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This paper presents a frequency domain analysis of spurious tones in frequency dividers. The results of the analysis are used to develop an event-driven model for system simulations which work entirely in the frequency domain. The proposed approach is able to provide a fast and accurate model in a SystemVerilog/C++ environment which takes the frequency conversion effects of the spurious tones into account. A virtual prototype which includes the model was simulated and due to the fast simulation speed it was possible to determine the influence of spurious tones on the bit error rate in a complex receive scenario.

Agriculture is the largest global consumer of water. Irrigated areas constitute 40 % of the total area used for agricultural production (FAO, 2014a) Information on their spatial distribution is highly relevant for regional water management and food security. Spatial information on irrigation is highly important for policy and decision makers, who are facing the transition towards more efficient sustainable agriculture. However, the mapping of irrigated areas still represents a challenge for land use classifications, and existing global data sets differ strongly in their results. The following study tests an existing irrigation map based on statistics and extends the irrigated area using ancillary data. The approach processes and analyzes multi-temporal normalized difference vegetation index (NDVI) SPOT-VGT data and agricultural suitability data – both at a spatial resolution of 30 arcsec – incrementally in a multiple decision tree. It covers the period from 1999 to 2012. The results globally show a 18 % larger irrigated area than existing approaches based on statistical data. The largest differences compared to the official national statistics are found in Asia and particularly in China and India. The additional areas are mainly identified within already known irrigated regions where irrigation is more dense than previously estimated. The validation with global and regional products shows the large divergence of existing data sets with respect to size and distribution of irrigated areas caused by spatial resolution, the considered time period and the input data and assumption made.

Abstract Whole-genome sequencing studies of parent–offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.

Abstract De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 × 10− 8 per bp). DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks.

This paper presents the results of thirty-seven interviews of senior library leaders at American Association of University (AAU) institutions conducted in Spring 2023. The author replicated a 2016 study from "portal," revealing an increased focus on strategic plan-based decision-making along with new priorities of open scholarship and diversity, equity, and inclusion (DEI). The COVID-19 pandemic had a drastic impact on staffing and budgets, requiring academic library leaders to balance internal operations and external collaboration. A younger, more diverse AAU library leadership population achieves success through strong advocacy to campus leadership and the inclusive leadership practices outlined in this paper.

The hygroscopic properties of atmospheric aerosols are highly relevant for the quantification of radiative effects in the atmosphere, but also of interest for the assessment of particle health effects upon inhalation. This article reports measurements of aerosol particle hygroscopicity in the highly polluted urban atmosphere of Beijing, China in January 2005. The meteorological conditions corresponded to a relatively cold and dry atmosphere. Three different methods were used: 1) A combination of Humidifying Differential Mobility Particle Sizer (H-DMPS) and Twin Differential Mobility Particle Sizer (TDMPS) measurements, 2) A Hygroscopic Tandem Differential Mobility Analyzer (H-TDMA), and 3) A simplistic solubility model fed by chemical particle composition determined from Micro Orifice Uniform Deposit Impactor (MOUDI) samples. From the H-DMPS and TDMPS particle number size distributions, a size-resolved descriptive hygroscopic growth factor (DHGF) was determined for the relative humidities (RH) 55%, 77% and 90%, and particle diameters between 30 and 400 nm. In Beijing, the highest DHGFs were observed for accumulation mode particles, 1.40 (±0.03) at 90% RH. DHGF decreased significantly with particle size, reaching 1.04 (±0.15) at 30 nm. H-TDMA data also suggest a decrease in growth factor towards the biggest particles investigated (350 nm), associated with an increasing fraction of nearly hydrophobic particles. The agreement between the H-DMPS/TDMPS and H-TDMA methods was satisfactory in the accumulation mode size range (100–400 nm). In the Aitken mode range (

Graft-versus-Host Disease (GvHD) is the most serious complication of allogeneic stem cell transplantation (SCT) and results from an activation of donor lymphocytes by recipient antigen-presenting cells (APCs). For a long time, it has been postulated that the intestinal microflora and endotoxin exert a crucial step in this APC activation, as there is early and severe gastrointestinal damage induced by pretransplant conditioning. With the detailed description of pathogen-associated molecular patterns and pathogen recognition receptors single nucleotide polymorphisms of TLRs and especially NOD2 have been identified as potential risk factors of GvHD and transplant related complications thus further supporting the crucial role of innate immunity in SCT, related complications. Gastrointestinal decontamination and neutralization of endotoxin have been used to interfere with this early axis of activation with some success but more specific approaches of modulation of innate immunity are needed for further improvement of clinical outcome.

