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Mycobacterium tuberculosis dethiobiotin synthase (MtDTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis. Here, we report a binder of MtDTBS, cyclopentylacetic acid 2 (KD = 3.4 ± 0.4 mM), identified via in silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of MtDTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with KD = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder (KD = 57 ± 5 nM) and inhibitor (Ki = 5 ± 1 μM) of MtDTBS. Our findings highlight the first reported inhibitors of MtDTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.

The 2.6 Å crystal structure of the apo form of Hip1 (hydrolase important for pathogenesis) has been previously reported. However, very little is known about the active site architecture of this M. tuberculosis (Mtb), serine hydrolase drug target. To begin mapping the active site of Hip1, we cocrystallized Hip1 with the irreversible serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonylfluoride (AEBSF). We chose AEBSF for cocrystallization with Hip1 since the similar inhibitor, phenylmethylsulfonyl fluoride (PMSF), interestingly exhibited no activity against Hip1. We obtained crystals that diffracted to 2.1 Å but to our bewilderment, we did not observe any electron density for the inhibitor in the omit map for the Hip1-AEBSF complex. Rather, in the active site, dehydroalanine (dAla) was found to occupy the expected position of the catalytic Ser228, thus yielding anhydrohip1. Here we present a comparative analysis of the crystal structures of anhydrohip1 and Hip1 and provide a mechanism for the conversion of the enzyme to the anhydro-form through reaction with AEBSF. With the aid of molecular docking, we propose an explanation for the differential inhibition of Hip1 by AEBSF and PMSF. We also present a preliminary definition of the S1 and S2 pockets of the protease's active site and propose a mechanism for a ligand-induced conformational change within the S2 pocket. Finally, we expand upon the previous demarcation of the putative lipid binding pocket in the α-domain of the enzyme. We believe that this detailed analysis of the structures of anhydrohip1 and Hip1 provides valuable information useful for the structure-based drug design of novel Hip1-directed Mtb therapeutics.

Premise During plant domestication, traits can be subject to a variety of types of selection, ranging from strong directional selection for traits such as seed or fruit size to diversifying selection for traits like color or flavor. These types of selection interact with other evolutionary processes including genetic bottlenecks and interspecific gene flow to generate different levels of genetic diversity across the genome and at target genes in domesticated lineages, but little is known about the impacts of these processes in perennial fruit crops. Methods We used sequence capture by hybridization to examine patterns of diversity at a suite of candidate domestication and anonymous background genes in domesticated apple (Malus ×domestica) in comparison to its wild relatives Malus sieversii and Malus orientalis. Results We found no change in average diversity at these candidate domestication genes across the three species. However, a subset of the genes did exhibit patterns of very high or very low diversity in M. ×domestica compared to its progenitor, M. sieversii. Of the genes with characterized function, the low-diversity genes mainly contributed to fruit quality traits like color and flavor, predicted to be under conscious, directional selection relatively late in the domestication process, while the high-diversity genes included a variety of functions. Conclusions Overall, these results are consistent with predictions based on the likely timing and nature of selection during domestication and open new avenues for understanding genes with high diversity in a perennial crop compared to its wild relatives.

A striking feature of Stravinsky’s neoclassical works is his simultaneous use of two or more topics. Robert S. Hatten (2014) has defined this process as troping, which involves four axes or “dimensions along which an imported topic and its potential tropological interaction may be marked with respect to its new environment,” defined as degrees of compatibility, dominance, creativity, and productivity. In this article, I use these four axes to demonstrate how combining analytical insights from each axis and adapting them for twentieth-century music can lead to nuanced expressive interpretations of Stravinsky’s neoclassical works.

Tigran Hamasyan (b. 1987) is an Armenian jazz pianist and composer whose music has been described as “grounded in serious reinterpretations of Armenian culture via his take on Bach, French romantics, jazz, dubstep, metal, and modern electronic music” (".fn_cite_year($manukian_2018).", 637). Hamasyan has recorded thirteen studio albums between the years of 2006–2020, and analyzing these recordings suggests that asymmetrical meter, ostinati, and cycles are not a random occurrence in Hamasyan’s music but rather a crucial component of his compositional language. This article defines three types of cycles—phrasal, structural, and developmental—each of which has a unique compositional function. Another important distinction made in this article is the difference between “complete” and “incomplete” cycles. Complete cycles are those that repeat two metrical layers without disruption until they return to a shared point of alignment, while incomplete cycles are those in which the meter used in one or more of the layers is disrupted before returning to a shared point of alignment. Several of my own transcriptions of Hamasyan’s music are analyzed to discuss how asymmetrical meter, ostinati, and cycles are used to create various formal processes in Hamasyan’s compositions.

