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Background Frailty is a common syndrome affecting older people and puts them at risk of hospitalisation, needing care or death. First signs of frailty include reduced muscle strength and mobility decline. A key cause of mobility decline as we age is sarcopenia (age related reduction in muscle strength and mass). Poor nutrition contributes to sarcopenia. A shortfall in protein is associated with reduced muscle mass and strength. This may be due to inadequate intake but also because older people have higher protein needs, especially those with multimorbidity. We need to develop effective treatment to reduce or slow the onset of frailty and mobility decline. Exercise is a recommended treatment. Protein supplements to address the shortfall in protein have the potential to enhance the benefit of regular exercise in frail or pre-frail older adults. This has yet to be definitively demonstrated. Aim To establish the feasibility of conducting an RCT evaluating mobility and strength training with or without protein supplements for people over 60 years old who are frail or pre-frail with a low protein intake. Methods A multicentre, parallel, 2-group, feasibility RCT. Participants (recruitment target = 50) with problems walking, low protein intake and classified as frail or pre-frail will be recruited from four NHS Physiotherapy community services. Participants will be randomised (secure computer-generated: 1:1) to receive 24 weeks of mobility and strength training (delivered in 16 group sessions plus home exercises) or 24 weeks of mobility and strength training with daily protein supplements. Primary feasibility objectives are to estimate 1) ability to screen and recruit eligible participants, 2) intervention fidelity, adherence, and tolerance and 3) retention of participants at follow up. Secondary objectives are to 1) test data collection procedures, 2) assess data completeness and 3) confirm sample size calculation for a definitive RCT. Registration ISRCTN Registry (ISRCTN30405954; 18/10/2022).

As people get older, they may become frail and become less able to deal with illness or injury. People with frailty are more likely to fall or need care. We need to find ways to stop people becoming frail or slow the progress of frailty so older people can live independently. Exercise is a treatment for frailty that can improve muscle strength and walking. Including extra protein in an older person's diet may also help. Protein provides the building blocks for muscles, but many older people do not eat enough protein. Taking extra protein while exercising may increase the benefits of exercise, but we do not know if it reduces frailty or improves walking and quality of life. We want to conduct a large clinical trial comparing mobility and strength training plus extra protein to training alone. This study aims to test if it is possible to carry out a large trial by finding out:       â€¢   Can we recruit enough participants with low protein intake?       â€¢   Do participants attend the exercise classes and take the protein supplements?       â€¢   Do participants attend follow-up assessments? We aim to recruit up to 50 older people who are frail/at risk of frailty and have low protein intake. We will identify participants via NHS Community Trusts, from an existing cohort study and by advertising in the community. Participants are randomly allocated to training plus protein or training only. Training involves muscle strengthening, balance, and walking exercises. Participants will attend a weekly exercise class with a physiotherapist for 16 weeks and do exercises at home once/week. They are then asked to exercise at home twice weekly for a further 8 weeks. Half the participants will take extra protein while exercising. At enrolment and 8 months later, we collect information on frailty, walking ability, muscle strength and quality of life.

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Appropriate responses of organisms to heat stress are essential for their survival. In eukaryotes, adaptation to high temperatures is mediated by heat shock transcription factors (HSFs). HSFs regulate the expression of heat shock proteins, which function as molecular chaperones assisting in protein folding and stability. In many model organisms a great deal is known about the products of hsf genes. An important exception is the filamentous fungus and model eukaryote Neurospora crassa. Here we show that two Neurospora crassa genes whose protein products share similarity to known HSFs play different biological roles. We report that heat shock factor 1 (hsf1) is an essential gene and that hsf2 is required for asexual development. Conidiation may be blocked in the hsf2 knockout (hsf2(KO)) strain because HSF2 is an integral element of the conidiation pathway or because it affects the availability of protein chaperones. We report that genes expressed during conidiation, for example fluffy, conidiation-10, and repressor of conidiation-1 show wild-type levels of expression in a hsf2(KO) strain. However, consistent with the lack of macroconidium development, levels of eas are much reduced. Cultures of the hsf2(KO) strain along with two other aconidial strains, the fluffy and aconidial-2 strains, took longer than the wild type to recover from heat shock. Altered expression profiles of hsp90 and a putative hsp90-associated protein in the hsf2(KO) strain after exposure to heat shock may in part account for its reduced ability to cope with heat stress.

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Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles.

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