Abstract Background Larvicides are critical for the control of mosquito-borne diseases. However, even sublethal exposure to a larvicide can alter development and life history traits, which can then affect population density and disease transmission dynamics. Photosensitive insecticides (PSIs) are a promising class of larvicide that are toxic when ingested and activated by light. We investigated whether the time of day when exposure occurs, or the process of pupation, affects larval susceptibility to PSI phototoxicity in the mosquito Anopheles gambiae, and whether sublethal exposure to PSIs alters life history traits. Methods Larvae were treated with lethal concentrations of the PSIs methylene blue (MB) and rose bengal (RB), and larval survival was measured at various times of day. Additionally, larvae were exposed to two concentrations of each PSI that resulted in low and medium mortality, and the life history traits of the surviving larvae were measured. Results Pupation, which predominantly occurs in the evening, protected larvae from PSI toxicity, but the toxicity of PSIs against larvae that had yet to pupate was unaffected by time of day. Larval exposure to a sublethal concentration of MB, but not RB, shortened the time to pupation. However, larval exposure to a sublethal concentration of RB, but not MB, increased pupal mortality. Neither PSI had a meaningful effect on the time to eclosion, adult longevity, or adult melanization potential. Conclusions PSIs are lethal larvicides. Sublethal PSI exposure alters mosquito development, but does not affect adult life history traits. Graphical Abstract

The rising interest and success in deploying inherited microorganisms and cytoplasmic incompatibility (CI) for vector control strategies necessitate an explanation of the CI mechanism. Wolbachia-induced CI manifests in the form of embryonic lethality when sperm from Wolbachia-bearing testes fertilize eggs from uninfected females. Embryos from infected females however survive to sustain the maternally inherited symbiont. Previously in Drosophila melanogaster flies, we demonstrated that CI modifies chromatin integrity in developing sperm to bestow the embryonic lethality. Here, we validate these findings using wMel-transinfected Aedes aegypti mosquitoes released to control vector-borne diseases. Once again, the prophage WO CI proteins, CifA and CifB, target male gametic nuclei to modify chromatin integrity via an aberrant histone-to-protamine transition. Cifs are not detected in the embryo, and thus elicit CI via the nucleoprotein modifications established pre-fertilization. The rescue protein CifA in oogenesis localizes to stem cell, nurse cell, and oocyte nuclei, as well as embryonic DNA during embryogenesis. Discovery of the nuclear targeting Cifs and altered histone-to-protamine transition in both Aedes aegypti mosquitoes and D. melanogaster flies affirm the Host Modification Model of CI is conserved across these host species. The study also newly uncovers the cell biology of Cif proteins in the ovaries, CifA localization in the embryos, and an impaired histone-to-protamine transition during spermiogenesis of any mosquito species. Overall, these sperm modification findings may enable future optimization of CI efficacy in vectors or pests that are refractory to Wolbachia transinfections.

IntroductionHead and neck squamous cell carcinoma (HNSCC) patients suffer from frequent local recurrences that negatively impact on prognosis. Hence, distinguishing tumor and normal tissue is of clinical importance as it may improve the detection of residual tumor tissue in surgical resection margins and during imaging-based surgery planning. Differences in O2 consumption (OC) can be used to this aim, as they provide options for improved surgical, image-guided approaches.MethodsIn the present study, the potential of a fluorescent sensor foil-based technology to quantify OC in HNSCC was evaluated in an in vitro 3D model and in situ in patients. ResultsIn vitro measurements of OC using hypopharyngeal and esophageal cell lines allowed a specific detection of tumor cell spheroids embedded together with cancer-associated fibroblasts in type I collagen extracellular matrix down to a diameter of 440 µm. Pre-surgery in situ measurements were conducted with a handheld recording device and sensor foils with an oxygen permeable membrane and immobilized O2-reactive fluorescent dyes. Lateral tongue carcinoma and carcinoma of the floor of the mouth were chosen for analysis owing to their facilitated accessibility. OC was evaluated over a time span of 60 seconds and was significantly higher in tumor tissue compared to healthy mucosa in the vicinity of the tumor.DiscussionHence, OC quantification using fluorescent sensor foil-based technology is a relevant parameter for the differentiation of tumor tissue of the head and neck region and may support surgery planning.

