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Development of photocatalytic systems that facilitate mechanistically divergent steps in complex catalytic manifolds by distinct activation modes can enable previously inaccessible synthetic transformations. However, multimodal photocatalytic systems remain understudied, impeding their implementation in catalytic methodology. We report herein a photocatalytic access to thiols that directly merges the structural diversity of carboxylic acids with the ready availability of elemental sulfur without substrate preactivation. The photocatalytic transformation provides a direct radical-mediated segue to one of the most biologically important and synthetically versatile organosulfur functionalities, whose synthetic accessibility remains largely dominated by two-electron-mediated processes based on toxic and uneconomical reagents and precursors. The two-phase radical process is facilitated by a multimodal catalytic reactivity of acridine photocatalysis that enables both the singlet excited state PCET-mediated decarboxylative carbon-sulfur bond formation and the previously unknown radical reductive disulfur bond cleavage by a photoinduced HAT process in the silane-triplet acridine system. The study points to a significant potential of multimodal photocatalytic systems in providing unexplored directions to previously inaccessible transformations.

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Stereoselective construction of conjugated dienes and polyenes has remained an enduring synthetic problem, due to the central roles they play in natural product synthesis, methodology, and medicine. This review focuses on the recent developments in dienylation as an emerging strategy for the direct installation of unsaturated four carbon atom units of conjugated π-systems, outlining the regio- and stereoselectivity, as well as the synthetic scope of reactions with various dienylating reagents and the mechanistic implications of the catalytic cross-coupling processes that are used to enable dienylation.

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Triazoles have major roles in chemistry, medicine, and materials science, as centrally important heterocyclic motifs and bioisosteric replacements for amides, carboxylic acids, and other carbonyl groups, as well as some of the most widely used linkers in click chemistry. Yet, the chemical space and molecular diversity of triazoles remains limited by the accessibility of synthetically challenging organoazides, thereby requiring preinstallation of the azide precursors and restricting triazole applications. We report herein a photocatalytic, tricomponent decarboxylative triazolation reaction that for the first time enables direct conversion of carboxylic acids to triazoles in a single-step, triple catalytic coupling with alkynes and a simple azide reagent. Data-guided inquiry of the accessible chemical space of decarboxylative triazolation indicates that the transformation can improve access to the structural diversity and molecular complexity of triazoles. Experimental studies demonstrate a broad scope of the synthetic method that includes a variety of carboxylic acid, polymer, and peptide substrates. When performed in the absence of alkynes, the reaction can also be used to access organoazides, thereby obviating preactivation and specialized azide reagents and providing a two-pronged approach to C-N bond-forming decarboxylative functional group interconversions.

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BACKGROUND Angiotensin-converting enzyme inhibitors (ACE-I) are one of the most frequently prescribed classes of medications with the rare adverse effect of angioedema, and isolated small bowel angioedema is a small subset of these cases. Isolated angioedema of the small bowel is a rare adverse effect of this commonly prescribed medication, and it mimics, symptomatically and radiographically, several other illnesses and is often misdiagnosed. While ACE-I are thought to be safe, the risk of angioedema is approximately 0.7%. Isolated small bowel angioedema is often not diagnosed in a timely manner, and misdiagnosis leads to significant morbidity in afflicted patients. CASE REPORT We present the case of a 63-year-old woman with angioedema of the small bowel causing abdominal pain, nausea, vomiting, and diarrhea. Computed tomography demonstrated small bowel edema and ascites. The patient had been taking lisinopril for 7 years prior to presentation and had previously been seen by multiple physicians for abdominal pain. A diagnosis of ACE-I-induced small bowel angioedema was made and lisinopril therapy was immediately stopped. Her symptoms improved with cessation of lisinopril, and follow-up imaging showed resolution of the angioedema 3 months later. CONCLUSIONS The course of ACE-I-induced angioedema is unpredictable and often overlooked as a cause of abdominal pain. It commonly presents soon after starting ACE-I therapy, but can present years after therapy initiation, as in this case. Significant morbidity, including unnecessary exploratory laparotomy, is associated with misdiagnosis of ACE-I-induced angioedema of the small bowel. Prompt recognition and cessation of the offending drug is crucial but often delayed.

