276 research outputs found
Phylogenetic analyses reveal multiple new stem-boring Tetramesa taxa (Hymenoptera: Eurytomidae): implications for the biological control of invasive African grasses
Many native South African grass species have become invasive elsewhere in the world. The application of biological control to invasive grasses has been approached with trepidation in the past, primarily due to concerns of a perceived lack of host specific herbivores. This has changed in recent times, and grasses are now considered suitable candidates. The Tetramesa Walker genus (Hymenoptera: Eurytomidae) has been found to contain species that are largely host specific to a particular grass species, or complex of closely related congeners. Very little taxonomic work exists for Tetramesa in the southern hemisphere, and the lack of morphological variability between many Tetramesa species has made identification difficult. This limits the ability to assess the genus for potential biological control agents. Species delimitation analyses indicated 16 putative novel southern African Tetramesa taxa. Ten of these were putative Tetramesa associated with Eragrostis curvula (Schrad.) Nees and Sporobolus pyramidalis Beauv. and S. natalensis Steud., which are alien invasive weeds in Australia. Of these ten Tetramesa taxa, eight were only found on a single host plant, while two taxa were associated with multiple species in a single grass genus. The Tetramesa spp. on S. pyramidalis and S. africanus were deemed suitably host-specific to be used as biological control agents. Field host range data for the Tetramesa species on E. curvula revealed that the wasp may not be suitably host specific for use as a biological control agent. However, further host specificity testing on non-target native Australian species is required
Continuous kisspeptin restores luteinizing hormone pulsatility following cessation by a neurokinin B antagonist in female sheep
Pulsatile secretion of the gonadotropin-releasing hormone (GnRH) drives pulsatile secretion of the luteinizing hormone (LH), with evidence that this depends on kisspeptin (Kiss) input to GnRH neurons. Kiss administration causes acute GnRH/LH secretion, and electrophysiological data suggest that Kiss neurons may act in a phasic manner to drive GnRH secretion, but there is not definitive evidence for this. The product of the Kiss-1 gene is proteolytically cleaved to smaller products, and the 10 amino acid C-terminal product (Kiss-10) displays full bioactivity. We have shown previously that continuous delivery of Kiss-10 to anestrous ewes can cause a surge in GnRH secretion and ovulation and increases LH pulse frequency in humans. Here, we tested the hypothesis that continuous Kiss-10 delivery can support pulsatile GnRH/LH secretion in the sheep. Neurokinin B (NKB) provides positive drive to Kiss neurons, so we therefore infused an NKB antagonist (ANT-08) intracerebroventricularly to induce cessation of pulsatile GnRH/LH secretion, with or without concomitant continuous Kiss-10 infusion. ANT-08 suppressed GnRH/LH pulsatility, which was immediately restored with continuous Kiss-10 infusion. These data support the notion that Kiss-10 action is downstream of NKB signaling and that continuous Kiss-10 stimulation of GnRH neurons is sufficient to support a pulsatile pattern of GnRH/LH secretion. This offers further support to the theory that GnRH pulse generation is intrinsic to GnRH neurons and that pulsatile GnRH release can be affected with continuous stimulation by Kiss-10.The Universities of Pretoria and Cape Town, South African Medical Research Council, and National Research Foundation. I.J.C. was funded by the National Health and Medical Research Council of Australia.https://academic.oup.com/endo2019-02-01hj2018ImmunologyPhysiolog
Evidence that neurokinin B controls basal gonadotropin-releasing hormone secretion but is not critical for estrogen-positive feedback in sheep
BACKGROUND : Loss-of-function mutations in genes encoding kisspeptin or neurokinin B (NKB) or their receptors cause infertility. NKB is coproduced in kisspeptin neurons in the arcuate nucleus (ARC), and these neurons also produce the NKB receptor (NK3R), allowing autosynaptic function. We tested the hypothesis that NKB action in ARC kisspeptin neurons is aligned with increased pulsatile secretion of luteinizing hormone (LH) and/or activation of the estrogen-induced LH surge in ewes. METHODS : Using in situ hybridization and immunohistochemistry, we examined NKB expression in kisspeptin neurons during the ovine estrous cycle. We infused kisspeptin, senktide (an NK3R agonist), or dynorphin into the lateral ventricle during the luteal phase of the