Designing a σ0π2 singlet ground state carbene from dicationic carbones.

Carbenes with a σ0π2 singlet ground state are rare and little is known about their chemistry. Here, we study the potential formation of such carbenes by removal of two electrons from carbones/donor-substituted allenes. The desired electron configuration becomes favorable in the case of bis-diiminium substitution (CAAC motif).

From Criegee to Breslow: How π-Donors Steer the Route of Olefin Ozonolysis.

While π-bonds typically undergo cycloaddition with ozone, resulting in the release of much-noticed carbonyl O-oxide Criegee intermediates, lone-pairs of electrons tend to selectively accept a single oxygen atom from O3, producing singlet dioxygen. We questioned whether the introduction of potent electron-donating groups, akin to N-heterocyclic olefins, could influence the reactivity of double bonds - shifting from cycloaddition to oxygen atom transfer or generating lesser-known, yet stabilized, donor-substituted Criegee intermediates. Consequently, we conducted a comparative computational study using density functional theory on a series of model olefins with increasing polarity due to (asymmetric) π-donor substitution. Reaction path computations indicate that highly polarized double bonds, instead of forming primary ozonides in their reaction with O3, exhibit a preference for accepting a single oxygen atom, resulting in a zwitterionic species formally identified as a carbene-carbonyl adduct. This previously unexplored reactivity potentially introduces aldehyde umpolung chemistry (Breslow intermediate) through olefin ozonolysis. Considering solvent effects implicitly reveals that increased solvent polarity further directs the trajectories toward a single oxygen atom transfer reactivity by stabilizing the zwitterionic character of the transition state. The competing modes of chemical reactivity can be explained by a bifurcation of the reaction valley in the post-transition state region.

Electron-Induced Damage by UV Photolysis of DNA Attached to Gold Nanoparticles.

Photolysis of DNA attached to gold nanoparticles (AuNPs) with ultraviolet (UV) photons induces DNA damage. The release of nucleobases (Cyt, Gua, Ade, and Thy) from DNA was the major reaction (99%) with an approximately equal release of pyrimidines and purines. This reaction contributes to the formation of abasic sites in DNA. In addition, liquid chromatography-mass spectrometry/MS (LC-MS/MS) analysis revealed the formation of reduction products of pyrimidines (5,6-dihydrothymidine and 5,6-dihydro-2'-deoxyuridine) and eight 2',3'- and 2',5'-dideoxynucleosides. In contrast, there was no evidence of the formation of 5-hydroxymethyluracil and 8-oxo-7,8-dihydroguanine, which are common oxidation products of thymine and guanine, respectively. Using appropriate filters, the main photochemical reactions were found to involve photoelectrons ejected from AuNPs by UV photons. The contribution of "hot" conduction band electrons with energies below the photoemission threshold was minor. The mechanism for the release of free nucleobases by photoelectrons is proposed to take place by the initial formation of transient molecular anions of the nucleobases, followed by dissociative electron attachment at the C1'-N glycosidic bond connecting the nucleobase to the sugar-phosphate backbone. This mechanism is consistent with the reactivity of secondary electrons ejected by X-ray irradiation of AuNPs attached to DNA, as well as the reactions of various nucleic acid derivatives irradiated with monoenergetic very-low-energy electrons (∼2 eV). These studies should help us to understand the chemistry of nanoparticles that are exposed to UV light and that are used as scaffolds and catalysts in molecular biology, curative agents in photodynamic therapy, and components of sunscreens and cosmetics.

Conformations and Rearrangements of Collinolactone - Experiments and Theory on a Dynamic Cyclodecatriene.

Collinolactone A is a microbial specialized metabolite with a unique 6-10-7 tricyclic bislactone skeleton which was isolated from Streptomyces bacteria. The unusual cyclodecatriene motif features dynamic interconversions of two rotamers. Given the biological profiling of collinolactone A as neuroprotective agent, semisynthetic modifications represent an invaluable strategy to enhance its efficacy. Since understanding conformations and reactions of bioactive substances is crucial for rational structure-based design and synthesis of derivatives, we conducted computational studies on conformational behavior as well as experiments on thermal and acid induced rearrangements of the cyclodecatriene. Experimental conformer ratios of collinolactone A and its biosynthetic ketolactone precursor are well reproduced by computations at the PW6B95-D3/def2-QZVPP//r2 SCAN-3c level. Upon heating collinolactone A in anhydrous dioxane at 100 °C, three collinolactone B stereoisomers exhibiting enollactone structures form via Cope rearrangements. Our computations predict the energetic preference for a boat-like transition state in agreement with the stereochemical outcome of the main reaction pathway. Constriction of the ten-membered ring forms collinolactone C with four annulated rings and an exocyclic double bond. Computations and semisynthetic experiments demonstrate strong preference for an acid-catalyzed reaction pathway over an alternative Alder-ene route to collinolactone C with a prohibitive reaction barrier, again in line with stereochemical observations.

