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Unlike cyclopropanes, the analogous B2C species (diboriranes) tend to adopt non‐classical Hückel‐aromatic structures with bridging moieties R between the boron atoms. The coordination of the thus generated cyclic 2e− π‐system to transition metals is completely unexplored. We here report that complexation of non‐classical diboriranes cyclo‐μ‐RB2Dur2CPh (R=H, SnMe3; Dur=2,3,5,6‐tetramethylphenyl) to Fe(CO)3 fragments allows for the carbonylative ring expansion of the B2C ring to either four‐ or five‐membered rings depending on the nature of the BRB 3‐center‐2‐electron bond (3c2e): The H‐bridged diborirane (R=H) initially reacts with Fe2(CO)9 to the allylic π‐complex with an agostic BH/Fe interaction. Subsequent formal hydroboration of CO from excess Fe2(CO)9 results in the side‐on ring expansion under formation of a five‐membered B2C2O ring, coordinated to the Fe(CO)3 moiety. In contrast, in case of the stannyl‐bridged diborirane (R=SnMe3) under the same conditions, CO is added end‐on to the B−B bond with the carbon terminus formally inserting into the B2Sn 3c2e‐bond. The two carbonylative ring expansion products can also be described as nido and closo clusters, respectively, according to the Wade‐Mingos rules. [ABSTRACT FROM AUTHOR]

Despite considerable interest in heteroatom‐containing conjugated polymers, there are only few examples with heavier p‐block elements in the conjugation path. The recently reported heavier acyclic diene metathesis (HADMET) allowed for the synthesis of a polymer containing Ge=Ge double bonds—albeit insoluble and with limited degree of polymerization. By incorporation of long alkyl chains, we now obtained soluble representatives, which exhibit degrees of polymerization near infinity according to diffusion‐ordered NMR spectroscopy (DOSY) and dynamic light scattering (DLS). UV/Vis and NMR data confirm the presence of σ,π‐conjugation across the silylene‐phenylene linkers between the Ge=Ge double bonds. Favorable intermolecular dispersion interactions lead to ladder‐like cylindrical assemblies as confirmed by X‐ray diffraction (XRD), small angle X‐ray scattering (SAXS) and DLS. AFM and TEM images of deposited thin films reveal lamellar ordering of extended polymer bundles. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A fluorenyl amido constrained geometry magnesium complex is described, which was obtained by deprotonation of the corresponding neutral ligand system with dibutyl magnesium. Its structure was determined by SC‐XRD and it was shown to be a potent catalyst for amine‐borane dehydrogenation/dehydrocoupling. [ABSTRACT FROM AUTHOR]

A series of triylenes of the heavy group 13 elements gallium, indium and thallium, carrying the pentaisopropylcyclopentadienyl ligand is reported. The compounds were characterized in solution and in the solid‐state and their donor ligand properties in heterobimetallic complexes were investigated, whereby a series of tungsten carbonyl complexes was isolated. Furthermore, a new synthetic route towards a previously described lithium‐aluminum heterobimetallic dimetallocene is reported, which also enabled the isolation of a heterobimetallic polydecker of lithium and gallium. [ABSTRACT FROM AUTHOR]

Nine different derivatives of piperidino alanes of the general formula (CH2)5N‐AlXY [X=Y=Cl (1), Br (2), I (3); X=(CH2)5N, Y=Cl (4), Br (5), I (6); X=H, Y=Cl (7), Br (8), I (9)] have been synthesized and compared with respect to their structures. All molecules form dimers with an Al2N2 central cycle and aluminum and nitrogen atoms in distorted tetrahedral environments as determined from X‐ray diffraction. The three dihalide derivatives 1, 2 and 3 have C2h (2/m) symmetries in solution of which they maintain the Centro symmetry in the crystal lattice. The bis(piperidino) derivatives 4, 5 and 6 have either C1 (1) symmetry with the bridging piperidino cycles oriented in the same direction (4, 5) or Ci (ī) point symmetry as found for 6 (in solution at least one other isomer is present). Whereas the chlorine derivative 7 has crystallographic Ci (ī) symmetry, the bromine 8 has almost C2 and the iodine 9 crystallographic C2 (2) point symmetry. In solution all derivatives 7, 8, 9 show equilibria between cis (C2) and trans (Ci) isomeric forms (27Al NMR). The longest Al−N bond lengths within the rings are found for 5 (1.969(4) Å) and the shortest for 8 (1.940(4) Å). The ratio of Al⋅⋅⋅Al to N⋅⋅⋅N non‐bonding distances in the almost square rings vary with the bulkiness of the terminal ligands at aluminum. [ABSTRACT FROM AUTHOR]

In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success. Currently, cancer screening in the general population is recommended for a limited set of cancers; as a result, most cancer types are not regularly screened. Thus, in recent years, we have seen a wave of novel, non‐invasive, single‐ and multi‐cancer detection tests (SCD and MCD), promising detection of cancer signals prior to the onset of symptoms and/or clinical diagnosis. To accelerate the development, access, and adoption of these tests, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices, established the Early Detection & Screening (ED&S) Working Group. The early detection space is in need of consensus around definitions for SCD and MCD tests that harmonize terminology across diverse stakeholders, thereby reducing communication barriers and ultimately advancing the discipline. To this end, the ED&S Working Group compiled a lexicon of terms, chosen based on perceived importance, frequency of use, lack of clarity, and unique challenges in the context of SCD and MCD tests. This lexicon was submitted to the FDA for their feedback, which was incorporated. In this work, we present the first installment of the lexicon, consisting of 14 primary terms, that will be part of an online dictionary and provide a foundation for future projects of BLOODPAC's ED&S Working Group. [ABSTRACT FROM AUTHOR]

