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Actinobacteria are prevalent in the rhizosphere and phyllosphere of diverse plant species where they help to enhance tolerance of plants against biotic and abiotic stresses. Here, we show that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) alter growth, development and specialized metabolism ofStreptomyces. Challenge ofStreptomyces coelicolorwith JA or MeJA led to strongly enhanced production of the polyketide antibiotic actinorhodin. JA is toxic toStreptomycetaceae, whereby members of the genusStreptacidiphilusare generally more sensitive than streptomycetes. As a defensive response, extensive amino acid conjugation of JA was observed; the most prevalent conjugation was with glutamine (Gln), while conjugates with Val, Tyr, Phe and Leu/Ile were identified after longer exposure to JA. Synthetic JA conjugates failed to activate antibiotic production and had strongly reduced toxicity, strongly suggesting that conjugation inactivates JA and serves to detoxify the hormone. Thus, for the first time we provide evidence that plant hormones modulate growth, development and secondary metabolism of streptomycetes, whereby amino acid conjugation serves as a defense strategy by the bacteria to circumvent plant hormone toxicity.IMPORTANCEMicroorganisms that live on or inside plants greatly influence plant health. Streptomycetes are considered to have an important role in defense against plant diseases, but the mechanisms through which they protect plants are currently not fully understood. It has been suggested that streptomycetes respond to changes in the plant’s physiology, among others by producing protective molecules; however, little is known of the signal transduction from plant to bacterium. We here demonstrate that the plant hormones jasmonic acid (JA) and methyljasmonate (MeJA) directly influence the life cycle of streptomycetes by modulating antibiotic synthesis and promoting faster development. Moreover, the plant hormones specifically stimulate the synthesis of the polyketide antibiotic actinorhodin inStreptomyces coelicolor. Jasmonic acid is then modified in the cell by amino acid conjugation, which reduces the bioactivity of the hormone and thus quenches the signal. To the best of our knowledge, this has not been reported previously. Collectively, these results suggest a relationship between plant physiological changes and the response of streptomycetes in multiple ways.

BackgroundWomen have been reported to have worse outcomes after endovascular treatment (EVT), despite a similar treatment effect in non-clinical trial populations. We aimed to assess sex differences at hospital presentation with respect to workflow metrics, prestroke disability, and presenting clinical symptoms.MethodsWe included consecutive patients from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in The Netherlands (MR CLEAN) Registry (2014–2018) who received EVT for anterior circulation large vessel occlusion (LVO). We assessed sex differences in workflow metrics, prestroke disability (modified Rankin Scale (mRS) score ≥1), and stroke severity and symptoms according to the National Institutes of Health Stroke Scale (NIHSS) score on hospital admission with logistic and linear regression analyses and calculated the adjusted OR (aOR).ResultsWe included 4872 patients (47.6% women). Compared with men, women were older (median age 76 vs 70 years) and less often achieved good functional outcome at 90 days (mRS ≤2: 35.2% vs 46.4%, aOR 0.70, 95% CI 0.60 to 0.82). Mean onset-to-door time was longer in women (2 hours 16 min vs 2 hours 7 min, adjusted delay 9 min, 95% CI 4 to 13). This delay contributed to longer onset-to-groin times (3 hours 26 min in women vs 3 hours 13 min in men, adjusted delay 13 min, 95% CI 9 to 17). Women more often had prestroke disability (mRS ≥1: 41.1% vs 29.1%, aOR 1.57, 95% CI 1.36 to 1.82). NIHSS on admission was essentially similar in men and women (mean 15±6 vs 15±6, NIHSS ConclusionWomen with LVO had longer onset-to-door times and more often prestroke disability than men. Raising awareness of these differences at hospital presentation and investigating underlying causes may help to improve outcome after EVT in women.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and may be improved by Vagus Nerve Stimulation (VNS) paired with rehabilitation. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, we assigned participants with moderate to severe arm weakness, at least nine months after ischaemic stroke, to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). All participants were implanted with a VNS device and received six weeks of in-clinic therapy followed by a home exercise program. The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. All analyses were by intention to treat. The trial was registered on ClinicalTrials.gov (NCT03131960). FINDINGS: We randomised 108 participants between Oct 2, 2017 and Sept 12, 2019 (53 to VNS and 55 to Control). A total of 106 completed the study. On the first day after completion of in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (p=0.001, between group difference 2.6, 95% CI 1.03 to 4.2). Ninety days later, a clinically meaningful response on the FMA-UE score was achieved in 47% with VNS versus 24% in controls (p=0.01; between group difference 24%, 95% CI 6 to 41%). The Wolf Motor Function Test (WMFT) functional score increased by 0.46 (±0.40) points in the VNS group compared to 0.16 (±0.30) points in the Control group (p