The aim of this study was to determine the combined effect of galvanic interaction and silicate addition on the dissolution of pyrite, the major contributor to acid and metalliferous drainage (AMD). Single (pyrite, sphalerite, and galena)- A nd bi-sulfide (pyrite-sphalerite and pyrite-galena) batch dissolution experiments were carried out with addition of 0.8 mM dissolved silicate for comparison to previously published data. The pyrite dissolution rate was reduced by 98% upon silicate addition at pH 7.4 with little effect at pH 3.0 and 5.0. The effect of galvanic interaction on reducing pyrite dissolution decreased with increasing pH and was greater in the presence of sphalerite than galena. In contrast, the effect of silicate addition increased with increasing pH and was greater in the presence of galena than sphalerite. The greatest combined effect was at pH 7.4, with

A series of dipeptide aldehydes containing different N-terminal heterocycles was prepared and assayed in vitro against α-chymotrypsin to ascertain the importance of the heterocycle in maintaining a β-strand geometry while also providing a hydrogen bond donor equivalent to the backbone amide nitrogen of the surrogate amino acid. The dipeptide containing a pyrrole constraint (10) was the most potent inhibitor, with >30-fold improved activity over dipeptides which lacked a nitrogen hydrogen bond donor (namely thiophene 11, furan 12 and pyridine 13). Molecular docking studies of 10 bound to α-chymotrypsin demonstrates a hydrogen bond between the pyrrole nitrogen donor and the backbone carbonyl of Gly216 located in the S3 pocket which is proposed to be critical for overall binding.

The presence of latent acidity in the form of the jarosite-alunite mineral group complicates assessment of the rates of acid and metalliferous drainage (AMD) generation from potentially acid-forming waste rocks and tailings.To enable better prediction of the contributions from these secondary sulfate minerals, the relationships between pH and the rate of dissolution for natrojarosite and alunite, for comparison with pyrite, have been determined.In single mineral unstirred systems, the dissolution rates of natrojarosite and alunite in the pH range 2–7 were in the range of 10⁻¹⁴ to 10⁻¹³ molm⁻² s⁻¹ and were found to be slowest at pH 3.4 and 5.5, respectively. At pH above these respective minima, alunite and natrojarosite dissolution results in acid release. The surface area normalised dissolution rates of both minerals were 2–3 orders of magnitude slower than that of pyrite under the same conditions, and were 2–4 orders of magnitude slower than the rates of stirred dissolution of syntheticjarosite and alunite reported in the literature. In mixed mineral mini-column dissolution tests, pyrite oxidation proceeded at almost the same rate in the longer term (> 50 days), regardless of the presence or absence of natrojarosite or alunite. As the presence of these secondary sulfate minerals does not impact significantly onpyrite oxidation, their contributions to AMD can be taken into account separately enabling accurate calculation of the neutralisation rates needed to effectively manage AMD. Refereed/Peer-reviewed

Selenium (Se) has been mobilised by leaching from coal and associated waste rock exposed by mining activities in Western Canada, with deleterious impact on aquatic wildlife. Waste rock characterisation indicates that up to 7% of the Se, as Se(IV), may be associated with organic matter, with ≈9%, as Se(0), associated with euhedral pyrite. Small 1−2 µm mineral particles with average Se concentration of 1.0 ± 0.4 wt% account for the remaining Se with the largest components likely to be associated with Fe oxide/hydroxide/carbonate as Se(0) and framboidal pyrite as Se(IV) and Se(0). No evidence was found for the presence of Se(−I), Se(−II) or Se(VI). In the first 8 weeks of leaching Se release was not correlated to the addition of aqueous silicate, added to aid pyrite passivation, but was reduced by approximately one third when the waste was treated with manure. This suggests the primary initial source of leached Se was not pyrite. Added organic C results in increased microbial numbers, particularly aerobic microbes, and promotes the formation of extensive coating of extracellular polymeric substances resulting in depletion of O2 at particle surfaces, reducing oxidation of Se(IV) and therefore reducing the leach rate of Se. Subsequent to 8 weeks of leaching the rates of release of Se from the treated wastes were similar regardless of treatment strategy but were reduced as compared to the untreated waste rock, suggestive of partial framboidal pyrite geochemical and microbial passivation. Se leaching was not correlated to S leaching, but the source(s) of the leached S was not known as approximately half of the S within the waste rock was non-sulfidic. These results indicate that utilisation of local organic carbon-containing wastes for coverage of coal waste rock may be a cost-effective strategy to reduce Se leaching to acceptable rates of release regardless of whether the Se is associated with framboidal pyrite or organics Refereed/Peer-reviewed