Molybdenum(III) Amidinate: Synthesis, Characterization, and Vapor Phase Growth of Mo-Based Materials.

The synthesis, characterization, and thermogravimetric analysis of tris(N,N'-di-isopropylacetamidinate)molybdenum(III), Mo(iPr-AMD)3, are reported. Mo(iPr-AMD)3 is a rare example of a homoleptic mononuclear complex of molybdenum(III) and fills a longstanding gap in the literature of transition metal(III) trisamidinate complexes. Thermogravimetric analysis (TGA) reveals excellent volatilization at elevated temperatures, pointing to potential applications as a vapor phase precursor for higher temperature atomic layer deposition (ALD), or chemical vapor deposition (CVD) growth of Mo-based materials. The measured TGA temperature window was 200-314 °C for samples in the 3-20 mg range. To validate the utility of Mo(iPr-AMD)3, we demonstrate aerosol-assisted CVD growth of MoO3 from benzonitrile solutions of Mo(iPr-AMD)3 at 500 °C using compressed air as the carrier gas. The resulting films are characterized by X-ray photoelectron spectroscopy, X-ray diffraction, and Raman spectroscopy. We further demonstrate the potential for ALD growth at 200 °C with a Mo(iPr-AMD)3/Ar purge/300 W O2 plasma/Ar purge sequence, yielding ultrathin films which retain a nitride/oxynitride component. Our results highlight the broad scope utility and potential of Mo(iPr-AMD)3 as a stable, high-temperature precursor for both CVD and ALD processes.

A Clustering Algorithm for Polygonal Data Applied to Scientific Journal Profiles.

Millions of papers are submitted and published every year, but researchers often do not have much information about the journals that interest them. In this paper, we introduced the first dynamical clustering algorithm for symbolic polygonal data and this was applied to build scientific journals profiles. Dynamic clustering algorithms are a family of iterative two-step relocation algorithms involving the construction of clusters at each iteration and the identification of a suitable representation or prototype (means, axes, probability laws, groups of elements, etc.) for each cluster by locally optimizing an adequacy criterion that measures the fitting between clusters and their corresponding prototypes The application gives a powerful vision to understand the main variables that describe journals. Symbolic polygonal data can represent summarized extensive datasets taking into account variability. In addition, we developed cluster and partition interpretation indices for polygonal data that have the ability to extract insights about clustering results. From these indices, we discovered, e.g., that the number of difficult words in abstract is fundamental to building journal profiles.

Conundrum of dehydroascorbic acid and homocysteine thiolactone reaction products: Structural characterization and effect on peptide and protein N-homocysteinylation.

An excessive blood level of homocysteine (HcySH) is associated with numerous cardiovascular and neurodegenerative disease conditions. It has been suggested that direct S-homocysteinylation, of proteins by HcySH, or N-homosteinylation by homocysteine thiolactone (HTL) could play a causative role in these maladies. In contrast, ascorbic acid (AA) plays a significant role in oxidative stress prevention. AA is oxidized to dehydroascorbic acid (DHA) and if not rapidly reduced back to AA may degrade to reactive carbonyl products. In the present work, DHA is shown to react with HTL to produce a spiro bicyclic ring containing a six-membered thiazinane-carboxylic acid moiety. This reaction product is likely formed by initial imine condensation and subsequent hemiaminal product followed by HTL ring opening and intramolecular nucleophilic attack of the resulting thiol anion to form the spiro product. The reaction product was determined to have an accurate mass of 291.0414 and a molecular composition C10H13NO7S containing five double bond equivalents. We structurally characterized the reaction product using a combination of accurate mass tandem mass spectrometry, 1D and 2D-nuclear magnetic resonance. We also demonstrated that formation of the reaction product prevented peptide and protein N-homocysteinylation by HTL using a model peptide and α-lactalbumin. Furthermore, the reaction product is formed in Jurkat cells when exposed to HTL and DHA.

A Metastable Ketenyl Radical-Water Complex from UV Photolysis of the Carboxymethyl Radical.

