Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation.

Radical hydrofunctionalizations of electronically unbiased dienes are challenging to render regioselective, because the products are nearly identical in energy. Here, we report two engineered FMN-dependent "ene"-reductases (EREDs) that catalyze regiodivergent hydroalkylations of cyclic and linear dienes. While previous studies focused exclusively on the stereoselectivity of alkene hydroalkylation, this work highlights that EREDs can control the regioselectivity of hydrogen atom transfer, providing a method for selectively preparing constitutional isomers that would be challenging to prepare using traditional synthetic methods. Engineering the ERED from Gluconabacter sp. (GluER) furnished a variant that favors the γ,δ-unsaturated ketone, while an engineered variant from a commercial ERED panel favors the δ,ε-unsaturated ketone. The effect of beneficial mutations has been investigated using substrate docking studies and the mechanism probed by isotope labeling experiments. A variety of α-bromo ketones can be coupled with cyclic and linear dienes. These interesting building blocks can also be further modified to generate difficult-to-access heterocyclic compounds.

Uncatalyzed Diboron Activation by a Strained Hydrocarbon: Experimental and Theoretical Study of [1.1.1]Propellane Diborylation.

The synthesis of strained carbocyclic building blocks is relevant for Medicinal Chemistry, and methylenecyclobutanes are particularly challenging with current synthetic technology. Careful inspection of the reactivity of [1.1.1]propellane and diboron reagents has revealed that bis(catecholato)diboron (B2cat2) can produce a bis(borylated) methylenecyclobutane in a few minutes at room temperature. This reaction constitutes the first example of B-B bond activation by a special apolar hydrocarbon and also the first time that propellane is electrophilically activated by boron. Mechanistic studies including in situ NMR kinetics and DFT calculations demonstrate that the diboron moiety can be directly activated through coordination with the inverted sigma bond of propellane, and reveal that DMF is involved in the stabilization of diboronate ylide intermediates rather than the activation of the B-B bond. These results enable new possibilities for both diboron and propellane chemistry, and for further developments in the synthesis of methylenecyclobutanes based on propellane strain release.

HSQC Spectra Simulation and Matching for Molecular Identification.

In the pursuit of improved compound identification and database search tasks, this study explores heteronuclear single quantum coherence (HSQC) spectra simulation and matching methodologies. HSQC spectra serve as unique molecular fingerprints, enabling a valuable balance of data collection time and information richness. We conducted a comprehensive evaluation of the following four HSQC simulation techniques: ACD/Labs (ACD), MestReNova (MNova), Gaussian NMR calculations (DFT), and a graph-based neural network (ML). For the latter two techniques, we developed a reconstruction logic to combine proton and carbon 1D spectra into HSQC spectra. The methodology involved the implementation of three peak-matching strategies (minimum-sum, Euclidean-distance, and Hungarian distance) combined with three padding strategies (zero-padding, peak-truncated, and nearest-neighbor double assignment). We found that coupling these strategies with a robust simulation technique facilitates the accurate identification of correct molecules from similar analogues (regio- and stereoisomers) and allows for fast and accurate large database searches. Furthermore, we demonstrated the efficacy of the best-performing methodology by rectifying the structures of a set of previously misidentified molecules. This research indicates that effective HSQC spectral simulation and matching methodologies significantly facilitate molecular structure elucidation. Furthermore, we offer a Google Colab notebook for researchers to use our methods on their own data (https://github.com/AstraZeneca/hsqc_structure_elucidation.git).

A mixed method study exploring similarities and differences in general and social services-specific barriers to treatment-seeking among individuals with a problematic use of alcohol, cannabis, or gambling.