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The intermediate oxidation state of sulfoxides is central to the plethora of their applications in chemistry and medicine, yet it presents challenges for an efficient synthetic access, limiting the structural diversity of currently available sulfoxides. Here, we report a data-guided development of direct decarboxylative sulfinylation that enables the previously inaccessible functional group interconversion of carboxylic acids to sulfoxides in a reaction with sulfinates. Given the broad availability of carboxylic acids and the growing synthetic potential of sulfinates, the direct decarboxylative sulfinylation is poised to improve the structural diversity of synthetically accessible sulfoxides. The reaction is facilitated by a kinetically favored sulfoxide formation from the intermediate sulfinyl sulfones, despite the strong thermodynamic preference for the sulfone formation, unveiling the previously unknown and chemoselective radicalophilic sulfinyl sulfone reactivity.

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How bacteria sense and respond to nitrogen levels are central questions in microbial physiology. In Gram-positive bacteria, nitrogen homeostasis is controlled by an operon encoding glutamine synthetase (GS), a dodecameric machine that assimilates ammonium into glutamine, and the GlnR repressor. GlnR detects nitrogen excess indirectly by binding glutamine-feedback-inhibited-GS (FBI-GS), which activates its transcription-repression function. The molecular mechanisms behind this regulatory circuitry, however, are unknown. Here we describe biochemical and structural analyses of GS and FBI-GS-GlnR complexes from pathogenic and non-pathogenic Gram-positive bacteria. The structures show FBI-GS binds the GlnR C-terminal domain within its active-site cavity, juxtaposing two GlnR monomers to form a DNA-binding-competent GlnR dimer. The FBI-GS-GlnR interaction stabilizes the inactive GS conformation. Strikingly, this interaction also favors a remarkable dodecamer to tetradecamer transition in some GS, breaking the paradigm that all bacterial GS are dodecamers. These data thus unveil unique structural mechanisms of transcription and enzymatic regulation.

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DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question, we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA A structure of the C-terminal portion of DriD revealed a WYL motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD structures reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated operator DNA binding activation. Biochemical and in vivo studies support the structural model. Our data thus reveal the molecular mechanism underpinning an SOS-independent DNA damage repair pathway.

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The reactivity of the sulfonyl group varies dramatically from nucleophilic sulfinates through chemically robust sulfones to electrophilic sulfonyl halides-a feature that has been used extensively in medicinal chemistry, synthesis, and materials science, especially as bioisosteric replacements and structural analogs of carboxylic acids and other carbonyls. Despite the great synthetic potential of the carboxylic to sulfonyl functional group interconversions, a method that can convert carboxylic acids directly to sulfones, sulfinates and sulfonyl halides has remained out of reach. We report herein the development of a photocatalytic system that for the first time enables direct decarboxylative conversion of carboxylic acids to sulfones and sulfinates, as well as sulfonyl chlorides and fluorides in one step and in a multicomponent fashion. A mechanistic study prompted by the development of the new method revealed the key structural features of the acridine photocatalysts that facilitate the decarboxylative transformations and provided an informative and predictive multivariate linear regression model that quantitatively relates the structural features with the photocatalytic activity.

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Our ability to interrogate and manipulate the genome far exceeds our capacity to measure the effects of genetic changes on plant traits. Much effort has been made recently by the plant science research community to address this imbalance. The responses of plants to environmental conditions can now be defined using a variety of imaging approaches. Hyperspectral imaging (HSI) has emerged as a promising approach to measure traits using a wide range of wavebands simultaneously in 3D to capture information in lab, glasshouse, or field settings. HSI has been applied to define abiotic, biotic, and quality traits for optimisation of crop management.

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Dual catalytic systems involving photocatalytic activation and transition metal-catalyzed steps have enabled innovative approaches to the construction of carbon-carbon and carbon-heteroatom bonds. However, the mechanistic complexity of the dual catalytic processes presents multiple challenges for understanding of the roles of divergent catalytic species that can impede the development of future synthetic methods. Here, we report a dual catalytic process that enables the previously inaccessible, broad-scope, direct conversion of carboxylic acids to aromatic sulfones-centrally important carbonyl group bioisosteric replacements and synthetic intermediates-by a tricomponent decarboxysulfonylative cross-coupling with aryl halides. Detailed mechanistic and computational studies revealed the roles of the copper catalyst, base, and halide anions in channeling the acridine/copper system via a distinct dual catalytic manifold. In contrast to the halide-free decarboxylative conjugate addition that involves cooperative dual catalysis via low-valent copper species, the halide counteranions divert the decarboxysulfonylative cross-coupling with aryl halides through a two-phase, orthogonal relay catalytic manifold, comprising a kinetically coupled (via antithetical inhibitory and activating roles of the base in the two catalytic cycles), mechanistically discrete sequence of a photoinduced, acridine-catalyzed decarboxylative process and a thermal copper-catalyzed arylative coupling. The study underscores the importance of non-innocent roles of counteranions and key redox steps at the interface of catalytic cycles for enabling previously inaccessible dual catalytic transformations.