estrous cycle to determine effects on pulsatile LH secretion. Finally, we examined the effect of an NK3R antagonist (MRK-08) in ovariectomized ewes. RESULTS : NKB (Tac3) mRNA expression in mid-ARC kisspeptin neurons was elevated during the mid-to-late follicular phase of the estrous cycle. The number of NKB-immunoreactive cells and NKB/kisspeptin terminals in the median eminence was similar during the estrous cycle. Kisspeptin and senktide increased LH pulse frequency and mean LH levels. Central MRK-08 infusion eliminated the LH pulses but did not prevent an estrogen-positive feedback on LH secretion. CONCLUSIONS : NKB expression in ARC kisspeptin neurons is upregulated during the late follicular phase of the estrous cycle, when the pulsatile secretion of gonadotropin-releasing hormone (GnRH)/LH is maximal. When GnRH/LH secretion is minimal, central senktide infusion induces LH secretion, similar to the response to kisspeptin. Although the increase in LH in response to senktide appeared surge-like, we did not observe any change in the surge following NK3R antagonist treatment. We conclude that NKB plays a role in increasing basal GnRH/LH pulsatility in the follicular phase of the cycle but is not essential for estrogen-induced positive feedback.Australian Research Council Discovery Project DP120100521.http://www.karger.com/Journal/Home/223855hb201
Onset of normal cycles in postpartum anovulatory dairy cattle treated with kisspeptin
The efficacy of a long-acting synthetic derivative of kisspeptin (Kp) to initiate normal oestrous cycles was tested in 24
mixed-aged, Holstein-Friesian cows that were 18–25 days postpartum on the day of treatment (D0). Groups of eight cows
received saline (Sal) vehicle by intramuscular injection at 8:00 and 16:00 h (Sal-Sal), Kp at 8:00 h and vehicle at 16:00 h
(Kp-Sal) or Kp on both occasions (Kp-Kp). The Kp dose was 15 nmol per 60 kg body weight. The ovaries of the cows were
examined daily by ultrasonography between D4 and D14. Blood samples were collected from a tail vessel at 0, 2, 4, 8,
10 and 12 h relative to the time of the first injection for luteinizing hormone (LH) and follicle-stimulating hormone assay.
Additional samples were collected daily from D4 until D14 and D19, 22, 26 and 29 for progesterone assay. LH surge-like
responses were observed in cows treated with Kp at 8:00 h. Ovulation was consistently induced by Kp within 48 h when a
dominant ovarian follicle of at least 10 mm in diameter was observed (8/14) but in no cases (6/14) during a new wave of
ovarian follicular development comprising follicles <10 mm in diameter. The subsequent ovulatory cycle was of normal
length in most cases as compared with short 8– to 12-day cycles observed in spontaneously ovulating cows. We conclude
that Kp treatment can induce ovulation in postpartum dairy cows, with ensuing oestrous cycles of normal length, if
administered when a mature dominant follicle is present in the ovaries.A partnership (DRCX1302) between the New Zealand Ministry of Business, Innovation and Employment and New Zealand dairy farmers through DairyNZ Inc.https://raf.bioscientifica.comdm2022Immunolog
The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis
Summary:
Expression of the initiator methionine tRNA (tRNAi
Met)
is deregulated in cancer. Despite this fact, it is not
currently known how tRNAi
Met expression levels influence
tumor progression. We have found that tRNAi
Met
expression is increased in carcinoma-associated
fibroblasts, implicating deregulated expression of
tRNAi
Met in the tumor stroma as a possible contributor
to tumor progression. To investigate how elevated
stromal tRNAi
Met contributes to tumor progression,
we generated a mouse expressing additional copies
of the tRNAi
Met gene (2+tRNAi
Met mouse). Growth
and vascularization of subcutaneous tumor allografts
was enhanced in 2+tRNAi
Met mice compared with
wild-type littermate controls. Extracellular matrix
(ECM) deposited by fibroblasts from 2+tRNAi
Met
mice supported enhanced endothelial cell and fibroblast
migration. SILAC mass spectrometry indicated
that elevated expression of tRNAi
Met significantly
increased synthesis and secretion of certain types of
collagen, in particular type II collagen. Suppression
of type II collagen opposed the ability of tRNAi
Metoverexpressing
fibroblasts to deposit pro-migratory
ECM. We used the prolyl hydroxylase inhibitor ethyl-
3,4-dihydroxybenzoate (DHB) to determine whether
collagen synthesis contributes to the tRNAi
Met-driven
pro-tumorigenic stroma in vivo. DHB had no effect
on the growth of syngeneic allografts in wild-type
mice but opposed the ability of 2+tRNAi
Met mice to
support increased angiogenesis and tumor growth.