Group contribution (GC) methods to predict thermochemical properties are eminently important to process design. Following earlier work which presented a GC model in which, for the first time, chemical accuracy (1 kcal/mol or 4 kJ/mol) was accomplished, we here discuss classes of molecules for which the traditional GC approach does not hold, i.e., many results are beyond chemical accuracy. We report new ring-strain-related parameters which enable us to evaluate the heat of formation of alkyl-substituted cycloalkanes. In addition, the definition of the appropriate group size is important to obtain reliable and accurate data for systems in which the electron density varies continuously but slowly between related species. For this and in the case of ring strain, G4 quantum calculations are shown to be able to provide reliable heats of formation which provide the quantitative data which we can use, in the case of absence of experimental data, to establish group and nearest-neighbour interaction parameters to extend the range of applicability of the GC method whilst retaining chemical accuracy. We also found that the strong van der Waals that overlap in highly congested branched alkanes can be qualitatively investigated by applying DFT quantum calculations, which can provide an indication of the GC approach being inappropriate.

Summary: The lacZ gene of Escherichia coli encodes β-galactosidase (β-gal), a lactose metabolism enzyme of the lactose operon. Previous chemical modification or site-directed mutagenesis experiments have identified 21 amino acids that are essential for β-gal catalytic activity. We have assembled over 10,000 lacZ mutations from published studies that were collected using a positive selection assay to identify mutations in lacZ that disrupted β-gal function. We analyzed 6,465 independent lacZ mutations that resulted in 2,732 missense mutations that impaired β-gal function. Those mutations affected 492 of the 1,023 lacZ codons, including most of the 21 previously known residues critical for catalytic activity. Most missense mutations occurred near the catalytic site and in regions important for subunit tetramerization. Overall, our work provides a comprehensive and detailed map of the amino acid residues affecting the structure and catalytic activity of the β-gal enzyme.

In clinical practice, the distinction between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) can be challenging, leaving patients with “ambiguous” diabetes type. Insulin-treated patients (n=115) previously diagnosed with T2DM had to be re-classified based on clinical phenotype and laboratory results, and were operationally defined as having an ambiguous diabetes type. They were compared against patients with definite T1DM and T2DM regarding 12 clinical and laboratory features typically different between diabetes types. Characteristics of patients with ambiguous diabetes type, representing approximately 6% of all patients with T1DM or T2DM seen at our specialized clinic, fell in between those of patients with definite T1DM and T2DM, both regarding individual features and with respect to a novel classification based on multi-variable regression analysis (P

Abstract Cardiovascular outcomes trials (CVOTs) with novel drugs to treat type 2 diabetes have uniformly chosen the composite “major adverse cardiovascular events (MACE)” as their primary endpoint, but they also report hazard ratios for individual cardiovascular outcomes (myocardial infarction, stroke, cardiovascular death, all-cause death, hospitalization for heart failure). We wanted to scrutinize the power to identify significant differences with respect to individual as compared to composite outcomes. We estimated post hoc the statistical power to detect significant differences of 10–25% for published studies, comparing the proportions of patients with an event (two-sided log-rank tests). For MACE, the power to detect a 15% difference ranged from 82.3 to 100.0% for larger trials, but was only 69.1 and 50.5 for smaller, preliminary trials (SUSTAIN-6 and PIONEER-6). For individual endpoints, the power, as a rule, was substantially lower. In conclusion, cardiovascular outcomes trials had appropriate power to detect significant reductions in hazard ratios with respect to the primary endpoint, but not for individual cardiovascular outcomes. This was particularly the case for small, preliminary studies. Our results call for caution when comparing results regarding individual endpoints between CVOTs, if the aim is to identify heterogeneity within or between medication classes.