BIM‐based assessment of sustainable maintenance measures for existing building structures In Germany, around 70 % of all building construction work is done on existing buildings. This high proportion emphasizes the need for the maintenance management of buildings. For this purpose, digital methods and technologies are combined with integrating sustainability aspects for optimized decision‐making. In this paper, a holistic method for the building maintenance is developed by using the BIM‐method in combination with the integration of sustainability aspects. Different digital technologies are combined within a semi‐automated workflow. In the first step, the status quo of digital maintenance on reinforced concrete structures is analyzed in a literature review. Subsequently, the process‐related and data‐technical basics are defined. Based on this, the concept development and validation are carried out by holding the steps ‐ data acquisition, an algorithmic data process and sustainability analysis as well as data provision via augmented reality and a common data environment. At the end, the process steps are validated using a real demonstrator. The result of the article demonstrates a semi‐automated process chain and decision support for resource‐efficient maintenance management of reinforced concrete structures. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to delineate 21‐year sex‐specific trends in recurrence and postrecurrence mortality. Methods: Between 2000 and 2020, first‐ever ischemic stroke (IS) patients, ascertained from the population‐based BASIC (Brain Attack Surveillance in Corpus Christi) project in South Texas, were followed for recurrent stroke and all‐cause mortality until December 31, 2020. Multivariable regression models with an interaction between calendar year and sex were used to estimate sex‐specific trends and sex differences in recurrence and postrecurrence mortality. Results: Of the 6,057 IS patients (median age = 69 years, 49.8% women), 654 (10.8%) had a recurrence and 399 (47.7%) had postrecurrence mortality during 5 years of follow‐up. In 2000, women had 2.5% higher albeit non‐statistically significant 5‐year risk of recurrence than men in absolute scale. With the trend declining in women by 7.6% (95% confidence interval [CI] = −10.8 to −4.5%) and in men by 3.6% (95% CI = −6.5% to −0.7%), the risk at the end of the study period was 1.5% (95% CI = −0.3% to 3.6%) lower among women than men. For postrecurrence mortality, the risk was 10.2% lower among women in 2000, but the sex difference was 3.3% by the end of the period, which was due to a larger overall increase in the risk among women than men over the entire time period. Interpretation: The declines in recurrent stroke suggest successful secondary stroke prevention, especially in women. However, the continued high postrecurrence mortality among both sexes at the end of study period emphasizes the need for ongoing interventions to improve prognosis in those who have had recurrent cerebrovascular events. ANN NEUROL 2024;96:332–342 [ABSTRACT FROM AUTHOR]

The synthesis of the phosphorus‐capped heptaphenylsilsesquioxane T7Ph7P is reported. We show that, unlike previous examples, it readily forms Lewis acid‐base adducts with boranes of different steric demand and the FeCO4 fragment. All complexes were characterized by multinuclear NMR and IR spectroscopy in solution and the solid state. The molecular structures of the adducts with BPh3 and B(C6F5)3 were determined from XRD suitable single crystals. The relative conformation of the Ph and C6F5 rings in T7Ph7P−B(C6F5)3 suggests favorable π‐interactions, stabilizing the adducts to such a degree that attempts to activate H2 or CO2 were unsuccessful. [ABSTRACT FROM AUTHOR]

Stainless steel (SST) is an important material for a variety of applications including construction, food, and medical. Highly hydrophobic wetting properties enhance the surface properties of SST to support processes such as self‐cleaning. However, applications also require long‐term stability of such properties against chemical and mechanical influences from the environment or technical processes. Therefore, the reduction of highly hydrophobicity of chemically modified, laser‐textured SST surfaces is investigated in relation to abrasive wear using hierarchical structures, micro‐/nanotextured surface, and support structures that shield the highly hydrophobic pattern. Surface textures comprising ridges, grooves (size: 50–500 μm; depth: up to 100 μm), and a nanostructured grooves bottom are machined by infrared ultrashort pulse laser ablation into SST and are subsequently chemically modified by a self‐assembled monolayer of a fluorinated, phosphonic acid‐modified alkane. Abrasive wear tests of these surfaces show decreasing water contact angles with increasing wear of the modified surface of the support structures. However, there is good stability of the highly hydrophobic properties due to the protection of modified areas at the groove bottom. The proposed wetting model for such designed functionalized laser textures shows possibilities for further optimization of such robust highly hydrophobic surfaces and adaptation to specific applications. [ABSTRACT FROM AUTHOR]

The National Aeronautics and Space Administration (NASA) has an ongoing Digital Transformation effort and to leverage and showcase the power of Digital Transformation, an effort is underway to develop an integrated, datacentric, model representing NASA's key process requirements. The task was divided into three phases: As Is modeling, Analysis, and To Be Planning. As part of this effort, a team has completed the first Phase I of the modeling task and is nearing completion of the second phase. This effort will capture the key elements as requirements, responsibilities, allocations, roles, products, and associated lifecycle elements. The scope of modeling included NASA's NPR 7120.5 (Project and Program Management), NPR 7123.1 (Systems Engineering) and NPRs 8705.2 (Risk classification for Robotic Missions) and 8705.4 (Human‐Rating Requirements for Space Missions). This paper will summarize the approach, scope, parsing patterns applied, metamodel, and associated workflows for the As‐Is modeling. It will also summarize the results and insights gleaned during that phase, including the review process. These insights have informed the analysis and will be discussed. The analysis modeling phase will also be summarized including how the stakeholders were engaged, how the common elements were handled and dispositioned, and will also describe some of the plans for the future of NASA NPDs and NPRs. [ABSTRACT FROM AUTHOR]