Background Secondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models, vagus nerve stimulation (VNS) inhibits these detrimental changes and thereby reduces tissue injury. The aim of this study is to investigate whether non-invasive cervical VNS (nVNS) in addition to the current standard treatment can improve penumbral recovery and limit final infarct volume. Methods NOVIS is a single-center prospective randomized clinical trial with blinded outcome assessment. One hundred fifty patients will be randomly allocated (1:1) within 12 h from clinical stroke onset to nVNS for 5 days in addition to standard treatment versus standard treatment alone. The primary endpoint is the final infarct volume on day 5 assessed with MRI. Discussion We hypothesize that nVNS will result in smaller final infarct volumes as compared to standard treatment due to improved penumbral recovery. The results of this study will be used to assess the viability and approach to power a larger trial to more definitively assess the clinical efficacy of nVNS after stroke. Trial registration ClinicalTrials.govNCT04050501. Registered on 8 August 2019

Actinomycetes are a diverse family of filamentous bacteria that produce a plethora of natural products relevant for agriculture, biotechnology and medicine, including the majority of the antibiotics we use in the clinic. Rather than as free-living bacteria, many actinomycetes have evolved to live in symbiosis with among others plants, fungi, insects and sponges. As a common theme, these organisms profit from the natural products and enzymes produced by the actinomycetes, for example, for protection against pathogenic microbes, for growth promotion or for the degradation of complex natural polymers such as lignocellulose. At the same time, the actinomycetes benefit from the resources of the hosts they interact with. Evidence is accumulating that these interactions control the expression of biosynthetic gene clusters and have played a major role in the evolution of the high chemical diversity of actinomycete-produced secondary metabolites. Many of the biosynthetic gene clusters for antibiotics are poorly expressed under laboratory conditions, but they are likely expressed in response to host-specific demands. Here, we review the environmental triggers and cues that control natural product formation by actinomycetes and provide pointers as to how these insights may be harnessed for drug discovery.

The cell wall is a shape-defining structure that envelopes almost all bacteria and protects them from environmental stresses. Bacteria can be forced to grow without a cell wall under certain conditions that interfere with cell wall synthesis, but the relevance of these wall-less cells (known as L-forms) is unclear. Here, we show that several species of filamentous actinomycetes have a natural ability to generate wall-deficient cells in response to hyperosmotic stress, which we call S-cells. This wall-deficient state is transient, as S-cells are able to switch to the normal mycelial mode of growth. However, prolonged exposure of S-cells to hyperosmotic stress yields variants that are able to proliferate indefinitely without their cell wall, similarly to L-forms. We propose that formation of wall-deficient cells in actinomycetes may serve as an adaptation to osmotic stress., Bacteria can be forced to grow without cell wall if cell wall synthesis is inhibited. Here Ramijan et al. show that, in filamentous actinomycetes, hyperosmotic stress induces formation of wall-deficient cells that can switch to normal mycelial growth, or mutate and proliferate indefinitely as wall-less forms.