Group contribution (GC) methods to predict thermochemical properties are eminently important to process design. We report on a GC parametrization for the heat of formation of organic molecules exhibiting chemical accuracy, i.e., a maximum 1 kcal/mol (4.2 kJ/mol) difference between experimental and model values, whilst having a minimum number of parameters to avoid overfitting. We report an extension of recent findings to chloro-alkanes, fluoro-hydrocarbons, benzylhalides, nitro-alkanes, and acetals. Compared to the existing literature, we obtained a superior model exhibiting chemical accuracy, with exceptions when the inherent GC assumption on linearity and additivity is not valid. Moreover, to have a reliable method and not only a low absolute average deviation as reported in most publications, we accepted no or exceptionally few outliers. The example of the 1,3-dioxolane acetals revealed that by adopting the appropriate size of a group representing the acetal leads to a model showing good accuracy. The overall conclusion of the three papers on this topic is that it is feasible to achieve chemical accuracy when using high-quality experimental data and the judicious definition of chemical groups. Despite the GC method being old, the present work shows substantial and necessary increase in performance can still be achieved.

Group Contribution (GC) methods to predict thermochemical properties are eminently important in chemical process design. Following our earlier work in which a Group Contribution (GC) model was presented to account for the gas-phase heat of formation of organic molecules which, for the first time, revealed chemical accuracy (1 kcal/mol or 4 kJ/mol), we here present Group Contribution parameters for a range of additional series of molecules allowing the application to a wider range of molecules whilst, mostly, retaining chemical accuracy. The new classes of molecules include amines, alkylesters, and various substituted benzenes, including t-butyl-benzenes, phenols, methoxybenzenes, anilines, benzaldehydes, and acetophenones, and finally furans and indoles/indolines. As in our previous works on this theme, again the critical selection of experimental data was crucial. Not meeting the criterion for chemical accuracy occurred when steric interactions such as nearest neighbour substituents on a benzene ring were present, something which does not fit with the characteristics of the Group Contribution method. We also report some cases for which the experimental value does not seem correct, but where both the G4 and GC model values agree well. In general, in line with accounts in the literature, the G4 method performs really well. Contrary to other related works, we have applied conformational averaging to obtain a slightly more realistic G4 result. Although the difference is generally only a few kJ/mol, this may still be relevant when attempting the development of a model with chemical accuracy, e.g., 4.2 kJ/mol.

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The Syrian hamster (SH) is an animal model used in virology, toxicology, and carcinogenesis, where a better understanding of epigenetic mechanisms is required. Finding genetic loci regulated by DNA methylation may assist in the development of DNA methylation-based in vitro assays for the identification of carcinogens. This dataset informs on the regulation of gene expression by DNA methylation. Primary cultures of SH male fetal cells (sex determined by differences in kdm5 loci on the X and Y chromosome) were exposed for 7 days to the carcinogen benzo[a]pyrene (20 µM) from which a morphologically transformed colony was collected and reseeded. The colony bypassed senescence and sustained growth. After 210 days of culture, the cells were collected and divided in 16 aliquots to create 4 experimental groups to test the effects of the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5adC). The experiment was initiated 24 h after cell seeding in 10 cm plates. The groups are naïve cells (N), cells exposed for 48 h to either 0.05% DMSO as vehicle (V), or to 5adC at 1 µM and 5 µM. DNA and RNA libraries were sequenced on an Illumina NextSeq 500. Gene expression was analysed by RNAseq and differentially methylated DNA regions (DMRs: clusters of 200 base pairs (bp), read depth >20, q< 0.05, methylation difference >|25%|) were identified by reduce representation bisulfite sequencing (RRBS). Global genome DNA methylation was similar between the N (mean±SD, 47.3%±0.02) and V groups (47.3%±0.01). Although 5adC reduced methylation, the reduction was larger in the 1 µM (39.2%±0.002) than in the 5 µM group (44.3%±0.01). 5adC induced a total of 612 and 190 DMRs by 1 µM and 5 µM, among which 79 and 23 were in the promoter regions (±3,000 bp from the transcription start site), respectively. 5adC induced a total of 1,170 and 1,797 differentially expressed genes (DEGs) by 1 µM and 5 µM, respectively. The 5 µM treatment induced statistically significant toxicity (% cell viability: group N 97%±8, V 98.8%±1.3, 1 µM 97.3%±0.5, 5 µM 93.8%±1.5), which perhaps reduced cell division and daughter cell numbers with inherited changes in methylation, but increased number of DEGs due to both toxicity and methylation changes. As usually observed in the literature, a small portion of DEGs (4% and 4% at 1 µM and 5 µM, respectively) are associated with DMRs in their promoters. These promoter DMRs by themselves are sufficient among other epigenetic marks to induce DEGs. The dataset provides the genomic coordinates of the DMRs and an opportunity to further examine their roles in distal putative promoters or enhancers (yet to be described in the SH) in contributing to gene expression changes, senescence bypass and sustained proliferation as essential carcinogenic events (see companion paper [1]). Finally, this experiment confirms the possibility in future experiments to use 5adC as a positive control for effects on DNA methylation in cells derived from SH.