Atomically precise nanoclusters hold promise for supramolecular assembly and (opto)electronic‐ as well as magnetic materials. Herein, this work reports that treating palladium(0) precursors with a triphosphirane affords strongly colored Pd8(PDip)6 that is fully characterized by mass spectrometry, heteronuclear and Cross‐Polarization Magic‐Angle Spinning (CP‐MAS) NMR‐, infrared (IR), UV–vis, and X‐ray photoelectron (XP) spectroscopies, single‐crystal X‐Ray diffraction (sc‐XRD), mass spectrometry, and cyclovoltammetry (CV). This coordinatively unsaturated 104‐electron Pd(0) cluster features a cubic Pd8‐core, µ4‐capping phosphinidene ligands, and is air‐stable. Quantum chemical calculations provide insight to the cluster's electronic structure and suggest 5s/4d orbital mixing as well as minor Pd─P covalency. Trapping experiments reveal that cluster growth proceeds via insertion of Pd(0) into the triphosphirane. The unsaturated cluster senses ethylene and binds isocyanides, which triggers the rearrangement to a tetrahedral structure with a reduced frontier orbital energy gap. These experiments demonstrate facile cluster manipulation and highlight non‐destructive cluster rearrangement as is required for supramolecular assembly. [ABSTRACT FROM AUTHOR]

Purpose: Periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) presents significant challenges, especially in elderly and comorbid patients, often necessitating revision surgeries. We report on a series of patients with confirmed PJI of the knee and concomitant soft‐tissue/extensor apparatus defects, treated by using pedicled myocutaneous medial or lateral sural artery perforator (MSAP/LSAP) gastrocnemius flaps. Methods: Our retrospective study at the Center for Musculoskeletal Infections, included patients with knee PJI undergoing pedicled myocutaneous MSAP/LSAP gastrocnemius flap reconstruction for combined soft tissue and extensor apparatus defects. The tendinous back of the gastrocnemius muscle was used and, if required, the Achilles tendon for extensor apparatus reconstruction, with the skin island addressing the cutaneous defect. Perioperative complications and postoperative outcomes after 1 year were evaluated, including functional and clinical assessments with the American Knee Society Score (AKSS). Results: Eight patients (mean age 73 years; five female) were included, predominantly with Staphylococcus aureus infections. Six patients involved isolated MSAP flaps, two were extended with the Achilles tendon. The median time for wound healing was 9 days. Short‐term follow‐up showed successful reconstruction in seven patients, with minor wound dehiscence in one patient. One patient required flap revision for a perigenicular haemato‐seroma and two patients were diagnosed with new haematogenous PJI infection. Significant improvement in AKSS scores after surgery was observed (functional AKSS: median 33–85; clinical AKSS: median 64–91, p = 0.001). Conclusion: Pedicled myocutaneous MSAP/LSAP gastrocnemius flaps offer a safe, reliable and versatile option for reconstructing combined soft tissue and extensor apparatus defects in PJI after TKA. This approach yields excellent functional outcomes with minimal peri‐ and postoperative complications, which is particularly beneficial in elderly and comorbid patients and feasible in settings without microsurgical availability. Level of evidence: Level IV. [ABSTRACT FROM AUTHOR]

Objective: To explore the impact of attending a clinical placement in considering a career in obstetrics and gynaecology. Design: Mixed methods study. Setting: London Medical School. Population: Fifth year medical students attending a clinical placement in obstetrics and gynaecology. Methods: Between January 2021 and January 2022, questionnaires were used and semi‐structured focus groups conducted, which were audio‐recorded. Descriptive statistics were conducted and a framework analysis on transcribed focus groups. Main outcome measure: The impact of the clinical placement on career choice. Results: Six main themes were identified from the analysis; three contributing to considering a career in obstetrics and gynaecology; pregnancy is not an illness, extraordinary experience of observing childbirth and variable specialty and three themes emerged contributing to not considering a career; lack of work–life balance, high stakes specialty and the emotional toll. Even at an undergraduate level, medical students exhibited concerns about the long‐term feasibility of achieving work–life balance and avoiding professional burnout, which was partly attributed to the responsibility of looking after both the woman and their baby. Conclusions: Obstetrics and gynaecology is perceived as an exciting and variable speciality by medical students. Students' experiences on the labour ward during a clinical placement appear to contribute to the consideration of a career in obstetrics and gynaecology. Students should be given opportunities to discuss their concerns about obstetrics, particularly over the potential psychological impact of adverse/traumatic birth events. It is crucial to provide a realistic introduction to obstetrics, to recruit enthusiastic junior doctors who will be resilient to the pressures of the speciality, to avoid burnout and minimise attrition rates. Linked article: This article is commented on by Charles Weissman, pp.969 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471‐0528.17751. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. Methods: We describe an integrated whole‐exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. Results: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke‐associated Asian iCCAs. Conclusions: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease. [ABSTRACT FROM AUTHOR]

Cellular debris resulting from large trauma might overwhelm the scavenger mechanisms and lead to autoimmune reactions. We analysed whether a major well‐defined trauma in humans induces laboratory signs of transient autoimmunity in the months after the insult. We included 50 patients with pertrochanteric femur fracture undergoing intramedullary nail osteosynthesis in a prospective cohort study and followed them at 3–4 days, 6 weeks, 12 weeks and 12 months postoperatively. By standard techniques, we assessed levels of total immunoglobulins, anti‐nuclear antibodies (ANA), anti‐cardiolipin antibodies, anti‐dsDNA antibodies and anti‐C1q antibodies, as well as antibodies against cytomegalovirus (CMV) as a control. Blood leukocyte differential and lymphocyte subpopulations were determined at baseline and in the first two postoperative samples. The mean age of the patients reached 80.1 years, and 23 (46%) completed all visits. Serum concentrations of total IgG, IgM and IgA increased at all follow‐up time points. The ANA fluorescence light intensity units increased at 12 weeks and 12 months postoperatively (p < 0.0001), but the proportion of ANA‐positive patients did not change (35%). The values of anti‐C1q mildly increased at all follow‐up visits, but not the ratio to total IgG. Anti‐dsDNA remained negative in all patients, and anti‐cardiolipin IgG/IgM antibodies did not change. Anti‐CMV IgG antibodies increased significantly at all follow‐up visits, without change in the ratio to total IgG. Flow cytometry showed an increased proportion of B‐cells 3–4 days postoperatively. In conclusion, major musculoskeletal trauma in elderly patients induces a generalized non‐specific increase in immunoglobulin production without laboratory signs for enhanced systemic autoimmunity. [ABSTRACT FROM AUTHOR]