Finally, collagen II expression predicts poor prognosis
in high-grade serous ovarian carcinoma. Taken
together, these data indicate that increased tRNAi
Met
levels contribute to tumor progression by enhancing
the ability of stromal fibroblasts to synthesize and
secrete a type II collagen-rich ECM that supports
endothelial cell migration and angiogenesis
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Hexapeptides from mammalian inhibitory hormone hunt activate and inactivate nematode reproduction
© 2022 Hart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/Background: Biopurification has been used to disclose an evolutionarily conserved inhibitory reproductive hormone involved in tissue mass determination. A (rat) bioassay-guided physicochemical fractionation using ovine materials yielded via Edman degradation a 14-residue amino acid (aa) sequence. As a 14mer synthetic peptide (EPL001) this displayed antiproliferative and reproduction-modulating activity, while representing only a part of the native polypeptide. Even more unexpectedly, a scrambled-sequence control peptide (EPL030) did likewise. Methods: Reproduction has been investigated in the nematode Steinernema siamkayai, using a fermentation system supplemented with different concentrations of exogenous hexapeptides. Peptide structure-activity relationships have also been studied using prostate cancer and other mammalian cells in vitro, with peptides in solution or immobilized, and via the use of mammalian assays in vivo and through molecular modelling. Results: Reproduction increased (x3) in the entomopathogenic nematode Steinernema siamkayai after exposure to one synthetic peptide (IEPVFT), while fecundity was reduced (x0.5) after exposure to another (KLKMNG), both effects being dose-dependent. These hexamers are opposite ends of the synthetic peptide KLKMNGKNIEPVFT (EPL030). Bioactivity is unexpected as EPL030 is a control compound, based on a scrambled sequence of the test peptide MKPLTGKVKEFNNI (EPL001). EPL030 and EPL001 are both bioinformatically obscure, having no convincing matches to aa sequences in the protein databases. EPL001 has antiproliferative effects on human prostate cancer cells and rat bone marrow cells in vitro. Intracerebroventricular infusion of EPL001 in sheep was associated with elevated growth hormone in peripheral blood and reduced prolactin. The highly dissimilar EPL001 and EPL030 nonetheless have the foregoing biological effects in common in mammalian systems, while being divergently pro- and anti-fecundity respectively in the nematode Caenorhabditis elegans. Peptides up to a 20mer have also been shown to inhibit the proliferation of human cancer and other mammalian cells in vitro, with reproductive upregulation demonstrated previously in fish and frogs, as well as nematodes. EPL001 encodes the sheep neuroendocrine prohormone secretogranin II (sSgII), as deduced on the basis of immunoprecipitation using an anti-EPL001 antibody, with bespoke bioinformatics. Six sSgII residues are key to EPL001’s bioactivity: MKPLTGKVKEFNNI. A stereospecific bimodular tri-residue signature is described involving simultaneous accessibility for binding of the side chains of two specific trios of amino acids, MKP & VFN. An evolutionarily conserved receptor is conceptualised having dimeric binding sites, each with ligand-matching bimodular stereocentres. The bioactivity of the 14mer control peptide EPL030 and its hexapeptide progeny is due to the fortuitous assembly of subsets of the novel hormonal motif, MKPVFN, a default reproductive and tissue-building OFF signal.Peer reviewe
Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting : a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV)
INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. METHODS AND ANALYSIS: The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. ETHICS AND DISSEMINATION: The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Tilray. PROTOCOL VERSION: 2.0, 9 June 2017
Heterogeneity in the diagnosis and prognosis of ischemic stroke subtypes: 9-year follow-up of 22,000 cases in Chinese adults
Background: Reliable classification of ischemic stroke (IS) etiological subtypes is required in research and clinical practice, but the predictive properties of these subtypes in population studies with incomplete investigations are poorly understood.
Aims: To compare the prognosis of etiologically classified IS subtypes and use machine learning (ML) to classify incompletely investigated IS cases.
Methods: In a 9-year follow-up of a prospective study of 512,726 Chinese adults, 22,216 incident IS cases, confirmed by clinical adjudication of medical records, were assigned subtypes using a modified Causative Classification System for Ischemic Stroke (CCS) (large artery atherosclerosis (LAA), small artery occlusion (SAO), cardioaortic embolism (CE), or undetermined etiology) and classified by CCS as “evident,” “probable,” or “possible” IS cases. For incompletely investigated IS cases where CCS yielded an undetermined etiology, an ML model was developed to predict IS subtypes from baseline risk factors and screening for cardioaortic sources of embolism. The 5-year risks of subsequent stroke and all-cause mortality (measured using cumulative incidence functions and 1 minus Kaplan–Meier estimates, respectively) for the ML-predicted IS subtypes were compared with etiologically classified IS subtypes.