The unpaired electron impacts the binding between radicals and ordinary closed-shell molecules in noncovalent complexes. Conversely, the complexation partner can enhance, decrease, or even control the reactivity of the interacting radical. Previously, such radical-molecule (and especially radical-water) complexes were studied by controlled assembly of the interacting partners which mostly leads to formation of the thermodynamically most stable species. Here, we show that UV photolysis of the resonance-stabilized carboxymethyl radical isolated in a cryogenic argon matrix at 4 K leads to the intermediary formation of a metastable, noncovalent complex of the ketenyl radical with a water molecule. In this complex, the ketenyl radical binds water at its terminal carbon atom, although a more stable isomer exists in which water interacts with the C-H bond of the radical. Rigorous W1 theory computations confirm that the ketenyl radical is a stronger donor in C-H···O interactions than ketene itself, while it performs comparably well as an acceptor. We propose that complex formation proceeds via an initial excited-state C-O bond breaking reaction in carboxymethyl under release of an OH radical, which is supported by multireference QD-NEVPT2 computations.

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

Leveraging IP for AI governance.

Copyleft AI with Trusted Enforcement (CAITE) can support an adaptable so ft law approach for ethics in AI.

The Effects of Long-term Molybdenum Exposure in Drinking Water on Molybdenum Metabolism and Production Performance of Beef Cattle Consuming a High Forage Diet.

Fifty-four multiparous beef cows with calves were used to evaluate the effects of Mo source (feed or water) on reproduction, mineral status, and performance over two cow-calf production cycles (553 days). Cows were stratified by age, body weight, liver Cu, and Mo status and were then randomly assigned to one of six treatment groups. Treatments were (1) negative control (NC; basal diet with no supplemental Mo or Cu), (2) positive control (NC + Cu; 3 mg of supplemental Cu/kg DM), (3) NC + 500 µg Mo/L from Na2MoO4·2H2O supplied in drinking water, (4) NC + 1000 µg Mo/L of Na2MoO4·2H2O supplied in drinking water, (5) NC + Mo 1000-water + 3 mg of supplemental Cu/kg DM, and (6) NC + 3.0 mg of supplemental Mo/kg diet DM from Na2MoO4·2H2O. Animals were allowed ad libitum access to both harvested grass hay (DM basis: 6.6% crude protein; 0.15% S, 6.7 mg Cu/kg, 2.4 mg Mo/kg) and water throughout the experiment. Calves were weaned at approximately 6 months of age each year. Dietary Cu concentration below 10.0 mg Cu/kg DM total diet reduced liver and plasma Cu concentrations to values indicative of a marginal Cu deficiency in beef cows. However, no production parameters measured in this experiment were affected by treatment. Results suggest that Mo supplemented in water or feed at the concentrations used in this experiment had minimal impact on Cu status and overall performance.

Oxidatively generated tandem DNA modifications by pyrimidinyl and 2-deoxyribosyl peroxyl radicals.

Molecular oxygen sensitizes DNA to damage induced by ionizing radiation, Fenton-like reactions, and other free radical-mediated reactions. It rapidly converts carbon-centered radicals within DNA into peroxyl radicals, giving rise to a plethora of oxidized products consisting of nucleobase and 2-deoxyribose modifications, strand breaks and abasic sites. The mechanism of formation of single oxidation products has been extensively studied and reviewed. However, much evidence shows that reactive peroxyl radicals can propagate damage to vicinal components in DNA strands. These intramolecular reactions lead to the dual alteration of two adjacent nucleotides, designated as tandem or double lesions. Herein, current knowledge about the formation and biological implications of oxidatively generated DNA tandem lesions is reviewed. Thus far, most reported tandem lesions have been shown to arise from peroxyl radicals initially generated at pyrimidine bases, notably thymine, followed by reaction with 5'-flanking bases, especially guanine, although contiguous thymine lesions have also been characterized. Proper biomolecular processing is impaired by several tandem lesions making them refractory to base excision repair and potentially more mutagenic.

Synthesis of Sterically Encumbered Thiourea S-Oxides through Direct Thiourea Oxidation.

Thiourea S-oxides can be viewed as formal analogs of the currently unknown diamino-substituted Criegee intermediates (urea O-oxides). However, the preparation of such S-oxides is rather challenging, and the direct oxidation of thioureas typically only leads to formation of desulfurized products. Employing the accurate revDSD-PBEP86-D4 double hybrid density functional, it was found that the peracid mediated oxidation of thiourea S-oxides exhibits a lower reaction barrier than the oxidation of the corresponding thiourea itself in contrast to most other ordinary thioketones. The undesired overoxidation reactivity, which is associated with strong π-donation from the thiourea's nitrogen atoms, can be partially suppressed by introduction of bulky substituents and the utilization of protic solvents. In this regard, we managed to prepare two sterically encumbered thiourea S-oxides in isolated yields of 35-40 %. The S-oxides are stable in the solid state and in alcoholic solutions at room temperature for extended periods of time, but swiftly decompose in aprotic solvents by disproportionation. A dimesityl-substituted thiourea S-oxide complexed with residual mCBA could be characterized by means of X-ray crystallography, confirming the importance of hydrogen bonding in the stabilization of the amino-substituted C=S+ -O- moiety.