The natural product chlorotonil displays high potency against multidrug‐resistant Gram‐positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late‐stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur‐mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug‐resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fine particulate matter (PM2.5) contains carcinogens similar to those generated by tobacco smoking, which may increase the risks of developing smoking‐related cancers, such as upper aerodigestive track (UADT) cancers, for both smokers and never‐smokers. Therefore, it is imperative to understand the relation between ambient PM2.5 exposure and risk of UADT cancers. A population‐based case–control study involving 565 incident UADT cancer cases and 983 controls was conducted in Los Angeles County from 1999 to 2004. The average residential PM2.5 concentration 1 year before the diagnosis date for cases and the reference date for controls was assessed using a chemical transport model. The association between ambient PM2.5 and the UADT cancers was estimated by unconditional logistic regression, adjusting for confounders at the individual and block‐group level. Stratified analyses were conducted by sex, tobacco smoking status and UADT subsites. We also assessed the interaction between PM2.5 and tobacco smoking on UADT cancers. PM2.5 concentrations were associated with an elevated odds of UADT cancers (adjusted odds ratio = 1.21 per interquartile range [4.5 μg/m3] increase; 95% confidence interval: 1.02, 1.44). The association between PM2.5 and UADT cancers was similar across UADT subsites, sex and tobacco smoking status. The interaction between PM2.5 and tobacco smoking on UADT cancers was approximately additive on the odds scale. The effect estimate for PM2.5 and UADT cancers was similar among never smokers. Our findings support the hypothesis that exposure to PM2.5 increases the risk of UADT cancers. Improvements in air quality may reduce the risk of UADT cancers. [ABSTRACT FROM AUTHOR]

Large uncertainty exists in the sign of long‐term changes in regional scale mean precipitation across the current generation of global climate models. To explore the physical drivers of this uncertainty for New Zealand, here we adopt a storyline approach applying cluster analysis to spatial patterns of future projected seasonal mean precipitation change across CMIP6 models (n = 43). For the winter precipitation change signal, the models split roughly into two main groups: both groups have a very robust wet signal across the west coast of the South Island but differ notably in terms of the sign of precipitation change across the north of the North Island. These far north winter precipitation differences appear related to how far the Hadley cell edge and regional eddy‐driven jet shift across the models relative to their historical positions. In contrast, for summer, most models have a markedly weaker and spatially non‐uniform response, where internal variability often plays a large role. However, a small group of models predict a robust wet signal across most of the country in summer. This "wet model" group is characterized by a regional La Niña‐like increase in high pressure shifted further to the south‐east of New Zealand, associated with more frequent north‐easterly flow over the country and accompanied by significant warming of local sea surface temperatures. This regional circulation response appears related to changes in stationary Rossby wave paths as opposed to changes in La Niña occurrence frequency itself. Plain Language Summary: At the regional scale, future changes to mean precipitation under climate change could carry large societal consequences. Unfortunately, large uncertainties still exist on regional scales which may hinder climate change adaptation efforts. Here we explore and characterize these uncertainties across the latest generation of global climate models for the New Zealand region. Across the models, winter precipitation changes are shown to be much more consistent compared to summer precipitation changes. In winter, changes in the jet stream and Hadley cell edge positions in the models are important for determining the regional spatial patterns of precipitation change. In summer, internal variability uncertainty plays a larger role, models that predict robust wet changes across the country are associated with more north‐easterly flow conditions in the future period. Changes to Rossby wave pathways appear important for setting up this regional circulation response in summer. Key Points: Storylines are used to characterize and explain the main precipitation change patterns across modelsSpatial patterns of precipitation change are more robust in winter, inter‐model differences relate to Hadley cell and jet changesSpatial patterns of precipitation change are less robust in summer, internal variability and Rossby wave pathway changes are important [ABSTRACT FROM AUTHOR]

Oligo‐ and polysiloxanes are usually prepared by condensation reactions in solvents without control of stereochemistry. Here we present a solventless thermal condensation of stable organosilanols. We investigated the condensation reactions of organosilanediols with different organic substituents, having in common at least one aromatic group. The condensation kinetics of the precursors observed by NMR spectroscopy revealed a strong dependence on temperature, time, and substitution pattern at the silicon atom. SEC measurements showed that chain length increases with increasing condensation temperature and time and lower steric demand of the substituents, which also influences the glass transition temperatures (Tg) of the resulting oligo‐ or polymers. X‐ray diffraction studies of the crystalline silanediols and their condensation products revealed a structural correlation between the substituent location in the crystalline precursors and the formed macromolecules induced by the hydrogen bonding pattern. In certain cases, it is possible to carry out topotactic polymerization in the solid‐state, which has its origin in the crystal structure. [ABSTRACT FROM AUTHOR]

While smaller polyhedral oligomeric silsesquioxanes TnRn (POSS) are readily accessible or even commercially available, unambiguously authenticated larger systems (n>12) have barely been reported. Synthesis and isolation procedures are lengthy, and yields are often very low. Herein, we present the surprisingly straightforward and high‐yielding access to the phenyl‐substituted derivative of a so far only postulated second D3h‐symmetric T14 isomer and with that the largest crystallographically characterized POSS cage with organic substituents. Treatment of the commercially available incompletely condensed T7Ph7(OH)3 silsesquioxane with catalytic amounts of trifluoromethanesulfonic acid results in high yields of the T14Ph14 framework, which is isolated in crystalline form by a simple work‐up. D3h‐T14Ph14 was analyzed by single crystal X‐ray diffraction, multinuclear NMR spectroscopy and thermal analysis. The relative energies of all four theoretically possible T14Ph14 isomers were determined by optimization of the corresponding structure using DFT methods. [ABSTRACT FROM AUTHOR]