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Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C-H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp3)-H sulfination reaction that can convert abundant aliphatic C-H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C-H functionalization approaches. We report herein a photoinduced C(sp3)-H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp3)-H functionalization.

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Sulfonamides feature prominently in organic synthesis, materials science and medicinal chemistry, where they play important roles as bioisosteric replacements of carboxylic acids and other carbonyls. Yet, a general synthetic platform for the direct conversion of carboxylic acids to a range of functionalized sulfonamides has remained elusive. Herein, we present a visible light-induced, dual catalytic platform that for the first time allows for a one-step access to sulfonamides and sulfonyl azides directly from carboxylic acids. The broad scope of the direct decarboxylative amidosulfonation (DDAS) platform is enabled by the efficient direct conversion of carboxylic acids to sulfinic acids that is catalyzed by acridine photocatalysts and interfaced with copper-catalyzed sulfur-nitrogen bond-forming cross-couplings with both electrophilic and nucleophilic reagents.

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Development of stereoselective and efficient reactions for construction of conjugated dienes and polyenes has remained at the forefront of organic chemistry, due to their key roles in medicinal chemistry, organic synthesis, and materials science. The synthesis of conjugated dienes and polyenes is typically accomplished in a multistep manner by sequential installation of individual C=C bonds because it allows for control of stereoselectivity and efficiency of formation of each double bond. A conceptually distinct dienylation approach entails a stereoselective appendage of a four-carbon unit, shortcutting diene synthesis. Dienylation with sulfolene provided a direct route to E-dienes, but the synthesis of substantially more challenging Z-dienes remained elusive. Here, we report that a highly Z-selective dienylation can be now achieved by a simple adjustment of a ligand, enabling stereodivergent synthesis of E- and Z-dienes from one reagent and in one step. A detailed mechanistic investigation of the E- and Z-selective dienylation provided insight into the divergent behavior of the two catalytic systems and revealed that differences in relative stabilities of catalytically active palladium phosphine complexes have a major impact on the stereochemical outcomes of the dienylation.

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Sex steroid hormones are potential biomarkers of reproductive function in teleost fish, but their measurement continues to rely on antibody-based assays. The objective of this study was to optimize a robust and simultaneous liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measurement of eight steroid hormones (cortisol, 11-ketotestosterone, estradiol, 17α-ethynyl estradiol, estrone, estriol, progesterone and testosterone) in fish plasma. The extraction was followed by liquid-liquid extraction with tert-butyl methyl ether and time scheduled multi-reaction monitoring (sMRM) was used for quantitation of steroids. Validation of method performance using charcoal-stripped human plasma showed extraction recoveries for eight steroids ranged from 85.5 to 108.2% with matrix effects > 80%. The limits of quantitation were 0.01 pg/µL for testosterone, 0.05 pg/µL for cortisol and progesterone, 0.1 pg/µL for 11-ketotestosterone, estradiol and estrone, 0.125 pg/µL for estriol and 0.25 pg/µL for 17α-ethynyl estradiol. The proposed method was applied to plasma samples of largemouth bass (Micropterus salmoides) collected from contaminated (Lake Apopka) and reference sites (Wildcate Lake) in Florida. Concentrations of testosterone, cortisol, estradiol and estrone were significantly different in female fish, but plasma concentration of cortisol was only statistically different in male fish between two sites (P < 0.05). This study demonstrates the application of a robust LC-MS/MS analysis for a range of sex steroid hormones representative of endocrine function in a top predator, largemouth bass.

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In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (Mpro). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with Mpro. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the Mpro active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2.

