Cln5 represents a new type of cysteine-basedS-depalmitoylase linked to neurodegeneration

Genetic CLN5 variants are associated with childhood neurodegeneration and Alzheimer’s disease; however, the molecular function of ceroid lipofuscinosis neuronal protein 5 (Cln5) is unknown. We solved the Cln5 crystal structure and identified a region homologous to the catalytic domain of members of the N1pC/P60 superfamily of papain-like enzymes. However, we observed no protease activity for Cln5; and instead, we discovered that Cln5 and structurally related PPPDE1 and PPPDE2 have efficient cysteine palmitoyl thioesterase (S-depalmitoylation) activity using fluorescent substrates. Mutational analysis revealed that the predicted catalytic residues histidine-166 and cysteine-280 are critical for Cln5 thioesterase activity, uncovering a new cysteine-based catalytic mechanism for S-depalmitoylation enzymes. Last, we found that Cln5-deficient neuronal progenitor cells showed reduced thioesterase activity, confirming live cell function of Cln5 in setting S-depalmitoylation levels. Our results provide new insight into the function of Cln5, emphasize the importance of S-depalmitoylation in neuronal homeostasis, and disclose a new, unexpected enzymatic function for the N1pC/P60 superfamily of proteins

Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague

The bacterial pathogenYersinia pestisgave rise to devastating outbreaks throughouthuman history, and ancient DNA evidence has shown it afflicted human populations asfar back as the Neolithic.Y. pestisgenomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to itsemergence from aYersinia pseudotuberculosis-like progenitor; however, the number ofreconstructed LNBA genomes are too few to explore its diversity during this criticalperiod of development. Here, we present 17Y. pestisgenomes dating to 5,000 to 2,500y BP from a wide geographic expanse across Eurasia. This increased dataset enabled usto explore correlations between temporal, geographical, and genetic distance. Ourresults suggest a nonflea-adapted and potentially extinct single lineage that persistedover millennia without significant parallel diversification, accompanied by rapid dis-persal across continents throughout this period, a trend not observed in other pathogensfor which ancient genomes are available. A stepwise pattern of gene loss provides fur-ther clues on its early evolution and potential adaptation. We also discover the presenceof theflea-adapted form ofY. pestisin Bronze Age Iberia, previously only identified inin the Caucasus and the Volga regions, suggesting a much wider geographic spread ofthis form ofY. pestis. Together, these data reveal the dynamic nature of plague’s forma-tive years in terms of its early evolution and ecology

Between the Vinča and Linearbandkeramik worlds: the diversity of practices and identities in the 54th–53rd centuries cal BC in south-west Hungary and beyond

Szederkény-Kukorica-dűlő is a large settlement in south-east Transdanubia, Hungary, excavated in advance of road construction, which is notable for its combination of pottery styles, variously including Vinča A, Ražište and LBK, and longhouses of a kind otherwise familiar from the LBK world. Formal modelling of its date establishes that the site probably began in the later 54th century cal BC, lasting until the first decades of the 52nd century cal BC. Occupation, featuring longhouses, pits and graves, probably began at the same time on the east and west parts of the settlement, the central part starting a decade or two later; the western part was probably abandoned last. Vinča pottery is predominantly associated with the east and central parts of the site, and Ražište pottery with the west. Formal modelling of the early history and diaspora of longhouses in the LBK world suggests their emergence in the Formative LBK of Transdanubia c. 5500 cal BC and then rapid diaspora in the middle of the 54th century cal BC, associated with the ‘earliest’ (älteste) LBK. The adoption of longhouses at Szederkény thus appears to come a few generations after the start of the diaspora. Rather than explaining the mixture of things, practices and perhaps people at Szederkény by reference to problematic notions such as hybridity, we propose instead a more fluid and varied vocabulary including combination and amalgamation, relationships and performance in the flow of social life, and networks; this makes greater allowance for diversity and interleaving in a context of rapid change

The Cultural Project : Formal Chronological Modelling of the Early and Middle Neolithic Sequence in Lower Alsace

Starting from questions about the nature of cultural diversity, this paper examines the pace and tempo of change and the relative importance of continuity and discontinuity. To unravel the cultural project of the past, we apply chronological modelling of radiocarbon dates within a Bayesian statistical framework, to interrogate the Neolithic cultural sequence in Lower Alsace, in the upper Rhine valley, in broad terms from the later sixth to the end of the fifth millennium cal BC. Detailed formal estimates are provided for the long succession of cultural groups, from the early Neolithic Linear Pottery culture (LBK) to the Bischheim Occidental du Rhin Supérieur (BORS) groups at the end of the Middle Neolithic, using seriation and typology of pottery as the starting point in modelling. The rate of ceramic change, as well as frequent shifts in the nature, location and density of settlements, are documented in detail, down to lifetime and generational timescales. This reveals a Neolithic world in Lower Alsace busy with comings and goings, tinkerings and adjustments, and relocations and realignments. A significant hiatus is identified between the end of the LBK and the start of the Hinkelstein group, in the early part of the fifth millennium cal BC. On the basis of modelling of existing dates for other parts of the Rhineland, this appears to be a wider phenomenon, and possible explanations are discussed; full reoccupation of the landscape is only seen in the Grossgartach phase. Radical shifts are also proposed at the end of the Middle Neolithic