The diagnosis of cerebral vein thrombosis (CVT) can be difficult. Patients with suspected CVT, in whom venous sinuses are affected by intracranial tumours or after intracranial surgery constitutes a particular challenging setting. Magnetic resonance non-contrast thrombus imaging (MR-NCTI) is a new magnetic resonance imaging (MRI) technique that has previously been shown to be accurate in the diagnosis of a first CVT and difficult-to-diagnose venous thrombosis in other anatomical locations. In this case report, a patient with a medical history of craniotomy for parieto-occipital meningioma was suspected of an acute CVT, but had an inconclusive computed tomography (CT) and MRI venography. MR-NCTI showed no abnormalities diagnostic for (sub)acute CVT and thus cerebral sinus occlusion was most likely a chronic thrombus or a result of residual meningioma tissue. Anticoagulant treatment was discontinued and she was discharged from hospital in good health. This case shows that MR-NCTI may be a valuable additional imaging test in complex cases in whom CT and MRI venography could not exclude acute CVT.

Levodopa-induced motor complications, including dyskinesia and wearing off, are troublesome side effects of treatment and impair quality of life in Parkinson's disease (PD) patients. The use of nondopaminergic agents as adjuncts to levodopa are potential options for managing these problems. Here, we asses the ability of the clinically available, selective histamine H(2) antagonist, famotidine (1, 3, and 30 mg/kg) to treat levodopa-induced dyskinesia and wearing off in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-macaque model of PD. Famotidine (3 mg/kg) increased peak activity, enhanced peak anti-parkinsonian action (1 and 3 mg/kg), and extended duration of action (3 mg/kg, by 38%) of a low dose of levodopa (compared to low dose levodopa alone). Enhancement of anti-parkinsonian actions of low dose levodopa by famotidine (3 mg/kg) was associated with only mild, nondisabling dystonia. Famotidine had no effect on the anti-parkinsonian actions of high dose levodopa (compared to high dose levodopa alone). However, famotidine (1, 3, and 30 mg/kg) had a significant effect on chorea, but not dystonia, induced by high dose levodopa (compared to high dose levodopa alone). Famotidine increased high dose levodopa-induced "good quality" on time, i.e., on time not associated with disabling dyskinesia, by up to 28% (compared to high dose levodopa alone). In conclusion, famotidine, a drug currently available for use in the clinic, can enhance the peak-dose anti-parkinsonian actions and extend total duration of action of a low dose of levodopa, without producing disabling dyskinesia. Furthermore, in combination with a higher dose of levodopa, famotidine can reduce peak-dose levodopa-induced chorea and improve the quality of on-time.

Levodopa-induced motor complications, including dyskinesia and wearing off, are troublesome side effects of treatment and impair quality of life in Parkinson's disease (PD) patients. The use of nondopaminergic agents as adjuncts to levodopa are potential options for managing these problems. Here, we asses the ability of the clinically available, selective histamine H(2) antagonist, famotidine (1, 3, and 30 mg/kg) to treat levodopa-induced dyskinesia and wearing off in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-macaque model of PD. Famotidine (3 mg/kg) increased peak activity, enhanced peak anti-parkinsonian action (1 and 3 mg/kg), and extended duration of action (3 mg/kg, by 38%) of a low dose of levodopa (compared to low dose levodopa alone). Enhancement of anti-parkinsonian actions of low dose levodopa by famotidine (3 mg/kg) was associated with only mild, nondisabling dystonia. Famotidine had no effect on the anti-parkinsonian actions of high dose levodopa (compared to high dose levodopa alone). However, famotidine (1, 3, and 30 mg/kg) had a significant effect on chorea, but not dystonia, induced by high dose levodopa (compared to high dose levodopa alone). Famotidine increased high dose levodopa-induced "good quality" on time, i.e., on time not associated with disabling dyskinesia, by up to 28% (compared to high dose levodopa alone). In conclusion, famotidine, a drug currently available for use in the clinic, can enhance the peak-dose anti-parkinsonian actions and extend total duration of action of a low dose of levodopa, without producing disabling dyskinesia. Furthermore, in combination with a higher dose of levodopa, famotidine can reduce peak-dose levodopa-induced chorea and improve the quality of on-time.