Aims: To test differential outcomes between three 6‐month text‐messaging interventions to reduce at‐risk drinking in help‐seeking adults. Design: A three‐arm single‐blind randomized controlled trial with 1‐, 3‐, 6‐ and 12‐month follow‐ups. Setting: United States. A fully remote trial without human contact, with participants recruited primarily via social media outlets. Participants: Seven hundred and twenty‐three adults (mean = 39.9 years, standard deviation = 10.0; 62.5% female) seeking to reduce their drinking were allocated to 6 months of baseline 'tailored statically' messaging (TS; n = 240), 'tailored adaptive' messaging (TA; n = 239) or 'drink tracking' messaging (DT; n = 244). Interventions: TS consisted of daily text messages to reduce harmful drinking that were tailored to demographics and alcohol use. TA consisted of daily, tailored text messages that were also adapted based on goal achievement and proactive prompts. DT consisted of a weekly assessment for self‐reported drinking over the past 7 days. Measurements The primary outcome measure was weekly sum of standard drinks (SSD) at 6‐month follow‐up. Secondary outcome measures included drinks per drinking day (DDD), number of drinking days (NDD) per week and heavy drinking days (HDD) at 1‐, 3‐, 6‐ and 12‐month follow‐ups. Findings At 6 months, compared with DT, TA resulted in significant SSD reductions of 16.2 (from 28.7 to 12.5) drinks [adjusted risk ratio (aRR) = 0.80, 95% confidence interval (CI) = 0.71, 0.91] using intent‐to‐treat analysis. TA also resulted in significant improvements in DDD (aRR = 0.84; 95% CI = 0.77–0.92) and drinking days per week (b = −0.39; 95% CI = −0.67, –0.10), but not HDD compared with DT at 6 months. TA was not significantly different from TS at any time‐point, except DDD at 6 months. All groups made improvements in SSD at 12‐month follow‐up compared with baseline with an average reduction of 12.9 drinks per week across groups. Conclusions: Automated tailored mobile messaging interventions are scalable solutions that can reduce weekly alcohol consumption in remote help‐seeking drinkers over time. [ABSTRACT FROM AUTHOR]

Domains known as von Willebrand factor type D (VWD) are found in extracellular and cell‐surface proteins including von Willebrand factor, mucins, and various signaling molecules and receptors. Many VWD domains have a glycine‐aspartate‐proline‐histidine (GDPH) amino‐acid sequence motif, which is hydrolytically cleaved post‐translationally between the aspartate (Asp) and proline (Pro). The Fc IgG binding protein (FCGBP), found in intestinal mucus secretions and other extracellular environments, contains 13 VWD domains, 11 of which have a GDPH cleavage site. In this study, we investigated the structural and biophysical consequences of Asp‐Pro peptide cleavage in a representative FCGBP VWD domain. We found that endogenous Asp‐Pro cleavage increases the resistance of the domain to exogenous proteolytic degradation. Tertiary structural interactions made by the newly generated chain termini, as revealed by a crystal structure of an FCGBP segment containing the VWD domain, may explain this observation. Notably, the Gly‐Asp peptide bond, upstream of the cleavage site, assumed the cis configuration in the structure. In addition to these local features of the cleavage site, a global organizational difference was seen when comparing the FCGBP segment structure with the numerous other structures containing the same set of domains. Together, these data illuminate the outcome of GDPH cleavage and demonstrate the plasticity of proteins with VWD domains, which may contribute to their evolution for function in a dynamic extracellular environment. [ABSTRACT FROM AUTHOR]

Background: Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal‐directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). Methods: Treatment‐seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12‐week, single‐arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. Results: We found that both the percentage of heavy drinking days (PHDD) and the overall self‐reported alcohol craving measured during the ROC task were significantly reduced from pre‐ to post‐CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation‐related activity in any brain region. We found a significant 3‐way interaction between the effects of cue‐induced craving, cue‐induced brain activity and timepoint of assessment (pre‐ or post‐CBT) on PHDD in the left DLPFC. Follow‐up analysis showed that cue‐induced craving was associated with cue‐induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre‐CBT and post‐CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. Conclusions: These results suggest that patients in whom DLPFC functioning is more strongly related to cue‐induced craving may preferentially respond to CBT. [ABSTRACT FROM AUTHOR]

This systematic review (SR) aimed to evaluate the antimicrobial potential of different types of platelet‐rich fibrin (PRF) often used in regenerative treatments. An electronic search was performed in four databases and in Gray literature for articles published until January, 2023. The eligibility criteria comprised in vitro studies that evaluated the antimicrobial effect of different types of PRF. For the analysis of the risk of bias within studies, the modified OHAT (Office of Health Assessment and Translation) tool was used. For the evaluation of the results, a qualitative critical analysis was carried out in the synthesis of the results of the primary studies. Sixteen studies published between 2013 and 2021 were included in this SR. The antimicrobial effects of PRF variations (PRF, injectable PRF [I‐PRF], PRF with silver nanoparticles [agNP‐PRF], and horizontal PRF [H‐PRF]), were analyzed against 16 types of bacteria from the oral, periodontal, and endodontic environments. All types of PRF showed significant antimicrobial action, with the antibacterial efficacy being more expressive than the fungal one. The I‐PRF, H‐PRF, and agNP‐PRF subtypes improve antimicrobial activity. According to the OHAT analysis, no study was classified as having a high risk of bias. Evidence suggests that PRF variations have significant antimicrobial activity, with bacterial action being greater than fungal. Evolutions such as I‐PRF, H‐PRF, and agNP‐PRF improve antimicrobial activity. Future studies analyzing the clinical effect of these platelets are fundamental. This SR was registered in INPLASY under number INPLASY202340016. [ABSTRACT FROM AUTHOR]