INTRODUCTION: The treatment gap for addictive disorders is one of the largest in health care. Several studies have investigated barriers to treatment for different addictive disorders, but very few studies conducted have explored whether the barriers differ depending on substance or behavior or if they are common among all addictive disorders. In Sweden, addiction care is provided both by the healthcare and social services, where the latter is common, but also less popular. To our knowledge, there are no studies exploring whether the barriers are different depending on where the treatment is given. AIM: The aim was to thoroughly explore both which general and social services-specific barriers to treatment that are common, which barriers that differs, and how the barriers are described among individuals with a problematic use of alcohol, cannabis and/or gambling. METHOD: A mixed method convergent parallel design was conducted. For the quantitative measures, surveys including the validated Barriers to Treatment Inventory as well as questions regarding barriers in the Swedish multi-provider landscape, were collected from individuals with a problematic use of alcohol (n = 207), cannabis (n = 51), and gambling (n = 37). In parallel, 17 semi-structured interviews from the same population were conducted and analyzed with thematic analysis. Thereafter, the quantitative and qualitative data was compared, contrasted, and at last, interpreted. RESULTS: The quantitative data showed that the largest general barriers in all groups were privacy concern and poor availability, and the largest barriers for seeking help from the social services was stigma, unawareness of what is offered, and fear of consequences for all groups. The qualitative data resulted in five general barriers: stigma, ambivalence, accessibility, fear of consequences, and lack of knowledge about addiction and its' treatments, and three barriers specifically towards social services: social services reputation, fear of meeting acquaintances, and lack of knowledge. The themes were developed from data from all groups, but different aspects of the themes were mentioned by different groups. CONCLUSION: There are details and aspects that differentiates both the general and social service-specific barriers to treatment between individuals with a problematic use of alcohol, cannabis, and gambling, but in large they perceive similar barriers.

Late-stage meta-C-H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step.

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)-H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C-H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

Investigating the added effects of guidance in digital psychological self-care for alcohol problems (ALVA)-protocol for a randomized factorial optimization trial.

BACKGROUND: The continual development and implementation of effective digital interventions is one important strategy that may serve to bridge the well-known treatment gap related to problematic alcohol use. Research suggests that clinician guidance, provided in different ways during the digital intervention (i.e., written weekly messages, phone calls etc.), can boost intervention engagement and effects. Digital psychological self-care (DPSC) is a new delivery format wherein an unguided digital intervention is provided within the framework of a structured care process that includes initial clinical assessment and follow-up interviews. In a recent feasibility study, a DPSC intervention for problematic alcohol use, ALVA, provided without any extra guidance, was found safe and credible and to have promising within-group effects on alcohol consumption. The aim of the current study is to gather information on the effects and efficiency of different forms of guidance added to ALVA, in order to optimize the intervention. METHODS: This protocol describes a randomized factorial trial where the effects of two different ways of providing guidance (mid-treatment interview, weekly written messages, respectively) in DPSC for problematic alcohol use are investigated. Optimization criteria will be applied to the results regarding how effective the intervention is at reducing alcohol consumption measured by the number of standard drinks per week together with the clinician time spent on guidance. DISCUSSION: This study will investigate the added benefit of different forms of guidance to DPSC for problematic alcohol use. These added effects will be compared to the added cost of guidance, according to pre-defined optimization criteria. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05649982. Registered on 06 December 2022. Prospectively registered.

Digital interventions targeting excessive substance use and substance use disorders: a comprehensive and systematic scoping review and bibliometric analysis.

Addictive substances are prevalent world-wide, and their use presents a substantial and persistent public health problem. A wide range of digital interventions to decrease use and negative consequences thereof have been explored, differing in approach, theoretical grounding, use of specific technologies, and more. The current study was designed to comprehensively map the recent (2015-2022) extant literature in a systematic manner, and to identify neglected and emerging knowledge gaps. Four major databases (Medline, Web of Science Core Collection, and PsychInfo) were searched using database-specific search strategies, combining terms related to clinical presentation (alcohol, tobacco or other drug use), technology and aim. After deduplication, the remaining n=13,917 unique studies published were manually screened in two stages, leaving a final n=3,056 studies, the abstracts of which were subjected to a tailored coding scheme. Findings revealed an accelerating rate of publications in this field, with randomized trials being the most common study type. Several meta-analyses on the topic have now been published, revealing promising and robust effects. Digital interventions are being offered on numerous levels, from targeted prevention to specialized clinics. Detailed coding was at times made difficult by inconsistent use of specific terms, which has important implications for future meta-analyses. Moreover, we identify several gaps in the extant literature - few health economic assessments, unclear descriptions of interventions, weak meta-analytic support for some type of interventions, and limited research on many target groups, settings and new interventions like video calls, chatbots and artificial intelligence - that we argue are important to address in future research.