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Progression to dorsal extension of the lunate after distal scaphoidectomy was described more than a decade ago. Still, this technique remains a popular choice for surgical treatment of isolated scaphotrapeziotrapezoid osteoarthritis (STT OA). This study aimed to investigate short-term postoperative function, patient satisfaction and radiographic outcomes of distal scaphoidectomy with tendon interposition for isolated STT OA in the wrist. Scaphoid resection width, amount of DISI and postoperative complications were also assessed. We evaluated all distal scaphoidectomies done at our hospital from 2012 to 2018. Postoperative clinical analysis consisted of grip and key pinch strength, joint amplitude, pain on visual analog scale (VAS), hand usability (VAS) and functional scores (QuickDASH and PRWHE scores). On follow-up radiographs, we measured the amount of DISI, resection height and scaphoid working length and compared them to functional scores. Eighteen patients with 21 operated wrists were eligible. Average time to postoperative evaluation was 36 (5-78) months. We observed DISI in 95% of the cases (n=19). A mean increase of 13° (±6) in radiolunate angle was noted when comparing pre- and postoperative radiographs. Neither the amount of DISI nor the resection height was significantly correlated with the functional scores. No revision surgery for advanced wrist collapse was reported. Four concomitant surgeries were needed. Distal scaphoid excision with tendon interposition yields good short-term results in isolated STT OA. While 95% of cases developed a DISI deformity, there were no cases of functional impairment. Longitudinal studies with long-term follow-up are required to further evaluate lunate extension and possible clinical implications.

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The development of efficient and selective C-N bond-forming reactions from abundant feedstock chemicals remains a central theme in organic chemistry owing to the key roles of amines in synthesis, drug discovery, and materials science. Herein, we present a dual catalytic system for the N-alkylation of diverse aromatic carbocyclic and heterocyclic amines directly with carboxylic acids, by-passing their preactivation as redox-active esters. The reaction, which is enabled by visible-light-driven, acridine-catalyzed decarboxylation, provides access to N-alkylated secondary and tertiary anilines and N-heterocycles. Additional examples, including double alkylation, the installation of metabolically robust deuterated methyl groups, and tandem ring formation, further demonstrate the potential of the direct decarboxylative alkylation (DDA) reaction.

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Wildfires are becoming more prevalent and are impacting forests, watersheds and important resources. Hydrologic and geomorphic processes following wildfires can include erosion flooding, and degraded water quality. To mitigate these secondary impacts, post-fire restoration treatments can be applied to a burned area to stabilize the land surface or promote vegetative regrowth. This research focuses on wood and straw mulch treatment implemented after the 2012 Waldo Canyon Fire in Colorado (United States) and estimates the spatial and temporal changes in annual and seasonal vegetation after a fire with respect to geomorphic factors. This study highlights the use of satellite-based remote sensing products to investigate the impacts of post-fire rehabilitation treatments on vegetation. Using Enhanced Vegetation Index as a proxy for vegetative growth, vegetation conditions are evaluated with respect to slope, slope aspect, and burn severity to understand the impact of the ground cover treatments on vegetation for five years before and after the fire (2007-2016). Sixty-three burned and untreated sites, forty-nine burned sites treated with wood mulch, and twenty-eight burned sites treated with straw mulch were analyzed. These sites were also compared to two control sites that were unburned and untreated, Hunter's Run and Fountain Creek. Generally, post-fire conditions did not return to pre-fire levels, where average vegetation levels were lower. By the end of the study, burned and untreated sites had larger vegetative levels than burned and treated sites. The vegetation levels of the burned sites were statistically different (α = 0.05) from pre-fire conditions in all areas of treatment. Burned sites treated with wood and straw recovered to 69% and 73% of pre-fire conditions, respectively. This work demonstrates the novel use of remote sensing to observe vegetation after post-fire treatment applications to augment the number of sites and length of time that can be analyzed. The observed change in vegetation conditions also contributes to furthering our understanding of the impacts of post-fire restoration, which is important for post-fire management.

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Boronic acids are centrally important functional motifs and synthetic precursors. Visible light-induced borylation may provide access to structurally diverse boronates, but a broadly efficient photocatalytic borylation method that can effect borylation of a wide range of substrates, including strong C-O bonds, remains elusive. Herein, we report a general, metal-free visible light-induced photocatalytic borylation platform that enables borylation of electron-rich derivatives of phenols and anilines, chloroarenes, as well as other haloarenes. The reaction exhibits excellent functional group tolerance, as demonstrated by the borylation of a range of structurally complex substrates. Remarkably, the reaction is catalyzed by phenothiazine, a simple organic photocatalyst with MW < 200 that mediates the previously unachievable visible light-induced single electron reduction of phenol derivatives with reduction potentials as negative as approximately - 3 V versus SCE by a proton-coupled electron transfer mechanism. Mechanistic studies point to the crucial role of the photocatalyst-base interaction.

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