Background: Cocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC). Methods: The analyses were conducted by pooling data from three case–control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face‐to‐face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models. Results: Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively. Conclusion: In this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history. [ABSTRACT FROM AUTHOR]

Background: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out‐of‐trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. Methods: Innovative therapies were defined as cancer‐directed drugs used (a) off‐label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. Results: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi‐targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA‐mTOR‐AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. Conclusion: This real‐world data collection illustrates an increasing use of "out‐of‐trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies. [ABSTRACT FROM AUTHOR]

Omega‐6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega‐6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans‐2,4‐decadienal (tt‐DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4‐hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt‐DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt‐DDE. Loss of Aldh9a1b increased tt‐DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b−/− zebrafish. Transcriptomic and metabolomic analyses revealed that tt‐DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt‐DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt‐DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance. [ABSTRACT FROM AUTHOR]

Upward lightning (UL) has become a major threat to the growing number of wind turbines producing renewable electricity. It can be much more destructive than downward lightning due to the large charge transfer involved in the discharge process. Ground‐truth lightning current measurements indicate that less than 50% of UL could be detected by lightning location systems (LLS). UL is expected to be the dominant lightning type during the cold season. However, current standards for assessing the risk of lightning at wind turbines mainly consider summer lightning, which is derived from LLS. This study assesses the risk of LLS‐detectable and LLS‐undetectable UL at wind turbines using direct UL measurements at instrumented towers. These are linked to meteorological data using random forests. The meteorological drivers for the absence/occurrence of UL are found from these models. In a second step, the results of the tower‐trained models are extended to a larger study area (central and northern Germany). The tower‐trained models for LLS‐detectable lightning are independently verified at wind turbine sites in this area and found to reliably diagnose this type of UL. Risk maps based on cold season case study events show that high probabilities in the study area coincide with actual UL flashes. This lends credibility to the application of the model to all UL types, increasing both risk and affected areas. Plain Language Summary: The need to produce renewable energy has recently led to an increase not only in the number of wind turbines, but also in their size. The taller the man‐made structure, the greater the likelihood of upward lightning (UL) to initiate from the wind turbine. Each UL flash has an initial continuous current, potentially making it much longer and much more destructive than a downward lightning flash. As UL has become a major weather‐related hazard to wind turbines, proper risk assessment has become essential. The problem: Ground‐truth current measurements at an instrumented tower in Austria show that less than 50% of UL is actually detected by lightning location systems (LLS). This study shows that a new approach based on vertically resolved larger‐scale meteorology and direct UL measurements from specially instrumented towers, combined with flexible machine learning techniques, succeeds in diagnosing the risk of both LLS‐detectable and LLS‐undetectable UL at wind turbines in the colder season over a larger study area. Key Points: Tower‐trained random forests can discriminate between high and low risk of upward lightning (UL) at wind turbines from larger‐scale meteorologyLarge values of convective precipitation, vertical velocity and ice crystals, together with convective available potential energy are most important for ULRegions with elevated terrain and coastlines perpendicular to the impinging wind field have an increased risk of UL [ABSTRACT FROM AUTHOR]

While much research has investigated how objective pull factors in the destination countries affect migration movements, and how subjective push factors affect migration aspirations, we know little about the interrelationship between subjective and objective factors. This paper therefore examines how people's perceptions of their political, economic and social structural environment affect their migration aspirations and to what extent these perceptions are determined by the objective situation in a country. Accounting for individual perceptions is important because individuals may be affected by structural factors to different degrees, and their knowledge of the objective situation may vary. Perceptions may also be affected by individuals' norms and values as well as people's different expectations. This study is based on data from Round 7 of the Afrobarometer survey, fielded between 2016 and 2018 in 34 African countries. Our findings show that positive perceptions of the structural environment are related to lower migration aspirations and that this relationship is only partly dependent on the objective situation in a country. [ABSTRACT FROM AUTHOR]

In the last decades, many C−C bond‐forming reactions have been developed, whereas less attention has been paid to the design of strategies involving C−C bond cleavage. We report a photocatalytic dehydroformylation sequence for the conversion of benzyl alcohols to arenes in a one‐pot two‐step process. Herein, the initial dehydrogenation of the benzyl alcohols to the corresponding benzaldehydes is combined with an additional decarbonylation step yielding arenes. As a result, a broad range of benzyl alcohols can be easily transformed in short times under mild photocatalytic conditions. The conducted mechanistic studies indicate that our cooperative hydrogen atom transfer (HAT)‐cobalt system proceeds through the formation of α‐alkoxy‐ and acyl radicals as key intermediates, involving concomitant syngas (CO+H2) generation. [ABSTRACT FROM AUTHOR]

Background: Individuals with Alzheimer's disease and Alzheimer's disease‐related dementias may lose the ability to drive safely as their disease progresses. Little is known about driving prevalence in older Latinx and non‐Hispanic White (NHW) individuals. We investigated the prevalence of driving status among individuals with cognitive impairment in a population‐based cohort. Methods: This was a cross‐sectional analysis of the cohort BASIC‐Cognitive study in a community of Mexican American (MA) and NHW individuals in South Texas. Participants scored ≤25 on the Montreal Cognitive Assessment (MoCA), indicating a likelihood of cognitive impairment. Current driving status was assessed by the Harmonized Cognitive Assessment Protocol informant interview. Logistic regression was used to assess driving versus non‐driving adjusted for pre‐specified covariates. Chi‐square and Mann–Whitney U tests were used to compare NHW and MA differences in driving outcomes from the American Academy of Neurology (AAN) questions for evaluating driving risk in dementia. Results: There were 635 participants, 77.0 mean age, 62.4% women, and 17.3 mean MoCA. Of these, 360 (61.4%) were current drivers with 250 of 411 (60.8%) MA participants driving, and 121 of 190 (63.70%) NHW participants driving (p = 0.50). In fully adjusted models age, sex, cognitive impairment, language preference, and Activities of Daily Living scores were significant predictors for the likelihood of driving (p < 0.0001). Severity of cognitive impairment was inversely associated with odds of driving, but this relationship was not found in those preferring Spanish language for interviews. Around one‐third of all caregivers had concerns about their care‐recipient driving. There were no significant differences in MA and NHW driving habits and outcomes from the AAN questionnaire. Conclusions: The majority of participants with cognitive impairment were currently driving. This is a cause for concern for many caregivers. There were no significant ethnic driving differences. Associations with current driving in cognitively impaired persons require further research. [ABSTRACT FROM AUTHOR]