The growing number of chemicals in the current consumer and industrial markets presents a major challenge for regulatory programs faced with the need to assess the potential risks they pose to human and ecological health. The increasing demand for hazard and risk assessment of chemicals currently exceeds the capacity to produce the toxicity data necessary for regulatory decision making, and the applied data is commonly generated using traditional approaches with animal models that have limited context in terms of human relevance. This scenario provides the opportunity to implement novel, more efficient strategies for risk assessment purposes. This study aims to increase confidence in the implementation of new approach methods in a risk assessment context by using a parallel analysis to identify data gaps in current experimental designs, reveal the limitations of common approaches deriving transcriptomic points of departure, and demonstrate the strengths in using high-throughput transcriptomics (HTTr) to derive practical endpoints. A uniform workflow was applied across six curated gene expression datasets from concentration-response studies containing 117 diverse chemicals, three cell types, and a range of exposure durations, to determine tPODs based on gene expression profiles. After benchmark concentration modeling, a range of approaches was used to determine consistent and reliable tPODs. High-throughput toxicokinetics were employed to translate in vitro tPODs (µM) to human-relevant administered equivalent doses (AEDs, mg/kg-bw/day). The tPODs from most chemicals had AEDs that were lower (i.e., more conservative) than apical PODs in the US EPA CompTox chemical dashboard, suggesting in vitro tPODs would be protective of potential effects on human health. An assessment of multiple data points for single chemicals revealed that longer exposure duration and varied cell culture systems (e.g., 3D vs. 2D) lead to a decreased tPOD value that indicated increased chemical potency. Seven chemicals were flagged as outliers when comparing the ratio of tPOD to traditional POD, thus indicating they require further assessment to better understand their hazard potential. Our findings build confidence in the use of tPODs but also reveal data gaps that must be addressed prior to their adoption to support risk assessment applications.

Abstract Background Individuals with type 1 diabetes and those with depression show differences in the composition of the gut microbiome from that of healthy people. However, these differences have not yet been studied in patients with both diseases. Therefore, we compared the gut microbiome of people with type 1 diabetes with or without depression with matched healthy controls. Methods A case-control study was conducted in 20 adults with type 1 diabetes (group A), 20 adults with type 1 diabetes and depression (group B), and 20 healthy adults (group C). Gut microbiota composition was determined by sequencing of the V3-V4 region of the bacterial 16S rDNA and alpha and beta diversity was compared between the groups. Results Groups A and B both showed higher alpha diversity than the healthy control group (P