Chalcopyrite, galena, and sphalerite commonly coexist with pyrite in sulfidic waste rocks. The aim of this work was to investigate their impact, potentially by galvanic interaction, on pyrite oxidation and acid generation rates under simulated acid and metalliferous drainage conditions. Kinetic leach column experiments using single-minerals and pyrite with one or two of the other sulfide minerals were carried out at realistic sulfide contents (total sulfide 47% for galena vs

Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.

Acid and metalliferous drainage (AMD) is a major environmental issue resulting largely from exposure to weathering of mine wastes containing pyrite (FeS2). At-source strategies to reduce the rate of formation of AMD have potential to be more cost-effective and sustainable than post-generation downstream treatments. The objective of this study was to examine the efficacy of geochemical and microbial treatments for at-source control through pyrite surface passivation. Six kinetic leach columns (KLCs), using a mine waste containing 3.8 wt% pyrite, were subjected to various treatments: 1) untreated, 2) blended calcite, and applications of 3) calcite-saturated water, 4) lime-saturated water followed by calcite-saturated water, 5) biosolids extract water (providing a source of organic carbon to promote microbial growth) and 6) biosolids extract in calcite-saturated water. The untreated KLC leachate pH was on average 5.7 for the first 12 weeks, followed by a gradual decrease to pH 4.5 at week 52. This slow pH decrease is attributed to neutralisation released upon Mg-siderite dissolution. The leachate pH from all treated KLCs was near-neutral at the end of the tests. Pyrite was surface-passivated and leaching supressed by all treatments except for calcite-saturated water. Leaching of Mn and Zn from the untreated waste identified the potential for adverse environmental impact. No evidence was found for surface passivation of Zn- or Mn-containing minerals in the treated KLCs. Blended calcite addition and lime-saturated water followed by calcite-saturated water were most effective at reducing release of Zn and Mn, likely due to precipitation as hydroxides/carbonates Refereed/Peer-reviewed

Refereed/Peer-reviewed Nectar analysis has been used to understand pollination systems, but nectar storage methods have rarely been considered as potential sources of inaccuracy in the recovery of data. Prompt nectar sugar analysis is not always possible and storage methods can affect results. We aimed to develop an effective method to store nectar on filter paper. Nectars from two subspecies of Eremophila maculata (Scrophulariaceae) and Strelitzia reginae (Strelitziaceae) were spotted on filter papers. Nectars were redissolved and assayed by high-performance liquid chromatography to determine the masses of sugars recovered from the papers from Day 0 to Day 30. We evaluated the effects of the method of elution, paper type and size, and storage treatments on sugar recovery. Liquid nectars were also stored in the refrigerator. Sugars were best eluted from filter papers in 15 mL of water and agitated for 1 min. Nectar sugars stored on small papers tended to be recovered more successfully than those stored on larger papers (significantly for glucose). Paper performed better than nylon for glucose. Desiccant had a marginal positive effect on nectar sugar recovery, and filter paper performed better than did refrigeration of liquid nectar for storage. If highly accurate measurements are needed, nectars should be eluted with large volumes of water from small filter papers stored with desiccant within a few days of collection.

Acid rock drainage (ARD) is generated when mineral sulfides, primarily pyrite (FeS2), are exposed to weathering. Pyrite oxidation and dissolution may also result in the precipitation of secondary sulfate minerals, commonly found in weathered mine wastes, that release ‘stored acidity’ on subsequent dissolution. To better understand the release of this stored acidity, a kinetic leach column experiment using a synthetic pyritic (5 wt%) mine waste was conducted for a period of 524 weeks. The first 260 weeks watering/flushing was carried out using Milli-Q water during which the leachate pH decreased from 6.0 to 2.0, pyrite passivation layers present initially were removed and secondary sulfate minerals formed. The rate at which acidity was generated from secondary sulfate mineral dissolution was significantly greater than from pyrite oxidation after the calcite-saturated silicate water treatment during the period from 260 to 440 weeks. This suggests that in weathered pyritic wastes, both the amount of acidity and the rate at which it is released may be dominated by acid sulfate minerals rather than residual pyrite. Importantly, it was found that passivation strategies appropriate for reducing pyrite oxidation rates were not effective for reducing the rate of acid release from secondary mineralisation. Significant amounts of lime-saturated water (with high alkalinity) were required to dissolve the secondary sulfate minerals containing the stored acidity before circum-neutral conditions necessary for pyrite passivation could be achieved. It follows therefore that it is necessary to quantify the amount of stored acidity in secondary minerals so that appropriate remediation and acid management strategies can be designed and implemented to achieve long-term sustainable ARD control and mine closure Refereed/Peer-reviewed

ZusammenfassungIn den letzten Jahren haben sich die Diagnose und die medizinische Behandlung von Lungenkarzinompatienten erheblich gewandelt. Auch wenn die Mehrzahl der Patienten weiterhin nicht von der Erkrankung geheilt wird, so können durch verschiedene, klug abgestimmte Therapieansätze eine deutlich längere Krankheitskontrolle und stark verlängerte Überlebenszeiten als noch vor wenigen Jahren erreicht werden. Diese Entwicklung ist nicht nur durch medizinische, sondern auch zahlreiche politische und organisatorische Aspekte charakterisiert. Diese verschiedenen Ebenen, die klinischen Konsequenzen und die resultierenden Herausforderungen werden im Folgenden kurz skizziert.

Acid and metalliferous drainage (AMD) remains a challenging issue for the mining sector. AMD management strategies have attempted to shift from treatment of acid leachates post-generation to more sustainable at-source prevention. Here, the efficacy of microbial–geochemical at-source control approach was investigated over a period of 84 weeks. Diverse microbial communities were stimulated using organic carbon amendment in a simulated silicate-containing sulfidic mine waste rock environment. Mineral waste in the unamended leach system generated AMD quickly and throughout the study, with known lithotrophic iron- and sulfur-oxidising microbes dominating column communities. The organic-amended mineral waste column showed suppressed metal dissolution and AMD generation. Molecular DNA-based next generation sequencing confirmed a less diverse lithotrophic community in the acid-producing control, with a more diverse microbial community under organic amendment comprising organotrophic iron/sulfur-reducers, autotrophs, hydrogenotrophs and heterotrophs. Time-series multivariate statistical analyses displayed distinct ecological patterns in microbial diversity between AMD- and non-AMD-environments. Focused ion beam-TEM micrographs and elemental mapping showed that silicate-stabilised passivation layers were successfully established across pyrite surfaces in organic-amended treatments, with these layers absent in unamended controls. Organic amendment and resulting increases in microbial abundance and diversity played an important role in sustaining these passivating layers in the long-term. Refereed/Peer-reviewed

Acid and metalliferous release occurring when sulfide (principally pyrite)-containing rock from mining activities and from natural environments is exposed to the elements is acknowledged as a major environmental problem. Acid rock drainage (ARI)) management is both challenging and costly for operating and legacy mine sites. Current technological solutions are expensive and focused on treating ARD on release rather than preventing it at source. We describe here a viable, practical mechanism for reduced ARD through the formation of silicate-stabilized iron oxyhydroxide surface layers. Without silicate, oxidized pyrite particles form an overlayer of crystalline goethite or lepidocrocite with porous structure. With silicate addition, a smooth, continuous, coherent and apparently amorphous iron oxyhydroxide surface layer is observed, with consequent pyrite dissolution rates reduced by more than 90% at neutral pH. Silicate is structurally incorporated within this layer and inhibits the phase transformation from amorphous iron (oxy)hydroxide to goethite, resulting in pyrite surface passivation. This is confirmed by computational simulation, suggesting that silicate-doping of a pseudo amorphous iron oxyhydroxide (ferrihydrite structure) is thermodynamically more stable than the equivalent undoped structure. This mechanism and its controlling factors are described. As a consequence of the greatly reduced acid generation rate, neutralization from on-site available reactive silicate minerals may be used to maintain neutral pH, after initial limestone addition to achieve neutral pH, thus maintaining the integrity of these layers for effective ARD management. Refereed/Peer-reviewed

In part two of this article, which began last month, Ted Schumann discusses contract issues to consider, including associate employment agreements, buy-in agreements, operating agreements, and buy-sell agreements. Plus - 10 things to avoid after the buy-in is concluded.