The flavonoid rutin is present in significant amounts in the flower buds of Sophora japonica L. It offers numerous desired pharmacological effects. Under certain extraction conditions quercetin is found as a hydrolysis product which needs to be separated from rutin. This paper describes the application of liquid chromatography to solve this task. Based on the determination of adsorption equilibrium constants and column efficiencies, the productivity of the separation process is estimated, and scale‐up considerations are presented. A comparison with alternatively directly crystallizing rutin from raw extracts is also reported. [ABSTRACT FROM AUTHOR]

Diboriranides are the smallest conceivable monoanionic aromatic cycles, yet only limited examples have been reported and their reactivity and complexation behavior remain completely unexplored. We report a straightforward synthesis of the first peraryl diboriranide c‐(DurB)2CPh− as its lithium salt in three steps via the corresponding non‐classical diborirane from a readily available 1,2‐dichlorodiborane(4) (Dur=2,3,5,6‐tetramethylphenyl). With the preparation and complete characterization of representative complexes with tin, copper, gold and zinc, we demonstrate the strong preference of the diboriranide for σ‐type coordination modes towards main group and transition metal centers under unperturbed retention of the three‐membered B2C‐ring's 2e− π‐system. [ABSTRACT FROM AUTHOR]

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Within the pancreas, Keratin 19 (KRT19) labels the ductal lineage and is a determinant of pancreatic ductal adenocarcinoma (PDAC). To investigate KRT19 expression dynamics, we developed a human pluripotent stem cell (PSC)‐based KRT19‐mCherry reporter system in different genetic backgrounds to monitor KRT19 expression from its endogenous gene locus. A differentiation protocol to generate mature pancreatic duct‐like organoids was applied. While KRT19/mCherry expression became evident at the early endoderm stage, mCherry signal was present in nearly all cells at the pancreatic endoderm (PE) and pancreatic progenitor (PP) stages. Interestingly, despite homogenous KRT19 expression, mCherry positivity dropped to 50% after ductal maturation, indicating a permanent switch from biallelic to monoallelic expression. DNA methylation profiling separated the distinct differentiation intermediates, with site‐specific DNA methylation patterns occurring at the KRT19 locus during ductal maturation. Accordingly, the monoallelic switch was partially reverted upon treatment with a DNA‐methyltransferase inhibitor. In human PDAC cohorts, high KRT19 levels correlate with low locus methylation and decreased survival. At the same time, activation of oncogenic KRASG12D signalling in our reporter system reversed monoallelic back to biallelic KRT19 expression in pancreatic duct‐like organoids. Allelic reactivation was also detected in single‐cell transcriptomes of human PDACs, which further revealed a positive correlation between KRT19 and KRAS expression. Accordingly, KRAS mutant PDACs had higher KRT19 mRNA but lower KRT19 gene locus DNA methylation than wildtype counterparts. KRT19 protein was additionally detected in plasma of PDAC patients, with higher concentrations correlating with shorter progression‐free survival in gemcitabine/nabPaclitaxel‐treated and opposing trends in FOLFIRINOX‐treated patients. Apart from being an important pancreatic ductal lineage marker, KRT19 appears tightly controlled via a switch from biallelic to monoallelic expression during ductal lineage entry and is aberrantly expressed after oncogenic KRASG12D expression, indicating a role in PDAC development and malignancy. Soluble KRT19 might serve as a relevant biomarker to stratify treatment. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Consequences of climate change are becoming increasingly clear and while resources are dwindling, extreme climatic situations become more frequent. This leads to higher temperatures and thermal stress on the one hand and to the construction of more wind power plants and respectively an increasing demand for gap compensation materials on the other hand. These materials are commonly made of epoxy resins, which perform well under certain circumstances, but have some disadvantages such as heat instability, high costs, high resource claim, and hazards for the environment and health. This paper presents the latest results from the development of a low‐viscosity, high‐temperature stable geopolymer for gap compensation. In several newly developed test rigs, experiments were carried out to investigate injectability, flow behavior, mechanical properties, high‐temperature stability, and the possibility to induce preload. Through inorganic additives, the geopolymer expands or, if expansion is constrained, preloads itself during the hardening. This is essential to retain or enhance the preload of connection bolts and ensure force transmission as any volume reduction would create a new (smaller) gap. [ABSTRACT FROM AUTHOR]