We study the generation of two-qudit entangling quantum logic gates using two techniques in quantum optimal control. We take advantage of both continuous, Lie algebraic control and digital, Lie group control. In both cases, the key is access to a time-dependent Hamiltonian, which can generate an arbitrary unitary matrix in the group SU(d^{2}). We find efficient protocols for creating high-fidelity entangling gates. As a test of our theory, we study the case of qudits robustly encoded in nuclear spins of alkaline earth atoms and manipulated with magnetic and optical fields, with entangling interactions arising from the well-known Rydberg blockade. We applied this in a case study based on a d=10 dimensional qudit encoded in the I=9/2 nuclear spin in ^{87}Sr, controlled through a combination of nuclear spin resonance, a tensor ac-Stark shift, and Rydberg dressing, which allows us to generate an arbitrary symmetric entangling two-qudit gate, such as CPhase. Our techniques can be used to implement qudit entangling gates for any 2≤d≤10 encoded in the nuclear spin. We also studied how decoherence due to the finite lifetime of the Rydberg states affects the creation of the CPhase gate and found, through numerical optimization, a fidelity of 0.9985, 0.9980, 0.9942, and 0.9800 for d=2, d=3, d=5, and d=7, respectively. This provides a powerful platform to explore the various applications of quantum information processing of qudits, including metrological enhancement with qudits, quantum simulation, universal quantum computation, and quantum error correction.

The conventional battery for genotoxicity testing is not well suited to assessing the large number of chemicals needing evaluation. Traditional in vitro tests lack throughput, provide little mechanistic information, and have poor specificity in predicting in vivo genotoxicity. New Approach Methodologies (NAMs) aim to accelerate the pace of hazard assessment and reduce reliance on in vivo tests that are time-consuming and resource-intensive. As such, high-throughput transcriptomic and flow cytometry-based assays have been developed for modernized in vitro genotoxicity assessment. This includes: the TGx-DDI transcriptomic biomarker (i.e., 64-gene expression signature to identify DNA damage-inducing (DDI) substances), the MicroFlow® assay (i.e., a flow cytometry-based micronucleus (MN) test), and the MultiFlow® assay (i.e., a multiplexed flow cytometry-based reporter assay that yields mode of action (MoA) information). The objective of this study was to investigate the utility of the TGx-DDI transcriptomic biomarker, multiplexed with the MicroFlow® and MultiFlow® assays, as an integrated NAM-based testing strategy for screening data-poor compounds prioritized by Health Canada’s New Substances Assessment and Control Bureau. Human lymphoblastoid TK6 cells were exposed to 3 control and 10 data-poor substances, using a 6-point concentration range. Gene expression profiling was conducted using the targeted TempO-Seq™ assay, and the TGx-DDI classifier was applied to the dataset. Classifications were compared with those based on the MicroFlow® and MultiFlow® assays. Benchmark Concentration (BMC) modeling was used for potency ranking. The results of the integrated hazard calls indicate that five of the data-poor compounds were genotoxic in vitro, causing DNA damage via a clastogenic MoA, and one via a pan-genotoxic MoA. Two compounds were likely irrelevant positives in the MN test; two are considered possibly genotoxic causing DNA damage via an ambiguous MoA. BMC modeling revealed nearly identical potency rankings for each assay. This ranking was maintained when all endpoint BMCs were converted into a single score using the Toxicological Prioritization (ToxPi) approach. Overall, this study contributes to the establishment of a modernized approach for effective genotoxicity assessment and chemical prioritization for further regulatory scrutiny. We conclude that the integration of TGx-DDI, MicroFlow®, and MultiFlow® endpoints is an effective NAM-based strategy for genotoxicity assessment of data-poor compounds.

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We established a group contribution (GC) parametrization for the heat of formation of organic molecules, but, and this is new, revealed chemical accuracy (1 kcal/mol). Compared to previous approaches which did not achieve this result, we succeeded by (i) taking reliable and consistent experimental data, (ii) not relying on computer-assisted automated parameter estimation, (iii) taking into account the physico-chemistry known for years, i.e., only introducing additional parameters when we understand the physico-chemistry, and finally, (iv) acknowledging that the linear additive GC method has its limits and cannot account properly for any molecule. Not only the averaged absolute deviations but also the individual results were almost without exception within chemical accuracy, except for some more heavily substituted molecules for which the group contribution approach breaks down.