Results: Among 7443 IS subtypes with evident or probable etiology, 66% had SAO, 32% had LAA, and 2% had CE, but proportions of SAO-to-LAA cases varied by regions in China. CE had the highest rates of subsequent stroke and mortality (43.5% and 40.7%), followed by LAA (43.2% and 17.4%) and SAO (38.1% and 11.1%), respectively. ML provided classifications for cases with undetermined etiology and incomplete clinical data (24% of all IS cases; n = 5276), with area under the curves (AUC) of 0.99 (0.99–1.00) for CE, 0.67 (0.64–0.70) for LAA, and 0.70 (0.67–0.73) for SAO for unseen cases. ML-predicted IS subtypes yielded comparable subsequent stroke and all-cause mortality rates to the etiologically classified IS subtypes.
Conclusion: This study highlighted substantial heterogeneity in prognosis of IS subtypes and utility of ML approaches for classification of IS cases with incomplete clinical investigations
Chronic Hepatitis B Virus Infection and Risk of Stroke Types: A Prospective Cohort Study of 500 000 Chinese Adults
BACKGROUND:
Stroke is a leading cause of mortality and permanent disability in China, with large and unexplained geographic variations in rates of different stroke types. Chronic hepatitis B virus infection is prevalent among Chinese adults and may play a role in stroke cause.
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METHODS:
The prospective China Kadoorie Biobank included >500 000 adults aged 30 to 79 years who were recruited from 10 (5 urban and 5 rural) geographically diverse areas of China from 2004 to 2008, with determination of hepatitis B surface antigen (HBsAg) positivity at baseline. During 11 years of follow-up, a total of 59 117 incident stroke cases occurred, including 11 318 intracerebral hemorrhage (ICH), 49 971 ischemic stroke, 995 subarachnoid hemorrhage, and 3036 other/unspecified stroke. Cox regression models were used to estimate adjusted hazard ratios (HRs) for risk of stroke types associated with HBsAg positivity. In a subset of 17 833 participants, liver enzymes and lipids levels were measured and compared by HBsAg status.
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RESULTS:
Overall, 3.0% of participants were positive for HBsAg. HBsAg positivity was associated with an increased risk of ICH (adjusted HR, 1.29 [95% CI, 1.16–1.44]), similarly for fatal (n=5982; adjusted HR, 1.36 [95% CI, 1.16–1.59]) and nonfatal (n=5336; adjusted HR, 1.23 [95% CI, 1.06–1.44]) ICH. There were no significant associations of HBsAg positivity with risks of ischemic stroke (adjusted HR, 0.97 [95% CI, 0.92–1.03]), subarachnoid hemorrhage (adjusted HR, 0.87 [95% CI, 0.57–1.33]), or other/unspecified stroke (adjusted HR, 1.12 [95% CI, 0.89–1.42]). Compared with HBsAg-negative counterparts, HBsAg-positive individuals had lower lipid and albumin levels and higher liver enzyme levels. After adjustment for liver enzymes and albumin, the association with ICH from HBsAg positivity attenuated to 1.15 (0.90–1.48), suggesting possible mediation by abnormal liver function.
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CONCLUSIONS:
Among Chinese adults, chronic hepatitis B virus infection is associated with an increased risk of ICH but not other stroke types, which may be mediated through liver dysfunction and altered lipid metabolism
An exploratory randomised controlled trial of a premises-level intervention to reduce alcohol-related harm including violence in the United Kingdom
<b>Background</b><p></p>
To assess the feasibility of a randomised controlled trial of a licensed premises intervention to reduce severe intoxication and disorder; to establish effect sizes and identify appropriate approaches to the development and maintenance of a rigorous research design and intervention implementation.<p></p>
<b>Methods</b><p></p>
An exploratory two-armed parallel randomised controlled trial with a nested process evaluation. An audit of risk factors and a tailored action plan for high risk premises, with three month follow up audit and feedback. Thirty-two premises that had experienced at least one assault in the year prior to the intervention were recruited, match paired and randomly allocated to control or intervention group. Police violence data and data from a street survey of study premises’ customers, including measures of breath alcohol concentration and surveyor rated customer intoxication, were used to assess effect sizes for a future definitive trial. A nested process evaluation explored implementation barriers and the fidelity of the intervention with key stakeholders and senior staff in intervention premises using semi-structured interviews.<p></p>
<b>Results</b><p></p>
The process evaluation indicated implementation barriers and low fidelity, with a reluctance to implement the intervention and to submit to a formal risk audit. Power calculations suggest the intervention effect on violence and subjective intoxication would be raised to significance with a study size of 517 premises.<p></p>
<b>Conclusions</b><p></p>
It is methodologically feasible to conduct randomised controlled trials where licensed premises are the unit of allocation. However, lack of enthusiasm in senior premises staff indicates the need for intervention enforcement, rather than voluntary agreements, and on-going strategies to promote sustainability
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