Simultaneous Encoding of Odors by Channels with Diverse Sensitivity to Inhibition

Odorant receptors in the periphery map precisely onto olfactory glomeruli (“coding channels”) in the brain. However, the odor tuning of a glomerulus is not strongly correlated with its spatial position. This raises the question of whether lateral inhibition between glomeruli is specific or nonspecific. Here we show that, in the Drosophila brain, focal activation of even a single glomerulus recruits GABAergic interneurons in all glomeruli. Moreover, the relative level of interneuron activity in different glomeruli is largely odor invariant. Although interneurons are recruited nonspecifically, glomeruli differ dramatically in their sensitivity to interneuron activity, and this is explained by their varying sensitivity to GABA. Interestingly, a stimulus is typically encoded in parallel by channels having high and low sensitivity to inhibition. Because lateral inhibition confers both costs and benefits, the brain might rely preferentially on “high” and “low” channels in different behavioral contexts

Transformation of Olfactory Representations in the Drosophila Antennal Lobe

Molecular genetics has revealed a precise stereotypy in the projection of primary olfactory sensory neurons onto secondary neurons. A major challenge is to understand how this mapping translates into odor responses in these second-order neurons. We investigated this question in Drosophila using whole-cell recordings in vivo. We observe that monomolecular odors generally elicit responses in large ensembles of antennal lobe neurons. Comparison of odor-evoked activity from afferents and postsynaptic neurons in the same glomerulus revealed that second-order neurons display broader tuning and more complex responses than their primary afferents. This indicates a major transformation of odor representations, implicating lateral interactions within the antennal lobe

Reasons for placement and replacement of crowns in general dental practice

Objectives The aim of this study was to investigate the reasons for placement and replacement of crowns in general dental practice. Methods Forty general dental practitioners recorded the principal reason for the provision of new (initial) and replacement crowns for a maximum of up to 20 patients over a 20-week period. Results A total of 664 patients received 783 crowns during the period of this study. Of these, 69% (n = 542) were new (initial) placements and 31% (n = 241) were replacements. Overall, tooth fracture (45%, n = 241) was the most frequently reported reason for new/ initial crown placements. Aesthetics (21%, n = 53) and secondary/recurrent caries (20%; n = 47) were the most frequent reasons for crown replacement. Maxillary premolars (27%, n = 145) and mandibular molars (25%, n = 137) were the teeth that received most initial crown placements. In contrast, maxillary incisors (50%, n = 115) were the most common teeth to receive a replacement crown. Dentists were more likely to replace a crown if they had not placed the original crown: 74% of replacement crowns (n = 178) were placed by a different dentist. Most patients had only one crown placed or replaced per course of treatment (n = 611; 90%). Conclusions The results of this study reveal the prescribing habits of dentists in relation to provision of initial and replacement crowns. The vast majority of patients had only one crown provided per course of treatment, which is probably a reflection of funding schemes and changing patterns of oral health. This sample reported fewer replacement crowns than previous studies. In keeping with existing literature, crowns were more frequently replaced when the treating dentist had not placed the initial crown. However, against this, more replacements were provided for more long-standing patients (5+ years attendance) compared to those with shorter attendance history (<5 years). In an area where high quality evidence is lacking, further consensus on the need for placement and replacement crowns is needed. Such information would assist dentists to provide high-quality care and commissioners in developing an evidence-based service

Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study

Abstract Background Despite the positive impact of targeted therapies on metastatic renal cell carcinoma (mRCC), durable responses are infrequent and an unmet need exists for novel therapies with distinct mechanisms of action. We investigated the combination of recombinant Interleukin 21 (IL-21), a cytokine with unique immunostimulatory properties, plus sorafenib, a VEGFR tyrosine kinase inhibitor. Methods In this phase 1/2 study, 52 mRCC patients received outpatient treatment with oral sorafenib 400 mg twice daily plus intravenous IL-21 (10–50 mcg/kg) on days 1–5 and 15–19 of each 7-week treatment course. The safety, antitumor activity, pharmacokinetic and pharmacodynamic effects of the combination were evaluated. Results In phase 1 (n = 19), the maximum tolerated dose for IL-21 with the standard dose of sorafenib was determined to be 30 mcg/kg/day; grade 3 skin rash was the only dose-limiting toxicity. In phase 2, 33 previously-treated patients tolerated the combination therapy well with appropriate dose reductions; toxicities were mostly grade 1 or 2. The objective response rate was 21% and disease control rate was 82%. Two patients have durable responses that are ongoing, despite cessation of both IL-21 and sorafenib, at 41+ and 30+ months, respectively. The median progression-free survival in phase 2 was 5.6 months. The pharmacokinetic and pharmacodynamic properties of IL-21 appeared to be preserved in the presence of sorafenib. Conclusion IL-21 plus sorafenib has antitumor activity and acceptable safety in previously treated mRCC patients. IL-21 may represent a suitable immunotherapy in further exploration of combination strategies in mRCC. Trial registration ClinicalTrials.gov Identifier: NCT0038928

Asymmetric neurotransmitter release enables rapid odour lateralization in Drosophila

In Drosophila, most individual olfactory receptor neurons (ORNs) project bilaterally to both sides of the brain. Having bilateral rather than unilateral projections may represent a useful redundancy. However, bilateral ORN projections to the brain should also compromise the ability to lateralize odours. Nevertheless, walking or flying Drosophila reportedly turn towards the antenna that is more strongly stimulated by odour. Here we show that each ORN spike releases approximately 40% more neurotransmitter from the axon branch ipsilateral to the soma than from the contralateral branch. As a result, when an odour activates the antennae asymmetrically, ipsilateral central neurons begin to spike a few milliseconds before contralateral neurons, and at a 30 to 50% higher rate than contralateral neurons. We show that a walking fly can detect a 5% asymmetry in total ORN input to its left and right antennal lobes, and can turn towards the odour in less time than it requires the fly to complete a stride. These results demonstrate that neurotransmitter release properties can be tuned independently at output synapses formed by a single axon onto two target cells with identical functions and morphologies. Our data also show that small differences in spike timing and spike rate can produce reliable differences in olfactory behaviour

Climate warming and elevated CO2 alter peatland soil carbon sources and stability

Peatlands are an important carbon (C) reservoir storing one-third of global soil organic carbon (SOC), but little is known about the fate of these C stocks under climate change. Here, we examine the impact of warming and elevated atmospheric CO$_{2}$ concentration (eCO$_{2}$) on the molecular composition of SOC to infer SOC sources (microbe-, plant- and fire-derived) and stability in a boreal peatland. We show that while warming alone decreased plant- and microbe-derived SOC due to enhanced decomposition, warming combined with eCO$_{2}$ increased plant-derived SOC compounds. We further observed increasing root-derived inputs (suberin) and declining leaf/needle-derived inputs (cutin) into SOC under warming and eCO$_{2}$. The decline in SOC compounds with warming and gains from new root-derived C under eCO$_{2}$, suggest that warming and eCO$_{2}$ may shift peatland C budget towards pools with faster turnover. Together, our results indicate that climate change may increase inputs and enhance decomposition of SOC potentially destabilising C storage in peatlands

Host-linked soil viral ecology along a permafrost thaw gradient

Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood1,2,3,4,5,6,7. The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans8,9,10, remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling