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Cholelithiasis and cholecystitis affect individuals of all ages and are often treated by surgical removal of the gallbladder (cholecystectomy), which is considered a safe, low-risk procedure. Nevertheless, recent findings show that bile and its regulated storage and excretion may have important metabolic effects and that cholecystectomy is associated with several metabolic diseases postoperatively. Bile acids have long been known as emulsifiers essential to the assimilation of lipids and absorption of lipid-soluble vitamins, but more recently, they have also been reported to act as metabolic signaling agents. The nuclear receptor, farnesoid X receptor (FXR), and the G protein–coupled membrane receptor, Takeda G protein–coupled receptor 5 (TGR5), are specific to bile acids. Through activation of these receptors, bile acids control numerous metabolic functions. Cholecystectomy affects the storage and excretion of bile acids, which in turn may influence the activation of FXR and TGR5 and their effects on metabolism including processes leading to metabolic conditions such as metabolic dysfunction–associated steatotic liver disease and metabolic syndrome. Here, with the aim of elucidating mechanisms behind cholecystectomy-associated dysmetabolism, we review studies potentially linking cholecystectomy and bile acid–mediated metabolic effects and discuss possible pathophysiological mechanisms behind cholecystectomy-associated dysmetabolism. [ABSTRACT FROM AUTHOR]

One of the prerequisites for successful organ xenotransplantation is a reasonable size match between the porcine organ and the recipient's organ to be replaced. Therefore, the selection of a suitable genetic background of source pigs is important. In this study, we investigated body and organ growth, cardiac function, and genetic diversity of a colony of Auckland Island pigs established at the Center for Innovative Medical Models (CiMM), LMU Munich. Male and female Auckland Island pig kidney cells (selected to be free of porcine endogenous retrovirus C) were imported from New Zealand, and founder animals were established by somatic cell nuclear transfer (SCNT). Morphologically, Auckland Island pigs have smaller body stature compared to many domestic pig breeds, rendering their organ dimensions well‐suited for human transplantation. Furthermore, echocardiography assessments of Auckland Island pig hearts indicated normal structure and functioning across various age groups throughout the study. Single nucleotide polymorphism (SNP) analysis revealed higher runs of homozygosity (ROH) in Auckland Island pigs compared to other domestic pig breeds and demonstrated that the entire locus coding the swine leukocyte antigens (SLAs) was homozygous. Based on these findings, Auckland Island pigs represent a promising genetic background for organ xenotransplantation. [ABSTRACT FROM AUTHOR]

External effects can be triggered through trade and depend on the locations of buyers and sellers who are matched. Inspired by electricity markets, we experimentally investigate markets in which net trades between two locations induce social costs. Based on a modified double auction setting, we compare the performance of market platforms that are location-blind with those where information on the location of (potential) trading partners or the level of the externality is given. We demonstrate that locational information is sufficient to reduce the externality. Imposing the full external costs on individual trades leads to maximal price differentiation between locations and further reduces net trades, while welfare improvements are limited. Reasons for not achieving the typically high efficiency of double auctions are discussed. [ABSTRACT FROM AUTHOR]

We report experimental findings on distribution decisions by Germans and Egyptians. We explore their sensitivity along three different dimensions: we study (i) the impact of the price of giving, (ii) how giving responds to the cultural and gender identity of the recipient, and (iii) how a threat of rejection in a bargaining situation affects the distribution choice. We show substantial differences in generosity between participants in Egypt vs. Germany, the former showing substantial equality-seeking behavior. Correspondingly, both genders in Egypt increase giving when it becomes more costly as do German females, in contrast to German males who give particularly when it is cheap. While Egyptian participants choose according to an equality norm independently of the recipient's identity, we detect substantial discrimination by German females when giving to Egyptian males. This discrimination is in line with prejudice as males in Egypt give significantly more than what Germans expect from them. Conversely, males in Egypt overestimate the generosity of Germans towards them. We finally show that, relative to giving in the dictator game, the ultimatum game offers increase among German participants, but not among participants in Egypt. Females in Egypt even decrease giving in UG relative to DG when allocating to males in Egypt. This finding is in line with highly favorable offers being rejected by a substantial fraction of participants in Egypt. [ABSTRACT FROM AUTHOR]

Wie können Medienangebote, Medienrezeption sowie aktive Medienbeteiligung zu einem guten gelingenden, glücklichen Leben beitragen? Dieser Frage wird im Kontext allgemeiner, soziologischer und psychologischer Glücks- und Zufriedenheitsforschung bezogen auf die Lebensphasen Kindheit, Jugend-, Erwachsenen- und Seniorenalter nachgegangen. Aufgezeigt wird die zentrale Rolle der Förderung von Selbstregulationsfähigkeiten und der Erfüllung menschlicher Grundbedürfnisse wie denjenigen nach Autonomie, Kompetenzerleben und Zugehörigkeit durch Mediengebrauch als vermittelnde Faktoren, die das Wohlbefinden situativ oder langfristig steigern können. Abschließend wird übergreifend diskutiert, wo Grenzen und Chancen der Steigerung des Wohlbefindens qua Medien zu verorten sind. [ABSTRACT FROM AUTHOR]

Abstract: During a shield TBM excavation in hard rock, the immediate backfill of the crown immediately behind the shield is technically difficult to realize. With the advance of the cutter head a relocation process of pea gravel within the annular gap is triggered, leading to an insufficient bedding distribution of the first segments behind the shield tail and to an ovalization of the segmental lining at a certain load level. During a test application as part of an ”TBM research initiative“ of the Austrian Federal Railways geotextile tubes were integrated into the exterior surface of the segments. Immediately after leaving the shield tail, the geotextile tube, which is placed all around one ring of segments, is expanded by injection with grout. As a result, an immediate bedding between the rock mass and segmental lining is established, also preventing the rearrangement of pea gravel within the annular gap when the shield is moved forward. The displacement measurements have shown that the ring of segments equipped with geotextile tubes experiences a more rigid body motion like behaviour after leaving the shield tail with a minimal ovalization only. Numerical simulations show the influence of bedding improvement on the ovalization of the ring of segments after leaving the shield tail. [ABSTRACT FROM AUTHOR]

We test the value of unconditional non-monetary gifts as a way to improve health worker performance in a low income country health setting. We randomly assigned health workers to different gift treatments within a program that visited health workers, measured performance and encouraged them to provide high quality care for their patients. We show that unconditional non-monetary gifts improve performance by 20 percent over a six-week period, compared to the control group. We compare the impact of the unconditional gift to one in which a gift is offered conditional on meeting a performance target and show that only the unconditional gift results in a statistically significant improvement. This demonstrates that organizations can improve the performance of health workers in the medium term without using financial incentives. [ABSTRACT FROM AUTHOR]

By means of a laboratory experiment we investigate the role of risk preferences for prosocial behavior. Modifying the way the decision-maker or the recipient are exposed to risk, our design allows to identify how risk preferences impact giving-decisions. By measuring the decision-makers’ risk preferences regarding both their own as well as the recipients’ payoff, we generate new insights into how social preference theories may extend to risky situations. [ABSTRACT FROM AUTHOR]

We systematically explore the impact of transparency and punishment on cooperation in the provision of public goods. Motivated by problems of embezzlement, we study variations of a public goods game where one player (the official ) may embezzle from an existing public good, while others ( citizens ) can only contribute. We show that transparency induces increased embezzlement in the absence of a punishment mechanism. The qualitative impact of transparency on contributions to the public good is reversed when a punishment mechanism is introduced. We identify stigmatization of the official when actions are not transparent. Only a combination of transparency of actions and peer-punishment options creates full accountability and increases contributions by all players. [ABSTRACT FROM AUTHOR]

We analyze the impact of ratification constraints on the optimal terms of international environmental agreements (IEAs). For this, we combine the literature on IEAs with the public choice literature on two-level games. By also incorporating uncertain preferences of the pivotal voter in the ratification stage, we make several important contributions: (i) we contribute to a more realistic modeling of the temporal structure of international agreements, (ii) we show a surprising, yet intuitive non-monotonic relationship between the optimal commitment level and the variance of ratification decisions, (iii) we identify reasons to expect a larger number of countries to join international negotiations than predicted by most of the coalition formation literature based on a representative agent model. Ratification constraints thereby can improve the welfare gains from stable international agreements. [ABSTRACT FROM AUTHOR]

Two fluorescein-labeled pyridinylimidazoles were synthesized and evaluated as probes for the binding affinity determination of potential kinase inhibitors to the c-Jun N-terminal kinase 3 (JNK3) and p38α mitogen-activated protein kinase (MAPK). Fluorescence polarization (FP)-based competition binding assays were developed for both enzymes using 1-(3′,6′-dihydroxy-3-oxo-3 H -spiro[isobenzofuran-1,9′-xanthen]-5-yl)-3-(4-((4-(4-(4-fluorophenyl)-2-(methylthio)-1 H -imidazol-5-yl)pyridin-2-yl)amino)phenyl)thiourea ( 5 ) as an FP probe (JNK3: K d = 3.0 nM; p38α MAPK: K d = 5.7 nM). The validation of the assays with known inhibitors of JNK3 and p38α MAPK revealed that both FP assays correlate very well with inhibition data received by the activity assays. This, in addition to the viability of both FP-based binding assays for the high-throughput screening procedure, makes the assays suitable as inexpensive prescreening protocols for JNK3 and p38α MAPK inhibitors. [ABSTRACT FROM AUTHOR]

We target the gatekeeper MET146 of c-Jun Nterminal kinase 3 (JNK3) to exemplify the applicability of X---S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QMcalculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cc of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%). [ABSTRACT FROM AUTHOR]

We report experimental findings on the role of social information and esteem for prosocial behavior of clinicians in Tanzania. For this we conduct a lab experiment on variants of a dictator game, which allows us to classify types of clinicians by their responses to being chosen by their partner and to knowing more about the person they are paired with. We link this lab data to the effort exerted by the same sample of clinicians to their patients in the field. We show that clinicians who are responsive both to information and to being chosen in the lab exert more average effort in the field. Responsiveness to being chosen is also correlated with a smaller variance of effort in the field, while variance is larger for clinicians who respond to social information. Our combination of lab and field results suggests that behavioral traits identified in the lab are informative of clinician’ choices in their actual workplace. [ABSTRACT FROM AUTHOR]

Exemptions from costly policy measures are frequently applied to alleviate financial burdens on specific market participants. Using a stated-choice experiment with around 6000 German household heads, we test how exemptions for low-income households and energy-intensive companies influence the political feasibility of additional cost for the promotion of renewable energies. We find that the policy support is substantially higher when low-income households are exempt rather than the industry. Introducing exemptions for low-income households on top of existing exemptions for the industry increases the acceptability of the policy. We show that the support for exemptions as one example of distributional policy design is associated with individual behavioral measures like inequality aversion and fairness perceptions. [ABSTRACT FROM AUTHOR]

Phosphotungstic acid (H3PW12O40 6H2O) was immobilized within a hierarchically structured silica matrix by sol-gel inclusion using polyethylene oxide as a phase separation initiator (one-pot synthesis). The macropore size of the SiO2-HPW composites was controlled by the polymer content. The hierarchically structured catalysts with different HPW loadings were tested against their counterparts with monomodal pore size distribution, applying the dehydration of glycerol as a test reaction. The catalysts with bimodal pore size distribution showed a significantly better long-term stability. The improved performance was attributed to their balanced acidity, excellent leaching stability, and enhanced mass transfer within the hierarchically structured pore system. [ABSTRACT FROM AUTHOR]

We investigate how burden sharing rules impact the voluntary provision of a public good which generates heterogeneous benefits to agents. We compare different rule-based contribution schemes where agents can first suggest a minimum provision level of the public good, before the smallest common denominator is implemented. We find that rule-based contribution schemes significantly increase payoff levels relative to the VCM, while significant differences exist between the rules. Importantly, the equal-payoff rule maximizes payoffs for all player types. This also holds relative to a scheme where different types of players separately can determine their minimum contribution levels. Our results lend insights into the efficient institutional design for voluntary private provision of public goods, and how burden sharing rules interact with efficiency when agents are heterogeneous. [ABSTRACT FROM AUTHOR]

Abstract: We study the introduction of new technologies when their costs are subject to idiosyncratic uncertainty and can only be fully learned through individual experience. We set up a dynamic model of clean experience goods that replace old polluting consumption options and show how optimal regulation evolves over time. In our base setting where social and private learning incentives coincide, the optimal tax on the polluting consumption is increasing over time. We show, however, that if social and private learning incentives diverge because the private discount rate exceeds the social discount rate, it may be optimal to temporarily increase the tax rate beyond net marginal external damages to induce more learning before reducing the tax rate to the steady state level. Alternatively, one could complement the tax with subsidies for first-time users which can be phased out over time. Similar results apply if consumers have biased expectations. We therefore give a rationale for introductory subsidies on new, clean technologies and non-monotonic tax paths from a perspective of consumer learning. [Copyright &y& Elsevier]

Highlights: [•] First study on actual prisoners’ behavior in Prisoners’ Dilemma situations. [•] Compare cooperation rates of inmates with those of students. [•] Higher cooperation among prisoners than among students in simultaneous PD game. [•] Identical conditional cooperation in sequential PD game. [ABSTRACT FROM AUTHOR]

The authors propose a novel approach to analyze core—periphery models. By expressing the model in terms of relative wages, the authors characterize market equilibria and full equilibria in which no migration incentives exist. The authors reconsider Krugman’s model and show that full equilibria are determined by a single function of relative nominal wage rates. This allows them to analytically derive the stability properties of all full equilibria. They further show that migration is more driven by differences in the price index than by differences in the nominal wage rate. [ABSTRACT FROM PUBLISHER]

Abstract: We study bidding behavior in first- and second-price sealed-bid auctions with loss-averse agents. Our model predicts overbidding in first-price induced-value auctions consistent with evidence from most laboratory experiments. Substantially different bidding behavior could result in commodity auctions where money and auction item are consumed along different dimensions of the consumption space. Differences also result in second-price auctions. Our study thereby indicates that transferring qualitative behavioral findings from induced-value laboratory experiments to the field may be problematic if subjects are loss-averse. [Copyright &y& Elsevier]

For many Philippine provinces, decentralization and more autonomous local development planning did not lead to the desired outcomes. This article examines the experiences of the two provinces of Cebu and Leyte. While Cebu became a centre of trade and industry, Leyte is still struggling with its local economy oriented to natural resources. A main reason for the divergent development paths of the two islands can be found in the emergence of different elite structures, which resulted in different path-dependent patterns of economic specialization. Despite this different historical experience, both provinces today suffer from similar institutional infirmities in their planning system for promoting local development. Local planning capacity constraints, such as regional and local co-ordination and co-operation patterns, local finances, human capital and knowledge are analysed. The Cebuano elites used the room for manoeuvre provided by decentralization reforms more successfully than elites in Leyte. This created pockets of efficiency in Cebu leading to more development-friendly investment policies. In order to increase local and regional planning capacity, short-term interventions and policy reforms at the local, regional and national level are discussed. [ABSTRACT FROM AUTHOR]

The identification of tumor-specific proteins located at the plasma membrane is hampered by numerous methodological pitfalls many of which are associated with the post-translational modification of such proteins. Here, we present a new combination of detergent fractionation of cells and of subtractive suppression hybridization (SSH) to gain overexpressed genes coding for membrane-associated or secreted proteins. Fractionation of subcellular components by digitonin allowed sequestering mRNA of the rough Endoplasmatic reticulum and thereby increasing the percentage of sequences coding for membrane-bound proteins. Fractionated mRNAs from the cutaneous T-cell lymphoma (CTCL) cell line HuT78 and from normal peripheral blood monocytes were used for SSH leading to the enrichment of sequences overexpressed in the tumor cells. We identified some 21 overexpressed genes, among them are GPR137B, FAM62A, NOMO1, HSP90, SLIT1, IBP2, CLIF, IRAK and ARC. mRNA expression was tested for selected genes in CTCL cell lines, skin specimens and peripheral blood samples from CTCL patients and healthy donors. Several of the detected sequences are clearly related to cancer, but have not yet been associated with CTCL. qPCR confirmed an enrichment of these mRNAs in the rough endoplasmic reticulum fraction. RT-PCR confirmed the expression of these genes in skin specimens and peripheral blood of CTCL patients. Western blotting verified protein expression of HSP90 and IBP2 in HuT78. GPR137B could be detected by immunohistology in HuT78 and in keratinocytes of dysplastic epidermis, but also in sweat glands of healthy skin. In summary, we developed a new technique, which allows identifying overexpressed genes coding preferentially for membrane-associated proteins. [ABSTRACT FROM AUTHOR]

We present how uncertainty and learning are classically studied in economic models. Specifically, we study a standard expected utility model with two sequential decisions, and consider two particular cases of this model to illustrate how uncertainty and learning may affect climate policy. While uncertainty has generally a negative effect on welfare, learning has always a positive, and thus opposite, effect. The effects of both uncertainty and learning on decisions are less clear. Neither uncertainty nor learning can be used as a general argument to increase or reduce emissions today without studying the specific intertemporal costs and benefits. Considering limits in applying the expected utility framework to climate change problems, we then consider a more recent framework with ambiguity-aversion which accounts for situations of imprecise or multiple probability distributions. We discuss both the impact of ambiguity-aversion on decisions and difficulties in applying such a non-expected utility framework to a dynamic context. [ABSTRACT FROM AUTHOR]

Abstract: The reaction of Cp*2NbBH4 (Cp*=η5-C5Me5) with Ru3(CO)12 gave a mixture of compounds, from which only [Cp*2Nb(CO)2]2[Ru6(CO)16C] (1) could be characterized by spectroscopic and crystallographic methods. 11B NMR spectroscopy proved that interstitial boron may be present in other Ru6 clusters, but these compounds did not crystallize. The reaction of Cp*2NbBH4 with Co2(CO)8 gave among others the salts [Cp*2Nb(CO)2]2[Co6(CO)15C] (4) and [Cp*2Nb(CO)2]3[Co13(CO)24C2] (5), which were examined by X-ray diffraction studies. The true nature of the interstitial atoms in 5 was deduced from electrochemical investigations, which reveal similar redox properties as for the already known [Co13(CO)24C2]3− anion. [Copyright &y& Elsevier]

The reaction of [Cp2*Rh2Cl4] (Cp* = C5Me5) with a slight excess of K3SbS3 in boiling THF gave the neutral clusters [Cp4*Rh4S5] (1), [Cp3*Rh3Sb2S5] (2), and after salt metathesis [Cp3*Rh3SbSn]PF6 (3; n = 5 and 6). The structures of 1-3 are heterocubane clusters with Cp*Rh, S, and Sb vertices but with sulfur inserted into one (1 and 2) or two (3) edges. X-ray diffraction analysis of 2 additionally reveals a very shod Sb-S distance of 2.297(1) Å within the novel μ3-Sb2S4 ligand. Density functional theory calculation of the model compounds [SSbS]3-, [HSSbS]2-, and [HSSbH2S]0 provided strong evidence for the existence of a stable terminal Sb=S double bond in 2. [ABSTRACT FROM AUTHOR]

The reaction of K3SbS3 with [Cp*2Co2I4] (Cp*=C5Me5) gave dark brown [Cp*3Co3(μ3-S)(μ3-SbS4I)] (1) in 22% yield. Complex 1 was characterized by 1H-NMR and mass spectra. The crystal structure determination reveals as the central feature a distorted Co3SbS4 cube with the fifth sulfur atom being inserted into one of the three Sb&z.sbnd;S edges. The coordination sphere around the Sb atom in the unprecedented tripodal ψ-Sb(S2)S2-ligand is extended by a weakly coordinated iodine atom [d(Sb&z.sbnd;I)=3.215(1) A˚]. [Copyright &y& Elsevier]

• Comparative evolutionary genomics has revealed that novel protein coding genes can emerge randomly from non-coding DNA. • The existence of de novo proteins seems at odds with decade-long attempts to construct proteins with novel structures and functions from scratch. • Recent results show that sequence properties of these de novo proteins are indistinguishable from randomly obtained sequences. • A better understanding of de novo proteins may fuel new strategies for protein design. Comparative evolutionary genomics has revealed that novel protein coding genes can emerge randomly from non-coding DNA. While most of the myriad of transcripts which continuously emerge vanish rapidly, some attain regulatory regions, become translated and survive. More surprisingly, sequence properties of de novo proteins are almost indistinguishable from randomly obtained sequences, yet de novo proteins may gain functions and integrate into eukaryotic cellular networks quite easily. We here discuss current knowledge on de novo proteins, their structures, functions and evolution. Since the existence of de novo proteins seems at odds with decade-long attempts to construct proteins with novel structures and functions from scratch, we suggest that a better understanding of de novo protein evolution may fuel new strategies for protein design. [ABSTRACT FROM AUTHOR]

Interoception is the sense of the physiological condition of the entire body. Impaired interoception has been associated with aberrant activity of the insula in major depressive disorder (MDD) during heartbeat perception tasks. Despite clinical relevance, studies investigating interoceptive impairments in MDD have never been reviewed systematically according to the guidelines of the PRISMA protocol, and therefore we collated studies that assessed accuracy in detecting heartbeat sensations (interoceptive accuracy, IAc) in MDD (databases: PubMed/Medline, PsycINFO, and PsycARTICLES). Out of 389 records, six studies met the inclusion criteria. The main findings suggest that (i) moderately depressed samples exhibit the largest interoceptive deficits as compared with healthy adults. (ii) difficulties in decision making and low affect intensity are correlated with low IAc, and (iii) IAc seems to normalize in severely depressed subjects. These associations may be confounded by sex, anxiety or panic disorder, and intake of selective serotonin reuptake inhibitors. Our findings have implications for the development of interoceptive treatments that might relieve MDD-related symptoms or prevent relapse in recurrent depression by targeting the interoceptive nervous system. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal musculature and myocardium. In DMD patients and in a corresponding pig model with a deletion of DMD exon 52 (DMDΔ52), expression of an internally shortened dystrophin can be achieved by skipping of DMD exon 51 to reframe the transcript. To predict the best possible outcome of this strategy, we generated DMDΔ51-52 pigs, additionally representing a model for Becker muscular dystrophy (BMD). DMDΔ51-52 skeletal muscle and myocardium samples stained positive for dystrophin and did not show the characteristic dystrophic alterations observed in DMDΔ52 pigs. Western blot analysis confirmed the presence of dystrophin in the skeletal muscle and myocardium of DMDΔ51-52 pigs and its absence in DMDΔ52 pigs. The proteome profile of skeletal muscle, which showed a large number of abundance alterations in DMDΔ52 vs. wild-type (WT) samples, was normalized in DMDΔ51-52 samples. Cardiac function at age 3.5 mo was significantly reduced in DMDΔ52 pigs (mean left ventricular ejection fraction 58.8% vs. 70.3% in WT) but completely rescued in DMDΔ51-52 pigs (72.3%), in line with normalization of the myocardial proteome profile. Our findings indicate that ubiquitous deletion of DMD exon 51 in DMDΔ52 pigs largely rescues the rapidly progressing, severe muscular dystrophy and the reduced cardiac function of this model. Long-term follow-up studies of DMDΔ51-52 pigs will show if they develop symptoms of the milder BMD. [ABSTRACT FROM AUTHOR]

We study a principal‐agent relationship between a politician and a researcher that captures stylized facts regarding the involvement of politics into scientific research. The politician has some ideal policy that he would like to implement, but needs to contract with a researcher to choose a policy that is supported by scientific advice. We study the implemented contracts under symmetric and under asymmetric information about the researcher's ability and concern for reputation, and discuss with which types of researchers the politician will contract. We identify several conflicts between the interests of voters and those of the politician. (JEL D72, D82, D83) [ABSTRACT FROM AUTHOR]

Halogen bonding has been known in material science fordecades,but until recently, halogen bonds in protein–ligand interactionswere largely the result of serendipitous discovery rather than rationaldesign. In this Perspective, we provide insights into the phenomenonof halogen bonding, with special focus on its role in drug discovery.We summarize the theoretical background defining its strength anddirectionality, provide a systematic analysis of its occurrence andinteraction geometries in protein–ligand complexes, and giverecent examples where halogen bonding has been successfully harnessedfor lead identification and optimization. In light of these data,we discuss the potential and limitations of exploiting halogen bondsfor molecular recognition and rational drug design. [ABSTRACT FROM AUTHOR]

Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipresent carbonyls of the protein backbone. We characterize energetics and directionality and elucidate their spatial variability in sub-optimal geometries that are expected to occur in protein-ligand complexes featuring a multitude of concomitant interactions. By deriving simple rules, we aid medicinal chemists and chemical biologists in easily exploiting them for scaffold decoration and design. Our work shows that carbonyl-halogen bonds may be used to expand the patentable medicinal chemistry space, redefining halogens as key features. Furthermore, this data will be useful for implementing halogen bonds into pharmacophore models or scoring functions making the QM information available for automatic molecular recognition in virtual high throughput screening. [ABSTRACT FROM AUTHOR]

Reimplementation of an EU-wide emissions trading system by means of National Allocation Plans is at the core of the European environmental policy agenda. EU Member States must allocate their national emission budgets under the EU Burden Sharing Agreement between energy-intensive sectors that are eligible for European emissions trading and the remaining segments of their economies that will be subject to complementary domestic emission regulation. We show that such hybrid emission regulation may lead to substantial excess costs compared to a comprehensive emissions trading system covering all segments of the economy. Furthermore, the hybrid system associated with the current design of National Allocation Plans is likely to discriminate against sectors that are not part of the emissions trading scheme. The interested reader can make use of a web-based interactive simulation model in order to specify and evaluate alternative settings of the EU emissions trading system. [ABSTRACT FROM AUTHOR]

The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to our well validated pyridinylimidazole scaffold varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the number of off-targets. The most promising covalent inhibitor, the tetrasubstituted imidazole 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (7) inhibits the JNK3 in the subnanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes, and displays excellent selectivity in a screening against a panel of 410 kinases. Covalent bond formation to Cys-154 was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry. [ABSTRACT FROM AUTHOR]

With the use of tunnel boring machines under different geological and geotechnical conditions, the support with precast elements has been state of the art for decades. For the verification of the load-bearing and deformation behaviour of these high-strength reinforced concrete elements under exact known loading conditions, a test rig has been developed and implemented in a cooperation between experts of Austrian Federal Railways (ÖBB-Infrastruktur AG, SAE Fachbereich Bautechnik/Tunnelbau) and the Montanuniverität Leoben (Chair of Subsurface Engineering). The newly developed segment test rig allows biaxial tests on real segments. Due to the modular construction it is feasible to test segments with different geometries and dimensions. The obtained findings should be included in the optimization of these elements. Furthermore, the optimisation of the reinforcement design and replacement of steel bar reinforcement with fibre reinforcement is being investigated. With this test rig, an important step has been taken towards new technologies and materials in the field of segment linings. Currently, tests with distributed fibre optic sensing systems are carried out in cooperation with the Graz University of Technology (Institute of Engineering Geodesy and Measurement Systems - IGMS). A fibre optic sensing cable can be embedded in the segment during production and used for lifelong in-situ deformation measurements of the segment. Bei einem kontinuierlichen Vortrieb mit Tunnelvortriebsmaschinen zählt der Ausbau des aufgefahrenen Hohlraums mit Tübbingen seit Jahrzehnten zum Stand der Technik. Zur Verifizierung des Trag- und Verformungsverhaltens der Tübbinge bei unterschiedlichen geologischen und geotechnischen Verhältnissen unter definierten Belastungs- und Auflagerbedingungen wurde in enger Kooperation zwischen der ÖBB-Infrastruktur AG (SAE Fachbereich Bautechnik/Tunnelbau) und dem Lehrstuhl für Subsurface Engineering der Montanuniversität Leoben ein Prüfstand geplant und realisiert, der biaxiale Versuche an Tübbingen ermöglicht. Durch den modularen Aufbau ist das Prüfen von unterschiedlichen Tübbinggeometrien sowie -abmessungen möglich. Die daraus gewonnenen Erkenntnisse sollen in die Tübbingoptimierung einfließen. Unter anderem sollen Optimierungen des Bewehrungsdesigns und die mögliche Verwendung von Faserbewehrung untersucht werden. Zukünftig bietet dieser Prüfstand neue Prüfmöglichkeiten zur Weiterentwicklung des Tübbingausbaus und dessen Materialien. Derzeit werden Versuche mit faseroptischen Messsystemen in Kooperation mit dem Institut für Ingenieurgeodäsie und Messsysteme (IGMS) der Technischen Universität Graz durchgeführt. Das faseroptische Sensorkabel wird während der Herstellung in den Tübbing eingebettet und kann zur In-situ-Deformationsmessungen über die gesamte Lebensdauer des Tübbings genutzt werden. [ABSTRACT FROM AUTHOR]

Monolithic forms are particularly suitable when using porous carbon materials in flow through apparatus. One method to synthesize these materials is the template-assisted synthesis. Porous carbon monoliths have been prepared using porous concrete as a template. Systematic investigations of the mechanical stability have shown the potential of these materials for technical applications. It could be proven that the monoliths are stable against compressive stress and flow-through of water, respectively. [ABSTRACT FROM AUTHOR]

Machine learning has been used for estimation of potential energy surfaces to speed up molecular dynamics simulations of small systems. We demonstrate that this approach is feasible for significantly larger, structurally complex molecules, taking the natural product Archazolid A, a potent inhibitor of vacuolar-type ATPase, from the myxobacterium Archangium gephyra as an example. Our model estimates energies of new conformations by exploiting information from previous calculations via Gaussian process regression. Predictive variance is used to assess whether a conformation is in the interpolation region, allowing a controlled trade-off between prediction accuracy and computational speed-up. For energies of relaxed conformations at the density functional level of theory (implicit solvent, DFT/BLYP-disp3/def2-TZVP), mean absolute errors of less than 1 kcal/mol were achieved. The study demonstrates that predictive machine learning models can be developed for structurally complex, pharmaceutically relevant compounds, potentially enabling considerable speed-ups in simulations of larger molecular structures. [ABSTRACT FROM AUTHOR]

Learning - i.e. the acquisition of new information that leads to changes in our assessment of uncertainty - plays a prominent role in the international climate policy debate. For example, the view that we should postpone actions until we know more continues to be influential. The latest work on learning and climate change includes new theoretical models, better informed simulations of how learning affects the optimal timing of emissions reductions, analyses of how new information could affect the prospects for reaching and maintaining political agreements and for adapting to climate change, and explorations of how learning could lead us astray rather than closer to the truth. Despite the diversity of this new work, a clear consensus on a central point is that the prospect of learning does not support the postponement of emissions reductions today. [ABSTRACT FROM AUTHOR]

Learning — i.e. the acquisition of new information that leads to changes in our assessment of uncertainty — plays a prominent role in the international climate policy debate. For example, the view that we should postpone actions until we know more continues to be influential. The latest work on learning and climate change includes new theoretical models, better informed simulations of how learning affects the optimal timing of emissions reductions, analyses of how new information could affect the prospects for reaching and maintaining political agreements and for adapting to climate change, and explorations of how learning could lead us astray rather than closer to the truth. Despite the diversity of this new work, a clear consensus on a central point is that the prospect of learning does not support the postponement of emissions reductions today. [ABSTRACT FROM AUTHOR]