Background Vitamin D deficiency occurs frequently in patients with Crohn’s disease (CD) and ulcerative colitis (UC). While recent cohort studies support an association of vitamin D with important clinical parameters and outcomes in IBD, the complex interplay of inflammation with vitamin D metabolism in IBD poses a viscious circle. We sought to further illucidate the relation between inflammation and different vitamin D parameters. To the best our knowledge, this was the first study to focus on the relationship between vitamin D binding protein (VDBP), circulating total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D), and inflammation, in adult IBD patients. Methods This was a comparative, single-centred, cross-sectional study in patients with IBD aged 18–65 years. Full blood count, transferrin, albumin and hsCRP were determined by standard methods. The presence/absence of inflammation was assessed based on serum hsCRP levels (cutoff Results In total, 129 subjects with IBD (70 male/59 female; 82 CD/47 UC; mean age 41.7 ± 12.6 years) were enrolled. Of these, 38/129 had inflammation (19 m/19 f; 26 CD/12 UC; 39.6 ± 12.9 years) while 91/129 had no inflammation (40 m/51 f; 56 CD/35 UC; 42.5 ± 12.5 years). Subjects with disease activity had significantly higher leukocyte, erythrocyte sedimentation rate (ESR) and hsCRP, but lower transferrin, transferrin saturation (TSAT) and albumin levels than those without inflammation (p < 0.05). Average serum levels of 25(OH)D (24.6[6.8–54.8] vs. 26.4[5.0–74.4]ng/ml), free 25(OH)D (5.9[1.3–13.3] vs. 1.0[1.0–21.4]ng/ml) and bioavailable 25(OH)D(2.3 [0.1–4.7] vs. 2.4[0.5–19.5]ng/ml) were similar in patients with vs. without inflammation (p > 0.05). However, VDBP levels were significantly higher in inflammatory conditions (359.6[252.2–530.6] mg/l vs. 327.4[183.5–560.3]mg/l; p < 0.05) and showed a positive correlation with CRP levels (0.293, p < 0.001). Ratio of free/total 25(OH)D correlated negatively with CRP levels (−0.282, p = 0.002). Conclusion High levels of circulating VDBP were associated with inflammatory activity. Moreover, free/total 25(OH)D ratio was inversely associated with inflammation. Other vitamin D parameters including total, free and bioavailable 25(OH)D showed no association with inflammation. These findings suggest that VDBP may play a bigger role than thought as a modulator of vitamin D and inflammation, and that simultaneous detection and investigation of plasma VDBP may provide additional insights into this complex interaction.

The aim of this study was to test the performance of a novel method for acid rock drainage(ARD) control through the formation of Al(OH)₃₋doped passivating surface layers on pyrite. At pH 2.0 and 4.0, there was no obvious inhibition of the pyrite oxidation rate on addition of 20 mg L⁻¹ Al³⁺ (added as AlCl3·6H2O). In comparison, the pyrite oxidation rate at circumneutral pH (7.4± 0.4) decreased with increasing added Al³⁺ with ≈98%reduction in long-term (282 days) dissolution rates in the presence of 20 mg L−1 Al³⁺. Al3³⁺ was added to the solution and allowed to equilibrate prior to pyrite addition (2 g L⁻¹).Consequently almost all Al³⁺ (>99.9%) was initially present as aluminum hydroxide precipitates at pH 7.4. X-ray photoelectron spectroscopy analysis showed a significant concentration of Al³⁺ (20.3 at. %) on the pyrite surface reacted at pH 7.4 with 20 mg L⁻¹ added Al³⁺, but no Al³⁺ on pyrite surfaces reacted at pH 2.0 and 4.0 with added Al³⁺. Transmission electron microscopy and synchrotron X-ray absorption near edge spectroscopy analyses indicated that compact surface layers containing both goethite and amorphous or nanocrystalline Al(OH)3 formed in the presence of 20 mg L⁻¹ Al³⁺ at circumneutral pH, in contrast to the porous goethite surface layers formed on pyrite dissolved in the absence of Al³⁺ under otherwise identical conditions. This work demonstrates the potential for novel Al-based pyrite passivation of relevance to the mining industry where suitable Al-rich waste materials are available for ARD control interventions. Refereed/Peer-reviewed

In recent years, the diagnosis and medical treatment of lung cancer patients has been changed profoundly. Still being a deadly disease for most patients, new developments in treatment approaches and therapy selection lead to significantly extended duration of disease control and overall survival. This development is evident not only in medical issues but also comprises various political and organisational aspects. These aspects will be briefly characterised and discussed in the following.In den letzten Jahren haben sich die Diagnose und die medizinische Behandlung von Lungenkarzinompatienten erheblich gewandelt. Auch wenn die Mehrzahl der Patienten weiterhin nicht von der Erkrankung geheilt wird, so können durch verschiedene, klug abgestimmte Therapieansätze eine deutlich längere Krankheitskontrolle und stark verlängerte Überlebenszeiten als noch vor wenigen Jahren erreicht werden. Diese Entwicklung ist nicht nur durch medizinische, sondern auch zahlreiche politische und organisatorische Aspekte charakterisiert. Diese verschiedenen Ebenen, die klinischen Konsequenzen und die resultierenden Herausforderungen werden im Folgenden kurz skizziert.

Performing rebiopsies for primary lung cancer and/or their metastases is becoming more and more prominent in daily practice, as the therapeutical spectrum increases and some newer strategies are dependent on immunohistochemical and/or molecular factors. In general, nearly all recurrent lesions or metastases can be reached. However, frequently invasive procedures are necessary with the need to carefully weigh risks and benefits of rebiopsies for the patient in each case. In this review indications for recurrent and progressive disease as well as risks are discussed and alternatives to rebiopsies are shown. This work is the joint opinion from both the endoscopic and thoracic oncology sections of the German Society of Pneumology (DGP).Rebiopsien bei primären Lungenkarzinomen sowie deren Metastasen werden im klinischen Alltag immer wichtiger, da sich die Therapien weiterentwickeln und häufig gezielte weitere Behandlungsstrategien erst nach immunhistochemischen oder/und molekularen Veränderungen zugelassen sind. Prinzipiell können fast alle Rezidive bzw. progrediente Tumore biopsiert werden, allerdings häufig nur mittels invasiver Maßnahmen. Hier muss der Aufwand und das Risiko des Patienten mit dem zu erwartenden Benefit durch die Rebiopsie in jedem einzelnen Fall überlegt und vorher mit dem Patienten besprochen werden. In der Übersichtsarbeit werden die Indikationen bei Rezidiv und progredienter Erkrankung sowie die Risiken diskutiert und Alternativen zur Rebiopsie aufgezeigt. Diese Arbeit stellt die Empfehlungen der Sektionen 2 (Endoskopie) und 11 (pneumologische Onkologie) der Deutschen Gesellschaft für Pneumologie (DGP) dar.

Although the acid generating properties of pyrite (FeS₂) have been studied extensively, the impact of galvanic interaction on pyrite oxidation, and the implications for acid and metalliferous drainage, remain largely unexplored. The relative galvanic effects on pyrite dissolution were found to be consistent with relative sulfide mineral surface area ratios with sphalerite (ZnS) having greater negative impact in batch leach tests (sulfide minerals only, controlled pH) and galena (PbS) having greater negative impact in kinetic leach column tests (KLCs, uncontrolled pH, >85 wt% silicate minerals). In contrast the presence of pyrite resulted consistently in greater increase in galena than sphalerite leaching suggesting that increased anodic leaching is dependent on the difference in anodic and cathodic sulfide mineral rest potentials. Acidity increases occurred after 44, 20, and 12 weeks in the pyrite-galena, pyrite-sphalerite, and the pyrite containing KLCs. Thereafter acid generation rates were similar with the Eh consistently above the rest potential of pyrite (660 mV, SHE). This suggests that treatment of waste rocks or tailings, to establish and maintain low Eh conditions, may help to sustain protective galvanic interactions and that monitoring of Eh of leachates is potentially a useful indicator for predicting changes in acid generation behavior. Refereed/Peer-reviewed

Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decisionmaking. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC.Das Lungenkarzinom ist weiterhin die häufigste zum Tode führende Krebserkrankung in Deutschland und durch eine frühe Metastasierung charakterisiert. Die systemische Therapie insbesondere des metastasierten, nicht kleinzelligen Lungenkarzinoms (NSCLC) hat sich in den letzten Jahren insbesondere durch die Identifikation von behandelbaren molekularen Alterationen und durch Einführung neuer Medikamente wie Tyrosinkinaseinhibitoren und Immunmodulatoren deutlich erweitert. Diese raschen Veränderungen der therapeutischen Möglichkeiten stellen auch eine Herausforderung für den behandelnden Arzt dar und erfordern neue diagnostische Vorgehensweisen sowie die Bildung molekular, histologisch oder klinisch definierter Patientensubgruppen. Zudem werden supportive Möglichkeiten immer bedeutsamer. Mit der Therapieempfehlung soll ein kurzer Überblick über aktuelle Therapieentwicklungen beim metastasierten NSCLC gegeben werden.

The effective control and treatment of acid mine drainage (AMD) from sulfide-containing mine wastes is of fundamental importance for current and future long-term sustainable and cost-effective mining industry operations, and for sustainable management of legacy AMD sites. Historically, AMD management has focused on the use of expensive neutralising chemicals to treat toxic leachates. Accordingly, there is a need to develop more cost-effective and efficient methods to prevent AMD at source. Laboratory kinetic leach column experiments, designed to mimic a sulfide-containing waste rock dump, were conducted to assess the potential of organic waste carbon supplements to stimulate heterotrophic microbial growth, and supress pyrite oxidation and AMD production. Microbiological results showed that the addition of biosolids was effective at maintaining high microbial heterotroph populations and preventing AMD generation over a period of 80 weeks, as verified by leachate chemistry and electron microscopy analyses. This research contributes to the ongoing development of a cost effective, multi-barrier geochemical-microbial control strategy for reduced mineral sulfide oxidation rates at source. Refereed/Peer-reviewed

A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.

In Europe, in addition to Borrelia burgdorferi sensu lato and tick-borne encephalitis (TBE) virus, other zoonotic pathogens, like B. miyamotoi, a species related to the relapsing fever spirochaetes, Candidatus Neoehrlichia mikurensis (N. mikurensis), Rickettsia helvetica, Rickettsia monacensis, and Anaplasma phagocytophilum have been reported in the ixodid tick Ixodes ricinus. No study was conducted to identify reservoir hosts for these pathogens. Here, we investigated the role played by wild rodents in the natural transmission cycle of B. miyamotoi, N. mikurensis, R. helvetica, R. monacensis, and A. phagocytophilum in Switzerland. In 2011 and 2012, small mammals were captured in an area where these pathogens occur in questing ticks. Ixodes ricinus ticks infesting captured small mammals were analysed after their moult by PCR followed by reverse line blot to detect the different pathogens. Xenodiagnostic larvae were used to evaluate the role of rodents as reservoirs and analysed after their moult. Most of the 108 captured rodents (95.4%) were infested by I. ricinus ticks; 4.9%, 3.9%, 24.0%, and 0% of the rodents were infested by Borrelia, N. mikurensis, Rickettsia spp., and A. phagocytophilum-infected larvae, respectively. Borrelia afzelii, B. miyamotoi, N. mikurensis, Rickettsia spp., and A. phagocytophilum were detected in 2.8%, 0.17%, 2.6%, 6.8%, and 0% of the ticks attached to rodents, respectively. Borrelia afzelii was transmitted by 4 rodents to 41.2% of the xenodiagnostic ticks, B. miyamotoi by 3 rodents to 23.8%, and N. mikurensis was transmitted by 6 rodents to 41.0% of the xenodiagnostic ticks. None of the tested rodent transmitted Rickettsia spp. or A. phagocytophilum to I. ricinus xenodiagnostic larvae. This study showed that rodents are reservoir hosts for B. miyamotoi and N. mikurensis in Europe.