whether Piezos are inherently mechanosensitive or rely on alternate cellular components to sense mechanical stimuli. Here, we show that mechanical perturbations of the lipid bilayer alone are sufficient to activate Piezo channels, illustrating their innate ability as molecular force transducers.
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•Purified wild-type and mutant Piezo1 channels are active in lipid bilayers•Piezo1 and MscS, but not KcsA, are active in bilayers with osmotic gradient•Piezo1 and MscS, but not KcsA, respond to perturbations in membrane tension•Piezo1 is activated in the absence of other cellular components
Piezo proteins transduce physical forces and are activated by mechanical indentation and stretching of cell membranes. By reconstituting these channels in lipid bilayers, Syeda et al. show that Piezo1 channels are stimulated in the absence of other cellular components via a variety of methods, including osmotic imbalance and membrane perturbation.
Summary Background Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have ...reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. Methods In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org , number ISRCTN54285094. Findings We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p=0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p=0·0003), but did not differ for APT (0·7 −0·9 to 2·3 points lower; p=0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p=0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p=0·0005), but did not differ for APT (3·4 −1·6 to 8·4 points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p=0·0027; GET p=0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group. Interpretation CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. Funding UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.
Recent rapid progress in the field of mechanobiology has been driven by novel emerging tools and methodologies and growing interest from different scientific disciplines. Specific progress has been ...made toward understanding how cell mechanics is linked to intracellular signaling and the regulation of gene expression in response to a variety of mechanical stimuli. There is a direct link between the mechanoreceptors at the cell surface and intracellular biochemical signaling, which in turn controls downstream effector molecules. Among the mechanoreceptors in the cell membrane, mechanosensitive (MS) ion channels are essential for the ultra-rapid (millisecond) transduction of mechanical stimuli into biologically relevant signals. The three decades of research on mechanosensitive channels resulted in the formulation of two basic principles of mechanosensitive channel gating: force-from-lipids and force-from-filament. In this review, we revisit the biophysical principles that underlie the innate force-sensing ability of mechanosensitive channels as contributors to the force-dependent evolution of life forms.
Mechanosensitive ion channels are cellular mechanosensors essential for ultra-rapid conversion of mechanical stimuli into biologically relevant signals. Cox et al. revisit the biophysical principles that underlie the innate force-sensing ability of these mechanoreceptors and conclude that the force-from-lipids principle is the most evolutionarily conserved paradigm for ion channel mechanotransduction.
Bacterial Mechanosensors Cox, Charles D; Bavi, Navid; Martinac, Boris
Annual review of physiology,
02/2018, Letnik:
80, Številka:
1
Journal Article
Recenzirano
Bacteria represent one of the most evolutionarily successful groups of organisms to inhabit Earth. Their world is awash with mechanical cues, probably the most ancient form of which are osmotic ...forces. As a result, they have developed highly robust mechanosensors in the form of bacterial mechanosensitive (MS) channels. These channels are essential in osmoregulation, and in this setting, provide one of the simplest paradigms for the study of mechanosensory transduction. We explore the past, present, and future of bacterial MS channels, including the alternate mechanosensory roles that they may play in complex microbial communities. Central to all of these functions is their ability to change conformation in response to mechanical stimuli. We discuss their gating according to the force-from-lipids principle and its applicability to eukaryotic MS channels. This includes the new paradigms emerging for bilayer-mediated channel mechanosensitivity and how this molecular detail may provide advances in both industry and medicine.
Are the results of RTOG 0617 mysterious? Cox, James D
International journal of radiation oncology, biology, physics,
03/2012, Letnik:
82, Številka:
3
Journal Article
In light of an increasing interest in experimental work, we provide a review of some of the general issues involved in the design of experiments and illustrate their relevance to sociology and to ...other areas of social science of interest to sociologists. We provide both an introduction to the principles of experimental design and examples of influential applications of design for different types of social science research. Our aim is twofold: to provide a foundation in the principles of design that may be useful to those planning experiments and to provide a critical overview of the range of applications of experimental design across the social sciences.
Background
The combination of chemotherapy with thoracic radiotherapy (TRT) compared with TRT alone has been shown to confer a survival advantage for good performance status patients with stage III ...non-small cell lung cancer. However, it is not known whether sequential or concurrent delivery of these therapies is the optimal combination strategy.
Methods
A total of 610 patients were randomly assigned to two concurrent regimens and one sequential chemotherapy and TRT regimen in a three-arm phase III trial. The sequential arm included cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 60 Gy TRT beginning on day 50. Arm 2 used the same chemotherapy regimen as arm 1 with 60 Gy TRT once daily beginning on day 1. Arm 3 used cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1. The primary endpoint was overall survival, and secondary endpoints included tumor response and time to tumor progression. Kaplan-Meier analyses were used to assess survival, and toxic effects were examined using the Wilcoxon rank sum test. All statistical tests were two-sided.
Results
Median survival times were 14.6, 17.0, and 15.6 months for arms 1-3, respectively. Five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (5-year survival: sequential, arm 1, 10% 20 patients, 95% confidence interval CI = 7% to 15%; concurrent, arm 2, 16% 31 patients, 95% CI = 11% to 22%, P = .046; concurrent, arm 3, 13% 22 patients, 95% CI = 9% to 18%). With a median follow-up time of 11 years, the rates of acute grade 3-5 nonhematologic toxic effects were higher with concurrent than sequential therapy, but late toxic effects were similar.
Conclusion
Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies.
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