Ceramide synthase TLCD3B is a novel gene associated with human recessive retinal dystrophy

PURPOSE: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration. METHODS: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses. RESULTS: Here we have identified four patients with cone-rod dystrophy or maculopathy from three families carrying pathogenic variants in TLCD3B. Consistent with the phenotype observed in patients, the Tlcd3bKO/KO mice exhibited a significant reduction of the cone photoreceptor light responses, thinning of the outer nuclear layer, and loss of cone photoreceptors across the retina. CONCLUSION: Our results provide a link between loss-of-function variants in a ceramide synthase gene and human retinal dystrophy. Establishment of the Tlcd3b knockout murine model, an in vivo photoreceptor cell degeneration model due to loss of a ceramide synthase, will provide a unique opportunity in probing the role of ceramide in survival and function of photoreceptor cells

Osteoarticular Infection in Three Young Thoroughbred Horses Caused by a Novel Gram Negative Cocco-Bacillus

© 2020 Bernard J. Hudson et al. We describe three cases of osteoarticular infection (OAI) in young thoroughbred horses in which the causative organism was identified by MALDI-TOF as Kingella species. The pattern of OAI resembled that reported with Kingella infection in humans. Analysis by 16S rRNA PCR enabled construction of a phylogenetic tree that placed the isolates closer to Simonsiella and Alysiella species, rather than Kingella species. Average nucleotide identity (ANI) comparison between the new isolate and Kingella kingae and Alysiella crassa however revealed low probability that the new isolate belonged to either of these species. This preliminary analysis suggests the organism isolated is a previously unrecognised species

Fine-Scale Genetic Structure Arises during Range Expansion of an Invasive Gecko

Processes of range expansion are increasingly important in light of current concerns about invasive species and range shifts due to climate change. Theoretical studies suggest that genetic structuring may occur during range expansion. Ephemeral genetic structure can have important evolutionary implications, such as propagating genetic changes along the wave front of expansion, yet few studies have shown evidence of such structure. We tested the hypothesis that genetic structure arises during range expansion in Hemidactylus mabouia, a nocturnal African gecko recently introduced to Florida, USA. Twelve highly variable microsatellite loci were used to screen 418 individuals collected from 43 locations from four sampling sites across Florida, representing a gradient from earlier (∼1990s) to very recent colonization. We found earlier colonized locations had little detectable genetic structure and higher allelic richness than more recently colonized locations. Genetic structuring was pronounced among locations at spatial scales of tens to hundreds of meters near the leading edge of range expansion. Despite the rapid pace of range expansion in this introduced gecko, dispersal is limited among many suitable habitat patches. Fine-scale genetic structure is likely the result of founder effects during colonization of suitable habitat patches. It may be obscured over time and by scale-dependent modes of dispersal. Further studies are needed to determine if such genetic structure affects adaptation and trait evolution in range expansions and range shifts

Signatures of arithmetic simplicity in metabolic network architecture

Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that several of the properties predicted by the artificial chemistry model hold for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity

Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice

<p>Abstract</p> <p>Background</p> <p>A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by <it>in vivo </it>electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice</p> <p>Results</p> <p>We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.</p> <p>Conclusions</p> <p>Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.</p

Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients

The aim of the present study was to define the activity and tolerability of a triplet regimen including oxaliplatin 130 mg m−2 (2 h i.v. infusion) and raltitrexed 3.0 mg m−2 (15 min i.v. infusion) given on day 1, followed by levo-folinic acid 250 mg m−2 (2 h i.v. infusion) and 5-fluorouracil 1050 mg m−2 i.v. bolus on day 2, every 2 weeks, in pretreated colorectal cancer patients. From April 1999 to December 2000, 50 patients were enrolled: 26 were males and 24 females, their median age was 63 (range, 43–79) years; ECOG performance status was 0 in 26 patients, ⩾1 in 24 patients; 26 patients had received previous adjuvant chemotherapy, 40 patients had been exposed to one or two lines of palliative chemotherapy (including irinotecan in 31 cases); 18 patients were considered chemo-refractory. A total of 288 cycles were administered, with a median number of 6 (range 1–12) courses per patient. A complete response was obtained in three patients, and a partial response in nine patients, giving a major response rate of 24% (95% confidence interval, 13–38%), while 15 further patients showed a stable disease, for an overall control of tumour growth in 60% of patients. Three complete responses and three partial responses were obtained in patients pretreated with irinotecan (response rate, 19%); among refractory patients, three achieved partial responses (response rate, 13%). After a median follow-up of 18 (range, 10–30) months, 40 patients showed a progression of disease: the growth modulation index ranged between 0.2 and 2.5: it was ⩾1.33 (showing a significant delay of tumour growth) in 16 (40%) patients. Actuarial median progression-free survival time was 7.6 months, and median survival time was 13.6 months: estimated probability of survival was 55% at 1 year. Main severe toxicity was neutropenia: World Health Organisation grade 4 affected 32% of patients; non-haematological toxicity was mild: World Health Organisation grade 3 diarrhoea was complained of by 8%, and grade 3 stomatitis by 4% of patients; neurotoxicity (according to Lévi scale) was scored as grade 3 in 8% of patients. In conclusion, this regimen was manageable and active as salvage treatment of advanced colorectal cancer patients; it showed incomplete cross-resistance with irinotecan-based treatments, and proved to delay the progression of disease in a relevant proportion of treated patients

Ethnic and gender specific life expectancies of the Singapore population, 1965 to 2009 - Converging, or diverging?

