Species identity dominates over environment in shaping the microbiota of small mammals.

The mammalian gut microbiota is considered pivotal to host fitness, yet the determinants of community composition remain poorly understood. Laboratory studies show that environmental factors, particularly diet, are important, while comparative work emphasises host genetics. Here, we compare the influence of host genetics and the environment on the microbiota of sympatric small mammal species (mice, voles, shrews) across multiple habitats. While sharing a habitat caused some microbiota convergence, the influence of species identity dominated. In all three host genera examined, an individual's microbiota was more similar to conspecifics living elsewhere than to heterospecifics at the same site. Our results suggest this species-specificity arises in part through host-microbe codiversification. Stomach contents analysis suggested that diet also shapes the microbiota, but where diet is itself influenced by species identity. In this way, we can reconcile the importance of both diet and genetics, while showing that species identity is the strongest predictor of microbiota composition.

Nutlin-3, the small-molecule inhibitor of MDM2, promotes senescence and radiosensitises laryngeal carcinoma cells harbouring wild-type p53.

BACKGROUND: Primary radiotherapy (RT) is a mainstay of treatment for laryngeal squamous cell carcinoma (LSCC). Although the cure rates for early (T1) vocal cord tumours are high, RT proves ineffective in up to a third of T3 carcinomas. Moreover, RT is associated with debilitating early- and late-treatment-related toxicity, thus finding means to de-escalate therapy, while retaining/augmenting therapeutic effectiveness, is highly desirable. p53 is a key mediator of radiation responses; we therefore investigated whether Nutlin-3, a small-molecule inhibitor of MDM2 (mouse double minute 2; an essential negative regulator of p53), might radiosensitise LSCC cells. METHODS: We performed clonogenic assays to measure radiosensitivity in a panel of LSCC cell lines (for which we determined p53 mutational status) in the presence and absence of Nutlin-3. RESULTS: LSCC cells harbouring wild-type p53 were significantly radiosensitised by Nutlin-3 (P<0.0001; log-rank scale), and displayed increased cell cycle arrest and significantly increased senescence (P<0.001) in the absence of increased apoptosis; thus, our data suggest that senescence may mediate this increased radiosensitivity. CONCLUSION: This is the first study showing Nutlin-3 as an effective radiosensitiser in LSCC cells that retain wild-type p53. The clinical application of Nutlin-3 might improve local recurrence rates or allow treatment de-escalation in these patients.

Motor innervation, motor unit organization and afferent innervation of m. extensor digitorum communis of the baboon's forearm.

1. One hundred and fifty efferent axons innervating m. extensor digitorum communis (EDC) were isolated in filaments of C7 and C8 ventral roots of baboons. Conduction velocities were measured antidromically by stimulating the muscle nerve and recording from the filaments, and fell into two groups: a fast (49-84 m/sec) and a slow (22-41m/sec), presumably fusimotor group. The threshold for these latter axons exceeded the strength needed to elicit the maximal motor twitch.2. Stimulation of ventral root filaments containing slow axons produced no contractile tension in EDC.3. Stimulation of ventral root filaments containing fast-group axons elicited all-or-nothing twitches of motor units of EDC. The twitch tensions of 66.3% of the units were < 2.0 g wt.; only 8.7% were > 5.0 g wt. Tetanus-twitch ratios were 1.4-4.7 in a sample of 14 units. Contraction times were between 15 and 35 msec in 97% of the units. There was no correlation between contractile properties and axonal conduction velocity.4. Afferent volleys from the stimulated EDC nerve were recorded from C6 or C7 dorsal roots. The threshold was below the threshold for a just-detectable motor twitch in ten out of eleven baboons. Conduction velocity of the earliest component of the muscle afferent volley was 67-83 m/sec.5. The conduction velocities of twenty-eight spindle afferents, identified by their responses to linear stretches of EDC and by their unloading by maximal twitches, were all < 70 m/sec. Higher dynamic sensitivity tended to be associated with higher conduction velocity.

Origin of synaptic noise.

The poison from puffer fish, tetrodotoxin, was applied to the kitten spinal cord. This application greatly reduced the synaptic noise recorded from lumbar motoneurons. The noise is largely evoked by nerve impulses.

Presynaptic inhibition evoked by muscle contraction.

1. Contractions of flexor and extensor muscles of the knee and ankle were used to investigate presynaptic inhibition at the spinal level.2. Contractions evoked dorsal root potentials, and increased the excitability of the central terminals of group Ia, Ib and low threshold cutaneous primary afferent fibres.3. The monosynaptic reflexes recorded in response to stimulation of flexor or extensor muscle nerves were depressed, in the presence of strychnine hydrochloride 0.1 mg/kg I.V., by the contractions.4. It is suggested that these presynaptic inhibitory effects are largely due to the activation of Golgi tendon organs by contraction.