From alcohol detoxification to treatment: A qualitative interview study on perceived barriers and assessed potential of mHealth among individuals postdetoxification.

OBJECTIVE: Most individuals attending detoxification clinics do not pursue subsequent treatment. Earlier research has suggested that emerging technologies like mHealth interventions could address the postdetoxification treatment gap, yet it remains unclear whether patients themselves endorse such approaches. Our study aimed to qualitatively explore perceived treatment barriers and assessed potential of mHealth among individuals who have undergone alcohol detoxification. METHOD: We conducted a single-interview-per-participant qualitative study, sampling participants (n = 23) that had visited the Stockholm substance use disorder emergency department for alcohol-related reasons, of whom n = 8 were purposively included due to having missed their scheduled follow-up outpatient appointment. Semistructured telephone interviews were conducted (2021-2022) and then systematically analyzed using reflexive thematic analysis. RESULTS: Across both areas of analysis, we identified six themes in total. We clustered barriers to postdetoxification treatment into three themes (10 subthemes) that may offer a nuancing perspective on previous research: "Misalignment between the treatment system and the individual," "Practical hurdles" and "Between reaching out and retreating." We identified three themes in participants' perspectives on mHealth as aftercare support, revealing expectations that such an approach may promote "self-awareness on own terms," assist in "navigating from solitary substance use struggles to supportive connections," and "offer a lifeline when needed most," thereby potentially resolving several barriers to treatment. CONCLUSIONS: This first qualitative study on barriers to alcohol treatment and mHealth potential postdetoxification offered various insights that may be translated into effective, real-world solutions to bridge the postdetoxification treatment gap. A natural next step for future research is to evaluate the impact of mHealth postdetoxification. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Impact of feed, light and access to manipulable material on tail biting in pigs with intact tails.

BACKGROUND: Tail biting (TB) is a welfare issue with economic consequences due to infections and ill-thrift. This study aimed to reduce tail injuries in a high-performing non-tail-docking pig herd. RESULTS: During eleven years preceding the trial, the annual incidence of tail injuries registered at slaughter in pigs from the herd increased from 3% (equivalent to the national mean) to 10%. It was positively correlated to a high weight gain and negatively correlated to daylight length. The overall incidence of tail injuries during the four years preceding the trial was 9.2% with significant differences between four identically structured buildings for fatteners (I < II < III < IV). The feed was enriched with amino acids, minerals and fibres. The buildings used different illumination strategies, I: standard fluorescent tubes with an invisible flickering light of 30-40% for 14 h daily, II: non-flickering led light for 14 h daily, III (control) and IV: standard fluorescent tubes for 2 h daily. IV had free access to manipulable material (hay-silage), while I-III was offered 100-200 g daily. During the adaptation period (6 months), the incidence of tail injuries decreased significantly in all buildings to a mean of 5.4%. The largest decrease (from 11.4 to 4.3%) was obtained in IV. During the trial period (12 months), the mean incidence of tail injuries decreased in all groups to a mean of 3.0%. There were no differences in treatment incidences of individual pigs due to TB between groups, but the use of enriched pellets due to TB in pens was lowest in II. The low incidence of tail injuries was retained during the post-trial period (6 months) when all buildings used artificial illumination for two hours per day. CONCLUSIONS: The incidence of TB in fast growing non-tail-docked pigs in the herd was successfully reduced by supplementing the feed with amino acids, minerals, vitamins and fibres. Additional manipulable material accelerated that process and non-flickering illumination may have had an impact in preventing TB. The results obtained do not support the need for tail-docking of pigs, provided that the needs of the pigs in terms of feed ingredients, stocking density and access to manipulable materials are fulfilled.

Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes.

In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)-C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic ß-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.