The year when total column ozone (TCO) returns to 1980 levels is commonly used to quantify recovery from disturbance caused by ozone‐depleting substances. This date is reasonable but somewhat arbitrary. Here we borrow an indicator from climate change research, the signal‐to‐noise (S/N) metric to investigate how TCO might return to statistically similar levels to those of the pre‐ozone hole era (1960–1970). We calculate S/N for ozone projections from the Chemistry‐Climate Model Initiative. In most regions, a return to 1980 levels doesn't represent TCO recovery to pre‐disturbance conditions because it does not account for internal variability or reflect when statistically significant TCO losses occurred. Future projections show that, in most regions, TCO "de‐emerges" (i.e., S/N becomes less than one standard deviation from the pre‐disturbance mean) before it returns to its 1980 value. We conclude that S/N is an appropriate, perhaps complementary metric for determining when TCO returns to a pre‐disturbance state. Plain Language Summary: The stratospheric ozone layer is expected to recover from the damaging effects of chlorofluorocarbons (CFCs) and other halogen‐containing source gases this century. Ozone recovery is traditionally but somewhat arbitrarily defined as the year when total column ozone (TCO) abundances return to 1980 levels. Here, we use a metric commonly used in the climate change emergence literature—signal‐to‐noise (S/N)—to quantify statistically significant changes in TCO in models and observations relative to a period before CFC‐induced ozone depletion began. The S/N framing ties recovery to unperturbed environmental conditions, rather than to the environment in a specific year. We argue that tying recovery to unperturbed local environmental conditions is at least as reasonable as tying it to the same global date. Our calculations, which account for natural variability, show that 1980 does not reflect the onset of statistically significant ozone loss. Using a return of TCO to 1980 levels underestimates the time of recovery in Antarctica, where losses have been most significant, and overestimates the time to recovery in other regions. We conclude that signal‐to‐noise is a useful metric to assess the return of TCO to its baseline state and evaluate the effectiveness of the Montreal Protocol. Key Points: We present signal‐to‐noise calculations of stratospheric ozone depletion in chemistry‐climate models relative to 1960–1970Statistically significant ozone depletion does not emerge in 1980, which is traditionally used as a benchmark for ozone recoveryIn most regions de‐emergence occurs before ozone returns to 1980 levels except in Antarctica where de‐emergence occurs 25 years later [ABSTRACT FROM AUTHOR]

Heavier tetrylenes attract attention for their potential in synthesis, catalysis and small molecule activation. The coordination by N‐heterocyclic carbenes (NHCs) and cyclic (alkyl)(amino)carbenes (CAACs) results in substantial structural and electronic differences although typically only one of these yields stable derivatives for one and the same tetrylene. We now report both NHC‐ and CAAC‐coordination to a bridged bis(germylene) motif. The NHC‐coordinated bis(germylene) exhibits pyramidal germanium centers with lone pairs of electrons, while with CAAC an unprecedented stable bis(germene) with two Ge=C bonds is isolated. Spectroscopic and crystallographic evidence as well as DFT calculations confirm the effects of σ,π‐conjugation between the two germanium centers in both cases. The coordination of NHC is reversible as the reaction with BPh3 liberates the transient bis(germylene) and thus provides an alternative low‐temperature route towards polymers with Ge=Ge bonds. [ABSTRACT FROM AUTHOR]

Glutathione transferases (GSTs) are a class of phase II detoxifying enzymes catalysing the conjugation of glutathione (GSH) to endogenous and exogenous electrophilic molecules, with microsomal glutathione transferase 1 (MGST1) being one of its key members. MGST1 forms a homotrimer displaying third‐of‐the‐sites‐reactivity and up to 30‐fold activation through modification of its Cys‐49 residue. It has been shown that the steady‐state behaviour of the enzyme at 5 °C can be accounted for by its pre‐steady‐state behaviour if the presence of a natively activated subpopulation (~ 10%) is assumed. Low temperature was used as the ligand‐free enzyme is unstable at higher temperatures. Here, we overcame enzyme lability through stop‐flow limited turnover analysis, whereby kinetic parameters at 30 °C were obtained. The acquired data are more physiologically relevant and enable confirmation of the previously established enzyme mechanism (at 5 °C), yielding parameters relevant for in vivo modelling. Interestingly, the kinetic parameter defining toxicant metabolism, kcat/KM, is strongly dependent on substrate reactivity (Hammett value 4.2), underscoring that glutathione transferases function as efficient and responsive interception catalysts. The temperature behaviour of the enzyme was also analysed. Both the KM and KD values decreased with increasing temperature, while the chemical step k3 displayed modest temperature dependence (Q10: 1.1–1.2), mirrored in that of the nonenzymatic reaction (Q10: 1.1–1.7). Unusually high Q10 values for GSH thiolate anion formation (k2: 3.9), kcat (2.7–5.6) and kcat/KM (3.4–5.9) support that large structural transitions govern GSH binding and deprotonation, which limits steady‐state catalysis. [ABSTRACT FROM AUTHOR]

Viral infections can modulate the widespread alternations of cellular splicing, favouring viral replication within the host cells by overcoming host immune responses. However, how SARS‐CoV‐2 induces host cell differential splicing and affects the landscape of transcript alternation in severe COVID‐19 infection remains elusive. Understanding the differential splicing and transcript alternations in severe COVID‐19 infection may improve our molecular insights into the SARS‐CoV‐2 pathogenesis. In this study, we analysed the publicly available blood and lung transcriptome data of severe COVID‐19 patients, blood transcriptome data of recovered COVID‐19 patients at 12‐, 16‐ and 24‐week postinfection and healthy controls. We identified a significant transcript isoform switching in the individual blood and lung RNA‐seq data of severe COVID‐19‐infected patients and 25 common genes that alter their transcript isoform in both blood and lung samples. Altered transcripts show significant loss of the open reading frame, functional domains and switch from coding to noncoding transcript, impacting normal cellular functions. Furthermore, we identified the expression of several novel recurrent chimeric transcripts in the blood samples from severe COVID‐19 patients. Moreover, the analysis of the isoform switching into blood samples from recovered COVID‐19 patients highlights that there is no significant isoform switching in 16‐ and 24‐week postinfection, and the levels of expressed chimeric transcripts are reduced. This finding emphasizes that SARS‐CoV‐2 severe infection induces widespread splicing in the host cells, which could help the virus alter the host immune responses and facilitate the viral replication within the host and the efficient translation of viral proteins. [ABSTRACT FROM AUTHOR]