[Older patients in abdominal surgery]. / Ältere PatientInnen in der Viszeralchirurgie.

BACKGROUND: The aging society imposes special challenges on operative medicine. OBJECTIVE: Characteristics in the perioperative treatment of older patients. Consequences for the daily practice. MATERIAL AND METHODS: Evaluation and summary of existing literature including recommendations for the (peri)operative management of older patients. RESULTS: Despite the growing relevance there are only few studies focusing on older patients. The altered (patho)physiology and comorbidities are challenging and can lead to complications. CONCLUSION: The evaluation of the indications for surgery should meticulously take the improvement to be expected into account by weighing up the individual wishes of patients and special risks. The adequate perioperative care including early mobilization and sufficient analgesia are decisive.

The impact of the COVID-19 pandemic on theatre use at the rahima moosa mother and child hospital

SARS-COV-2, the viral pathogen that resulted in the COVID-19 pandemic, was first identified by the World Health Organization (WHO) on 31 December 2019. Efforts to curb the spread of this virus, as well as the effects of viral infections and resulting complications thereof, have placed immense strain on healthcare systems throughout the world. In South Africa, a nationwide lockdown was instituted on 27 March 2020 which resulted in the suspension of all elective surgical services. The effect of this suspension of services has not been fully elucidated, but it has been postulated that a significant surgical backlog may have been created due to limited resources and massive pre-existing patient loads. Methods: We conducted a retrospective descriptive review of theatre records at the Rahima Moosa Mother and Child Hospital (RMMCH) for the time period 1 March 2019 to 28 February 2021. Results: A total of 8 176 cases amounting to 9 656 hours and 20 minutes of theatre time occurred from 1 March 2019 to 29 February 2020 (pre-COVID-19). From 1 March 2020 to 28 February 2021 (post-COVID-19), a total of 7 717 cases amounting to 9 148 hours and 2 minutes were conducted. This calculated to a 5.61% reduction in cases and a 5.26% reduction in theatre hours. There was a statistically significant reduction in theatre use both in terms of cases done and hours of theatre time after the onset of the COVID-19 pandemic. Conclusion: The onset of the COVID-19 pandemic significantly reduced the number of cases completed at the RMMCH. It also led to a significant reduction in total theatre use. Both of these findings were most pronounced in elective gynaecology and paediatric surgery services. There was, however, no statistically significant increase in intensive care unit (ICU) and high care (HC) admissions as well as mortalities for the period studied

Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide.

The activated reaction of dichlorocarbene with triplet molecular oxygen.

The well-known dichlorocarbene (CCl2, 1) is deemed to undergo an extremely facile addition reaction with triplet molecular oxygen (3O2) under formation of the corresponding singlet Criegee intermediate, phosgene O-oxide. This is unexpected, because the carbene possesses a singlet ground state with a large singlet-triplet gap and, typically, only triplet carbenes react swiftly with triplet dioxygen. Hence, we deployed a careful theoretical study of this reaction and computed the oxygen addition barrier at levels of electron correlation as high as CCSD(T) and BD(TQ) and basis sets as large as cc-pV5Z. Our results firmly establish the existence of a reaction barrier, and we estimate its height to amount to 8.8 kcal mol-1. Furthermore, the initially formed triplet dioxygen adduct is prone to facile O-O bond breaking rendering phosgene and triplet oxygen atoms likely products of the overall reaction. As a general conclusion, we find that carbenes are ambiphiles in oxygen additions and more electrophilic as well as that more nucleophilic carbenes show greater reactivity.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Molybdenum(IV) dithiocarboxylates as single-source precursors for AACVD of MoS2 thin films.

Tetrakis(dithiocarboxylato)molybdenum(IV) complexes of the type Mo(S2CR)4 (R = Me, Et, iPr, Ph) were synthesized, characterized, and prescreened as precursors for aerosol assisted chemical vapor deposition (AACVD) of MoS2 thin films. The thermal behavior of the complexes as determined by TGA and GC-MS was appropriate for AACVD, although the complexes were not sufficiently volatile for conventional CVD bubbler systems. Thin films of MoS2 were grown by AACVD at 500 °C from solutions of Mo(S2CMe)4 in toluene. The films were characterized by GIXRD diffraction patterns which correspond to a 2H-MoS2 structure in the deposited film. Mo-S bonding in 2H-MoS2 was further confirmed by XPS and EDS. The film morphology, vertically oriented structure, and thickness (2.54 µm) were evaluated by FE-SEM. The Raman E12g and A1g vibrational modes of crystalline 2H-MoS2 were observed. These results demonstrate the use of dithiocarboxylato ligands for the chemical vapor deposition of metal sulfides.