The authors here present geodetic and seismic data for a complete eruptive cycle (2005-2018) for Sierra Negra volcano, Galapagos Island. The data shows the largest pre-eruptive inflation (6.5 m) and rates of seismicity ever observed before a basaltic eruption and provides a rare illustration of caldera resurgence mechanisms.

Glia are involved in remodelling of neural circuits during development. Here, the authors show that FMRP is required within neurons to activate glial insulin receptor to facilitate Draper- and Shrub-dependent neuronal clearance during neurodevelopment in Drosophila.

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Insecticides reduce the spread of mosquito-borne disease. Over the past century, mosquito control has mostly relied on neurotoxic chemicals—such as pyrethroids, neonicotinoids, chlorinated hydrocarbons, carbamates and organophosphates—that target adults. However, their persistent use has selected for insecticide resistance. This has led to the application of progressively higher amounts of insecticides—known as the pesticide treadmill—and negative consequences for ecosystems. Comparatively less attention has been paid to larvae, even though larval death eliminates a mosquito’s potential to transmit disease and reproduce. Larvae have been targeted by source reduction, biological control, growth regulators and neurotoxins, but hurdles remain. Here, we review methods of mosquito control and argue that photoactive molecules that target larvae—called photosensitive insecticides or PSIs—are an environmentally friendly addition to our mosquitocidal arsenal. PSIs are ingested by larvae and produce reactive oxygen species (ROS) when activated by light. ROS then damage macromolecules resulting in larval death. PSIs are degraded by light, eliminating environmental accumulation. Moreover, PSIs only harm small translucent organisms, and their broad mechanism of action that relies on oxidative damage means that resistance is less likely to evolve. Therefore, PSIs are a promising alternative for controlling mosquitoes in an environmentally sustainable manner.

Higher-throughput, mode-of-action-based assays provide a valuable approach to expedite chemical evaluation for human health risk assessment. In this study, we combined the high-throughput alkaline DNA damage-sensing CometChip® assay with the TGx-DDI transcriptomic biomarker (DDI = DNA damage-inducing) using high-throughput TempO-Seq®, as an integrated genotoxicity testing approach. We used metabolically competent differentiated human HepaRG™ cell cultures to enable the identification of chemicals that require bioactivation to cause genotoxicity. We studied 12 chemicals (nine DDI, three non-DDI) in increasing concentrations to measure and classify chemicals based on their ability to damage DNA. The CometChip® classified 10/12 test chemicals correctly, missing a positive DDI call for aflatoxin B1 and propyl gallate. The poor detection of aflatoxin B1 adducts is consistent with the insensitivity of the standard alkaline comet assay to bulky lesions (a shortcoming that can be overcome by trapping repair intermediates). The TGx-DDI biomarker accurately classified 10/12 agents. TGx-DDI correctly identified aflatoxin B1 as DDI, demonstrating efficacy for combined used of these complementary methodologies. Zidovudine, a known DDI chemical, was misclassified as it inhibits transcription, which prevents measurable changes in gene expression. Eugenol, a non-DDI chemical known to render misleading positive results at high concentrations, was classified as DDI at the highest concentration tested. When combined, the CometChip® assay and the TGx-DDI biomarker were 100% accurate in identifying chemicals that induce DNA damage. Quantitative benchmark concentration (BMC) modeling was applied to evaluate chemical potencies for both assays. The BMCs for the CometChip® assay and the TGx-DDI biomarker were highly concordant (within 4-fold) and resulted in identical potency rankings. These results demonstrate that these two assays can be integrated for efficient identification and potency ranking of DNA damaging agents in HepaRG™ cell cultures.

The ever-increasing burden of type 2 diabetes mellitus (T2DM) worldwide, has led to the emergence of several antidiabetes drugs with different modes of action. Incretin hormones and their effect on glucose metabolism and pathogenesis of T2DM has been a landmark discovery in the management of this increasingly prevalent metabolic disorder. Glucagon like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are the two major classes of incretin-based therapies that regulate glucose mechanism through multiple pathways, demonstrate weight loss (GLP-1 receptor agonists) or a weight-neutral effect (DPP-4 inhibitors), and are associated with a low risk of hypoglycaemia and other adverse events. In addition, evidence reflects their possible therapeutic potential in the treatment of other clinical conditions such as obesity, cardiovascular disease and liver disorders. This review explores the availability and the impact of GLP-1 receptor agonists and DPP-4 inhibitors as potential therapeutic strategies for T2DM along with their future in the landscape of diabetes management and other clinical conditions.