10.1186/1471-2458-13-1012BMC Public Health131

A transcriptomic snapshot of early molecular communication between Pasteuria penetrans and Meloidogyne incognita

© The Author(s). 2018Background: Southern root-knot nematode Meloidogyne incognita (Kofoid and White, 1919), Chitwood, 1949 is a key pest of agricultural crops. Pasteuria penetrans is a hyperparasitic bacterium capable of suppressing the nematode reproduction, and represents a typical coevolved pathogen-hyperparasite system. Attachment of Pasteuria endospores to the cuticle of second-stage nematode juveniles is the first and pivotal step in the bacterial infection. RNA-Seq was used to understand the early transcriptional response of the root-knot nematode at 8 h post Pasteuria endospore attachment. Results: A total of 52,485 transcripts were assembled from the high quality (HQ) reads, out of which 582 transcripts were found differentially expressed in the Pasteuria endospore encumbered J2 s, of which 229 were up-regulated and 353 were down-regulated. Pasteuria infection caused a suppression of the protein synthesis machinery of the nematode. Several of the differentially expressed transcripts were putatively involved in nematode innate immunity, signaling, stress responses, endospore attachment process and post-attachment behavioral modification of the juveniles. The expression profiles of fifteen selected transcripts were validated to be true by the qRT PCR. RNAi based silencing of transcripts coding for fructose bisphosphate aldolase and glucosyl transferase caused a reduction in endospore attachment as compared to the controls, whereas, silencing of aspartic protease and ubiquitin coding transcripts resulted in higher incidence of endospore attachment on the nematode cuticle. Conclusions: Here we provide evidence of an early transcriptional response by the nematode upon infection by Pasteuria prior to root invasion. We found that adhesion of Pasteuria endospores to the cuticle induced a down-regulated protein response in the nematode. In addition, we show that fructose bisphosphate aldolase, glucosyl transferase, aspartic protease and ubiquitin coding transcripts are involved in modulating the endospore attachment on the nematode cuticle. Our results add new and significant information to the existing knowledge on early molecular interaction between M. incognita and P. penetrans.Peer reviewedFinal Published versio

Actions in Practice: On details in collections

Several of the contributions to the Lynch et al. Special issue make the claim that conversation- analytic research into epistemics is ‘routinely crafted at the expense of actual, produced and constitutive detail, and what that detail may show us’. Here, we seek to address the inappositeness of this critique by tracing precisely how it is that recognizable actions emerge from distinct practices of interaction. We begin by reviewing some of the foundational tenets of conversation-analytic theory and method – including the relationship between position and composition, and the making of collections – as these appear to be primary sources of confusion for many of the contributors to the Lynch et al. Special Issue. We then target some of the specific arguments presented in the Special Issue, including the alleged ‘over-hearer’s’ writing of metrics, the provision of so- called ‘alternative’ analyses and the supposed ‘crafting’ of generalizations in epistemics research. In addition, in light of Lynch’s more general assertion that conversation analysis (CA) has recently been experiencing a ‘rapprochement’ with what he disparagingly refers to as the ‘juggernaut’ of linguistics, we discuss the specific expertise that linguists have to offer in analyzing particular sorts of interactional detail. The article as a whole thus illustrates that, rather than being produced ‘at the expense of actual, produced and constitutive detail’, conversation-analytic findings – including its work in epistemics – are unambiguously anchored in such detail. We conclude by offering our comments as to the link between CA and linguistics more generally, arguing that this relationship has long proven to be – and indeed continues to be – a mutually beneficial one

SAVVY Vaginal Gel (C31G) for Prevention of HIV Infection: A Randomized Controlled Trial in Nigeria

The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk.This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly follow-up visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between September 2004 and December 2006 in Lagos and Ibadan, Nigeria, where we enrolled 2153 HIV-negative women at high risk of HIV infection. Participants were randomized 1 ratio 1 to SAVVY or placebo. The effectiveness endpoint was incidence of HIV infection as indicated by detection of HIV antibodies in oral mucosal transudate (rapid test) or blood (ELISA), and confirmed by Western blot or PCR testing. We observed 33 seroconversions (21 in the SAVVY group, 12 in the placebo group). The Kaplan-Meier estimates of the cumulative probability of HIV infection at 12 months were 0.028 in the SAVVY group and 0.015 in the placebo group (2-sided p-value for the log-rank test of treatment effect 0.121). The point estimate of the hazard ratio was 1.7 for SAVVY versus placebo (95% confidence interval 0.9, 3.5). Because of lower-than-expected HIV incidence, we did not observe the required number of HIV infections (66) for adequate power to detect an effect of SAVVY. Follow-up frequencies of adverse events, reproductive tract adverse events, abnormal pelvic examination findings, chlamydial infections and vaginal infections were similar in the study arms. No serious adverse event was attributable to SAVVY use.SAVVY did not reduce the incidence of HIV infection. Although the hazard ratio was higher in the SAVVY than the placebo group, we cannot conclude that there was a harmful treatment effect of SAVVY