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S

Wirkung einer Mundspülung mit Teebaumöl auf Plaque und Entzündung

English: The tea tree oil (melaleuca alternifolia) has antiseptic, fungicide and bactericide effects. The efficiency against oral bacteria was also evident. Xylitol is known for counterattacking the cariogenic effect caused by the streptococcus mutans. Less plaque was developed during the time of the study. Deutsch: Teebaumöl (Melaleuca alternifolia)verfügt über antiseptische, fungizide und bakterizide Wirkungen, welche auch gegen orale Keime nachgewiesen wurden. Xylitol ist bekannt als Zuckerersatzstoff und erwies sich als wirksam gegen Streptococci mutans und Plaquebildung. In der vorliegenden Studie wurde die Effizienz einer Testmundspülung, enthaltend 1,5% Teebaumöl und 10% Xylitol (Tebodont®), bezüglich Plaquebildung und Entzündung im Vergleich zu einer Placebospülung untersucht. Die Testmundspülung reduzierte die Entzündung von Anfang bis nach 3 Monaten Anwendung signifikant (26–32%). Die Reduktion erfolgte deutlicher an allen der Zahnbürste nicht so gut zugänglichen Stellen. Die Zahnbeläge haben bei der Testmundspülung abgenommen, während die Plaque an allen Flächen bei der Placebomundspülung zunahm. Der Unterschied betrug zwischen 10–21%, war aber statistisch nicht signifikant. Für die Testmundspülung kann demnach sowohl für die Entzündung als auch für den Plaquebefall von einer positiven Wirkung gesprochen werden. Die Tendenz ist eindeutig. Bei so kleinen Fallzahlen (13 Probanden/Gruppe) ist jedoch eine statistische Signifikanz zwischen den beiden Gruppen kaum zu erreichen oder höchstens mit ausserordentlich stark wirkenden Mundspülungen. Beide Mundspülungen haben in der Mundhöhle keine unerwünschten Veränderungen hervorgerufen. Der Geschmack der Testmundspülung wurde nach 3 Wochen als verbesserungswürdig beurteilt, wobei nach 3 Monaten bereits eine deutliche Anpassung stattgefunden hatte, indem deutlich weniger Bemerkungen registriert wurden

Distribution of Chernozems and Phaeozems in Central Germany during the Neolithic period

A well-based knowledge about the former distribution of Chernozems and Phaeozems is necessary to (i) better understand the factors influencing formation and degradation of these highly fertile soils, and (ii) better explain prehistoric settlement patterns that were also determined by natural factors such as soil fertility. During this archaeopedological study carried out in Central Germany we applied sedimentological and micromorphological methods to compare soils and pedosediments from the recent Chernozem/Phaeozem region with black-coloured pedosediments buried in early Neolithic structures of the recent Luvisol area directly to the east. Relocated clay coatings and significantly lower magnetic enhancement compared to Chernozem/Phaeozem-derived material were found in most black-coloured pedosediments in the Luvisol area. This demonstrates that despite their location next to an extensive Chernozem/Phaeozem area these sediments do not originate from Chernozems or Phaeozems. Instead, their dark colour must either originate from anthropogenic input similar to black-coloured Anthrosols (“Dark Earth”), or must stem from Ah-material of former Luvisols. Consequently, may be apart from a small relatively dry and carbonate-rich Luvisol region northwest of Leipzig there was obviously no significantly larger distribution of Neolithic Chernozems and Phaeozems in this region during the past. Consequently, the regional early Neolithic settlers of the Linear Pottery Culture settled intensively also in areas outside the distribution of Chernozems and Phaeozems, and the activities of these settlers did not lead to the formation of such soils. Thus, fertile soils were obviously only one factor among probably others to explain the regional Neolithic settlement pattern. Significantly lower carbonate contents were found for the parent material of the black-coloured pedosediments in the Luvisol region compared with the parent material of Chernzems and Phaeozems. This demonstrates that the decisive factor to explain the recent and former spatial distribution of Chernozems and Phaeozems in this relatively dry area is the carbonate dynamics. Anthropogenic activity since the early Neolithic period obviously helped to preserve the naturally formed Chernozems and Phaeozems by re-carbonatization processes, but humans were not the main soil forming factor in early settled regions