In the last decades, the spread of Elymus athericus has caused significant changes to the plant community composition and ecosystem services of European marshes. The distribution of E. athericus was typically limited by soil conditions characteristic for high marshes, such as low flooding frequency and high soil aeration. However, recently the spread of E. athericus has begun to also include low-marsh environments. A high-marsh ecotype and a low-marsh ecotype of E. athericus have been described, where the latter possess habitat-specific phenotypic traits facilitating a better adaption for inhabiting low-marsh areas. In this study, planar optodes were applied to investigate plant-mediated sediment oxygenation in E. athericus, which is a characteristic trait for marsh plants inhabiting frequently flooded environments. Under waterlogged conditions, oxygen (O2) was translocated from aboveground sources to the roots, where it leaked out into the surrounding sediment generating oxic root zones below the sediment surface. Oxic root zones were clearly visible in the optode images, and no differences were found in the O2-leaking capacity between ecotypes. Concentration profiles measured perpendicular to the roots revealed that the radius of the oxic root zones ranged from 0.5 to 2.6 mm measured from the root surface to the bulk anoxic sediment. The variation of oxic root zones was monitored over three consecutive light–dark cycles (12 h/12 h). The O2 concentration of the oxic root zones was markedly reduced in darkness, yet the sediment still remained oxic in the immediate vicinity of the roots. Increased stomatal conductance improving the access to atmospheric O2 as well as photosynthetic O2 production are likely factors facilitating the improved rhizosphere oxygenation during light exposure of the aboveground biomass. E. athericus’ capacity to oxygenate its rhizosphere is an inheritable trait that may facilitate its spread into low-marsh areas. Furthermore, this trait makes E. athericus a highly competitive species in marshes facing the effects of accelerated sea-level rise, where waterlogged sediment conditions could become increasingly pronounced.

Despite the benefits of early and effective glycemic control in the management of type 2 diabetes (T2D), achieving glycated hemoglobin (HbA1c) targets is challenging in some patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide effective reductions in HbA1c and body weight. Semaglutide is the only GLP-1RA that is available in both an injectable and oral formulation. The efficacy of once-weekly subcutaneous semaglutide and once-daily oral semaglutide has been investigated in the global SUSTAIN and PIONEER phase III clinical trial programs in a range of clinical settings, including early T2D managed with diet and exercise only, more established T2D uncontrolled on one to three oral antidiabetic drugs, and advanced disease treated with insulin. Across the SUSTAIN program, once-weekly subcutaneous semaglutide 1.0 mg reduced HbA1c by 1.5–1.8% after 30–56 weeks, which was significantly more than sitagliptin, liraglutide, exenatide extended release, dulaglutide, canagliflozin, or insulin glargine. Across the PIONEER program, once-daily oral semaglutide 14 mg reduced HbA1c by 1.0–1.4%, significantly more than sitagliptin or empagliflozin, and to a similar extent as liraglutide after 26 weeks. In addition, subcutaneous semaglutide reduced body weight significantly more than all active comparators tested, while oral semaglutide reduced body weight more than sitagliptin and liraglutide, and to a similar extent as empagliflozin. Neither formulation of semaglutide has been associated with an increased risk of hypoglycemia and both improve various measures of health-related quality of life. Semaglutide offers the benefits of a highly effective GLP-1RA in both injectable and oral formulations. Selection of the most appropriate formulation can be made on an individual basis to best suit the patient’s preferences and needs.

Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review: To summarize current knowledge about GLP-1 receptor agonist. Major conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Cold atom quantum simulation has had challenges in realising the tailored, dynamic types of disorder relevant to real materials. Here, the authors use synthetic momentum-space lattices to engineer spatially and dynamically controlled disorder to observe ballistic, diffusive, and arrested atomic transport.